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Register of rare disease models funded by the Foundation
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| Budget year | Project owner | Laboratory / City | Project financier | Disease group(s) concerned | Disease(s) concerned | Project title | Project summary | Results obtained | Call for projects |
|---|---|---|---|---|---|---|---|---|---|
| 2025 | Aude BELIARD | Paris Cité University | Foundation For Rare Diseases | Rare neurological diseases | Joubert syndrome | Fatigue and slowness in the experience of children living with Joubert syndrome and their families | CERMES3 (UMR8211), in partnership with the CRMR for Cerebellar Malformations and Congenital Diseases and the association “Living Better with Joubert Syndrome,” wishes to submit a research proposal focusing on the experience of fatigue and sluggishness among children living with Joubert syndrome and their families. | Humanities and Social Sciences 12 | |
| 2025 | Alessandro PORROVECCHIO | University of the Littoral Côte d'Opale | Foundation For Rare Diseases | Rare systemic and autoimmune diseases | Myasthenia Gravis or Autoimmune Myasthenia | Integrating Art Therapy and Adapted Physical Activity: Towards Improving the Quality of Life of Patients with Myasthenia Gravis | Joubert syndrome is characterized by early cerebellar symptoms (hypotonia, oculomotor apraxia, ataxia) but is frequently accompanied by other manifestations that are less well described in the medical literature: symptoms of fatigue and sluggishness, resulting from the effort children must exert to perform tasks given their motor and cognitive impairments. These symptoms limit their social participation and impact the inclusion and quality of life of the children and their families. | Humanities and Social Sciences 12 | |
| 2025 | Jerome DINET | Reims University Hospital (CHU) | Foundation For Rare Diseases | Rare head and neck malformations | Imperfect amelogenesis and imperfect dentinogenesis | Care pathways and patient experiences with amelogenesis imperfecta and dentinogenesis imperfecta: assessing and improving quality of life - PErrADI | Our research has three objectives: 1/ to explore the ways in which fatigue and sluggishness are described in the accounts of children and those around them, as well as the meanings attributed to them, depending on the context, social situations, and the children’s ages; 2/ to develop hypotheses regarding how these symptoms vary at the intersection of biological and social factors; 3/ to gain a better understanding of how these symptoms are managed on a daily basis and how they are addressed in support and care services. | Humanities and Social Sciences 12 | |
| 2025 | Magdalini Dargentas | Psychology Laboratory: Cognition, Behavior , and Communication (LP3C, EA 1285) / Brest | Overcoming Cystic Fibrosis | Rare lung diseases | Cystic fibrosis | Study of perceived psychological effects by patients with cystic fibrosis and non eligible for Kaftrio: patients, family and friends, and medical staff . | The research will follow a qualitative and inductive methodology: the creation of 15 case studies documenting the circumstances of 15 children or adolescents aged 6 to 16 who are being monitored by the CRMR (in each case, interviews will be conducted with the child, their parents, and volunteer members of their family and professional support network); analysis of the results by case, followed by comparative analysis; dissemination and promotion of the results. At each stage, the research will be jointly developed by the three partners (the SHS research team, the CRMR, and the association). | Humanities and Social Sciences 12 | |
| 2025 | Loïc GARCON | EA4666 HEMATIM Amiens University Hospital / Amiens | Alnylam | Other rare diseases | Ring sideroblast | Use of an interfering RNA approach in congenital sideroblastic anemia | This study aims to provide better information and a deeper understanding of the impact of these conditions on the school environment, daily life, and leisure activities, as well as on immediate family members (parents and siblings). It aims to contribute to improving care, particularly through the updating of the National Rare Disease Plan (PNDS); more broadly, it is part of the current movement toward recognizing the forms of fatigue experienced by people living with a rare disease or a disability, while focusing on the experience of children, which has so far been little described. | Alnylam Pharmaceuticals Award 2025 | |
| 2025 | Rozen THE PANCREAS | Center for Research in Myology, Paris | argenx | Rare systemic and autoimmune disorders | Myasthenia Gravis | Blocking Interleukin 23 improves thymic defects in autoimmune myasthenia gravis: Identification of treatment monitoring blood biomarkers | The findings of this research may be partially applicable to other cerebellar disorders, as well as to other neurological conditions or types of disorders or disabilities that, in addition to the most well-known primary symptoms, cause sluggishness and fatigue that are difficult to identify and describe. | argenx Award 2025 | |
| 2025 | Alain HOVNANIAN | Imagine Institute for Genetic Diseases, Paris | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | Ectodermal dysplasia, erythrokeratoderma, CANDLE syndrome, chronic lichenoid keratosis, Olmsted syndrome, Meleda's disease, congenital pachyonychia, transgressive palmoplantar keratoderma | Resolving undiagnosed rare genetic developmental and skin diseases | Enormous progress has been made in deciphering genetic developmental disorders and genetic skin disorders. In rare cases, patients present with comorbidity combining developmental abnormalities and skin inflammation. We have identified 10 families in which patients suffer from both types of abnormalities (5 families, 13 patients) and 5 families in which patients present with painful thickening of the skin on the palms and soles (5 families, 8 patients). The presence of several affected members in most families supports the genetic origin of these diseases. However, standard genetic diagnostic tests performed on all these individuals failed to identify the underlying genetic abnormalities. These tests included next-generation sequencing analysis of all known genes involved in this group of diseases (gene panel analysis), as well as sequencing of the coding parts (exons) of genes throughout the entire genome (exome). We propose to use cutting-edge technologies to identify the genetic basis of these serious diseases. We will combine the most powerful and accurate sequencing technique to sequence long stretches of DNA in order to identify large DNA structural abnormalities and other abnormalities in the genome that would not have been detected by previous analyses. We will combine this approach with a comprehensive analysis of the mRNAs expressed by all genes, with the aim of exploring quantitative or qualitative abnormalities in mRNAs. Through this strategy, we hope to identify the genetic basis of at least some of these serious genetic diseases. This project will be carried out at the genomics and bioinformatics platform of the Imagine Institute, which has expertise in the bioinformatic analysis of genomic and mRNA sequencing data. These results will be validated by functional studies on skin and/or blood cells derived from patients. This work has the potential to uncover new biological pathways and serve as a basis for identifying new therapeutic targets for precision medicine. This project will help elucidate the genetic basis of these rare and orphan inflammatory skin diseases. It will alleviate the burden of undiagnosed conditions in people with these debilitating genetic diseases. | Omics 2025 | |
| 2025 | David MICHONNEAU | Saint-Louis Research Institute, Paris | Foundation For Rare Diseases | Rare non-malignant hematological diseases | Acquired aplastic anemia | Hematopoiesis and immunopathophysiology of acquired aplastic anemia | Acquired aplastic anemia (AAA) is a blood disorder caused by an abnormal immune response directed against hematopoietic stem cells (HSCs), resulting in the bone marrow's inability to produce sufficient quantities of blood cells (red blood cells, platelets, white blood cells). The cause of this abnormal activation of the immune system is currently unknown. The most serious long-term complication of AMI is the development of cancers of the hematopoietic system (myelodysplastic syndrome or acute myeloid leukemia) in 15 to 20% of patients. Treatment is based on the use of immunosuppressive drugs, but these are only effective in about two-thirds of patients. One of the peculiarities of AML is the presence of acquired genetic mutations in HSCs, the origin and link with AML of which is currently poorly understood. These mutations are present in nearly 30% of patients at diagnosis and affect more than 60% of patients during the course of the disease, even in cases of good response to treatment. We hypothesize that clonal hematopoietic mutations present in AMA may play a causal role in the onset of the disease and promote the development of an abnormal chronic inflammatory response in the bone marrow of patients, altering the normal functioning of HSCs. To test our hypothesis, our project aims to study the bone marrow of patients with AMA, at the time of diagnosis and after treatment, using a national biological collection from the National Reference Center for Bone Marrow Aplasia. Given the highly heterogeneous cellular composition of bone marrow, we will combine several "single-cell" approaches. These approaches will enable us to determine how the presence of mutations in the DNA of certain bone marrow cells can alter the expression of genes involved in their normal function, and to determine the extent to which these acquired mutations impact both immune and hematopoietic function, by simultaneously studying the transcriptome of each cell (the set of genes expressed in a cell). Finally, we will use in vitro approaches to study the functional properties of HSCs in terms of their differentiation or proliferation capacity at the single-cell level, and we will study their mutational status a posteriori to determine the impact of mutations on hematopoietic function. This understanding could lead to the identification of new therapeutic targets capable of preventing cancer progression. More generally, this work could help identify the link between the presence of hematopoietic mutations and the occurrence of abnormal chronic immune and inflammatory responses. | Omics 2025 | |
| 2025 | Edoardo MALFATTI | Mondor Institute for Biomedical Research, Paris | Foundation For Rare Diseases | Neuromuscular disorders | congenital myopathies | MYOMICS: Whole-genome sequencing and sNuclei RNA sequencing for ultra-rare congenital myopathies | Congenital myopathies (CMYO) are rare conditions that cause muscle weakness early in life. They are genetically determined, yet approximately 30% of CMYO cases remain undiagnosed. This lack of diagnosis hinders the development of targeted therapies and potential cures. Using cutting-edge technologies, we will analyze the DNA of 20 patients with unresolved CMYO to establish a diagnosis and potentially identify therapeutic targets. | Omics 2025 | |
| 2025 | Emmanuel FLAMAND-ROZE | Brain Institute, Paris | Foundation For Rare Diseases | Rare neurological diseases | Paroxysmal kinesigenic dyskinesia | Unraveling the Genetic Causes of Paroxysmal Kinesigenic Dyskinesia with Genome Sequencing | Better understanding PKD for better diagnosis and treatment Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterized by sudden episodes of involuntary movements (dystonia, chorea) triggered by rapid voluntary movements. While some forms are well explained by mutations in the PRRT2 gene, more than half of patients remain without a genetic diagnosis, meaning that other genetic causes remain to be discovered. Our project aims to identify these as yet unknown causes using whole genome sequencing (WGS), a cutting-edge technology that allows the entire DNA to be explored, including regions that are difficult to analyze using conventional methods. Specifically, we plan to study the DNA of PKD patients with no known mutations, as well as that of their parents, to detect new genetic abnormalities. We will look for rare or complex mutations that are invisible with conventional genetic tools but could explain certain cases of PKD, enabling us to better understand the mechanisms of the disease in order to refine the diagnosis, provide patients and their families with more accurate answers, and ultimately pave the way for more targeted treatments. This project represents a major step forward in understanding PKD and could improve the diagnostic pathway for patients, while laying the foundations for more personalized medicine for these still poorly understood movement disorders. | Omics 2025 | |
| 2025 | Fabienne CHARBIT-HENRION | Imagine Institute for Genetic Diseases, Paris | Foundation For Rare Diseases | Rare hepato-gastroenterological diseases | CMUSE: cryptogenic multifocal ulcerating stenosing enteritis GURDP: recurrent gastrointestinal ulceration with dysfunctional platelets (OMIM number 618372) PHOAR2-enteropathy syndrome CNSU: chronic non-specific ulcers of the small intestine CEAS: chronic enteropathy associated with SLCO2A1 | PRO-GUT: Integration of lipidomics with spatial transcriptomics to resolve monogenic intestinal disorders affecting the prostaglandin pathway | The intestinal barrier consists of a single layer of epithelial cells that renew themselves every 3 to 5 days. When damaged, a highly complex and coordinated process is triggered to promote repair of the intestinal barrier. Disruption of this process can lead to inadequate repair, chronic inflammation, or excessive tissue damage. Prostaglandins (PGs) are eicosanoids, powerful bioactive lipids that exert a wide range of physiological effects throughout the body. PGE2, one of the most potent and well-studied PGs, is responsible for many inflammatory manifestations such as fever, inflammation, tissue repair, vasodilation, and pain. These symptoms can be relieved by steroids and nonsteroidal anti-inflammatory drugs (NSAIDs, aspirin) that target the PG synthesis pathway. It is important to note that these "PG inhibitors" are all known to potentially cause serious ulcers of the stomach or proximal small intestine. It is interesting to note that rare patients with genetic disorders affecting certain genes in the PG pathway, either phospholipase A2 (PLA2G4A) or the PGT transporter (SLCO2A1), suffer from very similar chronic recurrent gastrointestinal ulcers that are life-threatening. These rare patients develop circular, superficial, and patchy ulcers with healthy, non-inflammatory edges that are indistinguishable from those seen in patients taking "PG inhibitor" drugs. The aim of the PRO-GUT project is to help reduce the diagnostic delay in patients with rare genetic mutations in the PG pathway by establishing new biomarkers: 1- peripherally, by identifying a disturbance in the distribution of eicosanoid metabolites in the plasma and urine of patients compared to controls (using the MetaToul lipidomics platform); 2- in situ, by studying the spatial expression of genes in tissue samples containing ulcers from patients with PLA2G4A or SLCO2A1 mutations, comparing the ulcerated part and healthy areas with controls (spatial transcriptomics using the Visium HD 10X panel from Institut Curie Core Tech). The precise pattern of eicosanoid distribution in peripheral samples associated with the specific cellular signature obtained by in situ spatial transcriptomics could significantly reduce diagnostic time and help identify patients with severe ulcers due to PG pathway disruption. | Omics 2025 | |
| 2025 | Jean MONLONG | Institute for Digestive Health Research - IRSD, Toulouse | Foundation For Rare Diseases | Sensory disorders | microphthalmia anophthalmia | Boosting diagnosis yield for rare ocular disorders with long-read sequencing | A significant proportion of patients with rare diseases do not receive an accurate diagnosis, meaning that the genetic mutation and gene responsible for the disease are unknown. These patients typically have to see several specialists and undergo numerous tests to find the cause of their disease. In recent years, sequencing techniques have been increasingly used to detect a greater number of genetic mutations and thus diagnose more patients. Unfortunately, some mutations still cannot be detected by these techniques, or the mutations detected are difficult to interpret. For these reasons, many patients remain undiagnosed. Since sequenced DNA fragments are commonly compared to a reference genome, it is more difficult to place and analyze highly different fragments and the mutations they describe. This is why it is more difficult to find structural variants, mutations that affect hundreds or even thousands of nucleotides, with current sequencing technologies. Fortunately, new technologies make it possible to sequence DNA fragments that are ten to a hundred times larger, which simplifies the identification of mutations, even structural variants. This project aims to test the effectiveness of these new sequencing technologies in diagnosing rare diseases in patients who have reached a diagnostic impasse. Dr. Julie Plaisancié, at Toulouse University Hospital, coordinates the Reference Center for Rare Ophthalmological Genetic Anomalies with Dr. Nicolas Chassaing and has been able to collect samples from 20 of these patients who unfortunately still do not have a genetic diagnosis. The genomes of 12 of them are already being sequenced using Oxford Nanopore technology, which reads DNA fragments long enough to detect all types of mutations. Using the latest analysis tools we have developed, we are looking for mutations that could explain the patient's disease, such as mutations that disrupt a gene important in eye development. At the end of the project, we hope to find the mutations responsible for the disease in several of these 12 patients, and in the remaining eight patients. These results will end the diagnostic impasse in which they find themselves, help with genetic counseling in the family, and could lead to preventive and personalized measures to better manage their disease. We will also learn more about these rare diseases thanks to the new mechanisms or genes identified. Finally, we will have an initial idea of the effectiveness of these new technologies on real patients and the potential benefits for patients and the clinical system if these technologies were to become an integral part of diagnostic genetic testing. | Omics 2025 | |
| 2025 | Laïla EL KHATTABI | Sorbonne University, Paris | Foundation For Rare Diseases | Rare endocrine disorders | Turner syndrome due to an abnormality in the structure of the X chromosome | Contribution of long-read sequencing to the molecular diagnosis of premature ovarian insufficiency associated with chromosomal translocations | Premature ovarian failure (POF) is a condition that affects approximately 2% of women and is characterized by the premature cessation of ovarian function before the age of 40. This condition is a major cause of female infertility and can lead to secondary complications such as osteoporosis and cardiovascular disease. Although some forms of POF remain unexplained, genetic abnormalities, particularly chromosomal rearrangements, are frequently involved. Our project aims to better understand the impact of chromosomal translocations, where pieces of chromosomes are exchanged, in POI. These rare but potentially deleterious abnormalities could disrupt the expression of genes essential for ovarian function. To study them, we will use an innovative sequencing technology called long-read sequencing (lrGS), which allows for a more accurate and comprehensive analysis of the genome than conventional methods. This approach will help us map chromosome breakpoints with high definition and analyze their potential impact on the integrity of the genes themselves, their proximity to regions of the genome that regulate their level of expression in proteins, and even the impact on the epigenetic landscape of the regions around chromosomal breakpoints, which consists of chemical modifications to the DNA sequence that regulate the level of expression of neighboring genes. Through this work, we hope to identify new genetic mechanisms responsible for POF and improve the molecular diagnosis of this disease. These advances will refine genetic counseling for patients and lay the groundwork for future research on genes involved in ovarian function. By integrating these new technologies, our study will contribute to better care for patients with POI and a significant advance in understanding the genetic causes of this condition. | Omics 2025 | |
| 2025 | Leslie CARON | Marseille Medical Genetics, Marseille | Foundation For Rare Diseases | Neuromuscular disorders | Muscular Dystrophy (DMD, FSHD, SMA, LAMA2-CMD, DM1, Plectinopathy) | Proteomic analysis of undiagnosed muscular dystrophies | Neuromuscular diseases (NMDs), affecting both children and adults with a prevalence of 1 in 1,000, form a large and highly heterogeneous group of genetic diseases causing progressive degeneration of skeletal muscles. Most NMDs lead to long-term disability in patients, placing a significant burden on families and the public health system. In many cases, patients die prematurely from respiratory and, in some cases, cardiac muscle disorders. There are more than 200 NMDs, including more than 30 types of muscular dystrophy (MD) resulting from mutations in genes that control muscle function and structure. The classification of MDs is not fixed but evolves with the constant discovery of new genes/mutations responsible for these diseases. Although more than 100 genes involved in MDs have already been identified, many genes remain to be discovered. In France, thousands of patients with MDs currently have no precise diagnosis. Late or inaccurate diagnoses delay appropriate treatment and can have irreversible consequences for patients. Here, we propose to establish in vitro models of undiagnosed MD, based on patient stem cells, in order to recapitulate the muscle defects observed in these patients and to conduct an in-depth study of the affected cells. More specifically, we will examine protein expression in muscle cells derived from stem cells of patients with undiagnosed MD, which we will compare to control muscle cells (unaffected or affected by known MD). By identifying, for the first time, the proteins specifically modulated in undiagnosed MD, our study will reveal biomarkers and biological pathways contributing to the onset of these pathologies. This project will represent proof of concept for the classification of unlabeled muscle pathologies and will provide innovative avenues for the diagnosis and, ultimately, the treatment of these debilitating diseases. | Omics 2025 | |
| 2025 | Sylvie JAILLARD | Rennes University Hospital, Rennes | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | Mayer-Rokitansky-Küster-Hauser syndrome | MRKH syndrome Uterine agenesis/aplasia and long-read genome sequencing (MUSE project) | Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is a rare condition that results in the congenital absence of the uterus and upper part of the vagina, with external genitalia typically female in appearance and a 46,XX chromosome pattern. Thanks to advances in genetics, such as next-generation sequencing, researchers have been able to identify the genetic causes of this syndrome. It is now becoming increasingly clear that genetics, as well as epigenetics, play a key role in its occurrence. In addition, a major medical breakthrough, uterine transplantation, now offers women with MRKH syndrome the possibility of carrying a child. Therefore, appropriate genetic counseling is essential in this context. This research project aims to decipher the genetic basis of MRKH syndrome using innovative genetic technology: long-read genome sequencing, which provides access to genetic information that was previously difficult to obtain. The study will involve 10 patients who have already been analyzed using routine genetic techniques and who have MRKH syndrome associated with kidney abnormalities. The project will involve specialists in female infertility genetics and uterine transplantation, as well as experts in bioinformatics. This project could reduce the diagnostic uncertainty associated with MRKH syndrome, provide answers to patients seeking explanations, and ensure better medical and genetic support for those wishing to undergo uterine transplantation. | Omics 2025 | |
| 2025 | Valerie DELAGUE | Marseille Medical Genetics, Marseille | Foundation For Rare Diseases | Neuromuscular disorders | Charcot-Marie-Tooth disease | Long read sequencing of the SORD locus toward improving the diagnosis of Charcot-Marie-Tooth disease type 2 | Charcot-Marie-Tooth disease is a group of common neuromuscular disorders that affect the peripheral nerves connecting the brain and spinal cord to the muscles, enabling voluntary movement and perception of environmental stimuli (heat, pain, etc.). This group of diseases is genetically and clinically very heterogeneous, with more than 100 different genes that can cause it and many different clinical presentations. One form of this disease is CMT-SORD, which is caused by mutations in the SORD gene. This disease is transmitted in an autosomal recessive pattern, which means that patients must have two mutations: one on each version of the gene (allele). The region of the genome that contains chromosome 15 has a complicated structure that makes conventional molecular diagnosis, based on high-throughput next-generation sequencing known as "short-read," complicated and sometimes insufficiently sensitive, leading to missed mutations and the inability to correctly identify all patients with mutations in this gene. In this project, we propose an alternative high-throughput sequencing method based on the use of another, more recent technology known as "long-read" sequencing, which is well suited to the complexity of the region of the genome containing the SORD gene. Publications have shown that long-read sequencing can resolve these complicated regions, but this involved sequencing an entire genome, which remains expensive. We propose to test our strategies on a small sample of 10 patients for whom short-read technology has been used but has only identified one of the two mutations (a single allele). We will use targeted sequencing with Oxford Nanopore technology to identify the second mutation on the second allele and propose to test two different strategies for preparing the DNA for sequencing. Targeting the region to be sequenced allows us to sequence many more patients at the same time, thereby reducing sequencing costs while benefiting from the efficiency of long-read technology. If we demonstrate the effectiveness of the proposed methods on our small sample of patients with CMT-SORD, our results could be used to improve the molecular diagnosis of this disease and also other forms of CMT or other genetic diseases linked to complicated genomic regions. | Omics 2025 | |
| 2025 | Zineb SBIHI | Mondor Institute for Biomedical Research (IMRB), Paris | Foundation For Rare Diseases | Immune deficiency disorders | Inborn Errors of Immunity (IEI) Primary Immunodeficiencies (PIDs) | Improving the diagnosis of inborn errors of immunity through non-coding sequence analysis | Hereditary immune deficiencies (HIDs) are rare genetic diseases that affect the immune system and increase the risk of serious infections. Currently, genetic testing can only identify the cause of these diseases in about 30% of cases. Our project seeks to improve this diagnosis by studying parts of the genome that have been little explored until now: non-coding regions that do not directly code for proteins but may play an important role in controlling and regulating gene expression. Recent research shows that these non-coding regions may be involved in immune deficiencies. For example, our work has identified alterations in these regions that affect the expression of the XIAP gene, which is responsible for an immune deficiency. We will therefore analyze these regions in nearly 724 genes in young patients with immune deficiencies but without a genetic cause identified by conventional methods. We hope that this approach will improve the diagnosis and treatment of these diseases. It could also help to provide better genetic counseling to affected families and to better understand how the immune system works, based on these still mysterious parts of our DNA. | Omics 2025 | |
| 2025 | Fabien KAWECKI | Laboratory for the Bioengineering of Tissues - BioTis / Bordeaux | Foundation For Rare Diseases | Cardiovascular diseases | Tetralogy of Fallot | Long-Term Evaluation of a Biological Valve Made of Cell-Assembled Extracellular Matrix for Tetralogy of Fallot Surgical Correction | Tetralogy of Fallot (ToF) is a congenital heart defect that causes narrowing of the pulmonary valve. Surgery to correct this abnormality results in damage to the valve associated with leakage, which can cause serious complications and even sudden death in children. Until now, membranes made from chemically treated bovine pericardium or synthetic plastic membranes have been used in this surgery to repair the valve, but they carry a risk of infection or thrombosis and do not grow with the patient, requiring repeated operations. Our laboratory has developed an innovative biomaterial called Cell-Assembled Extracellular Matrix (CAEM). This material is produced by human or sheep cells cultured in the laboratory, without chemical modification. Thanks to its entirely biological composition, CAEM is well accepted by the patient's body and integrates naturally into the tissue without causing rejection. We propose to study the use of ECM sheets and threads in pulmonary valve repair. As this material is not chemically treated, it can be remodeled by the patient's cells, integrate with native tissue, and adapt its dimensions to the patient's growth. This study aims to test this biomaterial in an animal model (lamb) and evaluate its performance as a valve over a period of one year, as well as its capacity for growth. Ultrasound follow-ups will be performed at 4, 16, and 52 weeks, and final analyses after one year will measure valve performance and tissue integration. Histological examinations will also be used to observe the absence of inflammation and the long-term remodeling of the biomaterial. This project could represent a major breakthrough for children with tetralogy of Fallot, offering sustainable solutions adapted to their growth. | Translational Research 2024 | |
| 2025 | Stephan MATECKI | Physiology and experimental medicine of the heart and muscles - PhyMedExp / Montpellier | Foundation For Rare Diseases | Other rare diseases | Ventilation-Induced Diaphragm Dysfunction | Can diaphragmatic dysfunction induced by mechanical ventilation in intensive care be prevented using a calcium channel-stabilizing biomolecule? A preclinical clinical study in a large experimental model. | State of the art: Patients requiring mechanical ventilation (MV) develop ventilation-induced diaphragmatic dysfunction (VIDD). This condition, which affects 20-25% of ventilated patients, causes functional impairment of the diaphragm, complicating weaning from MV and prolonging the time spent in intensive care by 40%, with a significant increase in mortality and disability following intensive care. Despite its impact, there is no established strategy for treating VIDD, which has recently been classified as a rare disease (ORPHA:505395). The molecular mechanisms involve oxidative stress and disturbances in calcium (Ca2+) homeostasis, leading to diaphragmatic atrophy. Objectives: This project aims to evaluate the efficacy of a human-compatible biomolecule formulation derived from omega-3 fatty acids, 4F4t-NeuroP (VB558), in preventing VIDD using a large animal model (pigs). The objective is to determine whether VB558 can reverse the cellular mechanisms involved and maintain diaphragmatic strength after 3 days of MV. The pig model is chosen for its physiological similarity to humans, allowing for accurate assessment of the drug's efficacy, safety, and toxicity. Experimental protocol: In this study, 12 piglets will be divided into 2 groups (1 treated and 1 untreated). The pigs will be mechanically ventilated for 3 days on a large animal experimental platform, replicating the human intensive care environment. Treated pigs will receive an intravenous dose of VB558 prior to ventilation and daily maintenance doses. Validated preliminary data: Our team has obtained preliminary data showing that F4t-NeuroP effectively prevents VIDD in mouse and pig models, but this formulation required dilution in a solvent that is incompatible for humans. We have shown that a new formulation of 4F4t-NeuroP (VB558), compatible with human use, retains its efficacy in preventing VIDD in the mouse model, but not yet in the pig model. Expected results: We hope to demonstrate that VB558 significantly reduces diaphragmatic strength loss with a disappearance of the cellular mechanisms involved, as assessed by diaphragm biopsies. Positive results will support the transition to clinical trials, with the ultimate goal of preventing VIDD in intensive care patients. Expected therapeutic benefits: We hope to show that VB558 offers a potential preventive treatment for VIDD, improving the outcome for intensive care patients by reducing their length of stay while lowering healthcare costs. This project aims to develop the first preventive treatment for VIDD, significantly impacting the quality of life of patients and healthcare systems worldwide. | Translational Research 2024 | |
| 2025 | Audrey FAYARD | Atomic Energy Commission (CEA) / Fontenay-aux-Roses | Foundation For Rare Diseases | Rare neurological diseases | Progressive Supranuclear Palsy | Retinal and brain imaging biomarkers of Tau accumulation in a new non-human primate model of Progressive Supranuclear Palsy | Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by late onset, rapid progression, and lack of treatment. PSP is one of the tauopathies, a group of diseases characterized by the accumulation of abnormal tau proteins. These diseases vary clinically and anatomically depending on the distribution of tau protein in the brain. In PSP, tau aggregates in neurons, astrocytes, and oligodendrocytes, starting in the brainstem and basal ganglia and then spreading to the frontoparietal cortex. The main symptoms include oculomotor dysfunction, rigid and akinetic parkinsonism, postural instability, and cognitive impairment. Currently, no animal model completely replicates the characteristics of PSP. It is therefore necessary to develop models that more closely resemble the human pathology in order to advance therapeutic studies. The similar anatomical and functional organization of the brain and immune system of non-human primates (NHPs) makes them a preferred model. The use of adeno-associated virus (AAV) allows for long-term protein expression in specific regions and cell types of the brain. Using this technology, we recently developed a model of tauopathy in NHPs by overexpressing mutant tau in the hippocampus. Our current goal is to develop a PSP-specific model in NHPs. We propose to use two imaging biomarkers to detect and quantify tau aggregates in the brain and retina in our PNH model. This will provide potential clinical indicators for PSP patients. Thus, we plan to inject four PNHs into the substantia nigra and striatum with an AAV expressing mutant tau in neurons and astrocytes. These animals will be followed longitudinally for 12 months. Every 6 months, motor, cognitive, and oculomotor functions will be assessed, and tau protein propagation will be analyzed by brain imaging. After 12 months, the animals will be euthanized to assess tau pathology in the brain and visual system. We expect this model to induce neuropathology typical of PSP as well as functional deficits in the visual, motor, and cognitive systems. This predictive animal model of PSP will enable the evaluation of non-invasive biomarkers that can be transposed to humans, as well as innovative therapies for this fatal disease. | Translational Research 2024 | |
| 2025 | Yves BOUCHER | Paris | APICIL Foundation | Other rare diseases | Burning Mouth Syndrome | Burning Mouth Syndrome - creation of an animal model | Stomatodynia (Burning Mouth Syndrome, BMS) is a condition characterized by sensations of burning in the mouth, felt on the tongue, palate, and gums, without local mucosal lesions. It occurs mainly in menopausal women, is frequently associated with anxiety and depression, and significantly affects quality of life. Currently available treatments are not very effective and cause side effects. The causes and mechanisms leading to BMS remain unknown. Nerve damage can be detected through specialized tests, both in the peripheral and central nervous systems, but there is currently no diagnostic biomarker. There is also no animal model that would allow us to understand how the pathology develops and test therapeutic strategies. The proposed project aims to create such a model in female mice, based on the hypothesis of a cumulative role of stress and ovarian hormones, reproducing the nerve changes observed in patients. A dual behavioral and histological assessment will be performed. Oral sensitivity to capsaicin, the active ingredient in chili peppers, which evokes the same burning sensations as BMS, will be measured before and after exposure to stress, then after removal of the ovaries. Tongues will be collected for histological analysis of neurological changes. Alterations observed in humans, such as nerve density and the expression of certain nociceptive receptors, will be investigated in animals in order to validate the model. We will conduct this project within the framework of the new Inserm Unit 1333 dedicated to oral health at Paris Cité University. | APICIL Foundation Award 2025 | |
| 2025 | Kirsley CHENNEN | University of Strasbourg, Strasbourg, | Foundation For Rare Diseases | Sensory disorders | Retinal dystrophies | IMPatienT2: Multimodal artificial intelligence for the classification of hereditary retinal dystrophies | Hereditary retinal dystrophies (HRDs) are a group of rare genetic diseases that affect the retina and can lead to severe vision loss, particularly in children and young adults. They are the leading cause of blindness in these age groups in Europe. These diseases are highly diverse and complex, making them difficult to understand and diagnose. To date, most RDIs still have no treatment. To study them better, the FREDD health data repository, dedicated to rare eye diseases, has been created. It brings together the medical records of hundreds of patients monitored in several specialized centers. However, feeding this database with all the necessary information requires a lot of time and human resources. The IMPatienT2 project aims to meet this challenge using artificial intelligence (AI). The objectives are (i) to automate the processing of medical records in order to extract useful information more easily, and (ii) to develop AI to better classify HRDs for research and diagnosis. This project is based on an existing application called IMPatienT and aims to adapt it to HRDs. Three main areas of focus are planned: 1. Use AI tools capable of automatically reading medical reports (consultations, ophthalmological and genetic examinations, etc.) to extract important information; 2. Create, with the help of doctors, a specialized medical vocabulary that will facilitate the organization and analysis of data; 3. Develop an "intelligent and explainable" AI model capable of learning from a small number of examples (which is common for rare diseases) and better classifying the different types of HRD. All tools will be tested and validated with medical experts to ensure their reliability. Once ready, they will be integrated into FREDD, enabling patient records to be automatically structured and better exploited for research and clinical practice. Ultimately, this project will lead to a better understanding of these rare diseases, help healthcare professionals make more accurate diagnoses, and save valuable time in data management. It will also help to strengthen FREDD's position as the European reference platform for rare eye diseases. This project is an excellent opportunity for a Master's student wishing to train in artificial intelligence applied to healthcare, with the prospect of continuing on to a PhD or collaborative research. | 2025 e-Health Master's Scholarship | |
| 2025 | Mohamed Mounir EL MENDILI | Sorbonne University, Paris | Foundation For Rare Diseases | Rare neurological diseases | Amyotrophic lateral sclerosis | Stratification of patients with amyotrophic lateral sclerosis based on brain and spinal MRI scans and generative adversarial networks | Amyotrophic lateral sclerosis (ALS) is a rare and incurable neurodegenerative disease that affects motor neurons. In France, approximately 6,000 patients suffer from ALS, with 1,500 new cases each year. ALS causes a progressive loss of movement, speech, and breathing abilities. Each patient progresses differently, making it difficult to predict the progression of the disease and adapt care. Understanding this progression is essential to better support patients. Magnetic resonance imaging (MRI) allows visualization of the brain and spinal cord and detection of affected areas. The human eye and traditional analysis methods are insufficient for detecting the subtle signs of the disease. This is why this project proposes to use an artificial intelligence tool, Surreal-GAN, which is already effective in classifying patients with Alzheimer's disease. By analyzing brain and spinal MRIs of ALS patients, the goal is to identify patterns of atrophy relevant to the patients' clinical data (onset of symptoms, genetic mutations, rate of progression, etc.) to see if it is possible to classify patients according to the speed of their disease progression. This classification would enable doctors to predict the progression of ALS more accurately for each patient, tailor care, and improve quality of life. At the same time, it would help to design more targeted clinical trials. The results will be shared with the scientific community through publications and conferences, and the tools developed will be made available via a platform accessible to researchers and healthcare professionals. The long-term goal of the project is to provide a tool for more personalized care for ALS patients. | 2025 e-Health Master's Scholarship | |
| 2025 | Stephanie BOREL | Brain Institute (ICM), Paris | Foundation For Rare Diseases | Rare neurological diseases | Friedreich's ataxia | Modeling of voice changes in Friedreich's ataxia (acronym: AF_EVOLU_VOX) | Friedreich's ataxia (FA) (ORPHA:95) is a rare (1/50,000) progressive neurological disorder with autosomal recessive inheritance, and is the most common form of hereditary cerebellar ataxia. The clinical signs are varied, including cerebellar and sensory ataxia with muscle weakness and scoliosis, associated with sensory loss, visual difficulties, and cardiomyopathy. In 95% of cases, speech impairment (dysarthria) appears and worsens as the disease progresses, leading to changes in articulation, speech flow, and vocal tone that can result in unintelligibility and communication breakdown. Clinical researchers need to have a detailed understanding of how the disease progresses in order to better quantify the effectiveness of future treatments. The first and only treatment that has been shown to slow the progression of the disease is omaveloxolone. It has been available to patients on an early access basis since 2024. The aim of the project is to develop a predictive model of speech progression in Friedreich's Ataxia. It is being carried out as part of the international PROFA study, "Patient-Reported, Health Economics and Psychosocial Outcomes in Friedreich Ataxia," which aims to report on the real-life impact of the disease using an e-health application. Over an 18-month period, 102 people with FA registered via the application, every two months from M1 to M7, then at M12 and M18, on three consecutive days, repeating the days of the week continuously for 30 seconds. During a visit prior to the recordings, a comprehensive assessment by a neurologist collected medical and genetic data related to the disease for each patient. The population consists of 51 French-speaking patients and 50 German-speaking patients. The average age is 35±11.5 years, and 50 are women. The average duration since the onset of the disease is 15.8±8.6 years, and the average SARA score is 17.5±5.9 out of 40 (the higher the score, the more severe the ataxia). Participants also regularly completed questionnaires to measure the frequency and impact of their communication difficulties on their daily lives. Acoustic analyses of voice recordings were performed manually. The objective of this Master's project is now to compare automated analysis with manual analysis and to develop a predictive model of the progression of speech disorders in Friedreich's Ataxia using Machine Learning techniques. The multiparametric model will take into account not only the results of the voice recording and questionnaire analyses, but also medical and genetic data, as well as whether or not the patient is receiving treatment. | 2025 e-Health Master's Scholarship | |
| 2025 | Anaïs CAVARÉ | University of Bordeaux, Bordeaux | Foundation For Rare Diseases | Rare bone diseases | Osteogenesis imperfecta X-linked hypophosphatemia Mucopolysaccharidoses | MOSAIC (Morphology in Oral Rare Syndromes & Artificial Intelligence for Clinical Diagnosis) | Rare bone and cartilage diseases are often accompanied by oral and dental abnormalities such as abnormally shaped or missing teeth, dental structure defects, or jaw growth abnormalities. These dental characteristics can serve as valuable markers for better identifying these diseases, but their diagnosis remains complex and subjective. The MOSAIC project aims to address this issue by creating an innovative tool that uses 3D digital impressions, commonly taken during dental care, and artificial intelligence (machine learning) to diagnose these abnormalities objectively and automatically. The central idea is to demonstrate that certain specific shapes of the palate or teeth can be characteristic of specific groups of rare bone or cartilage diseases. To achieve this, the project is being carried out in three stages: first, the creation of a large database of 3D models from patients and healthy controls using an intraoral camera. Next, detailed analysis of the shapes of the teeth and palate will enable the identification of specific patterns characteristic of each disease. A machine learning algorithm will then be trained to recognize these specific patterns, and the algorithm's effectiveness will be clinically validated. By combining 3D digital imaging, advanced morphological analysis, and machine learning, MOSAIC promises to facilitate the diagnosis of rare diseases, thereby reducing diagnostic uncertainty and improving patient care. | 2025 e-Health Master's Scholarship | |
| 2025 | Romain FEIGEAN | Institute of Myology (AIM), Paris | Foundation For Rare Diseases | Neuromuscular diseases | Pompe disease | Quantifying gait progression using artificial intelligence: a new monitoring tool for neuromuscular diseases | The Institute of Myology proposes to transform a simple video filmed on a smartphone into a revolutionary medical monitoring tool for people with impaired mobility. Using artificial intelligence, our application will automatically identify key parameters—such as walking speed and symmetry between the right and left legs—and then compare this information with that collected by specialized sensors. By validating these measurements using patient monitoring data, we will create a reliable mobile device that is easy to use by any doctor or physical therapist. This new service will help to quantify and detect changes in mobility more quickly, personalize rehabilitation sessions, and prepare for future clinical trials, thereby contributing to a tangible improvement in the daily lives of patients and their families. | 2025 e-Health Master's Scholarship | |
| 2025 | Svetlana GOROKHOVA | Marseille Medical Genetics, Marseille | Foundation For Rare Diseases | Neuromuscular diseases | Calpain-3-related limb-girdle muscular dystrophy R1 Dysferlin-related limb-girdle muscular dystrophy R2 Central cores congenital myopathy Titin-related limb-girdle muscular dystrophy R10 Alpha dystroglycan-related limb-girdle muscular dystrophy R16 | Transcriptomic signatures for the diagnosis of muscle diseases. | Rare muscle diseases are often complex to diagnose. Approximately two-thirds of patients do not receive a clear genetic diagnosis, as the genetic variations (DNA abnormalities) responsible can be very difficult to identify among thousands of others unrelated to the disease. To better understand and diagnose these diseases, we use RNA sequencing (RNA-Seq) technology, which allows us to see the consequences of these genetic variations on gene function. If the same changes in RNA are found in different patients with the same disease, we can refer to this as a "signature." Indeed, certain known muscle diseases, such as myotonic dystrophy (DM1) or FSHD, show very characteristic RNA signatures. Our hypothesis is that other muscle diseases also have RNA signatures that could be used to diagnose and better understand these diseases. In this project, we will analyze RNA sequencing data from patients with rare muscle diseases and controls. The Master's 2 intern funded by this project will use artificial intelligence tools to group diseases according to their RNA profiles and try to link these profiles to the biological mechanisms involved. He/she will also test different ways of selecting and combining data to detect the most relevant signatures. These signatures could then become valuable tools for diagnosing muscle diseases and will help to better understand the mechanisms responsible for these diseases. | 2025 e-Health Master's Scholarship | |
| 2025 | Cecile Rouzier | University of the French Riviera, Nice | Foundation For Rare Diseases | Other rare diseases | Wolfram syndrome | Combating diagnostic impasses: Functional classification of WFS1 gene variants through structural modeling and geometric learning | Better understanding WFS1 gene mutations to improve the diagnosis of rare diseases The WFS1 gene plays a key role in the proper functioning of our cells, particularly in managing stress within a cellular compartment called the endoplasmic reticulum. When altered, it can be responsible for rare diseases such as Wolfram syndrome—a serious disease that combines diabetes, vision loss, and deafness—or certain forms of isolated deafness. These diseases can be transmitted in different ways, either by two defective copies of the gene (recessive form) or by a single copy (dominant form), depending on the type of mutation. The problem today is that many of the mutations identified in this gene are poorly understood: we do not know whether they are actually responsible for a disease, nor how they work. These uncertainties make diagnosis difficult and sometimes prevent us from naming the symptoms experienced by patients. This project therefore aims to remove this uncertainty by using cutting-edge methods based on artificial intelligence and 3D protein modeling. The idea is simple: if we can better understand how a mutation changes the shape or behavior of the WFS1 protein, we can deduce whether it is dangerous and in what way. To do this, researchers already have a database containing nearly 250 well-studied mutations: some are benign, while others are clearly linked to a recessive or dominant form of the disease. By observing where these mutations are located in the protein structure, in which flexible or critical regions they appear, and whether they disrupt areas of interaction with other proteins, we can hope to identify characteristic profiles. The core of the project consists of training a computer model capable of identifying these patterns from complex biological data. The challenge is to build a reliable tool to predict, when faced with a new mutation, whether it is dangerous and how it acts. A Master's 2 student will actively participate in this work, collaborating with experts in genetics and computer science. They will contribute to the analysis of mutations, the construction of models, and the implementation of prediction tools. Ultimately, this research could help doctors make faster and more accurate diagnoses in patients with rare diseases linked to WFS1, paving the way for better care. | 2025 e-Health Master's Scholarship | |
| 2025 | Damien OUDIN DOGLIONI | University of Grenoble Alpes (UGA) | Novo Nordisk | Rare non-malignant hematological diseases | Beta Thalassemia | Living with beta thalassemia in France: patients' subjective experiences, perceptions of beta thalassemia, and attitudes toward treatment (Vivre-BT). | Thalassemia is a genetic disorder of hemoglobin that affects 2.5 to 25% of the world's population, with prevalence varying by region and migration patterns. In Europe, an estimated 20,000 people have a severe form of the disease, including approximately 800 in France. The most common form, beta thalassemia (BT), is caused by deficient or absent hemoglobin synthesis, which can be caused by more than 500 genetic mutations. The severity of the disease is often defined by dependence on blood transfusions, which are necessary for life for patients with beta thalassemia major (BTM). The life expectancy of patients has improved significantly over the past 20 years, exceeding 50 years in developed countries. These advances are linked to improved medical care, the development of new treatments (oral chelators), and imaging techniques to locate iron in the body. However, despite these advances, the disease has a significant impact on quality of life. Patients face treatment constraints and side effects from medications, as well as chronic pain. In addition, they experience psychological and somatic repercussions, including feelings of disability, stigmatization, and uncertainty about the future. These factors can make adherence to treatment difficult. Although the elements we have just mentioned provide some insight into the condition and psychological functioning of patients, the number of studies worldwide is low, often qualitative, poorly reproducible, and French data are very fragmented. It is in this context that the "VivreBT" project is being developed, which aims to systematically and quantitatively explore patients' subjective experiences, their perception of TB, and their relationship to treatment in order to obtain an overview of the psychological functioning of people living with TB to serve as a basis for future interventions. | Novo Nordisk Prize 2025 | |
| 2024 | Caroline Baeza-Velasco | Paris | Foundation For Rare Diseases | Cardiovascular diseases | Vascular Ehlers-Danlos syndrome Loeys-Dietz syndrome Marfan syndrome | Adjustment to illness and psychosocial needs of people with hereditary aorthopathies: a mixed-methods study (APSAOR) | Introduction: Vascular Ehlers-Danlos syndrome (vEDS), Marfan syndrome (MS) and Loeys-Dietz syndrome (LDS) are rare genetic disorders in which connective tissue damage leads to severe vascular complications, including aortic aneurysms and dissections. These potential arterial events lead to an increased risk of premature death. Studies describing patients with these hereditary aortopathies (HA) from a psychosocial perspective are almost non-existent. Consequently, the impact of the disease on patients' daily lives and their psychosocial needs remain poorly understood. Aims: This cross-sectional observational study with mixed methodology (quantitative and qualitative) aims to: 1) explore the psychosocial adjustment to illness of people with HA (SEDv, SLD and SM) and compare it according to pathology. 2) to explore the sociodemographic, clinical and psychosocial factors associated with adjustment to illness, and 3) to explore, via a semi-structured interview, the subjective experience and meaning given to illness, as well as the perceived psychosocial needs of people with these HAs. Method: People aged 18 and over with a molecular diagnosis of SEDv, SLD and SM will be included. In the first part of the study (quantitative component), participants will complete a series of online self-questionnaires assessing adjustment to illness, quality of life, anxiety-depressive symptomatology, coping strategies and illness representations. In a second phase, they will complete a structured interview assessing mental disorders. For the qualitative component, a sub-group of patients will be selected according to pathology (between 8 and 12 per pathology) and availability for a more in-depth interview lasting around 40 min. This sub-group will be assessed with a semi-directive interview consisting of a series of open-ended questions to explore patients' illness experience and psychosocial needs. Expected results: Fill a gap in the literature concerning adjustment in people with HA. Identify new therapeutic targets for a psychologically understudied population, and sensitize the medical community to the need to consider psychosocial aspects in the overall management of patients in order to minimize their potential vulnerabilities. | Humanities and social sciences 11 | |
| 2024 | Hélène KANE | Rouen | Foundation For Rare Diseases | Rare non-malignant hematological diseases | Growing up and building your future with sickle cell disease (GrandCAD) | A rare genetic disease, sickle-cell anemia constrains participation in social, school, recreational and sporting activities in a multitude of ways. Within the framework of an anthropology that considers children as social actors with their own reasons for acting and developing personal strategies, we propose to study how children and adolescents suffering from sickle-cell anemia construct their social lives, their identities and their plans for the future. The aim is to question how they negotiate their postures to "grow up" between constraints linked to the management of their illness and expectations linked to the social constructions of age. This research is structured around four lines of inquiry: (1) adaptations to illness and treatment, (2) family relationships affected by illness, (3) activities and relationships with others, (4) perceptions of the future and plans. A case study methodology will be used, combining observations and interviews with around twenty children and adolescents and their parents. These investigations will enable a biographical approach to be deployed, putting into perspective the evolution of the pathology, care trajectories and bodily and social experiences; and will help identify the stages requiring readaptation. The specificity of sickle-cell anemia leads us to address situations where the experience of a rare disease is shaped by contexts of migration, mobility and transnational relations. This work will enable us to identify and valorize the solutions and adjustments found by young people in the face of the multiple difficulties they encounter, and through this research process to contribute to improvements in the support and care offered by health services and associations. (GrandCAD) | Humanities and social sciences 11 | ||
| 2024 | Catherine GOUEDARD | Paris | Foundation For Rare Diseases | Rare non-malignant hematological diseases | Developing the capacity to influence the work and health trajectories of patients with von Willebrand disease and their caregivers (DevCAP-Willebrand) | The aim of the research is to document the experiences of people affected by Willebrand's disease in relation to their career path, and more specifically the work they undertake to maintain their health. This is an unexplored area in the scientific literature, even though it raises crucial social issues from the point of view of patient associations. The aim is to shed light on how these people cope with episodes of vulnerability in the workplace, in relation to their illness, so as to remain the authors of their professional future, and rebuild the power to act despite the ordeals. This work of maintaining health relies on external resources, offered by the environment, and internal resources, in particular experiential knowledge, which is often implicit. The originality of the method lies in a support approach conceived from a developmental ergonomics perspective. Implemented with some fifteen participants, this method invites them to retrace their career path, to represent it using a mediating and innovative reflexivity tool (the chronicle of vulnerability) and to explain the significant moments and resources mobilized/created. Working with the researcher, this process of biographizing and clarifying lived experience is an opportunity to raise awareness, create meaning and develop the ability to act. Setting up focus groups with participants is a further opportunity to work on experience, and to develop peer recognition of resources and experiential knowledge useful to the community of sufferers. For those who support them, whether in a medical, professional or associative context, the analysis of the complexity of these experiences, carried out in collaboration with the researchers, will enable us to identify levers to support development processes for the people concerned. Together with our partners, the results will help to identify ways of creating a new support system within the care pathway, in line with the professional transitions and bifurcations experienced by the people concerned. By developing caregivers' ability to take action, the approach aims to promote empowering care pathways to articulate work and health issues, transferable to other rare disease support contexts. | Humanities and social sciences 11 | ||
| 2024 | Joanna Calderon | Montpellier | Foundation For Rare Diseases | Cardiovascular diseases | Tetralogy of Fallot Dextrotransposition of the great vessels Univentricular heart disease (Hypoplastic left heart syndrome, Double inlet left ventricle (single ventricle), Isolated right ventricular hypoplasia) | Decision-making and risk behaviours in rare congenital heart disease: QUALINEURO-REHAB Risk ancillary pilot study | Complex congenital heart disease (CHD) requiring open-heart surgery accounts for around ¼ of all CHDs, and is one of the rare diseases listed on ORPHANET, such as tetralogy of Fallot, d-transposition of the great vessels, or univentricular heart. Developmental and mental health disorders, particularly in relation to executive functions and emotional regulation, are the most widespread, and arguably the most disabling, long-term morbidity in the population living with complex CC. The negative repercussions are family, school and social. Crucially, problems with emotional regulation and decision-making may also increase their cardiovascular health risk. To date, no study has explored the psychological decision-making processes in CC and their influence on health risk behaviors in these rare diseases. Yet it is crucial to understand the underlying cognitive and psychopathological mechanisms. QUALINEURO-REHAB Risk is a pilot study ancillary to the QUALINEURO-REHAB (QNR) randomized controlled trial, and aims to 1/ characterize the decision-making abilities and risk behaviors of adolescents and young adults aged 13 to 25 with complex CC by means of direct quantitative and qualitative assessment, 2/ identify the psychological profiles, at executive level (i.e., working memory, cognitive flexibility) and emotional (i.e., anxiety levels, emotion regulation) profiles associated with decision-making abilities and risk-taking behaviours, and 3/ assess the impact of the intervention proposed in our randomized controlled QNR trial on decision-making and health risk-taking processes in this group. Indeed, a better understanding of the psychological processes at the root of health risk behaviours could considerably impact the development of prevention recommendations, vital in the care of young people with complex heart defects. If the results of the interventional study are positive, they would have major public health implications for the organization and management of young people with heart defects. | Humanities and social sciences 11 | |
| 2024 | Aurélie GAUCHET, Damien OUDIN DOGLIONI | Grenoble | UCB | Myasthenia gravis | Effectiveness of a therapeutic education program in myasthenia gravis: proof-of-concept study (MY-EDUC) | Myasthenia gravis is a rare neuromuscular disorder that affects one in every five thousand people. It is chronic and progresses in episodes. Its severity varies, ranging from the invisible disability of fatigue to respiratory distress requiring intensive care. This disease has a significant impact on quality of life, and medication alone is not enough. However, to date, there are almost no psychosocial interventions for patients with myasthenia gravis and no studies evaluating their effectiveness. In particular, studies indicate that the majority of patients with myasthenia gravis suffer from an anxiety disorder such as major anxiety, panic attacks, or phobia. The chronic nature of the disease, the variation in symptoms over time, and the unpredictability of flare-ups are cited as the main causes for this high prevalence of anxiety disorders. While anxiety remains a common comorbidity in chronic diseases, in myasthenia gravis it appears to be unrelated to the natural progression of the disease or its symptomatic variation. In addition, its treatment with medication is delicate, as certain psychoactive molecules may promote a flare-up of the disease. It therefore seems essential to offer specific psychosocial support. MY-EDUC aims to develop a program that includes both therapeutic education modules for patients with myasthenia gravis and stress and anxiety management modules based on cognitive behavioral techniques (CBSM). | UCB Award 2024 | ||
| 2024 | Virginie ESCRIOU | Paris | Alnylam | Eosinophilic gastrointestinal disease (EGID) | Therapeutic strategies based on siRNA administered orally | An interfering RNA is a small fragment of RNA capable of preventing the expression of a gene, thereby silencing it. An interfering RNA can be used as a drug if it is capable of silencing a gene whose expression induces a disease. Currently, there are five interfering RNA drugs that target genes expressed by the liver. To silence gene expression, RNA interference must be able to enter the cells that express that gene. However, it cannot do this on its own and must be combined with a system capable of carrying it to its site of action within the cell. These systems are called vectors. Our team has designed two types of RNA interference vectors that are capable of transporting RNA interferents to cells in the intestine after oral administration. This administration can be in the form of an oral suspension or a tablet to be swallowed. The aim of this project is to study more precisely which cells in the intestine the vectors are able to transport the interfering RNAs to, in order to determine whether it will be possible to offer interfering RNA drugs, administered orally, to treat rare diseases affecting the intestine such as Crohn's disease or eosinophilic gastrointestinal diseases. | Alnylam Pharmaceuticals Award 2024 | ||
| 2024 | Carine LE GOFF | Paris | Foundation For Rare Diseases | Cardiovascular diseases / Marfan syndrome | Role of FBN1 TB5 domain in MFS | Marfan syndrome is a rare disease characterized by aortic anomalies and large stature. Geleophysical dysplasia is also a rare disease, but with an opposite phenotype, short stature and other cardiovascular disorders. In both diseases, we have identified mutations in the same gene at the same location. This location is called the TB5 domain of fibrillin-1 (FBN1). The aim of this study is to understand how one gene, FBN1, can be involved in two opposite phenotypes. In this study, we aim to generate a new mouse model introducing an MFS mutation of the FBN1 gene into the mouse genome. This new mouse model will help us to understand the specific role of this TB5 domain in the FBN1 protein. | Models 2023 | ||
| 2024 | Claire PUJOL | Paris | Foundation For Rare Diseases | Rare neurological diseases / Hereditary Spastic Paraplegia | Tackling the complexity of mitochondrial diseases | This project aims to better understand the link between mitochondria, the "energy powerhouses" of our cells, and certain brain diseases. We are focusing specifically on a disease called "spinocerebellar degeneration", caused by changes in a gene called SPG7. This degeneration can cause problems such as walking difficulties, balance problems, vision problems, cognitive problems and symptoms similar to Parkinson's disease. The main objective is to understand whether mitochondria play a role in the variations observed in patients with the same mutation who have more or less severe impairments. To try to answer this question, we are using approaches that combine laboratory experiments with cell models and genetic analyses with patient DNA. To confirm our results, we want to use a simple model, Caenorhabditis elegans. This is a microscopic worm on which we can test our hypotheses and candidates, and observe the effects of genetic changes, to better understand the mechanism of the disease. | Models 2023 | ||
| 2024 | Hélène ROUMES | Bordeaux | Foundation For Rare Diseases | Rare neurological diseases / GLUT1 deficiency syndrome | Development of a genetically modified rat model for the GLUT1 deficiency syndrome to evaluate a new neuroprotection strategy. | GLUT1 deficiency syndrome is a rare genetic disorder characterized by a reduced supply of glucose to the brain, leading to treatment-resistant epilepsy, delayed psychomotor development and movement disorders. The only therapeutic treatment is the ketogenic diet (low-sugar, high-fat diet). However, not all patients tolerate it. Given the failure of this diet, it is necessary to develop new treatment modalities for this pathology, as well as an experimental model to test their efficacy. The aim of this project is to develop and characterize a rat model genetically modified for the GLUT1 glucose transporter, which closely mimics the symptoms of GLUT1-deficient patients. This experimental model will enable us to understand the mechanisms involved in this pathology and to test different therapeutic approaches. In addition, it will provide a universal model for the study of GLUT1 deficiency syndrome (knowledge and therapies), enabling the pooling of research worldwide to improve the management of GLUT1-DS patients. | Models 2023 | ||
| 2024 | Johann BOHM | Strasbourg | Foundation For Rare Diseases | Neuromuscular disorders / STAC3 disorder (formerly known as Native American Myopathy NAM) | A reliable mouse model for STAC3 disorder | STAC3-related disease, formerly known as Native American Myopathy (NAM) due to the first descriptions in the Lumbee tribe in the USA, is a serious muscle disease with high mortality rates in children and adolescents. Features include neonatal hypotonia, muscle weakness, scoliosis, delayed motor development, and susceptibility to malignant hyperthermia, an often fatal reaction to commonly used anesthetics. The disease is caused by mutations in the STAC3 gene, coding for a key regulator of excitation-contraction coupling (ECC), the mechanism converting nerve signals into muscle contraction. Mice depleted of STAC3 (KO) die at birth and only partially reproduce the human disease, which precludes investigation of the cellular pathways involved, identification of therapeutic targets and development of treatments. We propose to generate a new mouse model carrying the most common STAC3 mutation, found in over 85% of patients. Our preliminary results in the cell model show that this mutation involves a partial loss of function strongly reducing ECC, whereas STAC3 KO cells display a complete absence of ECC. These data underline that cell models and KO mice do not reflect human disease. To minimize the risk of the common STAC3 mutation causing early death in mice, we will generate a conditional mouse that allows expression of the mutation at different times before and after birth. STAC3 mice carrying the common mutation will be systematically analyzed macroscopically and microscopically. We will monitor growth and weight gain, assess general and specific muscle strength, study muscle architecture and determine lifespan. In addition, we will isolate muscle fibers to quantify ECC activity. We also plan to test fiber sensitivity to anesthetics to better understand susceptibility to malignant hyperthermia, which could improve patient protection during surgery. The new STAC3 mouse will make it possible to correlate cellular abnormalities with disease development, and help to understand the underlying molecular pathological mechanisms. As a final objective, we plan to inject the AAV virus containing STAC3 into the muscle and bloodstream of diseased mice to determine the therapeutic potential of this approach, which could pave the way for clinical trials in the future. | Models 2023 | ||
| 2024 | Maelle JOSPIN | Lyon | Foundation For Rare Diseases | Rare neurological diseases / IHPRF-2 Infantile Hypotonia with Psychomotor Retardation and characteristic Facies 2 | Investigating in vivo the functional repercussions of human mutations in UNC-80 - a regulatory subunit of the sodium leak channel NALCN - through a gene-editing approach in the model organism C. elegans. | UNC80 is a large protein found mainly in neurons. It plays an important role in the activation of neurons by regulating an ion channel, called NALCN, involved in various body behaviors, such as sleep, locomotion or the control of respiratory and circadian rhythms. Mutations in the UNC80 gene have been associated with a rare disease called IHPRF. This disease manifests itself in babies as muscle weakness, slow development and distinctive facial features. When a new variation in the UNC80 gene is discovered in a patient with neurodevelopmental disorders, it is not always easy to determine whether or not these variations are responsible for the disease. This project aims to use a small organism, the nematode Caenorhabditis elegans, to directly test how these genetic changes affect the function of the UNC80 protein. | Models 2023 | ||
| 2024 | Marion DELOUS | Lyon | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes / RNU4ATAC-associated diseases (Taybi-Linder syndrome, Roifman syndrome, Lowry-Wood syndrome, atypical Joubert syndrome) | GENERATION OF 'HUMANIZED' ZEBRAFISH MODELS TO STUDY RNU4ATAC-ASSOCIATED DISEASES | Several steps are required before our genes can be expressed in our body's cells. One of these steps is called splicing: it removes all unnecessary material from messenger RNAs, leaving only the material required for protein production. In 2011, our team demonstrated that a defect in a component of the splicing machinery, U4atac, is responsible for Taybi-Linder syndrome (TALS). Patients have inherited from both parents a mutation in the gene for this component, RNU4ATAC. This rare disease is extremely serious, leading to numerous malformations, including severe cerebral malformations, intellectual disability and death before the age of 2-3 years. Two other neurodevelopmental diseases have been associated with the U4atac gene: Roifman (RFMN) and Lowry-Wood syndromes, both less severe. Our team is seeking to understand the pathophysiological mechanisms behind these syndromes, and why mutations in this gene can lead to different pathologies. To this end, we use an animal model, the zebrafish, which enables us to study the different stages of embryonic development. Using this model, we have already demonstrated that transient loss of function of U4atac leads to dysfunction of a particular organelle in our cells, the primary cilium. Here, our project is based on the generation of mutant zebrafish lines, known as 'humanized', which express the human U4atac gene in place of the zebrafish gene. This strategy makes it possible to induce a stable loss of U4atac function, and to precisely reproduce two emblematic U4atac mutations seen in TALS and RFMN patients. Thanks to these models, we will be able to study in depth the morphology and activity, and even the function, of the larval zebrafish brain. We will also carry out molecular analyses to understand the splicing defects that underlie brain abnormalities. In this way, a better understanding of pathophysiological mechanisms will pave the way for longer-term projects in the search for therapeutic targets, based on the use of the zebrafish models generated and aimed at improving patients' quality of life. | Models 2023 | ||
| 2024 | Pascal DE SANTA BARBARA | Montpellier | Foundation For Rare Diseases | Rare hepato-gastroenterological diseases / Chronic intestinal pseudoobstruction; Familial visceral myopathy; Megacystis-microcolon-intestinal hypoperistalsis syndrome; Myopathic intestinal pseudoobstruction . | Generation of human-induced pluripotent stem cells-derived intestinal organoids to understand Chronic Intestinal PseudoObstruction syndrome | Pediatric Intestinal Pseudo-Obstruction Syndrome is a rare and severe disease, resulting in a chronic inability of the intestine to propel its contents. To date, there is no treatment, only artificial nutrition (enteral or parenteral) is offered to infants to ensure their growth, but morbidity remains high. Recently, pathogenic heterozygous missense mutations of the ACTG2 gene, which codes for smooth muscle gamma actin, have been found in over 40% of patients, but the pathological mechanisms induced by these variants are not known due to the lack of relevant models. Our project aims to set up human intestinal organoid models to study the impact of ACTG2 variants on digestive smooth muscle function, so as to be able in the longer term to develop approaches to counteract the deleterious effect of these variants. | Models 2023 | ||
| 2024 | Susanne SCHMIDT | Montpellier | Foundation For Rare Diseases | Rare neurological diseases / INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY | Development of hiPSC lines to study TRIO-associated neurodevelopmental disorders | Neurodevelopmental disorders (NDD) such as intellectual disability (ID) and autism spectrum disorders (ASD) are caused by disturbances in brain development, leading to impaired brain function. These pathologies represent a major public health challenge, as their clinical manifestations are quite heterogeneous and it is difficult to make a diagnosis and find an appropriate treatment, due to a lack of knowledge of the causes of these diseases, which are multiple. In the laboratory, we are working on the TRIO gene, which is essential for brain development and function. TRIO controls various stages of neuronal development, such as neuronal proliferation and migration, axon guidance and synapse formation. Recently, mutations in the TRIO gene have been found in patients with TNDs. In the course of our research, we have discovered that, depending on the location of the mutation in the gene, patients have different clinical syndromes. Thanks to our work and that of other teams, TRIO is now considered a new risk gene for TNDs. It is essential to develop a new experimental model for these diseases, in order to understand how mutations in the TRIO gene disrupt brain function, leading to these disorders. This will enable us to improve patient diagnosis, medical advice to patients and their families, and in the longer term, consider the future development of therapies. Our research program therefore aims to develop an in vitro model using induced pluripotent stem cells (iPSCs) obtained from patients carrying a particular mutation in the TRIO gene. This model will enable us to study the effect of heterozygous mutations in the patient's genetic context, and offers the possibility of assessing the effect of the TRIO mutation in cultured human neurons differentiated from iPS cells. | Models 2023 | ||
| 2024 | Thomas HENRY | Lyon | Foundation For Rare Diseases | Rare systemic and autoimmune disorders / ROSAH syndrome (Retinal dystrophy, Optic nerve oedema, Splenomegaly, Anhidrosis and migraine, Headache) | Development of a murine model of the rare ROSAH syndrome | ROSAH syndrome is a rare genetic disorder that affects multiple organs and leads to progressive vision loss, chronic migraines and a chronic autoinflammatory syndrome. This recently described disease is still very poorly understood. In particular, how the mutation leads to this diversity of symptoms across multiple organs remains unknown. Moreover, there are currently no relevant mouse models of the disease, which is a pitfall for the development of new drugs. We propose here to develop an original mouse model of ROSAH syndrome which should recapitulate the symptoms of the disease, increase our understanding of the disease and enable new drugs to be tested. | Models 2023 | ||
| 2024 | Valerie DELAGUE | Marseille | Foundation For Rare Diseases | Neuromuscular disorders / distal Hereditary Motor Neuropathy | New mouse model for Inherited Motor Peripheral Neuropathies and motor neuron diseases linked to mutations in VRK1 | Hereditary neuropathies, and more specifically Charcot-Marie-Tooth disease, are neuromuscular disorders in which the peripheral nerves, which transfer motor information to the muscles and sensory information from the extremities to the brain, are damaged. Although many of the genes responsible for these neuropathies have been identified, our understanding of how the disease develops remains incomplete, and there is unfortunately no effective treatment to date. We have recently described mutations in VRK1, a novel gene for CMT, and more specifically for motor forms of CMT, called dHMN. We have been able to model the disease by studying motor neurons (the neurons of the peripheral system that conduct information for voluntary movement from the brain to the muscles) derived from patient stem cells (obtained by a blood cell reprogramming technique) and identify several defects in these motor neurons (called hiPSC-MN). This will enable us to understand how mutations in the gene cause the disease, and which defects can be corrected by treatment. Using a gene therapy strategy that delivers the normal gene into mutated patient cells, we have been able to demonstrate in hiPSC-MN that re-expression of the normal VRK1 protein restores the abnormal parameters, and provide proof of concept that gene therapy can treat the disease. In order to go further in the development of a treatment, we need to test this treatment in a mouse model, in which we will invalidate the vrk1 gene. This is essential, in particular, to determine the route of injection of the drug gene, the doses to be used and the timing of treatment. In order to obtain a model as faithful as possible to the human disease, we want to create a so-called "conditional knock-out" model, i.e. one in which we invalidate the gene only in motor neurons, and not in the rest of the body's cells. Once we have characterized the model, i.e. determined whether the mice have locomotor problems like patients do, and what tests we need to perform to measure these abnormalities, we will test a treatment which will involve injecting a vector (virus) into the cerebrospinal fluid (intrathecal route) which will target the motor neurons and restore expression of the vrk1 gene in these gene knockout motor neurons. We hope that this project will enable us to demonstrate the efficacy of this treatment, and perhaps envisage similar treatments in humans. | Models 2023 | ||
| 2024 | François CLAUSS | Strasbourg | APICIL Foundation | Rare head and neck malformations, Developmental anomalies and malformation syndromes / Oligodontia WNT10A | Bioactive membranes for the treatment of oligodontia WNT10A | WNT10A pathology is a rare genetic disorder with various consequences including disorders in odontogenesis and osteogenesis. With a prevalence of 52% in dental dysplasia, this pathology represents a major public health problem . Currently, severe jaw atrophy is treated by oral rehabilitation. The procedure is complex: it requires bone harvesting (for example from the hip or skull) and then reimplantation, resulting in two surgical sites . Oral rehabilitation therefore carries significant risks of morbidity and pain, with unconvincing results due to genetic disorders in WNT10A patients. The difficulty is even greater for the treatment of young patients due to their growth and bone volume already reduced by the disease. We propose an efficient strategy using a bioactive membrane to replace bone grafts in order to regenerate bone in the jaw for a population suffering from severe bone atrophy in the context of WNT10A pathology. In particular, WNT10A pathology often affects young people in the form of oligodontia: the main objective is therefore to meet the need for oral rehabilitation, particularly for jaw reconstruction, using a procedure that is gentle and minimally traumatic for these patients, both psychologically and physically, with complications and postoperative pain greatly reduced compared to current standards. | APICIL Foundation Award 2024 | ||
| 2024 | Julien BARC | Thorax Institute, Nantes | Foundation For Rare Diseases | Cardiovascular diseases | congenital heart block | Trio-based whole genome sequencing to search for novel causes of congenital and young-onset isolated atrioventricular block | Atrioventricular block (AVB) is a condition in which the heart's rhythm slows down. As the disease progresses, it can lead to fatigue, fainting and, in some cases, cardiac arrest, necessitating treatment with pacemaker implantation. The frequency of AV block generally increases with age. In rare cases, however, it can occur in younger people. If you are diagnosed with AV block, it's important to investigate the cause. Some causes of AV block in young people are due to antibodies passed on by the mother, others to abnormalities in the shape of the heart, and still others to genetic mutations. Identifying these factors is important, as it directly affects the treatment plan. Indeed, some atrioventricular blocks can be cured when the primary cause is treated, while others require oral therapy as well as a pacemaker. Genetic testing is recommended, particularly in young people, as congenital factors such as genetic mutations are considered more important than in adults. On the other hand, there are many patients for whom the cause cannot be identified even after genetic testing. Current genetic testing looks for limited regions (coding regions: of some or all genes representing a maximum of 2% of the genome) in the genome, and cannot identify abnormalities if the mutation lies outside the area sought. It is also difficult to know whether the genetic structure has been significantly altered. Therefore, in order to cover the whole genome, we plan to sequence the entire genome of patients who develop AV block at a young age, but whose cause has not yet been identified. The challenge of this process is that it is difficult to find the desired mutation due to the scope of the search and the number of variants found in the general population. To overcome this problem, we will simultaneously carry out genetic testing on relatives who do not have AV block, in order to search for mutations that are new to the patient. We will also take advantage of the cardiac-specific information available to our team to select and target regions thought to have a significant impact on the heart when mutations are present. For novel causal genes associated with AV block, we plan to conduct cellular studies to confirm that the mutation is indeed the cause of AV block. If new causal genes or previously unknown mechanisms are discovered, they could be used to develop new treatment strategies for patients. | GenOmics 2024 | |
| 2024 | Michèle BERTACCHI | Valrose Biology Institute (iBV), Nice | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) | Modelling the neurodevelopmental optic atrophy syndrome BBSOAS in human retinal organoids | Bosch-Boonstra-Schaaf Optical Atrophy Syndrome is a rare disease caused by deletion of the NR2F1 gene, essential for brain and eye development. Patients present with vision problems, including severe optic atrophy. Currently, no human model exists to study this disease or test potential treatments. We have created three-dimensional structures grown in the laboratory, called organoids, which enable us to reproduce early eye development and study this disease. We have found that NR2F1 depletion leads to problems in retinal development, including reduced retinal cell production and abnormalities in the ganglion cells responsible for optic nerve formation. We propose to use an RNA sequencing technique to better characterize the different cell populations represented in these organoids in the presence or absence of the NR2F1 gene and understand the underlying mechanisms of the disease, opening up therapeutic opportunities for patients suffering from vision problems. | GenOmics 2024 | |
| 2024 | Marie-Christine CHABOISSIER | Valrose Biology Institute (iBV), Nice | Foundation For Rare Diseases | Rare endocrine disorders | 46,XX ovo-testicular DSD 46,XX testicular DSD | Identification of the genetic networks leading to ovo-testicular formation and to other Disorders of Sexual Development | Sex development disorders (also known as Differences in Sex Development, DSD) are rare, heterogeneous diseases that can manifest as dysfunctional genitalia, infertility or hormonal imbalances. All these diseases can cause severe psychological and social distress for the affected person. What's more, some DSD patients are at high risk of developing cancer. Despite intensive research over the past 30 years, only around 50% of DSDs can be explained at the molecular level to date. This underlines our ignorance of the mechanisms that control sexual development. In humans (and mice), the reproductive system comprises various organs, including the gonads, which are the organs that produce the sex cells or gametes. Sperm cells are produced by the testis in men (XY) and oocytes by the ovaries in women (XX). Depending on the sex of the embryo, different genes are activated, enabling the gonads to develop into testicles in the future boy or ovaries in the future girl, thus initiating the entire sexual development of the individual. Understanding normal and defective gonadal development has therefore become a key research issue, as it can have a major impact on the diagnosis of DSD patients. It can also inform medical advice to families in their decision for or against the removal of their children's gonads in cases where the pathology is accompanied by an increased risk of developing gonadal tumors. Mutations in the RSPO1 gene lead to DSD characterized by the presence of testes or ovo-testicles (gonads containing both testicular and ovarian tissue) in XX patients. We have shown that the RSPO1 gene is essential for ovarian formation from the very start of this process, but its mode of action remains poorly understood. Our project aims to understand how RSPO1 regulates the formation of the different cell types that make up the ovary, and to identify the gene cascade activated by RSPO1 in the gonads. To this end, we will analyze gene expression at the single-cell level in the gonads of mice carrying a mutation in the gene encoding RSPO1. Our work will provide new insights into the role of RSPO1 in sexual differentiation, and help clarify the origin of certain abnormalities in sexual development. In addition, our analysis offers an entry point for identifying new factors responsible for DSD, and may provide new tools for improving the diagnosis and management of these pathologies. | GenOmics 2024 | |
| 2024 | Maud DE DIEULEVEULT | Imagine Institute, Paris | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | Snijders-Blok-Campeau Syndrome | An episignature for the Snijders Blok-Campeau syndrome: diagnosis and pathophysiological mechanisms | Recent advances in sequencing technology have improved patient diagnosis. Unfortunately, for a significant number of patients, the causal mutations remain unknown due to a lack of knowledge of certain variants or regulatory sequences. In order to speed up diagnosis and facilitate pathology identification, new technologies and approaches are being developed. In recent years, the epigenetic landscape has been investigated for a number of pathologies. In particular, the mapping of DNA methylation, a highly stable epigenetic marker that remains the most widely explored, is possible thanks to the many study tools that have already been developed and are easily accessible. Its disease-specific pattern called episignature has made it a marker of choice for determining an identity card for each pathology. Pathologies linked to mutations in regulators of the epigenetic machinery (often associated with growth disorders and intellectual disability) are relevant disease models for characterizing specific episignatures. Among these pathologies, Snijders Blok-Campeau syndrome caused by pathological variants in the CHD3 gene remains unexplored. A new European cohort of 28 patients, whose DNA is available in the laboratory, will be analyzed on an Illumina EPIC chip. This analysis will identify differentially methylated regions specific to the syndrome. This episignature will serve both as a diagnostic aid for patients in diagnostic deadlock or for the identification of variants of unknown significance, and as a means of identifying deregulated regions and proposing deregulated signaling pathways in this syndrome. | GenOmics 2024 | |
| 2024 | Hervé KEMPF | IMoPA / Vandœuvre-lès-Nancy | Foundation For Rare Diseases | Pulmonary rare diseases | Keutel Syndrome | Identification of pathogenic pathways responsible for abnormal tracheal calcification in a mouse model of Keutel Syndrome | Keutel syndrome (KS) is a rare autosomal recessive genetic disorder. Patients with this syndrome exhibit abnormal calcification of various tissues, leading to skeletal malformations, cardiovascular defects and impaired respiratory function. KS has been attributed to loss-of-function mutations in the gene encoding the Gla matrix protein more commonly known as MGP. MGP-deficient mice (Mgp-/-), which mimic the clinical features of Keutel patients, represent a crucial model for understanding the molecular mechanisms responsible for the development of pathological calcification. Based on our recent solid findings on the dynamics of the onset of abnormal calcification in tracheal tissues of Mgp-/- mice, we propose to perform a high-throughput RNA-seq transcriptomic analysis of tracheal samples from wild-type and mutant mice at different stages of progression. Our project will identify the mechanisms responsible for tracheal calcification leading to severe respiratory complications in KS patients. | GenOmics 2024 | |
| 2024 | Wojciech KREZEL | IGBMC / Illkirch-Graffenstaden | Foundation For Rare Diseases | Rare neurological diseases | syndromic microphthalmia 12 | Cell-type specific mechanisms of neurodevelopmental and neurodegenerative process in MCOPS12. | The aim of the project is to better understand the mechanism of MCOPS12, a rare disease with progressive neurological symptoms caused by point mutations in the retinoic acid receptor beta (RARb). Although animal models of MCOPS12 have been generated and faithfully recapitulate the symptoms of the disease, the mechanism of pathogenesis of the different RARb variants remains unknown. Our published and preliminary data indicate that both developmental and postnatal dysfunction of RARb may contribute to the disease, and that compromised dopaminergic signaling contributes to but does not explain the entire neuropathology of MCOPS12. To address these questions, we propose to perform single-nucleus RNAseq analyses of brain samples from allelic series of RARb causing MCOPS12 in presymptomatic and symptomatic adult mice. In parallel, snRNAseq determination of RARb-dependent cell types in reporter mice will identify the key cellular and molecular players leading to the pathophysiology of MCOPS12. | GenOmics 2024 | |
| 2024 | Éric LETOUZÉ | CRCI2NA / Nantes | Foundation For Rare Diseases | Rare systemic and autoimmune disorders | Schnitzler's Syndrome | Schnitzler's syndrome, an autoinflammatory lymphoid disease caused by a somatic mutation? Bone marrow immunogenetic and transcriptomic analysis. | Introduction: Schnitzler syndrome (SdS) is a rare, late-onset inflammatory disease (50-60 years of age), combining proliferation of a B lymphocyte in the marrow called clone B, urticaria, fever with blood inflammation ± bone and joint pain. There is currently an effective treatment that blocks a pro-inflammatory molecule, anti-IL-1. This costly treatment is only suspensive, requiring daily injections, with relapse on discontinuation and a non-negligible risk of infection. In addition, there is a significant delay in diagnosis, averaging 5 years, due to the absence of a reliable diagnostic test, with diagnosis based solely on a set of clinical and biological criteria. Current research data suggest a dysfunction of inflammatory pathways in the innate immune system. To make the link with the B lymphocyte clone mentioned above, we hypothesize that a genetic mutation present only in this clone would stimulate inflammatory pathways in other immune cells. Our aim is therefore to identify this mutation by sequencing the whole genome of this clone, but also of other cells in the marrow of these patients, and to study its impact by studying the expression of genes, particularly inflammation genes, in the total marrow of the patients. Methods: We have 5 marrows from patients with SdS available in our laboratory. Patients' marrow is already sorted with a total marrow fraction and a cellular fraction very rich in B lymphocyte clones. This fraction will be screened for somatic mutations using WGS. We will then study its functional impact by comparing transcriptomes, i.e. gene expression in the B clone versus other B lymphocytes and other immune cells in marrow from patients with SdS versus marrow from patients without SdS. Results: The results of this project should highlight the mutation in the medullary B clone and provide a better understanding of the inflammatory pathways involved in the disease, as well as enabling the development of a simple genetic diagnostic test to confirm or refute the diagnosis of SdS and thus reduce the number of patients who are misdiagnosed. What's more, if this study comes back positive, it could pave the way for the exploration of other B-clone-related syndromes (Clarckson syndrome, etc.) using the same methodology. Conclusion: This study will represent a real advance in our knowledge of Schnitzler syndrome, the pathophysiology of which currently remains an enigma, and may lead to a diagnostic sequencing test to reliably confirm/infirm the disease. | GenOmics 2024 | |
| 2024 | Valérie MALAN | Imagine Institute / Paris | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | Developmental Language Disorders | Genetic bases of Developmental Language Disorders | Language acquisition is one of the fundamental stages in a child's neurodevelopment. Language disorders are extremely frequent and heterogeneous in both clinical and etiological terms. Specific oral language disorders (SOLD) are a highly specific clinical entity of neurodevelopmental disorders, as they are not associated with any other pathology (intellectual disability (ID), autism spectrum disorder (ASD), etc.). The prevalence of ODD is estimated at 7-8%, including 1% of severe forms. Regarding the etiology of OLSD, data on monozygotic twins and the presence of familial cases suggest the existence of genetic causes. Until recently, terminology has been confused internationally, leading to considerable heterogeneity in clinical cohorts. Moreover, despite technological advances, the genetic basis of OLT has been little studied. Our project aims to determine the nature and frequency of genetic lesions in a cohort of patients with severe OLST using chromosomal analysis and whole-genome sequencing technologies. In collaboration with the Centre Référent des Troubles du Langage et des Apprentissages at Garches Hospital, 23 families have already been included, 15 of whom have already benefited from genetic explorations using high-throughput Exome or Genome sequencing. We have detected genetic anomalies known to be involved in ASD and/or ID. These observations suggest a possible common origin between these different neurodevelopmental disorders. Moreover, according to our preliminary results, the genetic basis of ODD points to a complex pattern of inheritance (oligogenic) in multiplex families (several affected individuals). Interestingly, for a sporadic case (the only affected individual in the family), we were able to identify one of the first pathogenic variants in the ZNF292 gene in a patient with TSLO, enabling genetic counseling to be proposed. Language disorders represent a public health problem. In certain cases, genetic diagnosis can be used to establish a diagnosis and propose appropriate genetic counseling. Genetic data could also provide a better understanding of normal language development. Finally, the genetic dismemberment of ODD and an understanding of the associated pathophysiological bases constitute a first step in the exploration of other "dys disorders", in order to provide better care for these children. | GenOmics 2024 | |
| 2024 | Caroline NAVA | Pitié Salpêtrière University Hospital / Paris | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | corpus callosum agenesis neurodevelopmental disorders | Long-read genome sequencing for children with corpus callosum agenesis and neurodevelopmental disorders, with negative prenatal exome sequencing and postnatal short-read genome sequencing | Despite recent advances in genetics, more than half of patients with rare genetic diseases remain undiagnosed. This situation is particularly worrying for families with young children with neurodevelopmental disorders and/or congenital malformations. The aim of our project is to find the genetic diagnosis in children with a brain malformation, agenesis of the corpus callosum, detected during ultrasound scans during pregnancy, and a neurodevelopmental disorder after birth, for which conventional genetic techniques have failed to make the diagnosis. We will use a new DNA analysis technique, called long-read sequencing, to identify genetic variations not detected by other tests. In parallel, we will study gene expression to help interpret and validate results. This project is in line with our team's main theme, which is the characterization of new genes and mechanisms associated with neurodevelopmental disorders, particularly where there is an impact on prenatal diagnosis, such as corpus callosum anomalies. This study could help demonstrate the usefulness of this new technique in the neonatal diagnosis of rare genetic diseases, and improve care and genetic counseling for the family. | GenOmics 2024 | |
| 2024 | Lucie PELLISSIER | Physiology of Reproduction and Behavior / Tours | Foundation For Rare Diseases | Rare neurological diseases | Fragile X syndrome Phelan-McDermid syndrome | SOCIALOME of Fragile X and Phelan-McDermid syndromes in mice | Phelan-McDermid and Fragile X syndromes are rare, genetic neurodevelopmental diseases characterized by pronounced symptoms such as mental and language delays and severe forms of autism. Currently, the management of social interaction and communication deficits relies heavily on behavioral interventions, which are cumbersome to implement and of uncertain efficacy. Existing treatments focus mainly on comorbid symptoms, and attempts to develop compounds targeting social symptoms have failed in clinical trials. The nature of the therapeutic targets themselves may explain these failures. Indeed, as these targets are widely expressed in the brain, the beneficial effects of these compounds may have been undermined by other, unwanted effects. The aim of this project is therefore to identify more specific molecular targets, by elucidating deregulations within neurons involved in Phelan-McDermid and fragile X syndromes. To this end, we will use an original methodology to identify targets in mouse models of these syndromes. Encouragingly, our preliminary data confirm the feasibility of this approach for identifying therapeutic targets. In addition, the project will provide new insights into the underlying pathological mechanisms of these two syndromes. Overall, this project will provide invaluable resources, stimulating the development of new therapeutic strategies for people affected by these syndromes. | GenOmics 2024 | |
| 2024 | Amélie PITON | IGBMC, Illkirch-Graffenstaden | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | Neurodevelopmental disorders: DYRK1A syndrome | Characterization of molecular mechanisms altered in DYRK1A syndrome, a frequent genetic form of neurodevelopemental disorder, using cerebral organoids | Genetic abnormalities affecting the DYRK1A gene are at the root of a particular form of neurodevelopmental disorder (NDD). The protein produced by this gene regulates the addition of phosphate groups to numerous target proteins, and thus to many cellular processes. The role of DYRK1A in brain development has mainly been studied in mice and flies, but little is known about it in human brain cells. We have therefore developed in vitro "mini-brain" models differentiated from cells with or without genetic abnormalities in the DYRK1A gene. This project aims to characterize the alterations caused by these genetic anomalies in these "mini-brains" using single cell RNA-Seq technology: we will study the changes caused both in the type of brain cells obtained (neurons, neuronal precursors and other types) and in the regulation of the expression of other genes in these different cell types. These results will provide a better understanding of how abnormalities in the DYRK1A gene can lead to TND, and can also be used to test the effect of potentially therapeutic molecules. | GenOmics 2024 | |
| 2024 | Isabel PUNZON | Alfort National Veterinary School / Maisons-Alfort | Foundation For Rare Diseases | Neuromuscular disorders | Dynamin2-related Centronuclear Myopathy | Gene signature of disease and therapy, CRISPR/ Cas13 mediated, in the DNM2-related canine model of centronuclear myopathy. | Centronuclear myopathies (CNMs) are caused by mutations (errors in the DNA sequence) in three prevalent genes: MTM1, BIN1, and DNM2. The proteins encoded by these genes work together in a network that plays complementary roles in essential functions of muscle cells. Currently, there is no cure for CNMs, so innovative research is necessary to identify promising therapeutic options. We identified a DNM2 dog model that carries the most prevalent mutation found in humans and fully mimics the disease. This model offers clinical follow- up and opportunities of repeated muscle biopsies. Functional and histopathological output parameters can be used to further study the disease and evaluate the efficacy and safety of candidate therapies. Normalization of the DNM2 protein content has been shown to have a positive therapeutic effect in different mouse models of CNM. Our goal is to demonstrate the effectiveness of using the emerging CRISPR/Cas13 tool to reduce DNM2 as a treatment strategy for this group of diseases. We also want to perform a complete analysis of genomic differences between healthy and mutated muscles. | GenOmics 2024 | |
| 2024 | Fiona GEDEON ACHI | University of Bordeaux / Bordeaux | Foundation For Rare Diseases | Rare non-malignant hematological diseases | Sickle cell disease | Preventing pain and improving well-being: the experience of illness for children with sickle cell disease and their families in Bordeaux | Our research project examines the role played by mind-body techniques and non-drug interventions in the prevention and management of pain in children with sickle cell disease, a rare blood disorder (Ninot 2018). By mobilizing a qualitative survey focused on patients and their families, we propose to assess the feasibility and usefulness of the CrisALiDE-SAS pediatric program at Bordeaux University Hospital. This program offers a multimodal approach to the prevention of chronic pain and its psychosocial consequences, with interventions such as meditation, massage and hypnosis. Indeed, almost 50% of sickle cell patients will develop a chronic pain syndrome in adulthood, with lasting effects on their social, professional and emotional well-being (Taylor et al 2009). Despite being the most common genetic disease in France (Haute Autorité de Santé 2022), sickle cell disease remains poorly understood, as it is often perceived as an "exotic" disease affecting minority populations, particularly those of African, Caribbean, North African, Middle Eastern or Indian origin (Gernet et al 2012; Fullwilley 1998). A hereditary disease, sickle cell disease affects red blood cells, and more specifically is accompanied by a deformation of hemoglobin, the protein responsible for oxygen transport in the body (SOS GLOBI 2024). In sickle-cell patients, this abnormal hemoglobin can become rigid and deform the red blood cells, which, instead of being round and flexible, take on the shape of a crescent moon, thus blocking blood circulation and thus the flow of oxygen to the various organs. This phenomenon, known as "vaso-occlusion", is accompanied by intense attacks of pain in bones and joints, described by patients as "unbearable" and "unbearable" (Ricadat et al 2023). From childhood onwards, painful attacks due to the disease affect social integration, and in particular lead to interruptions in schooling and social involvement. Several studies also suggest that the experience of the healthcare system can accentuate the pain and suffering experienced by patients and their families in the short and medium term (Ciribassi et al 2016; Mann 2010). Our research therefore aims to understand how the CrisALiDE-SAS program can improve the experience of pain and thus the well-being of children and their families. This will be the first anthropological research on a proposal for preventive management of chronic pain in pediatrics in France. With a view to health promotion, the results of this research will help to increase children's power to act in the face of their pain, support parents in managing this suffering, and mediate between patients and carers to improve the pain prevention care on offer. | Novo Nordisk 2024 Prize | |
| 2024 | Nathalie ANGEARD | Paris Cité University / Paris | IRCEM Corporate Foundation | Neuromuscular diseases | Duchenne Muscular Dystrophy | Training Perspective Taking in Children with Duchenne Muscular Dystrophy: Contributions of New Ecological, Educational, and Virtual Reality Tools | DMD is a rare pediatric genetic disorder affecting the muscles and central nervous system. In addition to progressive muscle degeneration, DMD causes cognitive, executive, behavioral, and social cognition impairments (Angeard, 2021; Mennetrey et al., 2020). These symptoms, often associated with comorbidities such as ADHD, ASD, and OCD, impact the quality of life and social relationships as well as the independence of these patients (Powell & Carlton, 2022). Neuropsychological studies on DMD report language and executive difficulties that negatively impact school learning and the independent performance of daily activities (Chieffo et al., 2022; Fee et al., 2018; Mennetrey et al., 2020). Furthermore, given their motor difficulties and limited mobility ( ), children with DMD are less exposed to social experiences and, as a result ( ), more prone to isolation (Garcia et al., 2023). It therefore appears essential to offer early intervention ( ) targeting weakened functions and involving families to encourage a transition to (xml-ph-phrase_1). It therefore seems essential to offer early intervention targeting weakened functions, involving families to promote a transfer to activities of daily living. To our knowledge, no remediation program has been offered to children with DMD. This is why we propose to develop the PP-DMD project, an innovative intervention study aimed at remediation. The aim is to develop a program that will enable children with DMD to acquire the motor skills necessary for daily living. This is why we propose to develop the PP-DMD project, an innovative interventional study aimed at sociocognitive and emotional remediation, which will focus on Perspective Taking, the cornerstone of Theory of Mind (ToM) development and social relationships . Our main objective is to offer an ecological and fun training program called "PP-TRAINING" with six sessions spread over three weeks to boys with DMD aged 5 to 12 and age-matched control subjects , and to test its effect on their ToM and autonomy performance after the intervention. We also wish to evaluate the benefits on quality of life and interpersonal relationships at school and within the family. The secondary objective is to offer, as a complement, an educational intervention involving parents (PP-HOME). Inspired by the classic design of training studies in children, this project aims to conduct an initial assessment of PP abilities using the ecological PP-DEV tool (Ghimp et al., 2023) and TdE abilities using the Virtual Reality test (TOM- REV) (Doulou et al., 2021). Additional measurements of EF in daily life, quality of life, and social inclusion will be proposed via questionnaires. At the end of this study, we should have a PP-focused training protocol that has demonstrated its effectiveness in improving mentalization abilities, quality of life, and interpersonal relationships in children with DMD. | FE IRCEM 2024 | |
| 2024 | Anne-Sophie BONNET | University of Lorraine (UL) | IRCEM Corporate Foundation | Other rare diseases | Dental agenesis | Agenesis of the second mandibular premolars: the cantilever bonded bridge, a solution for the future? | Context: Dental agenesis refers to the absence of one or more teeth. In Europe, the prevalence is 4.34%. Agenesis can be isolated or syndromic and, in both cases, has aesthetic and functional consequences. Apart from wisdom teeth, the second mandibular premolars are the teeth most commonly affected (29.9%). Current treatments often involve orthodontic follow-up throughout growth with the placement of dental implants once alveolar bone growth is complete. Anterior cantilever bonded bridges are a recent and innovative therapeutic alternative for replacing incisors with good clinical results. They are less invasive and less expensive than dental implants and can also be used to treat adolescents who are still growing. However, since the mechanical stresses are greater on posterior teeth than on incisors, it is necessary to implement a rigorous scientific and clinical approach in order to test the possibilities of using cantilever bridges for posterior teeth. Objective: The aim of this project is to verify ex vivo and in silico the viability of cantilever bonded bridges for the treatment of mandibular second premolar agenesis. Materials and methods: Using finite element simulations based on a complete jaw model already available within the research group, the initial objective is to identify the forces that naturally act on posterior teeth during food mastication. Mechanical tests will then be carried out by applying the mechanical load identified previously to a cantilever bridge made up of artificial teeth and then natural teeth in order to test different techniques for preparing the supporting teeth. Finally, a finite element model reproducing the configuration tested experimentally will be constructed to evaluate the stresses on the bridge, the adhesive, and the supporting tissues in critical situations such as chewing hard foods. Expected results: The study will provide quantified data on the mechanical load-bearing capacity of posterior cantilever bridges for different support tooth preparations. If the proposed project confirms the viability of the posterior cantilever bonded bridge for the treatment of agenesis of the mandibular second premolars ex vivo and in silico, a multicenter PHRC will be conducted to clinically evaluate the survival rate of this alternative to dental implants in patients with agenesis. | FE IRCEM 2024 | |
| 2024 | Thomas EDOUARD | Toulouse University Hospital (CHU) / Toulouse | IRCEM Corporate Foundation | Cardiovascular diseases | Marfan syndrome and related disorders | Improving Quality of Life and Social Inclusion for Children and Adolescents with Marfan Syndrome through Adapted Physical Activity (APA) Monitoring | Marfan syndrome (MFS) is a rare genetic disorder characterized by ocular, cardiovascular, and musculoskeletal abnormalities. From childhood onwards, MFS causes a deficit in muscle mass, which worsens during adolescence and early adulthood. Children and adolescents with this condition often suffer from fatigue, physical limitations, and a reduced quality of life. These symptoms have a negative impact on their daily lives, their education, and their social inclusion. Several studies conducted at the Marfan Syndrome Reference Center at Toulouse University Hospital have demonstrated a correlation between endurance capacity and quality of life in young Marfan patients, as well as the effectiveness of exercise rehabilitation in improving their quality of life. These results suggest that educational and rehabilitation programs should be developed to improve the exercise capacity and quality of life of these patients. Currently, the needs of young patients with MFS are not fully met, particularly in terms of exercise rehabilitation support. This project proposes an innovative approach combining remote monitoring and adapted physical activity (APA) in a multidisciplinary, structured, and personalized approach. The APA program, based on the experience of the Marfan reference center at the Toulouse University Hospital ( ) and the results of the Marfan&Moves pilot study, aims to extend the scope of action to the national level ( ) and increase the impact on patient care. By adopting a holistic and innovative approach, this project aims to improve the quality of life and social inclusion of children and adolescents with Marfan syndrome. Combining remote monitoring, adapted physical activity, and multidisciplinary support, it effectively addresses currently unmet needs, offering promising prospects for young patients and their families. | FE IRCEM 2024 | |
| 2024 | Jocelyn LAPORTE | IGBMC, Illkirch-Graffenstaden | Foundation For Rare Diseases | Neuromuscular disorders | centronuclear and myotubular myopathies Charcot-Marie-Tooth peripheral neuropathies | Biomimetic peptides to cure neuromuscular diseases | Context: Neuromuscular diseases form a highly heterogeneous group of hereditary disorders, including with a prevalence of up to 1:2,500 worldwide, significantly impacting patients' independence and representing a heavy burden on our healthcare system. In addition, these genetic diseases have a high risk of recurrence in families already affected. Neuromuscular diseases are linked to malfunctions in the peripheral nerves that send signals to the muscles, the skeletal muscles responsible for muscle contraction and movement, and/or the neuromuscular junction connecting these two tissues. Motor deficit is the main sign of these diseases. There is no specific treatment for most neuromuscular diseases, hence an urgent need to validate proof-of-concept therapeutics and molecules to cure them. Here we focus on a therapeutic target we have recently identified for several neuromuscular diseases, the protein dynamin 2 (DNM2). It should be noted that mutations in DNM2 cause either Charcot-Marie-Tooth (CMT) peripheral neuropathy or a myopathy known as centronuclear myopathy (CNM). Objective: In this project, we propose to develop biomimetic peptides based on the mode of action of DNM2, in order to treat Charcot-Marie-Tooth neuropathy and centronuclear myopathy linked to DNM2 mutations. Our previous screenings have identified at least 11 candidate peptides. We propose to develop the efficacy of these peptides in several stages in vitro, in cultured cells and in vivo. Expected impacts: The validation of biomimetic peptides targeting the DNM2 protein will provide sufficient proof of concept to launch preclinical development of the human product to be tested in clinical trials. | Screening 2024 | |
| 2024 | Emmanuel RICHARD | University of Bordeaux / Bordeaux | Foundation For Rare Diseases | Hereditary metabolic diseases | Congenital erythropoietic porphyria (CEP) Hepatoerythropoietic porphyria (HEP) Erythropoietic protoporphyria (EPP) X-linked protoporphyria (XLPP) | Development of ALAS2 inhibitors for erythropoietic- porphyrias . | Porphyrias are rare diseases of heme biosynthesis, a component that is essential for the production of hemoglobin in red blood cells. Genetic abnormalities in this metabolic pathway lead to the accumulation of toxic compounds called porphyrins in the body. These molecules are responsible for the highly debilitating clinical symptoms observed in patients , such as neurological abnormalities, skin lesions caused by sun exposure, and anemia due to the destruction of red blood cells. Advances in understanding the biochemical mechanisms responsible for these diseases have led to the identification of an enzyme protein that regulates heme biosynthesis , ALA synthase or ALAS, as a therapeutic target. Acute hepatic porphyrias have benefited in recent years from the marketing of an innovative drug targeting the enzyme hepatic ALAS1 (Givosiran©). Erythropoietic porphyrias (EP) currently have no medical treatment. Recent work by our team has highlighted the major therapeutic potential of modulating the heme biosynthesis pathway by partially inhibiting ALAS2 activity through iron deficiency. We have been able to demonstrate its efficacy through preliminary studies in mouse models and EPP patients. We have recently identified molecular candidates that specifically target ALAS2 using a high-throughput screening approach of a chemical compound library. The objective of this project is to continue the preclinical development of these candidates using a hit-to-lead approach aimed at optimizing the chemical structure of these molecules in order to increase their efficacy, stability, and pharmacological properties prior to preclinical trials in animal models of the disease. This preliminary step to clinical trials in humans will enable us to identify the most promising drug candidates . | Screening 2024 | |
| 2024 | Aurelie DE THONEL | Epigenetics and Cell Fate – Joint Research Unit 7216 / Paris | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | Rubinstein-Taybi Syndrome | Identifying therapeutic molecules by high-throughput screening for the rare neurodevelopmental disorder Rubinstein-Taybi, based on a stress-responsive pathway | Rubinstein-Taybi syndrome (RSTS) affects approximately one in every 100,000 births. Although RSTS is a rare neurodevelopmental disorder (NDD), individuals diagnosed with RSTS represent one in every 300 people in specialized institutions. This underscores the human and societal importance of finding medicinal solutions capable of improving the condition of these individuals. This highlights the human and societal importance of finding drug solutions capable of improving the condition of these individuals. The clinical picture is associated with moderate to severe intellectual disability as well as numerous facial and skeletal malformations or malformations affecting other organs. The majority of affected individuals carry mutations in the CBP or EP300 proteins, which control the accessibility of genes to cellular machinery. They enable their expression and ensure, among other things, the integrity of neuronal and cognitive functions. These functions are compromised when CBP or EP300 is mutated. Using two-dimensional (2D) or three-dimensional (3D, known as "brain organoids ) cell models, we have identified phenotypes relevant to RSTS pathology that can serve as readers in a pharmacological screen. Armed with a toolbox consisting of these neural models and these interpretive keys, we propose, in association with the I-Stem platform, to conduct a screening of a bank of 4,000 active compounds approved by the FDA, in clinical phase II or III, and molecules whose function and targets are known. One of these has already shown an improvement in phenotypes in our models. Our project is also unique in that it is based on a common trait between RSTS and other TNDs: the deregulation of a stress response pathway, the HSF2 pathway, which, unexpectedly, is necessary for brain development (in the absence of stress). The HSF2 pathway is thus dysregulated in both RSTS and rare monogenic TNDs such as Angelman-like syndrome or other TNDs linked to intellectual disabilities that present mutations in the HSF2 gene. Its dysregulation is responsible in particular for phenotypes relevant to TND pathologies. Our pharmacological screening strategy therefore has the potential to benefit individuals with RSTS CBP or EP300, as well as other individuals with TND. | Screening 2024 | |
| 2024 | Gerard LAMBEAU | Institute of Molecular and Cellular Pharmacology (IPMC) / Valbonne | Foundation For Rare Diseases | Rare kidney diseases | Membranous Nephropathy (PLA2R1-associated) | High throughput screening of the Fr-PPIChem library against the CysR immunodominant epitopes targeted by autoantibodies: Towards a specific therapy in PLA2R1-associated Membranous Nephropathy? | Extramembranous glomerulonephritis (EMGN) is a rare but serious autoimmune kidney disease, with approximately 1,300 new cases per year in France and 10,000 in Europe. Patients differ in clinical progression and response to treatment. Better tools are needed to identify severe forms and optimize treatments. MEG is characterized by severe proteinuria. In 2009 and 2014, we discovered PLA2R1 and THSD7A as two major autoantigens, with autoantibodies in 55% and 3% of patients (NEJM 2009&2014, 2 patents). Clinically, these discoveries have had a major impact on patient management, with the licensing of patents to a German company and the development of commercial tests with our team. These tests are available on the global market and used in hospitals to detect autoantibodies (https:// www.pla2r.com). Over the past 10 years, we have shown that patients have several types of anti-PLA2R1 autoantibodies ( JASN, 2016&2018, unpublished data and 2 patents). Using molecular studies, we have just identified the major epitope present in the CR domain and recognized by AbCR antibodies in all patients (unpublished data, patent pending). Our project aims to identify molecules that inhibit CR-AbCR interaction. Technically, we will develop a rapid test to screen a set of 10,314 molecules constituting the Fr- PPIChem chemical library. Fr-PPIChem is an academic chemical library dedicated to screening protein-protein interactions (PPI) (Bosc et al, ACS, 2020). The project will be carried out in partnership with the CMBA platform in Grenoble. After validation and optimization of the hits, the identified inhibitors could become drug candidates for use in combination with immunosuppressants, which is the current treatment. There are two main tasks: 1. We will convert an already validated test (ELISA) into a miniaturized and automated fluorescent test (HTRF). We already have the necessary molecular tools: pure CR domains with tags and anti-CR antibodies from patients in the form of serum or pure monoclonal antibodies. Ideally, the HTRF test will be developed in two formats to screen molecules against serum AbCR antibodies (polyclonal anti-CR, pAb test) and against a representative monoclonal antibody (mAb test). 2. We will use both HTRF assays to screen the Fr-PPIChem chemical library. The identified molecules will be classified by structure and validated by various cross-cutting methods (competition assays, structural modeling, human cell assays including PLA2R1 binding inhibition and cytotoxicity). The best molecules could be tested in vivo in the future. Our project should pave the way for innovative, personalized therapy based on the identification of molecules that block the interaction of pathogenic antibodies with PLA2R1. | Screening 2024 | |
| 2024 | Marco PONTOGLIO | Inserm U1151, CNRS UMR8253, University of Paris / Paris | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | HNF1B deficiency Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) | Pharmacological Therapy for a Rare Genetic Kidney Disease | Project summary Transcription factors specifically expressed in the kidneys play a crucial role in the development and functioning of this organ. Mutations leading to reduced activity (haplo- insufficiency) can cause significant congenital and postnatal disorders, particularly affecting renal development. Our recent findings challenge the traditional idea that certain transcription factors are always constitutively active in the regulation of gene expression. We have discovered that their activity can be increased by specific chemical compounds, suggesting that they require activation to reach their full potential. This perspective opens up new therapeutic possibilities for diseases caused by the haploinsufficiency of these essential transcription factors . Project objectives and methodology The project aims to study the molecular mechanisms that regulate the activation of these transcription factors by certain compounds. We will explore how these compounds interact with transcription factors and influence their activity, including their ability to bind to DNA and chromatin, as well as the identification of other proteins and genes involved in the activation process. This research could significantly improve our understanding of the role of these transcription factors in cellular processes and their potential as therapeutic targets. By identifying compounds that increase their activity, we could develop new treatments for severe kidney diseases and potentially other conditions involving similar genetic mechanisms. | Screening 2024 | |
| 2024 | Maud FROT | Lyon Neuroscience Research Center, Lyon | Associative (Algo) | Rare neurological diseases | Algodystrophy | Dance therapy as a non-pharmacological intervention for chronic pain in adolescents | Pain and fear are two closely related negative experiences. Pain, when it becomes chronic, can itself represent a threat to patients, and fear of pain and movement are currently observed. This “kinesiophobia” can have very harmful consequences on the patient's overall quality of life and psychological state. Adolescents' heightened sensitivity to anxiety is a major risk factor for behaviors such as movement avoidance in cases of chronic pain. In these populations, it is essential to offer multidisciplinary pain management, with interventions targeting anxiety and catastrophizing, and actively involving the patient. In our project, we propose to set up and test the potential benefit of dance-therapy sessions, a technique involving the body and movement, in adolescents and young adults suffering from chronic pain with an associated high level of kinesiophobia, such as Complex Regional Pain Syndrome (Algodystrophy). We plan to compare dance therapy with two other therapeutic actions: another artistic technique not related to the body (art therapy) and a second one, related to the body but with no art-therapeutic connotation (yoga). Patients will be recruited in the Centre d'Etude et de Traitement de la Douleur (CETD) at Lyon Neurological Hospital. If they are willing to participate, they will be assigned to one of three groups (dance therapy, art therapy, or yoga) for 15 weekly one-hour sessions. Patients will be asked to complete regular questionnaires during the study, as well as at the beginning and end of each session. A "control" group will also be included, composed of patients who will not take part in any art therapy or yoga sessions but will complete the same measurement scales and questionnaires. The unique collaboration we are proposing between a dancer-choreographer/art therapist, a scientific research team, and a hospital-based CETD is a major asset for the realization of this project. Such studies are not currently carried out in France, and the project we are proposing represents an important innovation in the therapeutic management of chronic pain patients, and even more so of adolescents. | Spouse with association | |
| 2024 | Hélène DOLLFUS | Institute of Medical Genetics of Alsace, Strasbourg | Associative (BBS) | Rare neurological diseases | Bardet-Biedl syndrome | A pharmacological approach to alleviate retinal degeneration in Bardet-Biedl syndrome | Bardet-Biedl Syndrome (BBS) is a severe autosomal recessive syndromic ciliopathy with over 24 BBS genes identified. The disease, characterized by primary cilia dysfunction, results in multisystemic manifestations such as retinal degeneration (RD) leading to severe visual impairment, obesity, and renal dysfunction. Our research is based on both in vitro modeling, including patient fibroblast cultures, and in vivo modeling using BBS mouse models, to elucidate the pathophysiological mechanisms underlying BBS. These models have been instrumental in evaluating the therapeutic potential of gene replacement therapy and pharmacological interventions. However, to date, there are no available treatments specifically targeting RD in BBS nor any other ciliopathy-related RD. A small molecule therapeutic modality is relevant to address the photoreceptor degeneration and beyond, considering the multisystemic symptoms of the disease. The primary cilium plays a crucial role in numerous signaling pathways which are considered as druggable targets. Preclinical data from our collaborators have demonstrated that compounds regulating such signaling pathways may offer an effective means of partially rescuing renal and retinal phenotypes in 2 other ciliopathy models. In this context, our investigation of a related compound in BBS cell models revealed a significant improvement in a ciliary pathway in fibroblasts derived from BBS patients (2 BBS1 and 1 BBS10). This finding suggests a promising and novel therapeutic avenue for addressing RD in BBS. To further validate the therapeutic potential of the compound, our project addresses: (1) a comprehensive in vitro assessment of ciliary enhancement using a representative panel of BBS patient-derived fibroblasts (including BBSOme and chaperonin-related subtypes), (2) an evaluation of systemic in vivo administration (intraperitoneal) in the Bbs10-/- mouse model, and (3) administration to the murine model Bbs1M390R/M390R.Both models are generated and characterized for RD (ERG, OCT, and histology) in our laboratory. In conclusion, our approach aims to demonstrate the therapeutic efficacy of a specific compound for RD in BBS as an archetypical multisystemic ciliopathy, irrespective of specific gene/mutation subtypes. | Spouse with association | |
| 2024 | Emeline NANDROT | Vision Institute, Paris | Associative (BBS) | Rare neurological diseases | Bardet-Biedl syndrome | Deciphering cilia involvement in RPE functional defects in BBS-related pigmentary retinopathy (CILEPI) | Vision impairment places a serious burden on the aging society, affecting the lives of millions of people. Many retinal diseases are of genetic origin, of which over 50% are due to mutations in cilia-associated genes. This is predominantly due to the fact that photoreceptor cells contain a highly specialized primary cilium, whose function is essential for vision. However, numerous other ocular cell types also display a primary cilium, such as the retinal pigment epithelium (RPE). The RPE is a monolayer of highly polarized cells located between the neural retina and the vascular choroid, which is vital for photoreceptor health and integrity. One of the most important functions of the RPE is the phagocytosis of shed photoreceptor outer segments (POS), which is essential for photoreceptor functionality. Recent studies have shown the importance of a functional primary cilium during development of the RPE, yet nothing is known about the function of ciliary proteins in mature RPE. Specifically, very little is known about the role of the ciliary BBS proteins in these mechanisms. In this study, we will investigate the role of BBS primary cilia proteins in RPE mechanisms to obtain valuable insights into ciliary signaling processes and their dysfunction during disease processes. For this, we will examine the effect of ciliary dysfunction on RPE maturation and functionality, initially focusing on POS phagocytosis. We will generate ciliary gene and BBS gene knockout cell lines using CRISPR/Cas9 and examine POS phagocytosis as well as potential alterations in other RPE functions. In addition, ciliary and BBS mutant mouse models will be used to study potential effects in vivo via proteomic and transcriptomic screens, as well as through functional assays to support in vitro data. We hope to identify new disease mechanisms in vitro and in vivo, leading to a better understanding of how ciliary dysfunction can influence ocular disorders. | Spouse with association | |
| 2024 | Sara ANJOMANI VIRMOUNI | Brunel University London, London, UK | Association (AFAF) | Rare neurological diseases | Friedreich's ataxia | Preclinical efficacy of targeting sphingolipid-metabolizing enzymes for Friedreich's ataxia treatment | Friedreich’s ataxia (FRDA), a form of childhood ataxia, is a rare inherited neurodegenerative disorder that affects 1 in 50,000 Caucasians. Individuals with FRDA usually present in early childhood with difficulty walking due to poor coordination or “ataxia.” The condition progressively deteriorates, leading to the development of debilitating musculoskeletal deformities and immobility, while the majority die in early adulthood due to heart failure or associated complications. FRDA is caused by a defect (mutation) in the FRDA gene which codes for “Frataxin,” a protein which plays an essential role in mitochondrial health within the cell. A deficiency of this protein protein leads to disordered iron metabolism within mitochondria, leading to increased production of toxic molecules, oxidative cell stress and, ultimately, cell death. There is currently no effective therapy for FRDA. Evidence indicates that defective sphingolipid metabolism may contribute to different neurodegenerative conditions, including childhood associated Tuberous Sclerosis Complex and Fatty Acid Hydroxylase-associated Neurodegeneration, and Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. Sphingolipid is a group of lipids important for brain activity and, therefore, disturbances in their metabolism can have a huge impact on brain function. We have recently found that sphingolipid levels and their related genes are altered in FRDA mouse and human samples, which may play a critical role in disease progression. The aim of this project is to investigate the role of key regulators of sphingolipid metabolism in FRDA and to identify potential and novel targets for the development of therapeutic strategies in this childhood disease. There is an urgent, unmet need to alleviate the suffering and prolong the lives of individuals with FRDA. We expect our There is an urgent, unmet need to alleviate the suffering and prolong the lives of individuals with FRDA. We expect our research to yield novel disease targets for pharmaceutical therapy so that children with FRDA may, one day, experience long-term survival opportunities. There is an urgent, unmet need to alleviate the suffering and prolong the lives of individuals with FRDA. We expect our research to yield novel disease targets for pharmaceutical therapy so that children with FRDA may, one day, experience long-term survival opportunities. | Spouse with association | |
| 2024 | Richard FESTENSTEIN | Imperial College London, London, UK | Association (AFAF) | Rare neurological diseases | Friedreich's ataxia | Restoring Frataxin expression and inhibiting oxidative damage in FA: safety and efficacy in hiPSC-derived cardiomyocytes | There is currently no cure for the most common inherited ataxia—Friedreich's Ataxia (FA). Recent research has identified 1) nicotinamide as a potential radical therapy "switching" the pathologically silenced Frataxin gene back on on in patients and 2) the antioxidant, Omaveloxolone, which has been approved as a novel treatment in FA. This project will examine the potential synergistic effect of these treatments in FA-derived human cardiomyocytes to establish pre-clinical efficacy and safety of this novel combination therapy. FA is a multisystemic disorder prominently featuring sensory neuropathy characterized by the loss of neurons in the dorsal root ganglia, leading to afferent ataxia. However, more than half of the patients succumb to cardiac dysfunction (1–4). The majority of FA cases are caused by the expansion of a DNA triplet-repeat (GAA) sequence located within the first intron of the Frataxin (FXN) gene, resulting in epigenetic gene silencing (5–7). Currently, no effective treatment is available for FA, highlighting the urgent need for a cellular model that accurately recapitulates human pathology to investigate disease mechanisms and assess drug efficacy. Existing mouse models with GAA repeats exhibit a mild phenotype, making it difficult to correlate with human disease conditions (8). While in vitro cell models, such as PBMCs and skin fibroblasts derived from FA patients, contribute to our understanding of the disease mechanism, these cell types are not pathologically affected. Advancements in human induced pluripotent stem cell (hiPSC) culture and cardiomyocyte (CM) differentiation present a promising opportunity to use hiPSC-CMs from FA patients, thereby overcoming the limitations of current models. This approach facilitates the mechanistic investigation and drug screening for FA in a pathologically relevant human cell model that contains GAA repeat-triggered heterochromatic silencing. Here, we propose to utilize hiPSC-CMs derived from FA patients to evaluate the potential of small molecules in reactivating the epigenetically silenced FXN gene and ameliorating cellular deficits associated with FA, including impaired iron-sulfur (Fe-S) cluster (ISC) biogenesis, oxidative stress response, and mitochondrial respiration. Previously, our transcriptomic analysis identified dysregulation of the mitochondrial complex I (MC1) assembly pathway in FA hiPSC-CMs. This finding aligns with heart positron emission tomography (PET) scans of FA patients, which reveal a significant reduction in MC1 density compared to healthy individuals. Antagonizing the heterochromatic silencing of FXN represents a compelling therapeutic strategy for FA. We have demonstrated that a class III histone deacetylase inhibitor (HDACi), nicotinamide, can increase FXN expression in multiple FA in vitro and ex vivo models, as well as in human (7,9). Additionally, omaveloxolone, a novel Nrf2 activator, has shown potential in reducing oxidative stress and improving mitochondrial function in FA models (10). We propose a combinatorial approach using nicotinamide and omaveloxolone to synergistically enhance FXN expression and mitigate cellular deficits in FA. It is imperative to characterize the molecular and biochemical benefits in pathogenic- cells treated with these agents, alongside assessing their cardiotoxicity, to expedite the identification of an effective treatment for FA. | Spouse with association | |
| 2024 | Giancarlo IAROSSI | Bambino Gesù Children's Hospital, Rome, Italy | Association (AFAF) | Rare neurological diseases | Friedreich's ataxia | Early Visual System Involvement in Children and Young Adults with Friedreich's Ataxia | Friedreich's ataxia (FA) is an autosomal recessive progressive cerebellar condition that typically begins in childhood and leads to a decrease in quality of life and life expectancy. FA includes either neurological and non- neurological symptoms. Approximately 73% of FA patients experience visual system involvement, including optic nerve sub-atrophy or atrophy and abnormal bioelectrical responses in the visual cortex. Previously, optic nerve and retina changes were explored by optical coherence tomography (OCT), but specific retinal layer-to-layer involvement remains limited so far. Retinal ganglion cells (RGCs) are known to be primarily affected, leading to reduced thickness in the macular region. Alterations in the outer retinal layers, such as the photoreceptors and pigment epithelium, have been observed histologically in human tissues and animal models, but functional studies on the outer retina are limited. Multifocal ERG (MfERG) recordings could provide useful clinical insights into these functional aspects. Additionally, ocular motor dysfunction in FA patients has not been extensively studied, and its analysis could offer novel parameters for understanding neural circuits and disease progression. Additionally, ocular motor dysfunction in FA patients has not been extensively studied, and its analysis could offer novel parameters for understanding neural circuits and disease progression. This study aims to assess the extent of visual system involvement and identify early subclinical morpho- functional retinal manifestations in a cohort of children and young adults with FA over a one-year period. Moreover, wearable video-oculography will be employed to investigate the potential impact of oculomotor function on morpho-functional assessments. Our findings may enhance the understanding of FA natural history, leading to valuable insights for early detection and treatment strategies, thereby benefiting children and wheelchair-bound individuals and paving the way for future clinical trials. Ultimately, this study aims to validate potential biomarkers and improve patient care through correlation and longitudinal analyses. | Spouse with association | |
| 2024 | Ingrid BANOVIC | University of Rouen, Rouen | Association (AFMF) | Fanconi anemia | Needs, resources, and barriers to overall empowerment (existential and medical) for older adolescents and young adults with Fanconi anemia: an overview | Spouse with association | |||
| 2024 | Alessandro PORROVECCHIO | University of Artois, Lille | Associative (Dospital) | Neuromuscular disorders | Congenital myasthenia | Broken Links, Strengthened Links (LIBRIS): Navigating the psychosocial challenges of myasthenia for a better quality of life. Focus on congenital myasthenia | Spouse with association | ||
| 2024 | Nazim BENZERDJEB | University Hospital of Lyon, Lyon | Associative (AMARAPE Prize 2024) | Rare cancers | Rare disease of the peritoneum | Proposal for Research Prize 2024 AMARAPE – FMR | Spouse with association | ||
| 2024 | Marc POCARD | Lariboisière Hospital, Paris | Association (AMARAPE AAP) | Rare cancers | Rare peritoneal diseases | Presence of environmental pollutants in cases of pseudomyxoma peritonei. | Persistent organic pollutants (POPs) have been detected in the greater omentum, as in other human fatty tissues. In cases of surgery for peritoneal pseudomyxoma (PMP), the greater omentum is completely resected and can be preserved. Detection in fatty tissue is a record of exposure to pollutants and, if the concentration can be assessed, could represent the patient's specific level of exposure. Certain cancers, such as gastric adenocarcinoma (GAC), are associated with the detection of high concentrations of POPs, which could be linked to the origin of these cancers (publication by the INSERM U1275 Paris M Pocard team). Certain cancers, such as breast cancer, have an aggressive metastatic process when high concentrations of POPs are detected, which could be associated with a specific cancer progression process (publication by Prof. Barouki's team, Paris). The origin of PMP is unknown and the clinical course of a patient after complete surgery and CHIP is unpredictable. We have already analyzed omentums from patients with and without cancer with biologists from a specific research platform (LABERCA: Laboratory for the Study of Residues and Contaminants in Food). We obtained exposure results in the omentum and identified the specific exposure of patients with ADCI. Recently, we developed a specific solution to deduce the total tissue weight of the omentum using clinical data (gender, age, weight, and height) to determine the exact overall exposure to POPs. Samples of greater omentum from 20 patients with PMP (10 low-grade and 10 high-grade) who underwent surgery at CRS and CHIP were stored with the individual consent of each patient. The samples were calibrated and anonymized for analysis. The samples will be analyzed to determine the distribution of a wide range of POPs. POPs include polychlorinated dioxins/furans (PCDD/Fs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs), hexabromocyclododecanes, organochlorine pesticides, and polycyclic aromatic hydrocarbons (PAHs). The patient's clinical progression (relapse or survival) will be analyzed and correlated with POP results, in terms of specific POPs and concentration levels. After this pilot study, we will be able to determine whether or not the occurrence of PMP may be linked to exposure to pesticides, industrial and agrochemical derivatives, and whether the different outcomes of patients after surgery and CHIP could be related to exposure to these pollutants. | Spouse with association | |
| 2024 | Capucine TROLLET | Center for Research in Myology, Paris | Associative (Lama2) | genetic neuromuscular disease | Merosin-deficient congenital muscular dystrophy | Deciphering alterations in crosstalk between muscle fibers and fibroadipogenic progenitors to identify novel therapeutic targets for LAMA2-RD | Skeletal muscle is a highly adaptable tissue composed of contractile fibers and various cell types. Besides generating movement, it secretes molecules that communicate with nearby cells and organs through the bloodstream. This communication is crucial during muscle regeneration, especially after injury or in diseases such as muscular dystrophy. Muscle repair requires finely coordinated actions from muscle satellite cells, Fibroadipogenic Progenitors (FAPs), and inflammatory cells. Disruptions in this communication can lead to inefficient regeneration and cause fibrosis, where excess extracellular matrix (ECM) builds up around muscle fibers. Fibrosis not only affects muscle function but also hinders its ability to regenerate, and hinder gene and cell therapies efficacy. LAMA2-related dystrophy (RD) is one of the most common congenital muscular dystrophies in Europe, caused by mutations in the LAMA2 gene. This gene encodes the α2 chain of laminin (Lmα2), a key component of the muscle basement membrane (BM) that links the muscle fiber's membrane to surrounding tissue. LAMA2 mutations lead to a partial or complete loss of Lmα2, affecting BM integrity and resulting in varying degrees of muscle weakness and atrophy, and clinical severity. Muscle biopsies from LAMA2-RD patients display muscle fiber atrophy, degeneration, fibrosis, fatty tissue replacement, and inflammation. Research has uncovered several abnormal processes in LAMA2-RD, such as problems with cell death, energy production, calcium regulation, and ECM remodeling. These discoveries have led to gene therapy strategies that aim to restore the muscle-BM connection, with promising results in animal models. However, no treatment is currently available, and new therapeutic approaches are needed. This project aims to identify new therapeutic targets for LAMA2-RD by studying how communication between muscle fibers and FAPs is affected by Lmα2 deficiency. The goal is to pinpoint critical signaling molecules and their receptors between these cells and understand how they are disrupted in the disease. This information could lead to therapies that improve muscle repair and prevent or reverse fibrosis in LAMA2-RD. The project uses human muscle cells, myoblasts, and FAPs, grown together in in vitro models to study these interactions. This will also provide key insights into how muscle tissue maintains or restores its function through secreted molecules. The project has three main tasks: 1. Studying the secretome of LAMA2-RD FAPs and muscle cells. 2. Analyzing the communication between FAPs and muscle cells in LAMA2-RD. 3. Testing potential therapeutic targets to improve muscle function and reduce fibrosis." | Spouse with association | |
| 2023 | Aurélie BERLAND | Toulouse | Without funding | Any rare disease | Rare Diseases Route | Provide professionals who coordinate care pathways with a tool to help them support people with rare diseases or those who have been misdiagnosed. This digital tool, in the form of a mind map, will help professionals in their support process, from identifying the problem to finding appropriate solutions. | E-health 2023 | ||
| 2023 | Federico DI ROCCO / Sofia GUERNOUCHE | Lyon | Foundation For Rare Diseases | Developmental disorders / Craniostenosis | REDAPP CRANIO | Creation of a platform for the systematic screening of developmental disorders and the monitoring of patients with craniosynostosis. | The child's development is monitored by numerous parties, such as the attending physician. In the case of monitoring children with rare diseases, and more specifically in neurosurgery, more specific monitoring by dedicated professionals may be required at shorter intervals. In order to avoid placing an additional burden on parents, we have implemented a software solution that systematically sends out short questionnaires that parents can fill out using their usual communication tools, such as smartphones or computers. These questionnaires provide a basis for identifying children in difficulty and allow parents to express their questions or comments. This tool can be customized by caregivers according to the profile of the disease and the population being monitored. Data is sent and processed automatically and securely, allowing care teams and parents to monitor progress remotely at a lower cost and to be as responsive as possible regardless of distance. This tool complements other existing monitoring tools based on regular consultations and multidisciplinary collaboration, which remain irreplaceable in ensuring that each patient is considered holistically. | E-health 2023 | |
| 2023 | Florence RICCARDI | La Seyne-sur-Mer | Foundation For Rare Diseases | Any rare disease | Gyn & Gen | Develop an e-health application to provide gynecological and genetic expertise for rare diseases at the time of a parental project, pregnancy, and up to the first 1,000 days of a child's life. This project is intended for patients and healthcare professionals to facilitate the care pathway 1/ for couples affected by a rare disease, whether due to personal or family history, 2/ a pregnancy with abnormalities detected by non-invasive prenatal screening or ultrasound screening, or 3/ a child aged 0 to 1,000 days with a neurodevelopmental disorder and/or malformation. | E-health 2023 | ||
| 2023 | Iris MAROLLEAU | Paris | Without funding | Rare neurological diseases | Brain Mouv | A self-rehabilitation solution in the form of a web application aimed at patients suffering from rare neurological diseases, as well as the professionals who support them. This application will offer a digital pathway providing access to physical exercises tailored to each individual's functional category, and will also enable interaction and monitoring of the exercises by the professional supporting the patient. | E-health 2023 | ||
| 2023 | Martine TAILLEZ | Toulouse | Without funding | Idiopathic Nephrotic Syndrome | Idiopathic Nephrotic Syndrome Application | Creation of a mobile application for patients, for better daily monitoring, but also for the medical community. | E-health 2023 | ||
| 2023 | Xavier ZANLONGHI | Rennes | Foundation For Rare Diseases | Any rare disease | AI deafness blindness and medical and social rights | Based on simple rules such as the degree of visual and/or hearing impairment, the etiology of the rare disease (whether genetic or not), and age, the project aims to develop weak artificial intelligence using algorithms designed to determine typologies in order to identify medical and social rights. | E-health 2023 | ||
| 2023 | Amélie PITON | Strasbourg | Foundation For Rare Diseases | Neurodevelopmental disorders | Validation of the splicing factor RBMX2 as a novel gene involved in X-linked neurodevelopmental disorders | - | - | GenOmics 2022 | |
| 2023 | Aude MAGERUS | Paris | Foundation For Rare Diseases | Rare systemic and autoimmune disorders / Autoimmune hepatitis | Genetics of autoimmune hepatitis | - | Autoimmune hepatitis (AIH) develops when cells in our immune system, which are supposed to defend us against infectious agents, destroy cells in our liver. It affects 1 to 5 people in every 100,000. We know that there are genetic predispositions to AHI, indicating that genetic factors are likely involved, but the underlying mechanisms are unknown. We compared the DNA sequences of the coding part of all known genes in 42 patients (20 additional patients included thanks to this project) with IAH with the reference sequence in humans. In 11 patients (3 new patients in this study), we identified genetic variants in a single pathway regulating the activation of lymphocytes, the main cells of the immune system. These variants are associated with higher expression of a molecule called pS6, which we measure in blood cells. We now need to study the link between these variants and immune dysfunction in order to unravel the mechanisms involved. We also want to analyze pS6 expression in new HAI patients we receive to determine whether this pathway is overactive in them. This is particularly important given that there are drugs that inhibit this overactivation of pS6, which could then potentially be prescribed by doctors to these patients. | GenOmics 2022 | |
| 2023 | Aurélie DE THONEL | Paris | Foundation For Rare Diseases | Rare neurological diseases / Rubinstein-Taybi syndrome | Modelling Rubinstein-Taybi Syndrome: GenOmics of a rare, monogenic disease to address the therapeutic potential of stress response pathways in neuronal disorders | - | Neurodevelopmental disorders (NDDs) affect approximately 10% of children and result in defective brain development that causes lifelong disabilities. The wide clinical variability of affected patients compromises diagnosis and therapeutic solutions. Our project aims to study a characteristic common to NDDs: the disruption of stress response mechanisms. This could help us to better understand and treat these conditions. The actors in the stress response, called HSFs, have a dual role: on the one hand, they respond to stress signals by inducing molecular chaperones, HSPs, and on the other hand, they contribute to brain development by regulating genes useful for neurodevelopment. However, during prenatal stress, HSF factors prioritize the protection of neural cells, to the detriment of their "developmental" function. In various NDDs, several teams, including ours, have shown that these HSFs are severely disrupted and affect brain development; we therefore sought to understand their specific contribution in these diseases. To do this, we use a model of genetic NDD, Rubinstein-Taybi syndrome (RSTS), characterized by a deregulation of HSF action. Using stem cells derived from the skin cells of RSTS patients, we genetically restored the HSF factor in this model, then generated 2D (neural progenitors) and 3D (brain organoids) neural models. In addition to a decrease in HSF protein, we identified a deregulation of proteins important for both stress response and cell adhesion during neurodevelopment, HSPs and N-cadherin, respectively. Thanks to funding from the FMR, we were able to apply a cutting-edge approach to brain organoids, enabling us to analyze both their genome and molecular content at the single-cell level. This allowed us to identify candidate HSF-dependent genes and pathways, which we will soon validate, notably using confocal microscopy. The selected genes will serve as a reference for future screening of therapeutic molecules. | GenOmics 2022 | |
| 2023 | Béatrice PARFAIT | Paris | Foundation For Rare Diseases | Dermatological diseases, Rare bone diseases / Congenital Pseudarthrosis of the Tibia | Molecular bases of non-NF1 associated congenital pseudarthrosis of the tibia | - | GenOmics 2022 | ||
| 2023 | Benoit MIOTTO | Paris | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes / Meier-Gorlin Syndrome | Pan-tissue transcriptional analysis of ORC1 regulated genes in a mouse model of Meier-Gorlin Syndrome | - | Meier-Gorlin syndrome (MGS) is an extremely rare autosomal recessive disorder (1 in 1,000,000 births) that causes primordial dwarfism with developmental defects such as microtia, patellar hypoplasia, cardiac dysfunction, and muscular defects. Patients with MGS are rare (80 patients reported in the literature since 1979; 25 in France). It is therefore difficult to obtain samples for molecular or cellular analysis, and when samples are obtained, they are often limited to fibroblasts and lymphoblastoid cells cultured in vitro. It is therefore necessary to produce alternative models to obtain a comprehensive view of the signaling pathways and genes associated with the pathophysiology of the disease. With this in mind, the group produced a mouse model of Meier-Gorlin syndrome and conducted a gene expression analysis in six tissues from the mice. Tissue-by-tissue bioinformatics analysis revealed the genes differentially expressed in each tissue, and after functional annotation, the signaling pathways and genes associated with Meier-Gorlin syndrome in each tissue were characterized. This unique information provides a comprehensive description of the biological processes altered in each organ, which could enable better patient monitoring and anticipation of health problems. | GenOmics 2022 | |
| 2023 | Florence ROUCHER-BOULEZ | Lyon | Foundation For Rare Diseases | Rare endocrine disorders / Primary Adrenal Insufficiency (PAI), Intra Uterine Growth Restriction (IUGR), Variation of Sex Development (VSD) | Molecular Etiologies of Syndromic Presentation of Adrenal Insufficiency with Growth Restriction (MESPAG) | - | GenOmics 2022 | ||
| 2023 | Pauline MARZIN | Paris | Foundation For Rare Diseases | Connective tissue disorders / Stiff skin syndrome | Elucidation of molecular bases of stiff Skin Syndrome: identification of new genes in pre-screened patients | - | Acromelic dysplasias are a group of genetic disorders characterized by short stature, thickened skin, and joint stiffness. Within this group, Skiff Skin Syndrome is characterized by progressive skin fibrosis. This syndrome is sometimes linked to a mutation in the FBN1 gene, however, we remain without genetic causes in some patients. In the absence of genetic clarification, therapeutic management is limited. Through extensive genetic research, we have identified two new genes associated with acromelic dysplasias, enabling us to improve patient care by providing personalized follow-up. | GenOmics 2022 | |
| 2023 | Piera SMERIGLIO | Paris | Foundation For Rare Diseases | Neuromuscular disorders / Spinal Muscular Atrophy (SMA) | EpiSMA: Profiling the Epigenetic Landscape of Spinal Muscular Atrophy (SMA) patients to understand phenotypic variability of muscle atrophy | - | Motor neuron diseases (MNDs) encompass a group of degenerative disorders, including spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), characterized by the death of motor neurons. Although these diseases are traditionally considered motor neuron diseases, our group's work has characterized muscle atrophy before the onset of neurological symptoms, highlighting the importance of the periphery. SMA is caused by a homozygous mutation in the SMN1 (survival of motor neuron 1) gene, which leads to a loss of SMN protein and an incidence of death of 1 in 10,000 live births. The presence of the SMN2 homologous gene, which has a similar structure to the SMN1 gene but does not produce enough functional protein, partially compensates for the loss of the SMN1 gene. Although all SMA patients have a common genetic origin (SMN1 gene mutations), they present with a wide range of symptoms and degrees of muscle involvement. Various studies have suggested that there are other genetic modifiers of the disease, including genes such as SMN2, NAIP, PLS3, and NCALD, which may determine the severity of symptoms experienced by patients. There are three approved treatments for SMA. However, only a subset of patients respond favorably, particularly in the periphery. Understanding the variability in phenotype, disease progression, and therapeutic response in each patient is therefore a major unmet need in the treatment of SMA. In recent years, epigenetic modifications have attracted attention in SMA, as they may help explain the disparate phenotypes among patients with the same genetic basis. Using transcriptional and epigenetic sequencing technologies, we profiled a large group of patients with SMA type II after treatment and discovered specific pathways that are not restored by current treatments and may be targeted by new combination therapies. Among these pathways, we observed a loss of mitochondrial oxidative phosphorylation function. | GenOmics 2022 | |
| 2023 | Stéphanie TOME | Paris | Foundation For Rare Diseases | Neuromuscular disorders / Myotonic dystrophy type 2 | Accurately characterizing the DM2 locus in patients using Oxford Nanopore technologies | - | Myotonic dystrophy type 2 (MD2) is a complex neuromuscular disease that affects various parts of the body, including the muscles and heart. It is caused by a repetitive and complex sequence in the DNA. Patients with MD2 have a wide variety of symptoms, which differ considerably from one person to another and are still poorly understood. This variability could be explained by the complexity of the repeated DNA region. Unfortunately, current methods for analyzing these genetic repeats in patients with MD2 are limited. This makes it difficult to understand the link between genetic factors and symptoms, disease progression, and factors influencing disease severity. As a result, DM2 remains poorly understood, and the lack of clear links between genetic factors and symptoms complicates genetic counseling, offering little predictive information about the course of the disease. Our goal is to use advanced genome sequencing technologies to further study this repeated region and understand how genetic factors are related to the symptoms of DM2. Our study identified the repeat region in six patients. Our preliminary results also showed that this repeat region is composed of a TCTG motif, the number of which appears to vary between individuals. Our work has shown that the latest long-read sequencing technologies offer considerable potential for advancing our understanding of DM2, as well as other complex genetic disorders. | GenOmics 2022 | |
| 2023 | Sylvie MAZOYER | Lyon | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes, Immune deficiency disorders, Dermatological diseases / Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) or Taybi-Linder syndrome (TALS), Roifman syndrome (RFMN), Lowry Wood syndrome (LWS), OMIM 226960 | Long-read single cell sequencing to better characterise minor splicing defaults in RNU4ATAC associated diseases | - | GenOmics 2022 | ||
| 2023 | Loïc GUILLOT | Paris | Awards - Alnylam Pharmaceuticals | Cystic fibrosis | Preclinical evaluation of miR-222-5p as an anti-inflammatory agent, promoting epithelial repair and limiting infection in cystic fibrosis | Cystic fibrosis is a rare genetic disease affecting some 80,000 patients worldwide. The disease begins at birth, and cystic fibrosis patients have a limited life expectancy, as their lungs deteriorate over the course of their lives. In particular, they are susceptible to repeated bacterial attacks, which progressively trigger a major inflammatory response and impair their ability to breathe normally. Bacterial resistance to antibiotics is a public health problem, requiring the development of new, innovative therapeutic molecules. In cystic fibrosis patients, we propose to use a molecule called microRNA, which has the ability to bind to the RNA of a target gene and inhibit its action. This strategy will both reduce inflammation in the lungs and prevent bacteria from damaging them. | Alnylam Pharmaceuticals 2023 Award | ||
| 2023 | Nicolas CENAC | Toulouse | APICIL Foundation | Chronic Pseudo Intestinal Obstruction (CPIO) | Therapeutic value of metabolites derived from intestinal microbiota in visceral pain associated with chronic intestinal pseudo-obstruction (CIPO) in children "METADOLOMIC | Pediatric Chronic Pseudo-Intestinal Obstruction (CPIO) is a rare condition characterized by the chronic inability of the gastrointestinal tract to propel its contents, leading to mechanical obstruction. Visceral pain severely impairs the quality of life of patients suffering from this potentially fatal condition. There is no curative or symptomatic solution for this syndrome. In an exploratory clinical study, eight POIC patients were treated with fecal microbiota transfer. Eight weeks later, symptoms of pain and bloating were reduced. This suggests a link between microbiota and POIC pain symptoms. The main aim of our project is to characterize the taxonomic and functional composition of the microbiota of pain patients with POIC, and to assess whether metabolites derived from this microbiota can regulate the activity of sensory neurons. In collaboration with the AP-HP Robert-Debré Center for Rare Digestive Diseases, we will select painful and non-painful POIC pediatric patients to build up a bio-collection of ileal effluents. We will establish the taxonomic and functional profile of the ileal microbiota and evaluate the effect of its metabolites on the activity of sensory neurons. This study should enable us to determine whether the microbiota could represent a therapeutic opportunity in visceral pain associated with POIC. | Pediatric Chronic Pseudo-Intestinal Obstruction (CPIO) is a rare condition characterized by the chronic inability of the gastrointestinal tract to propel its contents, leading to mechanical obstruction. Visceral pain severely impairs the quality of life of patients suffering from this potentially fatal condition. There is no curative or symptomatic solution for this syndrome. In an exploratory clinical study, eight POIC patients were treated with fecal microbiota transfer. Eight weeks later, symptoms of pain and bloating were reduced. This suggests a link between microbiota and POIC pain symptoms. The main aim of our project is to characterize the taxonomic and functional composition of the microbiota of pain patients with POIC, and to assess whether metabolites derived from this microbiota can regulate the activity of sensory neurons. In collaboration with the AP-HP Robert-Debré Center for Rare Digestive Diseases, we will select painful and non-painful POIC pediatric patients to build up a bio-collection of ileal effluents. We will establish the taxonomic and functional profile of the ileal microbiota and evaluate the effect of its metabolites on the activity of sensory neurons. This study should enable us to determine whether the microbiota could represent a therapeutic opportunity in visceral pain associated with POIC. | APICIL 2023 Foundation Prize | |
| 2023 | Caroline DESOMBRE | Lille | Foundation For Rare Diseases | Rare chromosomal diseases | SCOlarization of children with rare chromosomal abnormalities: Levers and obstacles from the perspective of parents and teachers | The education of disabled students is a real challenge for the school system. Despite a proactive policy, many students with disabilities remain excluded. This is the case for the majority of children with inv dup del(8p) syndrome. In this research program, we will attempt to identify and understand the difficulties faced by these children and their parents in their schooling. To this end, two studies will be carried out. The first will involve interviews with parents of children with inv dup del(8p) syndrome and their teacher(s), to identify difficulties and possible levers. A second study will use a questionnaire with teachers to understand the effect of the combination of "genetic disease" and "rare disease" on their perceptions of schooling potential. Taken as a whole, these studies should make it possible to improve schooling for children with rare chromosomal diseases in general, and for children with inv dup del(8p) syndrome in particular. | En France, comme dans de nombreux pays européens, des lois ont été adoptées pour favoriser la scolarisation des élèves en situation de handicap dans les établissements scolaires. La loi de 2005 a permis de véritables progrès, permettant à davantage d’enfants en situation de handicap de suivre une scolarité en milieu ordinaire. Pourtant, malgré ces avancées, certains enfants, notamment ceux atteints de maladies chromosomiques rares comme le syndrome inv dup del(8p), restent souvent exclus des classes ordinaires après la maternelle et sont orientés vers des établissements spécialisés. Ce projet de recherche financé par la fondation maladie avait pour objectif de mieux comprendre les difficultés de scolarisation de ces élèves en interrogeant des parents d’enfants porteurs de cette maladie et des enseignants scolarisant ces élèves. Nous nous sommes intéressés particulièrement à l’impact de deux facteurs : le caractère génétique de la maladie et sa rareté. En effet, ces éléments semblent influencer la façon dont les enseignants et les parents perçoivent les possibilités de scolarisation. Pour explorer cette question, nous avons réalisé deux études. Une étude qualitative réalisée en interrogeant des parents et des enseignants et une étude quantitative centrée sur les enseignants à partir de questionnaires. Pour l’étude qualitative, nous avons réalisé des entretiens avec différentes questions sur les connaissances de l’école inclusive et les maladies génétiques, les difficultés d’inclusion et les attentes et besoins. Nous avons interrogé 18 parents et 12 enseignants. Les résultats montrent tout d’abord que les parents d’enfants atteints du syndrome inv dup del(8p) rencontrent des difficultés similaires à celles des parents d’autres enfants en situation de handicap. Selon eux, les adaptations proposées en classe ne correspondent pas toujours aux besoins réels de leur enfant. Ils soulignent aussi le manque de ressources, surtout en personnel formé. Ils ont par ailleurs le sentiment que les enseignants, sur-sollicités, ont du mal à répondre aux besoins spécifiques de leur enfant. Enfin, certains parents craignent que l’inclusion ne fasse baisser le niveau scolaire général, ce qui génère parfois des réticences. Les parents d’enfants présentant des difficultés dans la gestion du comportement sont ceux qui rencontrent le plus de difficultés pour maintenir leur enfant en classe ordinaire. Malgré ces obstacles, tous reconnaissent que l’inclusion a des effets très positifs, notamment concernant les relations sociales de leur enfant. Ils souhaitent aussi une meilleure collaboration avec les enseignants pour faciliter cette inclusion. Concernant les enseignants, ils déclarent ne pas toujours bien connaître les maladies génétiques rares, faute de formation initiale ou continue. Cette méconnaissance les empêche parfois d’identifier les besoins de ces élèves. Les enseignants soulignent aussi plusieurs défis auxquels ils sont confrontés. Tout d’abord, chaque élève atteint d’un syndrome rare a des besoins très variés (difficultés cognitives, motrices, besoin d’outils numériques, de supports visuels, etc.), ce qui rend complexe les réponses pédagogiques. De plus, ils déclarent manquer de formation et de moyens pour mettre en place des adaptations pertinentes. La charge émotionnelle en lien avec la scolarisation d’élèves à besoins éducatifs particuliers est aussi parfois importante : frustration, épuisement, sentiment de ne pas pouvoir faire assez sont des éléments régulièrement évoqués par les enseignants. Comme les parents, les enseignants reconnaissent aussi les bénéfices de l’inclusion avec une meilleure intégration sociale et une empathie accrue entre les élèves. Selon les enseignants, malgré la volonté d’inclure tous les enfants, le manque de soutien et de ressources rend l’inclusion difficile au quotidien. En résumé, ces entretiens ont permis d’identifier les obstacles et les leviers à l’inclusion des élèves atteints du syndrome inv dup del(8p). Les difficultés rencontrées dans la scolarisation de ces élèves sont analogues à celles rencontrées pour d’autres types de maladie/handicap. L’étude quantitative a été réalisée auprès de 299 enseignants. Ils étaient amenés à lire le descriptif d’un élève qui présente ou non une maladie rare et une maladie génétique. Le descriptif de l’élève n’était pas toujours le même. De manière aléatoire, les participants lisaient le descriptif d’un élève présentant une maladie génétique rare, ou une maladie rare non génétique, ou une maladie non rare génétique ou une maladie non rare non génétique. La description de l’élève (sur ses difficultés et points d’appui) est identique dans toutes les conditions de sorte que seules l’origine du trouble (génétique ou non) et sa rareté (rare ou non) varient en fonction de la condition. Notre étude montre que le caractère génétique et rare de la maladie n’influence pas directement l’acceptation de ces élèves en classe ordinaire. Ces deux études, initiées à la demande de parents et soutenue par des associations, permet d’envisager des pistes d’actions concrètes : - Améliorer la formation des enseignants : Intégrer les résultats de cette étude dans la formation initiale et continue des enseignants, des conseillers d’éducation et des psychologues scolaires. - Créer des outils pratiques : Une fiche d’information sera distribuée aux parents et aux enseignants pour expliquer les particularités de la maladie et donner des conseils pour faciliter l’inclusion. Renforcer la collaboration : Mieux associer parents et enseignants pour adapter les solutions aux besoins réels des enfants. Par ailleurs, les résultats de cette recherche pourraient aussi servir à améliorer la scolarisation d’autres élèves en situation de handicap ou de maladie chronique. En identifiant les obstacles et les leviers, nous espérons contribuer à une école plus inclusive, où chaque enfant, quelle que soit sa situation, pourrait trouver sa place. | Humanities and social sciences 10 | |
| 2023 | Christine PEYRON | Dijon | Foundation For Rare Diseases | Newborn screening, SeDeN-p3 | French parents' acceptability of extending first-line neonatal screening with or without genetics: SeDeN-p3 | Recent changes to France's bioethics laws, coupled with advances in treatment and technology, have prompted the question of whether newborn screening (NBS) should be extended in France. The University Hospital Federation TRANSLAD, in collaboration with the Société Française de Dépistage Néonatal, has therefore created the SeDeN Project (for Séquençage Dépistage Néonatal). Its aim is to measure expectations and obstacles to the extension of neonatal screening in France. This includes information for parents (by whom, when, how to be informed about DNN), the type of diseases to be screened (accessibility to treatment or care, age of symptom revelation, etc.) and the techniques used (place of genetic tools in particular). To this end, the SeDeN Project is interviewing the various stakeholders in France: healthcare professionals, parents and decision-makers (public and influential groups). The SeDeN-p3 study is the part of the SeDeN Project that focuses on parents' opinions. This part is entitled "Acceptability, by parents in France, of the extension of neonatal screening with or without genetic testing in 1st intention". It gathers parents' opinions in different situations: birth, infancy, whether the child has a disease or not, and so on. Indeed, parents are the first to decide whether or not to undergo DNN, since it is not mandatory in France. Depending on the outcome, they are also the 1st to be impacted on their life and that of their child. A study of their perceptions, expectations and motivations for choosing DNN is therefore essential before any new screening is actually implemented. As the extension of DNN is underway in France, the SeDeN-p3 study will provide the elements needed to ensure that it is, in the light of parents' expectations. | Contexte Depuis plusieurs décennies, le dépistage néonatal (DNN) permet de détecter certaines maladies rares dès les premiers jours de vie du nourrisson. Ce programme repose sur une prise de sang réalisée à la naissance, permettant d’identifier des maladies pouvant être traitées rapidement pour éviter des complications graves. Aujourd’hui, grâce aux avancées de la recherche et aux progrès en génétique, de nouvelles technologies permettent d’envisager un dépistage plus large, basé sur l’analyse de l’ADN. L’intégration de tests génétiques dans le dépistage néonatal ouvre la possibilité d’identifier un plus grand nombre de maladies rares, bien avant l’apparition des premiers symptômes. Toutefois, cette évolution soulève des questions éthiques, médicales et sociales : - Comment informer les parents sur ces nouvelles possibilités ? - Quelles maladies doivent être dépistées ? - Quels sont les impacts psychologiques et éthiques de l’extension du dépistage à la naissance ? - Comment assurer un consentement éclairé et adapté aux besoins des familles ? C’est pour répondre à ces interrogations que le projet SeDeN (Séquençage et Dépistage Néonatal) a été mis en place. Mené en collaboration par l’équipe de Génétique du CHU de Dijon avec plusieurs centres hospitaliers et experts en génétique, éthique et sciences sociales, cette étude a exploré les perceptions des parents sur l’éventuelle extension du DNN et les spécificités liées à l’utilisation de la génétique dans cette extension. Objectifs Le projet SeDeN a été conçu pour mieux comprendre comment les parents perçoivent le dépistage néonatal élargi, ainsi que les facteurs influençant son acceptation. Pour cela, plusieurs aspects ont été étudiés : 1. Comprendre l’acceptabilité parentale - Dans quelle mesure les parents sont-ils favorables à un dépistage élargi ? - Quels sont leurs freins et leurs motivations ? - Les parents sont-ils favorables à un dépistage basé sur la génétique dès la naissance ? - Quelles sont leurs attentes et leurs craintes vis-à-vis de ces analyses ? 2. Identifier les critères d’acceptabilité des maladies dépistées - Les parents jugent-ils que toutes les maladies doivent être dépistées ? - Quels sont les critères les plus importants pour eux : la possibilité de traitement, l’âge d’apparition des symptômes, ou encore la gravité de la maladie ? 3. Évaluer l’impact psychologique et éthique - Quels sont les impacts émotionnels d’un diagnostic précoce sur les parents ? - Les parents vivent-ils différemment la réception d’un résultat génétique pour leur enfant à la naissance ? - Quelles sont les préoccupations éthiques soulevées par un dépistage basé sur la génétique ? 4. Améliorer les modalités d’information et d’accompagnement - Quels sont les meilleurs moyens d’informer les parents sur ces nouvelles pratiques ? - Comment assurer un accompagnement adapté en cas de résultat positif ? Appel à projets de recherche en Sciences Humaines et Sociales – Rapport de mi parcours 18 Pour répondre à ces questions, l’étude a interrogé près de 1 700 parents à travers des questionnaires et des entretiens. Les participants comprenaient des parents ayant récemment eu un enfant, ainsi que des parents confrontés à des maladies rares, permettant ainsi d’explorer des perspectives variées. Intérêt social des résultats obtenus Les résultats de SeDeN apportent des éléments essentiels pour orienter les décisions de santé publique sur l’extension du dépistage néonatal. Ils révèlent plusieurs enseignements majeurs qui pourraient guider l’évolution des pratiques. 1. Une acceptabilité globalement positive, mais conditionnée - Une large majorité de parents se montrent favorables à un dépistage élargi, à condition que celui-ci concerne des maladies pouvant être prises en charge. - Certains expriment des réserves lorsque le dépistage concerne des maladies pour lesquelles il n’existe pas encore de traitement. 2. L’importance d’une information claire et d’un accompagnement adapté - Une majorité de parents exprime le besoin d’être informée avant la naissance sur les enjeux du dépistage néonatal (et son extension) pour pouvoir prendre une décision éclairée. - Les résultats montrent que les parents préfèrent un accompagnement personnalisé, avec la possibilité d’échanger avec un professionnel de santé plutôt que de recevoir uniquement une documentation écrite. 3. Des préoccupations éthiques à ne pas négliger - L’idée d’un dépistage élargi est perçue comme positive, mais certains parents en population générale s’inquiètent de l’impact émotionnel d’un diagnostic précoce. - L’incertitude des résultats (faux positifs et faux négatifs) est un facteur important influençant l’acceptabilité. 4. Vers un dépistage mieux encadré et plus éthique - Les résultats de SeDeN suggèrent que l’extension du dépistage néonatal pourrait être bénéfique, à condition d’être accompagnée de mesures adaptées pour garantir une information claire et un suivi personnalisé. - Ces travaux contribuent aux réflexions des autorités de santé et des experts en génétique pour construire un modèle de dépistage qui soit éthique, acceptable et bénéfique pour les familles. En conclusion, l’étude SeDeN apporte des éléments essentiels pour guider les décisions futures sur l’extension du dépistage néonatal en France Elle souligne l’importance d’une information claire, d’un accompagnement adapté et d’une réflexion approfondie sur les implications éthiques des nouvelles technologies. Grâce à ces résultats, les professionnels de santé et les décideurs disposent d’une base solide pour améliorer les pratiques et proposer un dépistage mieux adapté aux attentes des parents. | Humanities and social sciences 10 | |
| 2023 | Elise RICADAT | Paris | Overcoming Cystic Fibrosis | Sickle cell disease, Mucosviscidosis | Psychosocial challenges of new treatments for cystic fibrosis and sickle cell disease | The Institut La Personne en Médecine (ILPEM), with the support of CERMES 3 (UMR 8211), wishes to submit a research project on the psychosocial experience of patients who have received innovative and recent treatments for two rare diseases: allogeneic hematopoietic stem cells for adolescents and young adults with sickle cell disease, and CFTR modulators for adults with cystic fibrosis. It takes place against a backdrop of major therapeutic innovations that have led to significant progress in the symptomatic expression of these two diseases, as well as to significant changes in therapeutic approach and outcome. Their effects on the individual, psychic and social experience of the disease are still largely undocumented due to their recent nature. A paradox common to both pathologies, although very different, emerges in particular: while they undeniably lead to a clear improvement in symptoms from a medical point of view, and even to a cure in the case of sickle cell disease, they seem to provoke increased psychic and identity-related malaise in some patients. This 18-month exploratory project aims to gain a better understanding of the subjective experiences of patients and their families, as well as clinicians and healthcare professionals, in order to improve support and care. Using a qualitative, inductive, participatory and interdisciplinary approach, our results aim to propose hypotheses to highlight the apparent paradox produced by the introduction of these new treatments; to produce general data on the psycho-social aspects of their effects; to identify whether these new treatments modify the caregiver/patient relationship. And ultimately, to create a multi-disciplinary and multi-professional dynamic to build more ambitious future projects concerning each of these two pathologies and ensure their participative feasibility in the longer term. | Humanities and social sciences 10 | ||
| 2023 | Nadine PRIOA-LELOUEY | Caen | Foundation For Rare Diseases | Rare kidney diseases / Autosomal dominant polycystic kidney disease | Assessment of anxiety at the first nephrology consultation in patients with polycystic kidney disease. | Autosomal dominant polycystic kidney disease (ADPKD) is a rare disease affecting one in every 2,500 people in Europe. The 2015 survey of rare disease patients highlights the psychosocial impact of the disease. Due to its genetic nature, PKRAD patients most of the time have knowledge of Chronic Kidney Disease through the experiences of their loved ones. They therefore anxiously anticipate their future as a curse. Nephrology guidelines make care anxiety a priority area for research. Psychological research points to a feeling of guilt linked to the transmission of a genetic disease, and denial is the most common psychological defense in patients with hereditary nephropathy. In our practice, patients regularly report avoidance of the first specialist consultation, with deleterious consequences for disease progression. This first consultation in a specialist department is therefore a key stage in the management of the disease. The aim of this study is therefore to evaluate anxiety during this first consultation in patients with CKD, in comparison with those with polycystic fibrosis. In the medium term, it will enable us to improve the care of these patients by designing a dedicated reception system. This evaluation will be quantitative (anxiety measurement scales proposed to 390 MRC patients coming for their first nephrology consultation at Caen University Hospital). It will also be qualitative (face-to-face interview and analysis of the discourse and psychological protection mechanisms of 10 patients with polycystic kidney disease and 10 patients with other kidney diseases). The results should highlight a higher rate of anxiety at the first consultation in polycystic patients, and more extreme psychological protection mechanisms. | Humanities and social sciences 10 | ||
| 2023 | Fabrice ANTIGNY | Paris | Foundation For Rare Diseases | Pulmonary rare diseases, Cardiovascular diseases / Pulmonary hypertension | - | Translational Research 2023 | |||
| 2023 | Juliane ISAAC | Paris | Foundation For Rare Diseases | Rare head and neck malformations, Developmental anomalies and malformation syndromes / Oligodontia | - | Translational Research 2023 | |||
| 2023 | Fabrice ANTIGNY | Paris | AFM Telethon | Rare lung diseases / Pulmonary hypertension | Orai1 Ca2+ channel: a new therapeutic target in PAH | Pulmonary arterial hypertension (PAH) is a rare and always fatal disease. PAH is a major and growing economic and health burden worldwide, requiring the development of new therapies, as current treatments are not curative. A promising approach is to counter the adverse effects of deregulation of intracellular intracellular calcium concentration. We have recently shown that increasing expression and function of the Orai1 calcium channel in pulmonary arteries contributed to the the pathogenesis of PAH. We have demonstrated that Orai1 could be a new therapeutic to reduce PAH. Our aim is to treat PAH by repositioning an inhibitor of PAH, an Orai1 inhibitor already used in several clinical trials. We will evaluate the benefit of this drug candidate in different preclinical models of PAH. We expect this project to validate the drug candidate through this repositioned Orai inhibitor, so that clinical trials in PAH can be envisaged in the near future. The proposal is supported by a strong rationale and a large amount of data generated in a favorable environment (French reference center for pulmonary hypertension and INSERM U999). We aim to validate the relevance of this Orai1 inhibitor as an innovative to overcome the current limitations of PAH treatment options. | Proof of therapeutic concept 2023 | ||
| 2023 | Bénédicte CHAZAUD | Lyon | AFM Telethon | Neuromuscular disorders / Duchenne muscular dystrophy | Promoting regenerative inflammation to improve muscle homeostasis in Duchenne Muscular Dystrophy | Degenerative myopathies are characterized by permanent damage to muscle tissue, chronic inflammation and fibrosis. chronic inflammation and fibrosis. The latter are important pathological in Duchenne muscular dystrophy (DMD), and represent obstacles to the efficacy the efficacy of gene therapies aimed at correcting the genetic defect at the root of the pathology. of the disease. We have shown that, in contrast to the regeneration of healthy muscle, the resolution of of inflammation is impaired in DMD muscles, with the presence of a pro-inflammatory pro-inflammatory/profibrotic macrophages. Activation of the metabolic regulator AMPK is beneficial in inducing resolution of inflammation by macrophages, leading to improved muscle function in mice. This establishes the inflammatory macrophage inflammatory change as a relevant therapeutic target in DMD. However, effective molecules can be toxic. Our approach is to specifically target macrophages to induce regenerative inflammation in the muscle. regenerative inflammation in DMD muscle. Our results show that encapsulated AMPK allosteric activators inhibit the properties of fibrotic macrophages in vitro and in vivo in the DMD mouse model without adverse effects, establishing proof-of-concept for their use. The aim of the project is to optimize treatment and improve the efficacy of targeting macrophage targeting. | Proof of therapeutic concept 2023 | ||
| 2023 | Gilles LAVERNY | Strasbourg | AFM Telethon | Autosomal recessive infantile hypercalcemia, Idiopathic hypercalciuria | Consolidation of an innovative strategy for the treatment of calcitriol-mediated hypercalcemia | High levels of bioactive vitamin D (1,25D3 or calcitriol) cause hypercalcemia and, associated with low parathyroid hormone levels, are the hallmark of a rare and refractory disorder called calcitriol-mediated hypercalcemia (CMH). CMH has an impact on growth growth and induce lethal renal dysfunction. Current treatments are based on non-selective agents, with low efficacy and significant side-effects. It is therefore urgent to develop new therapies. The activities of 1,25D3 are relayed by its receptor VDR. We have recently identified a VDR antagonist that normalizes its activity and serum calcium levels in mice mice intoxicated with 1,25D3, without inducing side effects. This compound is therefore a drug candidate for the treatment of MHC. In this project, we aim to determine the activities and therapeutic window of this VDR antagonist in Cyp24a1- and Slc34a1-null mice, two preclinical models of MHC MODELS. The efficacy of this compound will be compared with that of fluconazole, a drug used outside the in clinical use. In addition, its hepatic stability and pharmacokinetic parameters will be parameters. At the same time, clinicians from the OSCAR and ORKID SMRFs will identify CMH patients for clinical trials. The results obtained will provide important leverage convince investors to pursue clinical development of this compound. molecule. | Proof of therapeutic concept 2023 | ||
| 2023 | Peter LENTING | Paris | AFM Telethon | Rare non-malignant haematological diseases / Hemophilia, congenital factor X deficiency | Inducing albumin-mediated recycling of endogenous proteins: a novel strategy to treat quantitative deficiencies of plasma proteins | Patients with moderate or minor bleeding disorders are rarely eligible for prophylactic treatment, despite the idea that frequent minor bleeding has a major impact on their quality of life, both mentally and physically. This is particularly true for women and girls, who may experience heavy menstrual bleeding. Our aim is to propose a new treatment strategy for these patients, characterized by a simple (subcutaneous) application on a weekly or fortnightly basis. In this context, we have developed a nanobody-based therapeutic platform that raises endogenous protein levels (which are reduced but not absent in these patients) by binding them to their own albumin. A proof-of-concept study has already been carried out, demonstrating that raising von Willebrand factor levels using this approach in a mouse model of type 1 von Willebrand disease corrects the bleeding tendency in these mice. In this study, we will focus on rare coagulation disorders, in particular hemophilia A, hemophilia B and Stuart's disease/factor X deficiency. | Proof of therapeutic concept 2023 | ||
| 2023 | Laurent SCHAEFFER | Lyon | AFM Telethon | Neuromuscular disorders / Duchenne muscular dystrophy | HDAC6 inhibitors to treat Duchenne Muscular Dystrophy | Unlike other histone deacetylases (HDACs), HDAC6 is strictly cytoplasmic and does not deacetylates histones. Its substrates are cytoplasmic proteins such as α-tubulin. We have recently shown that HDAC6 represses TGF-β signaling via deacetylation of SMAD3. In vivo, we have shown that pharmacological inhibition of HDAC6 improves the phenotype of the DMD mouse model (mdx) through a combined action that we have of TGF-β signaling and microtubule stabilization. microtubule stabilization. Selective HDAC6 inhibitors (HDAC6i) therefore offer additional advantages advantages over pan-HDACi inhibitors (Osseni et al., 2022). The mdx mouse models present a mild phenotype and partially recapitulate the trajectory and severity of DMD in humans. Frédéric Relaix's laboratory has created a rat model of DMD which faithfully reproduces the human pathology (Taglietti et al., 2022 & 2023). Before considering clinical trials on DMD patients, we propose to test a promising HDAC6i drug candidate in this highly relevant model. In addition, the effect of HDAC6i will be tested on primary muscle cells from patients with DMD patients in order to gain a first insight into their beneficial effects on human muscles. Overall, this study will provide sufficient proof-of-concept to advance a selective HDAC6i as a potential oral treatment for Duchenne muscular dystrophy. Duchenne muscular dystrophy. The variability of the DMD rat genetic background and the use of cells will enable us to approach this stage of translation to patients with a focus on precision medicine. on precision medicine. | Proof of therapeutic concept 2023 | ||
| 2023 | Xavier DEZITTER | Lille | Foundation For Rare Diseases | Pulmonary rare diseases / Idiopathic Pulmonary Fibrosis | Positive modulators of P2RX7 as a therapeutic strategy in Idiopathic Pulmonary Fibrosis | Idiopathic pulmonary fibrosis (IPF) is a rare (ORPHA:2032), chronic disease that progressively evolves into established fibrosis and respiratory failure. This devastating and incurable disease affects hundreds of thousands of people worldwide, underscoring the need for new therapeutic approaches. We have demonstrated that a molecule that increases the activity of the P2X7 purinergic receptor, a so-called "positive modulator" of P2X7, can lead to remodeling of the immune compartment and improve fibrosis in a mouse model of fibrosis. This molecule establishes proof of concept for the use of P2X7 positive modulators in fibrosis. However, the positive modulators already described are few in number and not very active in vivo, which limits their therapeutic use. The aim of our project is to carry out a high-throughput screening of chemical libraries in order to identify potent P2RX7 positive modulators as drug candidates in pulmonary fibrosis. To this end, we have already developed a method for screening P2X7 modulators based on the measurement of P2X7's ability to bring calcium into cells. This method is based on fluorescence measurement, which can be carried out at high throughput. We would now like to carry out high-throughput screening of compounds using the "Ariadne-Criblage" screening platform, based at the Institut Pasteur in Lille. This platform has all the equipment needed to miniaturize and automate our test, as well as a bank of over 90,000 compounds selected for their chemical diversity and structural properties compatible with future drug development. Among these compounds, we will be testing the Prestwick chemical library, made up of drugs already on the market, in order to reposition an existing drug for pulmonary fibrosis. Once P2R7-modulating compounds have been identified, our team has the knowledge and know-how to test and/or optimize these compounds, then test them in vivo, to rapidly demonstrate their potential as drug candidates in pulmonary fibrosis. | High throughput screening / Hit to lead 2023 | ||
| 2023 | Arnaud MONTEIL | Montpellier | Foundation For Rare Diseases | Rare neurological diseases / CLIFAHDD syndrome | Discovering new therapies for patients with the CLIFAHDD syndrome, a sodium leak channel NALCN-Related Disease | CLIFAHDD syndrome (for "Congenital contractures of the Limbs and FAce, Hypotonia, and Developmental Delay") is a genetic disease classified as ultra-rare which, to date, affects fifty children worldwide. Nevertheless, new cases are regularly described on a regular basis. The disease begins at birth and is characterized by a wide range of symptoms symptoms of varying severity, including developmental delays, apnea and motor problems apnea and motor problems, distal arthrogryposis and premature death. CLIFAHDD syndrome syndrome results from mutations in the NALCN gene. The NALCN channel protein is a key player in the proper several cell types in the body, including neurons and endocrine cells. endocrine cells. We now know that the mutations that induce CLIFAHDD syndrome are mutations that mutations that render NALCN too active. In this context, drugs likely to specifically reduce activity of NALCN represent promising therapeutic avenues for a disease for which there is no pathology for which no treatment currently exists. Against this background, this project brings together a team of researchers specialized in the study of NALCN and a technological platform, the ARPEGE platform, whose expertise in molecule screening is internationally recognized. L' objective is to develop and implement a method for identifying molecules that inhibit NALCN function, using a high-throughput automated screening system. L' identification and validation of such molecules will enable us to propose new therapeutic approaches for patients suffering from CLIFAHDD syndrome. | High throughput screening / Hit to lead 2023 | ||
| 2023 | Aline GHINET | Lille | Foundation For Rare Diseases | Rare neurological diseases / Creutzfeldt-Jakob disease (CJD), Fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker syndrome (GSS syndrome) | Structural optimization of pre-identified hits to obtain novel first-in-class anti-prion compounds | Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia are rare neurodegenerative diseases known as spongiform encephalopathies. Creutzfeldt-Jakob disease (CJD) affects one person per million population per year, or 100 to 150 cases per year in France. The first symptoms of CJD are often non-specific, such as depression or anxiety. This is followed by problems with memory, orientation and language. This dementing syndrome is progressively associated with involuntary muscle spasms, disturbances of balance or vision, tremors and epileptic seizures. CJD is the only human disease that can be either sporadic (80%), genetic (15%) or acquired through contamination (<5%). Les cas sporadiques apparaissent en moyenne vers l'âge de 60 à 65 ans. Le syndrome de Gerstmann–Sträussler–Scheinker touche entre 1 à 10 personnes pour 100 000 000. Ce syndrome est d’origine génétique. L'insomnie familiale, qui a une prévalence <1 >
During the recent in vitro screening of our 3,000-molecule JUNIA-HEI chemical library, carried out by Dr. Cécile Voisset's team at the University of Brest, on S. cerevisiae prions [PSI+] and [URE3], molecules with sufficient activity to be considered hits were identified. The most promising hits, positive against the yeast prions [PSI+] and [URE3], were then tested against the mammalian prion PrPSc in a cell-based assay. Our aim is to optimize the activity of the most promising compounds identified by performing chemical modulations on the skeleton of pre-identified hits. These structural modifications will enhance affinity against the mammalian prion PrPSc, optimize solubility of the newly synthesized congeners, improve pharmacokinetic parameters and generate structure-activity relationships (SARs). This will result in an optimized lead compound, a candidate for preclinical testing as a potential anti-prion drug. This research program will make it possible to identify new anti-prion compounds and thus new therapeutic avenues for patients suffering from prion diseases for which no therapeutic solution is currently available. | High throughput screening / Hit to lead 2023 | ||
| 2023 | Sandrine GULBERTI | Nancy | Foundation For Rare Diseases | Mucopolysaccharidoses | Towards the hit to lead stage in a new substrate reduction therapy strategy in mucopolysaccharidoses targeting the 4GalT7 glycosyltransferase | Mucopolysaccharidoses are rare genetic diseases caused by a defect in the degradation of large sugar molecules called mucopolysaccharides or glycosaminoglycans. As these molecules are not degraded, they accumulate in tissues, causing severe damage to organs, notably the brain, and reducing the quality and length of life of patients. Various types of treatment have been proposed for certain forms of the disease, but their complexity and cost mean that their efficacy remains insufficient to provide lasting relief. The overall aim of the project is to develop compounds that could lead to more effective treatments, in particular by improving the most severe symptoms of the disease, such as those affecting the nervous system. We are looking for small-scale compounds that would specifically block a step in the synthesis of molecules that accumulate in tissues, in order to reduce their deleterious effects. To this end, we have chosen as our target one of the players involved in the early stages of the synthesis process of these molecules in tissues. In the first stage of the project, we tested over a thousand chemical compounds for their ability to block the targeted synthesis pathway, and selected around ten candidate molecules. The activity of these candidate compounds was confirmed in a second series of tests, enabling us to select five molecules which are currently being tested in human cells. In this project, the identification of active molecules will enable us to identify chemical families to target and optimize their structure to obtain even more effective molecules through complementary approaches using medicinal chemistry and molecular modeling. The two to three most active molecules will serve as a basis for proposing new chemical structures. After a feasibility study, these molecules will be chemically synthesized and tested for their biological activity using models available from our partners. The best candidate molecules resulting from these tests will be validated on our target and in human cells, before finally being tested on patient cells, with the longer-term prospect of clinical trials if successful. We hope that this project will provide a new avenue of treatment for the various forms of mucopolysaccharidosis, including the most severe forms involving the nervous system. | High throughput screening / Hit to lead 2023 | ||
| 2023 | Alexis OSSENI | Lyon | Foundation For Rare Diseases | Neuromuscular disorders / Duchenne muscular dystrophy | Design and development of new HDAC6 inhibitors to treat Duchenne Muscular Dystrophy | Duchenne muscular dystrophy (DMD) is the most common and fatal form of muscular dystrophy. It is a devastating and fatal X-linked progressive degenerative muscle disease affecting around 1 in 3,500 boys. This myopathy is characterized by a mutation in the gene coding for dystrophin. Duchenne patient muscles are characterized by continuous cycles of degeneration and regeneration, and this pathological process is accompanied by inflammation and fibrosis, which contribute to fatal muscle wasting and loss of function of skeletal muscles and the heart. Despite detailed characterization of the pathogenesis of this myopathy and considerable research efforts, no cure is yet available for Duchenne myopathy patients. Gene-based therapeutic strategies, such as exon skipping, stop codon deletion, adeno-associated virus (AAV) delivery of mini or micro-dystrophin or CRISPR/Cas9 gene editing, are being actively studied to treat this myopathy. Nevertheless, glucocorticoids remain the reference treatment, acting primarily as anti-inflammatory drugs. However, in recent years, a large number of pharmacological treatments have been explored and developed to improve the quality of life of patients with this myopathy. Over the past decade, an enzyme called HDAC6 has attracted considerable interest as a potential therapeutic target for several neuromuscular diseases. Pharmacological inhibition of this enzyme markedly improves the phenotype of mouse models of DMD by reducing muscle atrophy, reducing fibrosis, increasing protein synthesis, and restoring neuromuscular junctions. However, no HDAC6 inhibitor is currently available on the drug market. Our aim is to identify, design and develop new selective, orally bioavailable HDAC6 inhibitors, based on the best HDAC6 inhibitor known to date: tubastatin A. This inhibitor is composed of three domains, and our strategy is based on modifying these 3 domains to identify non-proprietary compounds. The results of this study will therefore prove essential in paving the way for the development of a completely new class of selective HDAC6 inhibitors for human use, which do not have the disadvantages of the older classes of HDAC inhibitors developed to date. We plan to propose strong candidates for entry into regulatory studies with a view to eventually initiating human clinical trials. | Duchenne muscular dystrophy (DMD) is the most common and fatal form of muscular dystrophy. It is a progressive, X-linked, degenerative muscle disease that is devastating and fatal, affecting approximately 1 in 3,500 boys. Despite detailed characterization of the pathogenesis of this myopathy and considerable research efforts, no cure is yet available for patients with Duchenne muscular dystrophy. However, in recent years, a large number of pharmacological treatments have been explored and developed to improve the quality of life of patients with this myopathy. Our goal is to identify, design, and develop new selective HDAC6 inhibitors that are orally bioavailable, based on the best HDAC6 inhibitor known to date: tubastatin A. The results of this study were therefore essential in paving the way for the development of a whole new class of selective HDAC6 inhibitors for use in humans that do not have the disadvantages of the older classes of HDAC inhibitors developed to date. | High throughput screening / Hit to lead 2023 | |
| 2023 | Damien OUDIN DOGLIONI | Grenoble | Novo Nordisk | Sickle cell disease | Adaptation and evaluation of the feasibility of the FACETS fatigue management program in adult patients with sickle cell disease. | Sickle cell disease is the most common genetic disorder in the world. While pain is the most obvious of the disease, fatigue is also a very common symptom. It is the second most reported symptom (93.6%) after pain, with 75% of respondents reporting significant fatigue. fatigue. Fatigue can be explained by several factors: disease-specific factors (eg. (e.g. severity, worsening over time, hospitalization), personal factors (e.g. age, gender) and psychological factors. psychological factors. The way in which people react to fatigue at cognitive, emotional and behavioural levels plays a role, behavioral response to fatigue plays an important role in its perpetuation or worsening. Moreover fatigue is complicated to treat, given its multifactorial nature. However, French recommendations recommendations for the management of sickle cell disease do not offer any support. This finding is surprising, given the existence of fatigue management programs for other chronic diseases, such as the such as the FACETS program validated for people living with multiple sclerosis. In this study, we aim to adapt this program to adults with sickle cell disease, and to verify its feasibility in this population. feasibility in this population. | Sickle cell disease is the most common genetic disorder in the world. While pain is the most obvious symptom of the disease, fatigue is also very common. It is the second most commonly reported symptom (93.6%) after pain, with 75% of respondents experiencing significant fatigue. Several factors may explain this fatigue: factors specific to the disease (e.g., severity, worsening over time, hospitalization), personal factors (e.g., age, gender), and psychological factors. The way people respond to fatigue on a cognitive, emotional, and behavioral level plays an important role in its perpetuation or aggravation. In addition, fatigue is difficult to treat given its multifactorial nature. However, French recommendations for the management of sickle cell disease do not offer any support. This is surprising, given that fatigue management support programs exist for other chronic conditions, such as the FACETS program, which has been validated for people living with multiple sclerosis. In this study, we aim to adapt this program to adults with sickle cell disease and verify its feasibility in this population. | Novo Nordisk Award 2023 | |
| 2023 | Régis GIET | Rennes | Fondation Les Ailes / Groupama Loire Bretagne | Epileptic and developmental encephalopathies (EED) | Functional study of TACC1, a new gene involved in a rare form of developmental epileptic encephalopathy | Epileptic and developmental encephalopathies (EED) are a group of severe childhood epilepsies. These diseases are characterized by abnormal brain development associated with frequent epileptic seizures. The identification of a new gene responsible for EED therefore represents a major step forward, enabling us to better understand the cellular mechanisms that cause the disease, inform families about the risk of recurrence, and ultimately consider participation in clinical trials. An international collaboration has led to the discovery of a new gene involved in EED in an American family and a French family from the Grand Ouest region, whose affected children have EED resistant to the therapies usually used. We propose to examine the role of this new gene using cellular approaches coupled with high-resolution microscopy. These studies will enable us to gain a better understanding of the deficient cellular mechanisms in these two patient families and, in the longer term, to envisage alternative therapeutic approaches. | Outside AAP | ||
| 2023 | Fabrice LEJEUNE | Lille | ROTARY Linselle | Cystic fibrosis | Combinatorial therapeutic approach for more effective correction of certain mutations in cystic fibrosis | The aim of the project will be to evaluate the efficacy of combinations of NMD-inhibiting molecules and transcriptase-activating molecules in correcting nonsense mutations in cystic fibrosis. | Nonsense mutations affect 10% of patients with genetic diseases, and there is no treatment to specifically correct these mutations, which have a significant impact as they very often lead to the total absence of expression of the mutated gene. Thanks to funding from the Rare Diseases Foundation and the Rotary Club of Linselles, we have undertaken to test 150,000 molecules to detect compounds capable of correcting nonsense mutations. We were able to select 10 molecules and ultimately retain 4 compounds whose activity has been validated on several cell models carrying a nonsense mutation. These 4 molecules are currently being characterized to determine their toxicity and mode of action. We were also able to evaluate combinations of molecules in order to optimize their action. | Outside AAP | |
| 2023 | Agnès DUMAS / Hélène MELLERIO | Paris | Foundation For Rare Diseases | Transition platforms: Understanding the expectations of parents of young rare disease carriers | The transition from pediatric to adult services is a major step in the life course of young people living with a chronic and/or rare disease. For parents, this means accompanying the young person and finding their own place in a new health system. To help parents who are very busy or socially disadvantaged, we have created 4 short videos. They are aimed at all parents concerned by the transition of care for their child with a rare disease, to support them by: - Providing information and links to existing resources, as well as legal, sociological, and psychological expertise to help parents better understand and deal with the transition of a sick child into adulthood; - Providing testimonials from other parents to help them identify with the same issues and show them that the questions they ask and the difficulties they face are shared by many other parents. Four videos have been produced, involving parents of young people with rare diseases, patients, professionals (physicians, sociologists, coordinator of "rare disease interfiliere"): 1 = "Transition, what, where, when"; 2 = "Transition, the role of parents"; 3 = "Transition, professional project"; 4 = "Transition, rights and social services." The video will be published in September 2024. | Outside AAP | |||
| 2023 | Catherine BUI | Nancy | Roquette | Ehlers Danhlos syndrome | Understanding to Cure: Functional exploration of β1,3 galactosyltransferase 6 (B3GALT6) deficiency in a rare genetic connective tissue disease | The aim of the present project is to gain a better understanding of the pathogenesis of a rare form of SED using a global, multidisciplinary approach, and to highlight the different biological pathways or cellular mechanisms affected by these mutations, which could be targets for future treatments. To this end, we propose to: (A) To analyze and compare the transcriptomic profiles of our three-dimensional cell model (2) (eukaryotic cells invalidated for the B3GALT6 gene versus control cells) by RNA-sequencing. (B) Establish and compare the proteomic profiles of our three-dimensional cellular model (eukaryotic cells invalidated for the B3GALT6 gene versus control cells) by mass spectrometry. (C) To validate the "omics" data generated in (1) and (2) by biochemical and functional studies, and to carry out an integrative analysis of these data to identify new molecular players and biological pathways involved in the pathogenesis of this rare form of EDS. Taken together, this knowledge will provide a global view of the consequences of 3GalT6 deficiency, and identify the metabolic pathways and cellular mechanisms altered as a result. This work is necessary to better understand patient symptomatology, and in the longer term will enable us to propose new therapeutic avenues with a view to personalized medicine. | Outside AAP | ||
| 2023 | Mathieu ANHEIM | Strasbourg | Associative (CSC) | Rare neurological diseases | Natural History and Causes of Sporadic Tardive Cerebellar Ataxia (STARAC) | - | Spouse with association | ||
| 2023 | Vincent CANTAGREL | Paris | Associative (CSC) | Rare neurological diseases | Development of cerebellar organoids to study early developmental defects and improve disease genes and mechanisms discovery | - | Spouse with association | ||
| 2023 | Roland CHAPURLAT | Lyon | Associative (VMOV) | Rare bone diseases | In vitro and in vivo study of the regulation of microRNAs in Osteogenesis Imperfecta, the TargetMiROI study | Osteogenesis imperfecta (OI) is a heterogeneous group of rare hereditary connective tissue disorders responsible for bone and/or extra-osseous matrix defects, the variable association and severity of which cause considerable phenotypic variability, particularly in terms of growth. The correlation between genetics and phenotypic profile remains unclear. This observation suggests the existence of other factors that may be involved in the expression of these genetic variations, in particular microRNAs (miRNAs). The potential involvement of 19 circulating miRNAs identified by RNA sequencing, including 2 miRNA clusters (miR-183/96/182 and miR-25/93/106b), was demonstrated during the miROI study that we conducted from 2019 to 2021 on a small group of patients, then confirmed on a larger group (50 OI versus 50 controls) by RT-qPCR. The miRNAs identified are already known to be involved in the regulation of bone homeostasis, among other things. Expected results: A better understanding of the involvement of miRNAs in the pathophysiology of the disease could lead to the identification of a target for a future treatment of OI, by varying the level of expression or the circulating level of the miRNA(s) of interest. Methods: To this end, the TargetMiROI project will study the variation in expression levels of miRNAs 182, 183, 93, and 25 in in vitro models (non-OI murine osteoblasts MC3T3E1, OI murine oim+/-, human pluripotent cells) with expression vector construction and deletion and the use of miR-mimics or inhibitors in order to analyze the differentiation profile and the qualitative and quantitative aspects of the collagen produced. Then, using healthy and OI (oim+/-) mouse models in vivo with the addition of miR-mimics or inhibitors, we will study the phenotypic impact of this variation in miRNAs on morphometric and bone characteristics in particular. | Spouse with association | ||
| 2023 | Valérie CORMIER-DAIRE | Paris | Associative (VMOV) | Rare bone diseases | Osteogenesis imperfecta and growth_Effect of ossification | Understanding and treating the short stature of patients with osteogenesis imperfecta (OI) is a significant challenge. Very little data on this subject is available in the literature, and the bisphosphonates commonly used in the treatment of OI are not effective on growth. Recently, anti-TGF-beta neutralizing antibodies have been proposed as a new therapy. This approach is based on studies showing that the level of TGF-beta released in bone tissue is abnormally high in OI patients. This new treatment appears promising because it can treat both growth defects and bone fragility. However, no trials have been conducted in mice. Only data on adult mice are available. The aim of our study is, on the one hand, to evaluate the effect of Fresolimimab on growth in young mice and, on the other hand, to study the growth of OI patients followed at the Necker Reference Center for Rare Bone Diseases and to search for a correlation between the pathogenic variant of the COL1A1 and COL1A2 genes and stunted growth. We propose to test the efficacy of fresolimimab in OI mice in order to evaluate its effectiveness on growth and to conduct a genotype/phenotype study based on data from the reference center for rare bone diseases at Necker University Hospital. The aim of this study will be to establish a correlation between the pathogenic variant of the COL1A1 and COL1A2 genes responsible for OI and stunted growth. Our project will provide valuable information on the growth of children with OI and could demonstrate the benefits of early treatment with Fresolimumab to treat both bone fragility and stunted growth . | Spouse with association | ||
| 2023 | Lionel LE BOURHIS | Paris | Association (AMARAPE) | Rare cancers | Modulation of the immune response in peritoneal carcinomatosis from colorectal cancer | Colorectal cancer (CRC) is a major public health issue. Peritoneal carcinomatosis (PC) affects between 7 and 10% of CRC cases, with an overall 5-year survival rate of less than 50%. New therapies have been developed over the past 10 years, including immunotherapy. However, these therapies are rarely used in CRC because they are only effective in the 15% of tumors that present microsatellite instability. Recent laboratory data have shown an increase in KLRG1+ T lymphocytes and a decrease in CD103+ T lymphocytes in primary tumors compared to healthy mucosa. Other studies have shown the presence of T lymphocytes in secondary tumors with a phenotype similar to that found in the primary tumor. The objective of this project is therefore to study the tumor microenvironment of the primary tumor and peritoneal metastasis , particularly the lymphocyte phenotype. Then, to test, ex vivo, the modulation of the KLRG1 pathway in the immune response against organoids from primary or metastatic tumors. The aim of this study is, ultimately, to improve the prognosis of colorectal PC through immunotherapy. | Spouse with association | ||
| 2023 | Véronique MONNIER | Paris | Association (AFAF) | Rare neurological diseases | Identification of dietary and genetic conditions leading to suppressive effects in Drosophila models of Friedreich Ataxia with GAA expansions | Friedreich's ataxia (FA) is a neurodegenerative and cardiac disease caused by expansions of GAA repeats in the FXN gene. This gene encodes frataxin, a mitochondrial protein that regulates the biosynthesis of iron-sulfur centers, protein cofactors involved in many essential biological functions . GAA expansions lead to a decrease in gene expression, resulting in a deficiency of Fe-S centers. We have generated models of FA in Drosophila called fh-GAA in which GAA expansions of different sizes are inserted into the fh gene encoding Drosophila frataxin. These models recapitulate the characteristics of the disease. These models recapitulate the characteristics of the disease. In particular, fh-GAAs flies, carrying a short expansion of 42 GAA, show reduced frataxin levels, reduced lifespan, hypersensitivity to oxidative stress, decreased aconitase activity, heart dilation, severe locomotor dysfunction, and iron accumulation in the brain. This project has two objectives based on recent observations made on this model. First, treatment with a compound known to reduce intestinal iron absorption in flies increases the lifespan of fh-GAAs flies, suggesting that it is possible to target iron absorption to treat the disease. Our first objective is to study the impact on disease progression of diets aimed at reducing intestinal iron absorption. Second, we observed that populations of the fh-GAAs lineage show increased survival compared to the initial lineage, with a more than 2.5-fold increase in average lifespan . The study of these natural drifts provides a unique opportunity to identify new genetic suppressors in an in vivo model. Our second objective is to develop a functional genomics approach to identify these suppressors. We believe that the two strands of this project will provide valuable data on the environmental and genetic factors that lead to protective effects in the context of frataxin deficiency. | Spouse with association | ||
| 2023 | Helen PUCCIO | Lyon | Association (AFAF) | Rare neurological diseases | Deciphering the neurodevelopmental component in Friedreich's Ataxia | Friedreich's ataxia (FA) is a rare genetic disorder caused by mutations in the frataxin gene. Patients suffer from multiple impairments, affecting the central and peripheral nervous systems, the heart, and the pancreas. The loss of proprioception, which is the perception of the body's position in space, is the result of the degeneration of proprioceptive neurons in the dorsal root ganglia. Numerous studies using patient tissue and cells highlight a developmental component. Our study aims to determine whether neurodevelopmental defects could weaken and then contribute to the degeneration of proprioceptive neurons. Knowing when neurological damage first appears would enable therapeutic strategies for this disease to be adjusted. | Spouse with association | ||
| 2023 | Agnès ROTIG | Paris | Association (AFAF) | Rare neurological diseases | Protein palmitoylation in Friedreich's ataxia | Friedreich's ataxia is caused by a deficiency of a mitochondrial protein, frataxin, which enables the formation of iron-sulfur centers that are subsequently incorporated into many other proteins in the mitochondria, but also in other cellular compartments. The frataxin deficiency therefore leads to a more or less pronounced dysfunction of many other proteins. We have identified a new consequence of the frataxin deficiency that explains the iron overload observed in cultured cells from patients. We have shown that three proteins that allow iron to enter the cell need to be bound to a fatty acid, palmitic acid, in order to function properly , which is not the case in Friedreich's ataxia. These proteins are under-palmitoylated, leading to iron overload in the cells. There are undoubtedly many other sub-palmitoylated proteins, and our project aims to identify them through proteomics studies in order to better understand the different facets of the disease. We have also previously shown that artesunate, a molecule used to treat malaria and certain cancers, restores normal palmitoylation of these iron transporters and reduces iron overload. We have begun a phase I/II trial to study the toxicity and efficacy of artesunate, which shows that it has no toxicity. The second part of our project is to determine whether artesunate restores normal palmitoylation after oral treatment. This project will give us a better understanding of the consequences of frataxin deficiency, define the effect of treatment with artesunate, and determine the conditions for this treatment. | Spouse with association | ||
| 2023 | Piera SMERIGLIO | Paris | Associative (VMOV) | Rare bone diseases | Enhancing Bone-Muscle Crosstalk in Osteogenesis Imperfecta | Osteogenesis imperfecta (OI) is a rare connective tissue disorder that affects approximately one in every 15,000 people. One of the main complications for patients is bone fragility and loss of bone density. However, several recent studies have highlighted specific alterations in muscles, both in terms of mass and functionality, observed in 80% of patients. Despite considerable progress in understanding OI, including the genetic basis and molecular pathways involved, effective therapies remain elusive. Current therapeutic approaches focus primarily on improving bone strength, but they often overlook the broader physiological context in which OI operates. We believe that OI growth deficits may, in part, be due to disruptions in the interaction between muscle and bone. These two organs—among the largest in the body—are important regulators of hormones and other secreted proteins, as well as the metabolism of the entire body. Bones and muscles are closely linked, although their interactions are only beginning to be appreciated. The inherently interconnected nature of bone and muscle means that deterioration in bone health in patients will naturally lead to deterioration in muscle health and vice versa. Our hypothesis is that a better understanding of the altered bone-muscle communication in OI could lead to the discovery of new therapeutic targets. The main objective of this project is therefore to exploit the natural beneficial relationship between bone and muscle health in order to improve the bone health of patients with OI. It leverages our expertise in bone and muscle biology and therapeutics, as well as our relationships with clinicians who treat patients with OI, to create a new map of bone-muscle interaction in OI. | Spouse with association | ||
| 2023 | Marc BITOUN | Paris | Associative (PACS1) | Developmental anomalies and malformation syndromes | Rescue of phenotype in patient-derived fibroblasts by allele-specific siRNAs | - | Spouse with association | ||
| 2023 | Muriel PERRON | Paris | Associative (BBS) | Sensory disorders (rare eye diseases and deafness) | Regenerative Therapy for Retinal Degenerative Diseases | Regenerative medicine refers to therapeutic approaches aimed at replacing ("regenerating") damaged cells in order to restore the function of a diseased organ. This innovative and rapidly growing field is based on the manipulation of endogenous stem cells. The study of the mechanisms that control the activity of these cells is our team's main area of research. In the human retina, stem cells are dormant and therefore unable to compensate for cell loss in the event of injury or degenerative diseases. Conversely, stem cells in the retinas of amphibians and fish have an incredible capacity for regeneration. Our goal is to identify molecules capable of awakening our dormant stem cells and thus stimulating self-repair mechanisms. To do this, we are using two animal models with distinct properties: the Xenopus, a frog with exceptional regenerative mechanisms, and the mouse, which, like humans, is unable to spontaneously regenerate its retina. Our current project consists of evaluating the impact of inflammatory signals on the different stages of the regenerative process. Based on numerous preliminary data that show great promise, we strongly believe that modulating inflammation is essential to the creation of a cellular microenvironment conducive to regeneration. The molecules identified at the end of the project could therefore constitute therapeutic targets and pave the way for the development of regenerative medicine strategies for a wide range of patients with retinal dystrophies, such as AMD, non-syndromic retinitis pigmentosa or syndromic retinitis pigmentosa such as Usher syndrome or Bardet-Biedl syndrome. | Spouse with association | ||
| 2023 | Catherine LEJEUNE | Dijon | COSY RHU | Hypergrowth syndromes | Unmet needs of patients with hypertrophic syndromes: perspectives from patients, caregivers, and healthcare and medical-social professionals | Hypertrophic syndromes are conditions characterized by abnormal growths and sometimes associated with intellectual disabilities or learning disorders. They impact patients' quality of life on a daily basis. Our goal is to identify the difficulties encountered by patients with this syndrome. To this end, researchers will meet with patients of all ages with varying degrees of impairment and their caregivers. They will also meet with healthcare and social sector professionals. These meetings will aim to identify the areas in which patients encounter difficulties (activities of daily living, access to recreational activities, schooling, professional life, access to healthcare) and to understand the reasons for these difficulties. The project's impact is intended to be pragmatic, as we will use the results to consider concrete actions to be implemented in order to help patients better cope with their illness and integrate into society. | Background Hypertrophic syndromes are conditions characterized by abnormal growths and sometimes associated with intellectual disabilities or learning disorders. They impact the quality of life of patients on a daily basis. Objectives Our objective was to identify the difficulties encountered by patients with this syndrome. To this end, researchers met with patients of all ages, with varying degrees of impairment, as well as their parents. They also met with healthcare professionals. These interviews aimed to identify the areas in which patients encounter difficulties (activities of daily living, access to recreational activities, schooling, professional life, access to care) and to understand the reasons for these difficulties. The objective was also to identify the difficulties and needs of parents, as well as those of the healthcare professionals involved in patient care. These interviews aimed to identify the areas in which patients encounter difficulties (activities of daily living, access to recreational activities, schooling, professional life, access to care) and to understand the reasons for these difficulties. The objective was also to identify the difficulties and needs of parents, as well as those of the healthcare professionals involved in the care of patients. The project's outcomes were intended to be pragmatic, with the ambition of using the results to consider concrete actions to be implemented in order to help patients better live with their illness and integrate into society. Social significance of the results obtained Our results highlighted significant needs that call for a general reflection on how to understand rare diseases, optimize care, and put in place the means for social integration that is more suited to children's skills and abilities. 1/For patients, these needs concern: - information about possible treatments, their side effects, and their long-term effects in order to promote informed decision-making and avoid disappointment with the results. - psychological support and counseling to break isolation but also to help children and adolescents through important transitional periods in their lives (transition to adolescence and transition to adulthood). - adapting work and school life by adjusting programs and teaching methods to students' physical and cognitive limitations, but also promoting policies for adjusting working hours and adapting workstations, as well as measures to help people stay in the workplace. - managing chronic pain and fatigue by informing patients and their parents, but also professionals about the use of non-pharmacological techniques and by promoting more regular monitoring of pain management by specialists. 2/ Families Families faced with diagnostic uncertainty for MCAP and rapid but demanding care for Cloves express the importance of greater recognition of their role and appropriate support. Administrative procedures and the search for inclusive school facilities represent daily challenges, but also illustrate a quest whose goal is to provide their children with the resources they need to grow and thrive. Finally, the balance between professional life and supporting the child is a shared concern , encouraging the exploration of flexible solutions to better respond to these realities. Call for research projects in the humanities and social sciences – Final report 19 3/ Professionals Professionals and families share uncertainties regarding the cognitive, emotional, and behavioral care of children with MCAP syndrome. In addition, the results highlight multidisciplinary (educational and medical) issues and coordination of care that require vigilance to ensure continuity in the care of patients. | Humanities and Social Sciences - COSY | |
| 2022 | Alice LEPELLEY | Paris | Foundation For Rare Diseases | Rare bone diseases | Characterisation of the role of IFN signalling in neural cells in ATAD3A disease | Neurodegenerative diseases are increasingly associated with abnormal brain inflammation, the origin of which is poorly understood. Type I interferons represent the first line of defense against viruses. However, type I interferonopathies are rare genetic diseases associated with an inappropriate increase in interferon signaling, often leading to neurological pathology. To better understand the presence and consequences of abnormal interferon levels on neuropathology, we propose to generate brain cell models of patients with type I interferonopathy. These models will be studied as part of a research project. Their study will enable us to design and test therapeutic strategies that are also relevant to more common neurological diseases. | Neurodegenerative diseases are increasingly correlated with the presence of an inflammatory response in the brain, the origin of which is poorly understood. Type I interferons are the first line of defense against viruses. Type I interferons are the first line of defense against viruses. However, genetic diseases called type I interferonopathies are associated with an inappropriate increase in interferon levels, often leading to neurological symptoms. To better understand the origin and consequences of these abnormal interferon levels on neurological pathologies, we propose to generate models of neurons from patients with type I interferonopathies. We have currently generated one model out of the three planned models. Their study will enable the design and testing of therapeutic strategies, which can also be applied to diseases. Studying these models will enable the design and testing of therapeutic strategies that may also be applicable to more common neurological diseases . | Models 2022 | |
| 2022 | Dimitri MOREAU | Geneva | Associative (PACS1) | Developmental anomalies and malformation syndromes | Development of a robust cell-based microscopy assay for compound screening project on PACS1 (R203W) rare disease | PACS1 syndrome (203) is a rare disease responsible for severe neurodevelopmental disorders and for which no treatment has yet been approved. The main objective of this project is the development of a cell-based assay using automated optical microscopy for the future large-scale screening of molecules with drug potential. This will require the identification of cellular effects specifically induced by the mutation on the PACS1 gene (W203R) in comparison with healthy cells. It has been reported that the PACS1 protein plays an essential role in regulating transport between the Golgi apparatus and the plasma membrane. Although little is known and understood about the cellular consequences of the dominant PACS1 (R203W) mutation, it is likely that it affects the proteins involved in this transport. Our team has long specialized in cellular membrane transport processes, particularly the mechanisms of secretion and the endolysosomal pathway, which are precisely the processes thought to be affected by the PACS1 (R203W) mutant expression. In addition, we are also experts in high-throughput screening , particularly in the context of studies on rare diseases: Cohen syndrome and Niemann Pick type C. We propose to develop an experiment capable of very specifically quantifying the effect of the PACS1 (WmR203W) mutant at the cellular level. This experiment could then be used in one or more large-scale screening campaigns aimed at discovering new molecules capable of correcting the defect induced by the mutation. | Spouse with association | ||
| 2022 | Gaëlle BOUGEARD | Rouen | Associative (Li-Fraumeni) | Rare cancers | TP53 wt allele as a modifier factor in Li-Fraumeni syndrome | Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome resulting from a heterozygous constitutional mutation in the TP53 gene, characterized by significant phenotypic heterogeneity in terms of both the age of tumor onset and their highly varied location. Brain tumors, particularly pediatric tumors, and especially choroid plexus tumors, are highly suggestive of LFS. Through the study of French families affected by LFS, we have been able to show that the type of mutation can influence the age of onset, with dominant-negative missense mutations being associated with an earlier form than loss-of-function mutations alone. However, nonsense mutations are sometimes associated with pediatric tumors. Variations in other genes in the p53 pathway could play a modifying role, but in this project we are interested in the role of the other TP53 allele. Polymorphic variations, which are therefore present in the general population, could decrease the overall activity of p53 and accelerate tumorigenesis. As proof of concept, we wish to study the cumulative effect of a nonsense mutation and a polymorphism that is relatively common in some patients of African origin but rare in France. This genotype was observed in a young girl who died at 19 months of age following the rapid development of bilateral adrenocortical carcinoma and metastatic choroid plexus carcinoma. In order to understand the genesis of brain tumors in LFS, a collaborative project is underway to develop an innovative model of LFS based on brain organoids, derived either from fibroblasts from LFS patients or from stem cells into which we introduce TP53 gene mutations using CRISPR-Cas9 molecular scissors technology. We therefore wish to use the same strategy to dissect the biological effect of these variations using the p53 functional test developed in the laboratory, which is currently being adapted for iPSCs. Genetic counseling is currently based solely on the search for deleterious variations, so the functional characterization of polymorphic or difficult-to-classify variations is essential for patient management. | Spouse with association | ||
| 2022 | Nathalie JONCA | Toulouse | Associative (AIF) | Dermatological diseases | RARESKINLIP: Innovative in vitro models of ichthyosis to assess the efficiency of a novel lipid substitutive therapy in the rescue of the epidermal barrier | Hereditary ichthyoses are rare monogenic diseases that occur at birth or in early childhood. They are characterized by thick skin with scaling, dryness, and redness. Patients also experience pruritus and skin pain, which impair their quality of life. All forms of ichthyosis are caused by an alteration in the "epidermal barrier." In more than a third of cases, this alteration is caused by a defect in the synthesis or maturation of a very specific epidermal lipid, a ceramide esterified by linoleic acid. This type of lipid is essential for building the outermost layer of the epidermis called the stratum corneum, which supports the barrier function. Current treatments for ichthyosis are symptomatic, non-targeted, often ineffective, and have significant side effects. Replacing the missing ceramide therefore seems to be a promising therapeutic approach . We are working in collaboration with chemists capable of synthesizing lipids identical to those found in the skin and "packaging" them in nanoparticles formulated for topical application to the skin. The goal of RARESKINLIP will be to produce a wide range of "diseased skin" models that reflect the great genetic diversity of ichthyosis. These reliable, reproducible, and high-perfor in vitro reconstructed epidermis models will be produced without using patient skin, thanks to a cutting-edge technology called "genome editing." The different formulations of nanoparticles loaded with therapeutic lipids will be applied to the surface of these "diseased" epidermis to test their ability to repair the epidermal barrier. RARESKINLIP should thus enable the development of future, original, and highly effective therapies, targeting different types of ichthyosis caused by a defect in the synthesis or maturation of esterified ceramide. This approach should improve our understanding of these ichthyoses and substantially expand the pool of patients potentially eligible for this lipid replacement therapy. | Spouse with association | ||
| 2022 | Pierre-Olivier FERNAGUT | Poitiers | Association (ARAMISE) | Rare neurological diseases | Alpha-synuclein and the fate of oligodendrocytes in Multiple System Atrophy | Multisystem atrophy (MSA) is a fatal neurodegenerative disease with severe motor disability and dysautonomia affecting 5,000 people in France and more than 30,000 in Europe. There is currently no treatment available to alleviate the severity of symptoms or the clinical progression of this orphan disease. The accumulation and aggregation of the neuronal protein α-synuclein in oligodendrocytes in the form of glial cytoplasmic inclusions is the cytopathological hallmark of AMS. It is considered to play a central role, leading to glial and neuronal dysfunction and neurodegeneration. The accumulation of α-synuclein in oligodendrocytes has significant effects on oligodendroglial fate, as evidenced by postmortem studies showing an increased number of oligodendrocyte precursor cells and impaired function and size of mature oligodendrocytes. It is unclear whether these alterations in proliferation, maturation, and function are related to the accumulation of α-synuclein during specific stages of oligodendroglial differentiation. Despite significant advances in our understanding of the pathogenesis of AMS, the key mechanisms underlying the failure of oligodendroglial function remain largely unknown. To address these issues, we will isolate different oligodendrocyte populations from preclinical models of AMS and perform high-throughput transcriptome sequencing to uncover the key molecular mechanisms underlying oligodendroglial failure in AMS. We will also determine the potential of molecules associated with oligodendrocytes to be detected in biological fluids (blood, cerebrospinal fluid) from AMS models and AMS patients, and their ability to serve as biomarkers of the pathological process. By improving our understanding of the key mechanisms involved in oligodendrocyte dysfunction, this project will pave the way for the development of new therapeutic approaches and contribute to improving the diagnosis and monitoring of the disease in patients with AMS through the development of new biomarkers. | Spouse with association | ||
| 2022 | Audrey PUTOUX | Lyon | Foundation For Rare Diseases | Anencephaly | Towards the identification of genes involved in recurrent anencephaly | - | Anencephaly is a rare and lethal malformation that occurs in utero or shortly after birth. It most often occurs sporadically, meaning that there are few familial cases. The genetic cause is unknown in most cases. We collected DNA from individuals belonging to five families with recurrent anencephaly, present in several fetuses from the same couple (between two and four fetuses with anencephaly among siblings), suggestive of a genetic form. We performed linkage analysis and whole genome sequencing in the five families to try to find the gene responsible for the condition. We have identified some interesting DNA variants, but we need to continue our analysis with functional studies to understand whether these variants have an impact on the functioning of the gene and the corresponding protein. To this end, we would like to launch studies to see whether the genes carrying these variants are expressed normally or not (RNA study), which would enable us to answer the question of the consequences of these variants. | GenOmics 2021 | |
| 2022 | michot | Paris | Foundation For Rare Diseases | Chondrodysplasias with multiple dislocations (CMD) form a group of severe disorders including : -Desbuquois dysplasia type 2 (MIM: 615777/AR) -Neonatal short limb dysplasia (MIM: -/AR) -Ehlers-Danlos syndrome (EDS) progeroid variant or EDS spondylodysplastic type 1 (EDSSPD1), including Larsen syndrome, la Reunion variant (MIM: 130070/AR) -Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type (MIM: 271640/AR) or EDS spondylodysplastic type 2 (EDSSPD2) (MIM: 615349/AR) -Larsen-like syndrome (MIM: 245600/AR) -Joint dislocations and skeletal dysplasia, Desbuquois-like (MIM: 618870/AR) -Temtamy preaxial brachydactyly syndrome (TPBS) (MIM: 605282/AR) -Ehlers-Danlos musculocontractural syndrome type 2 (MIM: 615539/AR) -Diastrophic dysplasia (MIM: 222600/AR) -Recessive Larsen syndrome or spondyloepiphyseal dysplasia with congenital joint (MIM: 143095/AR) -Ehlers-Danlos syndrome musculocontractural type 1 (MIM: 601776/AR) -Chondrodysplasia with joint dislocations, gPAPP type (MIM: 614078/AR) -Multiple congenital malformation syndrome including vertebral malsegmentation and joint dislocations (MIM: -/AR) -Skeletal dysplasia, osteoporosis, multiple dislocations and amelogenesis imperfecta (MIM: 618363/AR) -Desbuquois dysplasia type 1, including Kim variant (MIM: 251450/AR) -Recessive multiple epiphyseal dysplasia (MIM: 617719/AR) -TMEM-CDG (MIM: 614727/AR) | Identification of new pathogenic variants in individuals with Chondrodysplasias with multiple dislocations (CMD) combining WGS and RNASEQ | - | Les chondrodysplasies avec luxations multiples forment un groupe de maladies rares graves, caractérisées par une laxité articulaire, des luxations multiples affectant les grosses articulations (telles que la hanche, le genou et l'épaule), un retard de croissance pré- et postnatale, des anomalies de la main et/ou des anomalies vertébrales. D’un point de vue radiologique les chondrodysplasies avec luxations multiples se caractérisent par un âge avancé des os du carpe et du tarse et des cols fémoraux en forme de clé anglaise. Des malformations cardiaques congénitales, des anomalies dentaires, des déficiences intellectuelles et une obésité peuvent également être observées chez ces patients. À ce jour, 32 syndromes ont été identifiés et la plupart d'entre eux ont été associés à des variants pathogènes dans 25 gènes codant pour des protéines impliquées directement ou indirectement dans la biosynthèse des glycosaminoglycanes (GAG), polysaccharides (glucides complexes) qui associaient avec une protéine forme les protéoglycanes, composants essentiels de la matrice extracellulaire. La biosynthèse des GAG est un processus qui se produit principalement dans l’appareil de Golgi et qui nécessite l’action coordonnée de nombreuses enzymes et de transporteurs ainsi qu'un environnement adéquat. Chaque individu, porteur de chondrodysplasie avec luxations multiples, reçu en consultation bénéficie d'une étude moléculaire par NGS ciblée comprenant tous les gènes identifiés à ce jour. Si aucun variant n’a pu être identifié dans un gène connu, la famille est alors étudiée en exome. Notre cohorte comprend 80 familles et nous avons ainsi pu mettre en évidence des variants pathogènes chez 60% d'entre eux, dans des gènes connus ou de nouveaux gènes tels que CANT1, XYLT1, SLC10A7 et SLC35B2. De nouveaux variants pathogènes ont été identifiés dans des gènes codant pour des protéines sans fonction connue directement liée à la synthèse des protéoglycanes, tels que la nucléotidase-1 activée par le calcium (CANT1), associée avec une synthèse défectueuse des protéoglycanes. Plus récemment nous avons identifié des variants dans le gène SLC10A7. Pour mieux comprendre la fonction cellulaire et moléculaire de SLC10A7, nous avons développé un modèle murin déficient en Slc10a7 qui imite le phénotype humain et dans lequel un retard de croissance sévère a été observé. Nous avons montré une forte diminution spécifique du taux d'héparane sulfate dans les fibroblastes et le cartilage des souris mutées. Et pour finir des variants, identifié dans le gène SLC35B2, sont responsables d'une forme grave de chondrodysplasie avec luxations multiples associée à une déficience intellectuelle sévère. Ses variants conduisent à une mauvaise localisation de la protéine SLC35B2 provoquant un défaut sur la sulfatation des GAG. Notre objectif est de poursuivre l'identification de nouveaux variants pathogènes chez nos 32 individus porteurs de chondrodysplasie avec luxations multiples non mutés. Pour 10 d'entre eux nous disposions d'une quantité d'ADN suffisante pour réaliser un whole genome (cas index et parents) et de fibroblastes extraits d'une biopsie cutanée (cas index + témoins (sexe et âge correspondant aux cas index)) pour réaliser une étude RNAseq, étude des transcrits des arns présents dans les fibroblastes des individus atteints par rapport aux individus sains. Le but de l’étude en whole genome est d’identifier des variants situés en dehors des exons, donc dans les introns des gènes et pouvant entrainer un défaut d’épissage des exons donc des protéines anormales. Ainsi, l’étude whole genome, combiné au RNASeq, nous permettra d’identifier parmi tous les variants introniques qui seront détectés, ceux qui ont une incidence sur l’expression des arns et donc des proteines, nous permettant ainsi d’identifier de nouveaux variants voir de nouveaux gènes responsables de chondrodysplasies avec luxations multiples. L’étude RNAseq nous permettra également d’étudier l’ensemble des voies de signalisation qui sont activées ou non chez les individus atteints par rapport aux individus sains et ainsi avoir un profil d’expression pour chaque individu atteint que nous pourrons comparer au profil d’expression de nos individus mutés SLC10A7 par exemple. L’appel à projet Genomics_2022 de la Fondation Maladies Rares, nous a permis de financer l’étude RNaseq pour nos 10 indvidus. Nous avons pu établir leur profil d’expression et mettre en évidence l'implication des voies de glycosylation et d'homéostasie calcique, en particulier la voie de signalisation WNT/Ca+. L’étude whole genome est actuellement en cours. Nous n'avons pu réaliser cette étude pour 6 familles, et ainsi identifier des variants probablement pathogènes pour 2 d’entre elles. La recherche d'autres patients mutés dans ces deux gènes ainsi que des études fonctionnelles sont actuellement en cours pour nous permettre de valider l'implication de ces variants dans les chondrodysplasies avec luxations multiples. Les chondrodysplasies avec luxations multiples forment un groupe de maladies rares graves, caractérisées par une laxité articulaire, des luxations multiples affectant les grosses articulations (telles que la hanche, le genou et l'épaule), un retard de croissance pré- et postnatale, des anomalies de la main et/ou des anomalies vertébrales. D’un point de vue radiologique les chondrodysplasies avec luxations multiples se caractérisent par un âge avancé des os du carpe et du tarse et des cols fémoraux en forme de clé anglaise. Des malformations cardiaques congénitales, des anomalies dentaires, des déficiences intellectuelles et une obésité peuvent également être observées chez ces patients. À ce jour, 32 syndromes ont été identifiés et la plupart d'entre eux ont été associés à des variants pathogènes dans 25 gènes codant pour des protéines impliquées directement ou indirectement dans la biosynthèse des glycosaminoglycanes (GAG), polysaccharides (glucides complexes) qui associaient avec une protéine forme les protéoglycanes, composants essentiels de la matrice extracellulaire. La biosynthèse des GAG est un processus qui se produit principalement dans l’appareil de Golgi et qui nécessite l’action coordonnée de nombreuses enzymes et de transporteurs ainsi qu'un environnement adéquat. Chaque individu, porteur de chondrodysplasie avec luxations multiples, reçu en consultation bénéficie d'une étude moléculaire par NGS ciblée comprenant tous les gènes identifiés à ce jour. Si aucun variant n’a pu être identifié dans un gène connu, la famille est alors étudiée en exome. Notre cohorte comprend 80 familles et nous avons ainsi pu mettre en évidence des variants pathogènes chez 60% d'entre eux, dans des gènes connus ou de nouveaux gènes tels que CANT1, XYLT1, SLC10A7 et SLC35B2. De nouveaux variants pathogènes ont été identifiés dans des gènes codant pour des protéines sans fonction connue directement liée à la synthèse des protéoglycanes, tels que la nucléotidase-1 activée par le calcium (CANT1), associée avec une synthèse défectueuse des protéoglycanes. Plus récemment nous avons identifié des variants dans le gène SLC10A7. Pour mieux comprendre la fonction cellulaire et moléculaire de SLC10A7, nous avons développé un modèle murin déficient en Slc10a7 qui imite le phénotype humain et dans lequel un retard de croissance sévère a été observé. Nous avons montré une forte diminution spécifique du taux d'héparane sulfate dans les fibroblastes et le cartilage des souris mutées. Et pour finir des variants, identifié dans le gène SLC35B2, sont responsables d'une forme grave de chondrodysplasie avec luxations multiples associée à une déficience intellectuelle sévère. Ses variants conduisent à une mauvaise localisation de la protéine SLC35B2 provoquant un défaut sur la sulfatation des GAG. Notre objectif est de poursuivre l'identification de nouveaux variants pathogènes chez nos 32 individus porteurs de chondrodysplasie avec luxations multiples non mutés. Pour 10 d'entre eux nous disposions d'une quantité d'ADN suffisante pour réaliser un whole genome (cas index et parents) et de fibroblastes extraits d'une biopsie cutanée (cas index + témoins (sexe et âge correspondant aux cas index)) pour réaliser une étude RNAseq, étude des transcrits des arns présents dans les fibroblastes des individus atteints par rapport aux individus sains. Le but de l’étude en whole genome est d’identifier des variants situés en dehors des exons, donc dans les introns des gènes et pouvant entrainer un défaut d’épissage des exons donc des protéines anormales. Ainsi, l’étude whole genome, combiné au RNASeq, nous permettra d’identifier parmi tous les variants introniques qui seront détectés, ceux qui ont une incidence sur l’expression des arns et donc des proteines, nous permettant ainsi d’identifier de nouveaux variants voir de nouveaux gènes responsables de chondrodysplasies avec luxations multiples. L’étude RNAseq nous permettra également d’étudier l’ensemble des voies de signalisation qui sont activées ou non chez les individus atteints par rapport aux individus sains et ainsi avoir un profil d’expression pour chaque individu atteint que nous pourrons comparer au profil d’expression de nos individus mutés SLC10A7 par exemple. L’appel à projet Genomics_2022 de la Fondation Maladies Rares, nous a permis de financer l’étude RNaseq pour nos 10 indvidus. Nous avons pu établir leur profil d’expression et mettre en évidence l'implication des voies de glycosylation et d'homéostasie calcique, en particulier la voie de signalisation WNT/Ca+. L’étude whole genome est actuellement en cours. Nous n'avons pu réaliser cette étude pour 6 familles, et ainsi identifier des variants probablement pathogènes pour 2 d’entre elles. La recherche d'autres patients mutés dans ces deux gènes ainsi que des études fonctionnelles sont actuellement en cours pour nous permettre de valider l'implication de ces variants dans les chondrodysplasies avec luxations multiples. | GenOmics 2021 | |
| 2022 | Djihad HADJADJ | Paris | Foundation For Rare Diseases | Predisposition to familial midgut carcinoid tumors (FMCT). Predisposition to neuroendocrine tumors. | Identification of constitutional genetic abnormalities predisposing to Familial midgut carcinoid tumors | - | The FMCTs cohort is a national retrospective and prospective study that was set up in France in 2012 under the direction of the Endocrine Tumor Study Group (GTE): 108 relatives from 46 families (as of September 1, 2021) were recruited in twenty French centers, making it the largest cohort to date to our knowledge. Our team has the expertise to design, implement, and analyze a targeted NGS panel that will enable rapid analysis of candidate regions in all patients and tumors in the cohort to confirm the involvement of non-coding sequence variations as a cause of FMCT predisposition. Thanks to funding from the Rare Diseases Foundation, we are currently prioritizing one or more candidate genetic abnormalities that predispose to FMCT. This project is made possible by the integration of innovative high-throughput sequencing approaches and the study of the 3D conformation of our chromosomes. The non-coding regions/variations identified using this integrated approach will be confirmed by targeted analysis within other families in the French FMCT cohort. In addition, functional genomics on human tumors, cell models, and mouse models of the disease will be established with the identified variants. Cell models relevant for targeting candidate regions are already being used by our team. Recent genome editing tools enable rapid intervention strategies to generate in vitro and in vivo models. This study will improve our understanding of the genetic basis of hereditary midgut carcinoid tumor syndrome. Our study will therefore also provide new insights into the pathogenesis of this particular cell type proliferation. | GenOmics 2021 | |
| 2022 | Kim MINCHUL | Illkirch | Foundation For Rare Diseases | Tubular aggregate myopathy (TAM) | Tracking the origin of tubular aggregate myopathy by single-nucleus transcriptomics | - | Tubular aggregate myopathy (TAM) is a complex muscle disease characterized by muscle function problems and the accumulation of abnormal structures in cells. It occurs when calcium levels in cells are unbalanced due to genetic mutations. Normally, we think calcium helps muscles contract smoothly, but recent research suggests that different parts of muscle cells may process calcium differently. We wanted to see if TAM developed from specific parts of muscle cells. We studied mice with symptoms similar to those of MTA at different stages of the disease. By examining the gene expression profile of each nucleus in healthy mice and mice with TAM-like symptoms, we sought to find differences that could explain TAM. We collected a large data set from mice of different ages and are carefully analyzing it. We hope this research will give us new clues about the causes of TAM and how to treat it. | GenOmics 2021 | |
| 2022 | Marie-Louise FREMOND | Paris | Foundation For Rare Diseases | Rheumatoid factor positive arthritis Type I interferonopathies | Identifying Novel Monogenic Interferon-Mediated Juvenile Rheumatoid Arthritis | - | Rheumatoid factor-positive juvenile idiopathic arthritis (JIA) is a rare form of this disease in children. Researchers have taken an interest in this topic because of their expertise in diseases related to type I interferon signaling, a group of genetic diseases affecting the immune system. They propose to identify new types of genetic mutations in patients that could predispose them to this particular form of JIA using an advanced genetic sequencing technique . In doing so, they have already identified three candidate genes that they are studying in the laboratory . In addition to improving the diagnosis and management of rare forms of the disease, this research could also have implications for more common diseases, such as rheumatoid arthritis in adults. This research could also have implications for more common diseases, such as rheumatoid arthritis in adults. | GenOmics 2021 | |
| 2022 | Marion DELOUS | Lyon | Foundation For Rare Diseases | Taybi-Linder Syndrome, TALS or Microcephalic Osteodysplastic Primordial Dwarfism type I (MOPDI), OMIM 210710 Roifman Syndrome, RFMN, OMIM 616651 Lowry-Wood Syndrome, LWS, OMIM 226960 | TRANSCRIPTOMIC STUDY DURING NEURONAL DIFFERENTIATION OF RNU4ATAC-ASSOCIATED RARE DISEASES: CONNECTING SPLICING DEFECTS TO BRAIN DEVELOPMENTAL ABNORMALITIES | - | Taybi-Linder syndrome (TALS) is a rare genetic disorder characterized by microcephaly and caused by mutations in the RNU4ATAC gene. These mutations affect a little-known process of pre-messenger RNA maturation, possibly altering the expression of nearly 750 genes. In order to identify the most altered genes and the cellular processes in which they are involved, I studied all the mRNAs expressed in a unique model of neuronal cells mutated for RNU4ATAC. The results obtained confirmed the expected mRNA maturation defect and highlighted a set of candidate genes that could be the most significant contributors to the TALS phenotype. Some of these genes encode proteins of the primary cilium, a surface organelle important for neurodevelopment. After confirming the involvement of candidate genes, the longer-term prospects of this study will be to develop therapeutic approaches targeting the identified candidate genes, with a view to improving patients' quality of life. | GenOmics 2021 | |
| 2022 | Sandrine VUILLAUMIER-BARROT | Paris | Foundation For Rare Diseases | congenital disorder of glycosylation | Research of homozygous variant in 5' or 3'UTR ALG12 region or cis regulating elements by whole genome for one ALG12-CDG suspected patient | - | GenOmics 2021 | ||
| 2022 | Stéphane VIVILLE | Strasbourg | Foundation For Rare Diseases | Infertility Male infertility Azoospermia Non-obstructive azoospermia | Deciphering genetic causes of non-obstructive azoospermia via exome sequencing; a way to personalize treatments and to develop new diagnostic tools. | - | Non-obstructive azoospermia (NOA) is the most serious and common cause of male infertility. It is defined as the absence of sperm in the ejaculate, with no obstruction in the delivery system. Based on family studies, it is believed that most men with NOA have a genetic etiology. We recruited six consanguineous families with at least one man with NOA, diagnosed with arrested spermatogenesis or Sertoli-only cells. We applied whole-exome sequencing to 24 pooled samples, including infertile men, parents, and siblings, to identify the causal genetic variant. The analysis enabled us to identify two new genes responsible for NOA, RAD51AP2 and C11orf80 (TOP6BL). These new genes have been added to our panel of genes used for the genetic diagnosis of male infertility in our clinical practice. | GenOmics 2021 | |
| 2022 | Xavier PUECHAL | Paris | Foundation For Rare Diseases | Whipple disease | Deciphering genetic and molecular bases of Whipple disease | - | Collaboration between teams at Cochin Hospital and Imagine at Necker Hospital, and the creation of cohorts of patients with Whipple's disease, a severe chronic infectious disease caused by an inability to defend against a common bacterium, has revealed a very rare variant involved in anti-infectious defense in some patients. The presence of this very rare variant has also been confirmed in another independent cohort. The mechanisms linking these variants and the inability to defend against the bacteria in question are currently being analyzed. Understanding these mechanisms will enable earlier diagnosis of this rare but potentially fatal disease in the absence of appropriate antibiotic treatment. | GenOmics 2021 | |
| 2022 | Barbara BARDONI | Valbonne | Foundation For Rare Diseases | Fragile X Syndrome Autism Spectrum Disorder Intellectual disability | Identification of drug candidates to treat the Fragile X Syndrome | Fragile X syndrome (FXS) is a rare disorder (ORPHA908) (1/4000 males and 1/7000 females). The syndrome is characterized by intellectual disability of varying severity, facial dysmorphia and macro-orchidism in males. However, patients may also present behavioral disorders (hyperactivity, autistic behavior), language delay, sleep disorders and epileptic seizures. Today, FXS is also considered the most common form of hereditary autism spectrum disorder. The syndrome is due to the absence of the FMRP protein, an RNA-binding protein thought to be involved in controlling the translation of proteins involved in nervous system development. No specific therapy is currently available to treat this disease. There is therefore a need to identify new drugs for this disease that can act singularly or in combination with other drugs, so that they can be administered to patients at different stages of their lives and thus alter the trajectory of this very serious disease. To this end, we have generated a model cell line for the disease. We have already used this cell line to screen a collection of drugs, and have identified a drug - SM4 - which has the capacity to improve the altered morphology of the cells in the model line. Moreover, administration of this drug to mice - which are FXS models - improves their socio-cognitive deficits. In order to increase the number of molecules that can be used to treat FXS, we are going to carry out a new screening using two new collections of bioactive molecules with the same strategy that already gave positive results in the first screening. From a molecular point of view, it has been shown that other forms of intellectual disability and/or autism spectrum disorders share the same abnormalities as FXS. For this reason, it may be hypothesized that drugs developed to treat FXS could subsequently also be used successfully to treat other diseases characterized by intellectual disability and/or autism spectrum disorder. | High throughput screening / Hit to lead 2021 | ||
| 2022 | Cécile VOISSET | Brest | Foundation For Rare Diseases | Creutzfeldt-Jakob disease (CJD) Gerstmann-Sträussler-Scheinker (GSS) syndrome Fatal familial insomnia (FFI) | Identification and structural optimization of novel first-in-class anti-prion compounds | Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia are rare neurodegenerative diseases known as spongiform encephalopathies. Creutzfeldt-Jakob disease (CJD) affects one person per million population per year, or 100 to 150 cases per year in France. The first symptoms of CJD are often non-specific, such as depression or anxiety. This is followed by problems with memory, orientation and language. This dementing syndrome is progressively associated with involuntary muscle spasms, disturbances of balance or vision, tremors and epileptic seizures. CJD is the only human disease that can be either sporadic (80%), genetic (15%) or acquired through contamination (<5%). Les cas sporadiques apparaissent en moyenne vers l'âge de 60 à 65 ans. Le syndrome de Gerstmann–Sträussler–Scheinker touche entre 1 à 10 personnes pour 100 000 000. Ce syndrome est d’origine génétique. L'insomnie familiale, qui a une prévalence <1 >
Using an original screening method based on [PSI+] and [URE3] prions from the baker's yeast S. cerevisiae, we have in the past identified several compounds active against prions from drug libraries with marketing authorization. Most of the anti-prion drugs identified by this approach were found to be active against the mammalian prion PrPSc in different cell models, and also in vivo in a mouse model of prion disease. These results indicate that yeast prions are good models for identifying compounds active against the PrPSc prion affecting humans. The screening strategy proposed by C. Voisset's group (Brest Faculty of Medicine) involves testing the ability of the 3,800 molecules in the JUNIA's library to eliminate yeast prions. Molecules capable of eliminating prions from yeast will then be tested for their ability to eliminate the PrPSc prion. The most promising anti-prion molecules thus identified will then be modified by A. Ghinet's team of chemists (JUNIA Grande Ecole d'Ingénieurs, Lille) to improve their activity. The proposed screening program will make it possible to identify new anti-prion compounds and thus new therapeutic avenues for patients suffering from prion diseases for which no therapeutic solution is currently available. | Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia are rare neurodegenerative diseases known as spongiform encephalopathies. Creutzfeldt-Jakob disease (CJD) affects one person per million population per year, or 100 to 150 cases per year in France. The first symptoms of CJD are often non-specific, such as depression or anxiety. This is followed by problems with memory, orientation and language. This dementing syndrome is progressively associated with involuntary muscle spasms, disturbances of balance or vision, tremors and epileptic seizures. CJD is the only human disease that can be either sporadic (80%), genetic (15%) or acquired through contamination (<5%). Les cas sporadiques apparaissent en moyenne vers l'âge de 60 à 65 ans. L'insomnie familiale, qui a une prévalence <1 >
C. Voisset's group (Brest Faculty of Medicine) has previously identified several compounds that are active against prions. The PRiCOM project, funded by the Rare Diseases Foundation, tested 2,110 molecules from the JUNIA molecule bank of A. Ghinet's team of chemists (JUNIA Grande Ecole d'Ingénieurs, Lille) in order to improve their activity. Three original molecules capable of eliminating prions were identified during this project. The structure of these three molecules will be modified by A. Ghinet's team of chemists (PRiCOM2 project funded by the Rare Diseases Foundation in 2024) in order to improve their effectiveness against prions. This research program has therefore identified new anti-prion compounds that will serve as the basis for the development of new drug candidates for patients with prion diseases for which no therapeutic solution is currently available. | High throughput screening / Hit to lead 2021 | |
| 2022 | Izabela SUMARA | Illkirch | Foundation For Rare Diseases | Fragile X syndrome | Therapeutic dissolution of aberrant nucleoporin condensation in Fragile X syndrome using small molecule inhibitors | Nuclear pores (NPs) are the only gateways between nucleus and cytoplasm, ensuring cell function and survival. We have discovered a novel pathway by which FMRP directs the spatial assembly of nucleoporins at the nuclear envelope to form functional NPs. In the absence of FMRP, nucleoporins assemble aberrantly in the cytoplasm into aggregate-like structures, and the transport function of NPs is disrupted. Models of the rare disease fragile X syndrome (FXS), in which FMRP is absent, show the same nucleoporin aggregates, suggesting that these defects may contribute to the pathology of this disease. FXS is the most common form of hereditary mental retardation, for which there is currently no treatment. We hope our results will create a basis for the future development of new gene therapy strategies to cure this disease. | High throughput screening / Hit to lead 2021 | ||
| 2022 | Mahel ZEGHOUF | Saclay | Foundation For Rare Diseases | X-linked non-syndromic intellectual disability (ORPHA:777) IQSEC2-related syndromic intellectual disability (ORPHA:397933) | High Throughput Screening of IQSEC2 activity modulators: towards new pharmacotherapeutic approaches in X-linked intellectual disability (SCREENXLID) | X-linked intellectual disabilities (XLIDs) are a heterogeneous group of over 200 rare disorders that share the common feature of varying degrees of intellectual impairment associated with impaired adaptive behaviors, and manifest in childhood, predominantly in boys. More than 70 different mutations in the IQSEC2 gene have been associated with multiple XLIDs with associated symptoms such as epilepsy and autism. These mutations result in the loss of the IQSEC2 protein or the production of deregulated forms, whose activity is either increased or decreased. A major challenge in treating these diseases is to discover molecules that target the defective proteins precisely and effectively. Such molecules are sorely lacking both in basic research as tools to better understand the biological function of IQSEC2 during brain development, and as starting points for the development of new therapies. For this, a sensitive, robust and miniaturized assay is needed to efficiently test a large number of compounds. We are able to reconstitute the activity of the IQSEC2 protein on artificial membranes which mimic those of cells. Introducing membranes into the assay is an original approach, as it reproduces as closely as possible the conditions required for the protein to function properly in the cell. To observe the activity of the IQSEC2 protein, we look at changes in the fluorescence of its target Arf, a light emission that increases when it changes shape following activation. Fluorescence has the advantage of being highly sensitive, enabling precise quantification of this activation over time. Our initial results indicate that the miniaturization of this assay on an artificial membrane is possible, an essential step if we are to be able to test a large number of chemical compounds. The aim of the SCREENXLID project is to automate this assay in miniaturized form in order to screen a library of around 10,000 natural or chemical compounds. Compounds capable of modifying IQSEC2 activity will be ranked according to their efficacy and subjected to a second, more robust screening for validation. We will select compounds capable of either increasing or decreasing IQSEC2 activity. The best candidates will be selected on the basis of their physico-chemical properties, which will enable us to predict potential toxicity, administration possibilities and future optimization. The SCREENXLID project will discover small molecules capable of modifying the activity of the IQSEC2 protein, either by acting directly on its activity or on its ability to bind to the membrane, a binding essential for its activity. Such molecules will be powerful tools for better understanding how IQSEC2 functions, and for explaining defective mechanisms in XLID-associated mutants. Their detailed characterization in cellular and animal models will open up new prospects for the development of personalized therapeutic strategies, bringing help and hope to affected children and their families. | High throughput screening / Hit to lead 2021 | ||
| 2022 | Marco PONTOGLIO | Paris | Foundation For Rare Diseases | HNF1B-Cakut (Congenital abnormalities of the Kidney and the Urogenital tract HNF1B-ADTKD (Autosomal Dominant Tubulo-Interstitial Kidney Disease) | A pharmacological therapy for HNF1B-deficiency | Chronic kidney disease (CKD) is characterized by the progressive decline of renal function towards end-stage renal failure. Some rare forms of CKD are caused by mutations in a gene called "Hepatocyte Nuclear Factor 1 beta" HNF1B, which codes for a nuclear protein that plays an important role in the expression of many kidney genes. Patients with mutations in this gene develop renal failure, which can be severe. There is currently no pharmacological treatment available for these patients, who often end up needing dialysis or transplantation. An important feature is that these patients are heterozygous for mutations that nullify HNF1B activity. Interestingly, these patients still carry a wild-type allele for HNF1B. We believe that in these patients there is a haploinsufficiency that will result in insufficient biological activity of HNF1B. This raises the possibility that a pharmacological treatment capable of stimulating residual activity in these patients could play a beneficial role in the treatment of the disease. The aim of this research project is therefore to validate the use of certain chemical compounds which have been shown to increase HNF1B transcriptional activity. To do this, we have a mouse model that is deficient in HNF1B, which will enable us to validate our compounds. | Certain transcription factors specifically expressed in the kidneys play a crucial role in the development and functioning of this organ. Mutations leading to reduced activity (haploinsufficiency) can cause significant congenital and postnatal disorders, particularly affecting renal development. Our recent findings challenge the traditional idea that certain transcription factors are always constitutively active in regulating gene expression. We have discovered that their activity can be increased by specific chemical compounds, suggesting that they require activation to reach their full potential. This perspective opens up new therapeutic possibilities for diseases caused by haploinsufficiency of these essential transcription factors. | High throughput screening / Hit to lead 2021 | |
| 2022 | Alban BARUTEAU | Nantes | IRCEM Corporate Foundation | Cardiovascular diseases | OSCAR: Outil de Suivi CARdiop diatrique domicile | - | Affecting 12 million people worldwide, heart defects are the leading cause of congenital malformations (1% of births, 7,400 births/year in France), a major cause of morbidity and mortality in childhood, and a considerable drain on healthcare resources. In cases of heart surgery in the first month of life, the newborn who has undergone surgery usually returns home around the seventh postoperative day with postoperative monitoring, the procedures for which are standardized across all centers in the M3C national network. It has been shown that the first six months after surgery are a high-risk period for this vulnerable patient population, both for the newborn (major cardiovascular events, 20% morbidity and mortality in specialist centers) and for both parents (post-traumatic stress disorder in 20% of cases). This situation is exacerbated by significant regional disparities in the provision of pediatric cardiology care and, consequently, significant inequalities in access to care in the event of postoperative complications for these newborns who have undergone surgery. A home monitoring program combined with standard follow-up has shown very promising results in Anglo-Saxon countries, although the level of evidence in published studies is relatively low. In France, there is no similar program due to a lack of resources. The OSCAR clinical research project is a type 1, pragmatic, multicenter, national, hybrid randomized controlled trial of superiority, which aims to evaluate the impact on the reduction of cardiovascular morbidity and mortality at 6 months of home monitoring combined with standard postoperative follow-up after neonatal cardiac surgery. This study has the potential to significantly improve the performance of the healthcare system by improving its efficiency, the quality of care and the quality of life of newborns who have undergone surgery and their parents, and by reducing its cost and inequalities in access to care across the country. | Outside AAP | |
| 2022 | Damien BREZULIER | Rennes | Groupama Loire Bretagne | Connective tissue disorders | Validation of a porcine model of bone defects in growth sites for reconstruction | - | In France, the incidence of lip and palate clefts is 1 per 2,000 to 5,000 births. Their management requires several stages of surgical repair. Secondary alveolar bone grafting (SABG) concerns children undergoing craniofacial growth, between the ages of 5 and 7. Although biomaterials are used in adult bone reconstruction, their use in cleft repair remains uncommon. Yet they would make it possible to do away with the need for iliac harvesting, with its many complications. What's more, the improvement of biomaterials must be confronted with a limited number of animal models capable of transcribing the particularities of a graft in a site undergoing craniofacial growth. The aim was to validate a large animal (porcine) model dedicated to the evaluation of bone substitute biomaterials for SABGs performed during craniofacial growth, via in-vivo implantation of conventional materials and new biomaterials shaped by 3D printing. This study provides proof of concept that implantation in the mandibular area, close to the dental germ, is possible, and that it is also possible to monitor bone formation around the implanted materials using X-ray techniques, histological sectioning, and tissue staining. These results confirm the validity of the model developed here. | Outside AAP | |
| 2022 | Gaëlle BOUGEARD | Villejuif | Patron of the Rare Diseases Foundation | Li-Fraumeni syndrome | Technological innovation for improved management and treatment of Li-Fraumeni syndrome | - | Outside AAP | ||
| 2022 | Guillaume CANAUD | Paris | IRCEM Corporate Foundation | Hypergrowth syndromes | PIK3CA is the therapeutic target of choice for vascular malformations associated with mutations in the RAS pathway | - | An arteriovenous malformation is an abnormal connection between arteries and veins. The capillary network that normally exists between these arteries and veins is absent and replaced by a completely disorganized network. Malformations can affect the brain or peripheral parts of the body, and can be isolated or complex. They are accompanied by pain, disability, bleeding, and can sometimes be life-threatening. In the vast majority of cases, they are caused by genetic mutations located in the tissues. Thanks to the funding obtained, we were able to create preclinical models that recapitulate the same abnormalities as those seen in patients. These models have given us a better understanding of how these abnormalities develop and progress. We then identified a molecule authorized for another indication as being very promising and demonstrated its effectiveness in the various models. The funding has therefore enabled us to make significant advances in terms of understanding the disease and therapeutic prospects. The next step will be a clinical trial in this new indication. | Outside AAP | |
| 2022 | Hamid-Reza REZVANI | Bordeaux | International Order of Anysetiers | Dermatological diseases | Modelling of pigmentary abnormalities in xeroderma pigmentosum type c (XPC) | - | Xeroderma pigmentosum is a rare genetic disorder characterized by a defect in DNA repair, resulting from a malfunction of XP proteins, which leads to the development of cancers, particularly skin cancers. The first signs of the disease are pigmentation disorders and dry skin, hence the name xeroderma pigmentosum (XP). Patients cannot be exposed to ultraviolet light, particularly sunlight, and require enhanced protection (protective creams and clothing, domestic UV screens). They are known as "children of the moon." To date, there is no treatment for this disease. While the role of XP proteins in DNA repair is well known, their role in skin physiology is not. XP patients have dry skin and hypo- and hyperpigmentation disorders. Such disorders are found in other rare diseases such as Cole's disease and Chediak Higashi syndrome, or in less rare diseases such as senile lentigo or systemic scleroderma, a very harmful disease. Our objective is to identify the factors involved in the early onset of these hyper- and hypopigmentation disorders, which occur in areas where skin cancers develop. Our study focuses more specifically on XPC, which is the most carcinogenic form in the Caucasian population. A mammalian model routinely used in the laboratory is based on chronic irradiation of mice, which mimics the onset of cancer in humans. Despite the significant data obtained using this model, it takes a long time to set up (4-6 months) and has limitations, as it only imperfectly reproduces the pathophysiology of melanocytes (cells that produce melanin, the pigment in the skin). To carry out our study, we proposed using the Xenopus amphibian embryo as an alternative and complementary model to the mammalian model. Melanocytes and pigment phenotypes are easily analyzable in this model. Our results indicate that this embryo is a highly relevant model for studying the effects of UV radiation on melanocyte homeostasis (proliferation, apoptosis, and migration). We are evaluating the response to UV radiation in terms of pigmentation in XPC-deficient embryos. This project is highly innovative. It lays the foundations for future studies aimed at defining the cellular and molecular mechanisms involved in the pathophysiology of melanocytes in response to UV radiation. In this sense, it should provide a better understanding of the role of XPC in the response of melanocytes to UV exposure and enable the identification of therapeutic targets to prevent the appearance of hypo- and hyperpigmented areas that appear early in XPC patients in tumor development areas. | Outside AAP | |
| 2022 | Lucile SESE | Paris | OXYVIE | Pulmonary rare diseases | Role of socio-economic and environmental factors on the natural history of idiopathic pulmonary fibrosis: EXPOSOMFPI | - | Outside AAP | ||
| 2022 | Régis GIET | Rennes | Groupama Loire Bretagne | Rare infantile epileptic and developmental encephalopathy | Functional study of TACC1, a new gene involved in a rare form of infantile Epileptic and Developmental Encephalopathy | - | Epileptic and developmental encephalopathies (EEDs) are a group of severe childhood epilepsies. These diseases are characterized by abnormal brain development associated with frequent epileptic seizures. The identification of a new gene responsible for an EED therefore represents an important advance that provides a better understanding of the cellular mechanisms that cause the disease, informs families about the risk of recurrence, and ultimately allows them to consider participating in clinical trials. An international collaboration has led to the discovery of a new gene involved in an EED in an American family and a French family from the Grand Ouest region, whose affected children have an EED that is resistant to commonly used therapies. We propose to examine the role of this new gene (TACC1) using cellular and molecular approaches combined with high-resolution microscopy. These studies will provide a better understanding of the defective cellular mechanisms in these two families of patients and, in the longer term, enable us to consider alternative therapeutic approaches. | Outside AAP | |
| 2022 | Anne-Cécile REYMANN | Strasbourg | Foundation For Rare Diseases | Rare neurological diseases, Other rare diseases | CRISPR targeted mutagenesis of C. elegans actin: novel insights into the understanding of human non-muscle actinopathies | With a team of scientists, we are deciphering the fundamental mechanisms behind the symptoms in relation to spontaneous de novo genetic variations in an essential cytoskeletal gene, actin, corresponding to the rare disease known as non-muscular actinopathies. My team is specifically using the model organism C. elegans, a soil nematode a few millimetres long, to reproduce the same variants found in some patients in order to explore the consequences at different scales in a simpler living model system but with an almost identical set of cytoskeletal proteins. Data obtained from experiments at several scales - molecular, cellular, organism, patient - are compared to better characterize the mechanisms leading to pathological conditions and the causes of symptoms in humans. Our ultimate goal is to lay the foundations for future clinical studies and provide widely applicable functional tests for establishing genotype-phenotype correlations. | Models 2022 | ||
| 2022 | David HICKS | Strasbourg | Foundation For Rare Diseases | Sensory disorders (rare eye diseases and deafness) | Creation of a diurnal rodent model of Stargardts Disease STGD1 | Stargardts disease (SD) is a rare form of progressive blindness that manifests itself in childhood, leading to irreversible loss of sight and suffering. There is no treatment to limit or cure this disease, and existing animal models (mice) do not faithfully reflect human symptoms. Indeed, mice have no macula and few cone photoreceptors, the cell type mainly affected. We propose that diurnal rodents, which have 10 to 15 times more cones than mice, are better models. Recently, we have shown that blocking the SD causal gene, known as abca4, in these animals creates retinal degeneration similar to that in human patients. We aim to extend these results to model different forms of the disease and distribute the animals to other institutes. | Models 2022 | ||
| 2022 | Florian LESAGE | Nice | Foundation For Rare Diseases | Rare neurological diseases, Developmental anomalies and malformation syndromes | Mouse models of human Birk Barel syndrome | Birk-Barel syndrome (BBS) is a rare genetic disorder combining hyperactivity and mental retardation. The 15 mutations identified are all located in KCNK9, one of the rare genes subject to parental imprinting, with only the copy inherited from the mother being active. KCNK9 codes for the TASK3 ion channel. BBS mutations increase or decrease TASK3 activity. We have shown that gene inactivation of TASK3 is associated with learning difficulties and hyperactivity in mice, and that re-expression of the paternal gene by inhibitors of enzymes involved in parental imprinting corrects these symptoms. We propose to prepare mice carrying BBS mutations, either activating or inhibiting, and to verify that these mutations cause BBS symptoms. Once validated, these mice will be used to study disease mechanisms and test new therapeutic strategies adapted to the different mutation types. | Birk-Barel syndrome is a rare neurodevelopmental disorder caused by a genetic alteration in the KCNK9 gene, which codes for the TASK3 potassium channel. Initially identified in an Arab-Israeli family with the causative variant G236R, this syndrome has now been found in European and US patients with 14 other alterations of KCNK9 in 47 people affected by BBS, including the M159I mutation found in a French patient. BBS is characterized by pathophysiological symptoms of varying severity, including mental retardation, hyperactivity, congenital hypotonia, and dysmorphic features with an elongated face. The two mutations G236R and M159I were introduced by the CRISPR Cas9 technique in the mouse genome by the CIPHE platform, creating germline mutations as observed in BBS patients. KCNK9, which codes for TASK3, is one of a small number of paternally imprinted genes where only the maternal allele is transcribed, with no paternal KCNK9 expression. As expected, we found that transmission of the paternal mutated alleles encoding Task3-G236R and M159I had no effect in the mice. However, transmission of the maternal mutated alleles resulted in a very severe phenotype that led to perinatal death of the animals. These results confirm that G236R and M159I are causative mutations. However, the perinatal death of the mutated animals prevented any further characterization. | Models 2022 | |
| 2022 | Justine MASSON | Paris | Foundation For Rare Diseases | Rare neurological diseases | Cortical and cerebellar organoids, new models to study a rare neurodevelopmental disease caused by mutations in the YIF1B gene | The ciliopathies represent a group of rare diseases affecting the brain and caused by dysfunction of a highly specialized cellular organelle, the cilium. Ciliopathies are genetic diseases, and patients carry mutations in genes essential for cilium function. We have identified patients with mutations in a gene encoding an intracellular trafficking protein and suffering from ciliopathic neurological abnormalities. We have demonstrated that loss of function of this protein affects brain anatomy in a mouse model. In addition, we showed that ciliogenesis (the ability of cells to develop a cilium) was abnormal. As the mouse model does not recapitulate all the cerebral alterations observed in patients, our project aims to study the cellular processes affected by the loss of function of this protein by developing cerebral organoids, tiny self-organizing three-dimensional tissue cultures derived from patient stem cells that mimic cerebral structures. | Models 2022 | ||
| 2022 | Matthieu GIRAUD | Nantes | Foundation For Rare Diseases | Rare systemic and autoimmune disorders, Immune deficiency disorders | A new rat model of deficient anterior pituitary gland with variable immune deficiency syndrome by mutation of the NFKB2 gene | The variable immune deficiency-pituitary insufficiency syndrome or DAVID syndrome is a rare genetic disorder combining early common variable immune deficiencies, causing recurrent and severe infections, and later symptomatic endocrine deficiencies, such as pituitary hormone deficiency. Studies have reported that patients with this syndrome have specific mutations in the NF-kB2 gene. We aim to generate a rat model carrying one of these mutations to reproduce the symptoms observed in these patients. This animal model will enable us to study in greater detail the role of pathways involving NF-kB2 in the function of certain immune system populations, in autoimmunity processes and in certain neuro-endocrine functions. Ultimately, this model could be useful for identifying new therapeutic strategies in the context of autoimmune or inflammatory diseases. | Anterior pituitary insufficiency-variable immunodeficiency syndrome, or DAVID syndrome, is a rare genetic disorder that combines early-onset variable immunodeficiencies, causing recurrent and severe infections, with later-onset symptomatic endocrine deficiencies, such as pituitary hormone deficiency. Studies have reported that patients with this syndrome have specific mutations in the NFkB2 gene. We generated a rat model carrying one of these mutations to reproduce the symptoms observed in these patients and to study more precisely the role of NF-kB2 pathways in the function of certain immune system populations, in autoimmunity processes, and in certain neuroendocrine functions. Rats carrying this mutation have a reduced life expectancy, associated with significant immune deficits, such as the absence of lymph nodes, structural abnormalities of the spleen and thymus, an absence of regulatory T cells, and low antibody levels. The endocrine deficiencies observed in patients were not found in these animals. We also did not observe any autoimmune symptoms. This model could be useful for identifying new therapeutic strategies in the context of immune or inflammatory diseases. | Models 2022 | |
| 2022 | Sarah BECK-CORMIER | Nantes | Foundation For Rare Diseases | Rare neurological diseases | Generation of a new mouse model for the rare PFBC disease | Primary cerebral calcification (PCC) is a rare neurological disorder characterized by calcium and phosphate deposits in the blood vessels of the brain. Why these deposits form remains an unanswered question, and there is no treatment to prevent them or cure the disease. However, recent research has uncovered mutations in the genes responsible for this disease. The aim of our project is to understand why and how mutations in these genes induce calcifications. To this end, we aim to create a model for studying the human disease by reproducing in mice the XPR1 gene mutation most frequently found in patients. We will call on the Institut Clinique de la Souris to generate this model. The study of these mice will enable us to elucidate the mechanisms at the origin of MCC and its evolution, and provide leads for the development of new treatments. | - | Models 2022 | |
| 2022 | Stéphanie TRUDEL | Toulouse | Foundation For Rare Diseases | Rare neurological diseases | Generation and characterization of iPSCs from Sanfilippo type B patients fibroblast | Mucopolysaccharidosis type III (MPS III) is a disease in which patients have a defect in the function of lysosomes, which are involved in the degradation of heparan sulfates (HS). HS accumulation is at the root of neurological disorders in these patients. However, the molecular mechanisms underlying neurodegeneration are not yet fully understood. No treatment is available, but clinical trials are underway to deliver the deficient enzyme to the brains of MPS III patients. To carry out research into therapies and pathophysiology, we need good models of the disease. But in the case of MPS IIIB, we are faced with a lack of human models. The aim of this project is to obtain pluripotent stem cells from MPS IIIB patient cells and transform them into brain cells in order to develop new therapies and better understand this disease. | Mucopolysaccharidosis type III (MPS III) is a disease in which patients have a defect in the functioning of lysosomes, which are involved in the degradation of heparan sulfates (HS). The accumulation of HS is responsible for neurological disorders in these patients. However the molecular mechanisms underlying neurodegeneration are not fully elucidated. No treatment is available, but clinical trials are underway to deliver the deficient enzyme to the brains of MPS III patients. To conduct research on therapies and pathophysiology, we need good models of the disease. However, when it comes to MPS IIIB, we are faced with a lack of human models. The aim of this project is to obtain pluripotent stem cells from MPS IIIB patients and transform them into brain cells in order to develop new therapies and better understand this disease. Thanks to this funding, we were able to generate pluripotent stem cells from fibroblasts of MPS IIIB patients with different mutations. These cells were validated by very strict quality controls. | Models 2022 | |
| 2022 | Cécile CONTIN-BORDES | Bordeaux | AFM Telethon | Systemic Sclerosis, Rare systemic and autoimmune disorders | Endothelial cell-induced macrophages efferocytosis alteration during Systemic Sclerosis: mechanistic dissection and new therapeutic intervention to limit fibrosis. | Systemic scleroderma (SSc) is an incurable fibrotic autoimmune disease affecting almost 10,000 people in France. Treating fibrosis in SSc is a major medical challenge. Uncontrolled inflammation promotes deregulation of the tissue repair process and contributes to fibrosis during SSc. Efferocytosis is essential to limit inflammation and promote controlled tissue repair. Our group has shown that platelet-mediated activation of endothelial cells plays a major role in the pathophysiology of SSc. IL-1β-activated endothelial cells promote fibrosis by inducing a cytokine microenvironment capable of differentiating DC-SIGN+ macrophages with pro-inflammatory functions. DC-SIGN+ macrophages have impaired efferocytosis capacity, and the expression of efferocytosis-associated genes is altered in the skin of ScS patients. Our industrial partner has developed an innovative treatment composed of pro-resolving factors produced by efferocytic macrophages capable of controlling inflammation and promoting normal tissue repair. The objectives of this project are (i) to understand the mechanisms by which endothelial cells and platelets alter the efferocytosis capacities of macrophages (ii) to propose innovative treatments aimed at compensating for efferocytosis defects to limit inflammation and fibrosis in ScS. | Systemic scleroderma is a rare, serious, and disabling autoimmune disease that combines vascular damage and fibrosis. To date, there is no treatment that can significantly reduce fibrosis, particularly in the skin. It is therefore important to better understand the complex mechanisms that govern the development of fibrosis and to propose new therapeutic approaches. Thanks to the support of the AFM/Fondation Maladies Rares, we have been able to describe a new pathological pathway contributing to the inflammatory and fibrotic skin processes of systemic scleroderma. It involves complex interactions between vascular cells, cytokines, and macrophages in contact with the vessels. In collaboration with the French start-up MIP, which is developing a new, original and innovative drug candidate using the anti-inflammatory and reparative properties of healthy macrophages, we were able to demonstrate the benefits of its use in limiting fibrosis in animal models of scleroderma, as well as in vitro on patient cells. This work could now enable this new therapeutic approach to be proposed for clinical trials in scleroderma patients. | Therapeutic proofs of concept 2021 | |
| 2022 | David BONNAFE | Orsay | AFM Telethon | Sjögren's Syndrome, Rare systemic and autoimmune disorders | A new way of targeting IFN-g for ocular dryness of primary Sjögren's Syndrome: towards eye-drops of glycomimetics endowed with nanomolar anti-IFN-g activities. | Primary Sjögren's Syndrome (pSS) is a rare autoimmune disease affecting the glandular epithelium, mainly the salivary and lacrimal glands. It leads to dry mouth and eyes, pain and fatigue that severely impact patients' quality of life. Systemic complications occur in 30-50% of patients. To date, there is no validated treatment for systemic pSS, and no specific treatment for dry mouth and dry eyes has been developed to treat dryness syndromes. Experts in the synthesis of cytokine-targeted glycomimetics and clinicians from a pSS reference center propose to combine their expertise and strengths to address this patient need. Based on respective previous work: identification of glycomimetics with nanomolar anti-IFN- g activities in vitro and identification of a deleterious activation loop involving IL-7 and IFN-g as a characteristic dysfunction in pSS, we propose to: i. establish the therapeutic potential, in the context of pSS, of direct targeting of IFN-g by a glycomimetic; ii. improve the potency and selectivity of our anti-IFN-g hit validated in vitro. The physico-chemical properties of the target molecules mean that they can be formulated as eye drops, a significant advantage for subsequent first-line development as a treatment for pSS-associated dry eye syndrome. | Therapeutic proofs of concept 2021 | ||
| 2022 | Isabelle MARTY | La Tronche | AFM Telethon | Neuromuscular disease | Nanoblades as a genome editing tool for neuromuscular disorders | Gene editing is a promising approach for myopathies, particularly those linked to RYR1, as this gene is too large to be inserted into a viral vector as tested in other myopathies. Different strategies are currently used to introduce gene-editing tools into muscle cells and remove a DNA fragment, each with its advantages and disadvantages. The current method of choice uses viral vectors with high transduction efficiency but the disadvantage of importing foreign DNA into the target cell, which can lead to damaging integration into the genome. The aim of this project is to determine the in vitro efficacy of a new method compared with reference viral and non-viral methods, and its potential for improvement for future in vivo use: i) transfer of the CAS9 gene and gRNAs by lentivirus, routinely used at GIN (reference viral method), ii) electroporation of ribonucleoproteins (RNPs) with Cas9 protein and gRNAs, routinely used at INMG (reference non-viral method), iii) transduction of "Nanoblades", viral pseudoparticles loaded with Cas9-gRNA RNPs without any gene transfer, developed at ENS. The project will be carried out using immortalized patient cells previously used to establish the POC of exon skipping efficiency. The function of the corrected protein will be assessed by calcium imaging. | Therapeutic proofs of concept 2021 | ||
| 2022 | Isabelle TALON | Strasbourg | AFM Telethon | Developmental anomalies and malformation syndromes | Pediatric mesh innovation with 3D bioprinting process : the first prosthesis design for children | Several rare childhood diseases are characterized by a defect, such as congenital diaphragmatic hernia, esophageal atresia or giant omphalocele. There is no ideal replacement biomaterial for these rare pathologies, and children may require several major surgeries with high morbidity. Biodegradable prostheses have little place in infants, due to their rapid degradation and lack of sufficient tissue renewal at the end of this resorption. The polytetrafluoroethylene prosthesis currently used for the diaphragm and any other non-absorbable prosthesis do not meet the biomechanical criteria for pediatric implantation with high growth potential. We are working on an already patented biodegradable albumin-based prosthesis (originally designed for other clinical applications) and an electrospun urethane-based synthetic prosthesis specifically designed for children. We are combining these two innovative biomaterials with 3D bioprinting of different cell types to optimize early tissue colonization and, above all, achieve genuine regeneration of the organ and its function. The objectives of this new stage of our research are threefold: - Optimize the architectural characteristics of our prostheses, - Evaluate the impact of printing architecture on colonization, - Find the best ratio between different cell types. | Therapeutic proofs of concept 2021 | ||
| 2022 | Olivier TABARY | Paris | AFM Telethon | Cystic Fibrosis, Other rare diseases | Development of a new microRNA therapeutic approach for the treatment of all patients with Cystic Fibrosis | Cystic fibrosis is the most common hereditary disease in Caucasian populations. It is estimated that around 200 children with cystic fibrosis are born each year in France. The CFTR (Cystic Fibrosis Transmembrane conductance Regulator) gene responsible for the disease codes for the CFTR protein, which regulates chloride ion transport. Respiratory abnormalities are the main cause, but other organs are also affected. Patients benefit from symptomatic treatments and, in recent years, curative therapies that target the CFTR channel. However, there is still an unmet clinical need for therapies for patients with mutations that are not compatible with these drugs, such as class I patients, who account for 10% of patients plus non-responders. Antisense oligonucleotides (ASOs) offer new avenues for the development of personalized treatments for certain hereditary diseases, including cystic fibrosis. We have developed an ASO oligonucleotide TMEM16A which increases the expression and activity of the chloride channel anoctamin 1 (TMEM16A), and which can constitute an alternative channel to CFTR in all cystic fibrosis patients regardless of their mutations. The aim of this project is to test the efficacy of the TMEM16A ASO on cells from patients and mice whose mutation does not allow them to benefit from curative treatments. | This project presents a promising new approach to treating cystic fibrosis, a serious genetic disease that primarily affects the lungs and digestive system. Currently, available treatments often depend on a specific mutation in the CFTR gene, which excludes approximately 15% of patients. In this project, we proposed an alternative solution by activating another protein, which compensates for the defects caused by abnormalities in the cystic fibrosis gene. Using an antisense oligonucleotide (a small modified DNA molecule), we have succeeded in the laboratory in correcting aspects that are dysregulated in cystic fibrosis by improving ion movement and the viscosity of the mucus that accumulates on patients' cells. This has been achieved in patients who are not eligible for current treatments. This method has been successfully tested on human cells as well as on mice with cystic fibrosis, showing a reduction in symptoms, prolonged survival, and improved fertility in males. Tests have also confirmed that this approach is well tolerated and has no major side effects. This breakthrough could offer a new therapeutic option for all patients with cystic fibrosis, regardless of their genetic mutation, and opens up prospects for the treatment of other symptoms associated with this disease. Despite this, issues related to oligonucleotide treatments remain and would require more advanced development. | Therapeutic proofs of concept 2021 | |
| 2022 | Valérie ALLAMAND | Paris | AFM Telethon | Neuromuscular disease, connective tissue disorders | Suppression of premature termination codons by anticodon-edited tRNAs | At least 10% of mutations responsible for human genetic diseases are nonsense mutations, affecting a single base of a gene sequence and creating a premature stop codon (PTC). The presence of a PTC can lead to the synthesis of a shorter protein, often non-functional and deleterious, or to the absence of protein synthesis as transcripts are degraded by nonsense-mediated decay (NMD). The aim of the proposed project is to counteract the effect of nonsense mutations and restore protein synthesis, using modified transfer RNAs (tRNAs). This strategy replaces the PTC with the correct amino acid, without altering the natural stop codons. As the same modified tRNA can correct PTCs in any gene, this approach will benefit a large number of genetic diseases. The project focuses on several rare diseases: neuromuscular (collagen VI and laminin alpha2 related, Duchenne muscular dystrophy, laminopathies), classical Ehlers-Danlos syndromes and a metabolic disease (Pseudoxanthum elasticum). We will evaluate the efficacy of modified tRNAs alone or in combination with NMD inhibitors, in vitro in patient cells, and in vivo in animal models. This project will provide robust proof of concept to propose an innovative therapeutic response for these diseases for which no treatment currently exists. | Therapeutic proofs of concept 2021 | ||
| 2022 | Christine LEAUTE-LABREZE | Bordeaux | Awards - Alnylam Pharmaceuticals | Sturge-Weber syndrome, Dermatological diseases | RNA interference approach targeting the GNAQ gene mutation in vascular anomalies | Our research team has extensive experience in developing innovative therapies for rare skin diseases and vascular anomalies. Our work has led to the filing of 2 patents on the treatment of infantile hemangiomas and the prevention of tumors in "moon children" (Xeroderma Pigmentosum). Since the discovery of the efficacy of propranolol in Bordeaux by Dr Christine Léauté-Labrèze, the treatment has been validated in many countries around the world, enabling the successful treatment of severe infantile hemangiomas. Today, with the Centre de Référence des maladies rares de la peau, we wish to invest in an unresolved issue - the treatment of vascular anomalies of genetic origin, such as angiomas planus - and propose an innovative therapeutic approach that targets the mutations present in the diseased zone visually delimited by the angioma. To ensure that this treatment targets the diseased cells without affecting other skin cells, we will develop an interfering RNA approach. This is the approach that holds the greatest therapeutic promise for these sometimes disfiguring diseases, with a major impact on patients for whom no satisfactory solution exists. | RNA interference technology is regularly used in research to inhibit the effects of a gene. Today, this technology makes it possible to target the gene responsible for a disease in a patient, when the affected area is accessible. We therefore propose to target the mutated GNAQ gene, which is causal in certain proliferative flat angiomas. The choice of sequence for this small RNA is crucial to the effectiveness of the approach, as it must not have a significant effect on the healthy gene also present in the patient's cells (heterozygous). Proof-of-concept work is needed on human cells in culture. We have selected one small RNA from among 19, and are testing its potential therapeutic effect in vitro. | Alnylam Pharmaceuticals 2022 Award | |
| 2022 | Nicolas PENEL | Lille | APICIL Foundation | Rare cancers | Prospective clinico-biological database of desmoid tumors | Desmoid tumors (ORPHA:873) are rare benign tumors (less than 400 cases/year in France), diagnosed around the age of 40 and affecting women 4 times more frequently than men. They can appear under the skin, on the abdomen, arms, legs, chest, neck or deeper in the belly. These tumors present 2 important clinical characteristics: their evolution cannot be predicted, and they are painful. ALTITUDES is a prospective clinico-biological database that has included 630 patients with incidental cases of desmoid tumors. Recruitment has been completed and we are now starting the various sub-projects. In this study, we prospectively collected pain (visual analog scale), quality of life (QLQ-c30), anxiety/depression (HADS), employment status, marital status and income at inclusion (diagnosis), on an annual basis and in the event of a tumor event (relapse, progression, etc.). The ALTITUDES_TR2 project has 4 objectives, aimed at estimating the frequency of pain, identifying associated factors, assessing whether pain is associated with a higher risk of disease relapse/progression, and comparing the outcome of pain and non-pain patients. This is an ancillary and exploratory project (ALTITUDES_TR2) in the human and social sciences of the ALTITUDES study. | - | Fondation APICIL 2022 Prize | |
| 2022 | Daniel Loïc POULIQUEN | Angers | Association (AMARAPE) | Rare cancers | Biomarkers of invasiveness in diffuse malignant peritoneal mesothelioma, identification of potential tumor microenvironment/cancer cell crosstalk targets. | The aim of this project is to identify proteomic biomarkers for diffuse peritoneal mesothelioma in order to differentiate it from other benign mesothelial proliferations and peritoneal carcinomatosis. To achieve this objective, we intend to use around fifteen blocks of tumor/tissue fixed and embedded in paraffin from patients for each of these three types of pathology, listed in biobanks and with the assistance and expertise of the RENAPE and BIG-RENAPE networks. Thick sections of these 45 blocks will be processed for quantitative proteomic analysis based on the highly effective SWATH-MS technique, which our laboratory has specialized in over the last few years, applying this technique to the biological study of malignant mesothelioma in experimental models. We believe we can detect approximately 3,000 proteins in each type of sample, from which the files will be cross-referenced for differential analysis. Lists of proteins corresponding to differences in abundance between the three groups and satisfying the condition p < 0.05 will then be established, and those corresponding to the most significant variations and the most relevant biological functions will be the subject of further investigations in immunohistochemistry. Within the first cohort corresponding to diffuse malignant mesothelioma, cases that are particularly invasive and associated with a poor prognosis (involving, in particular, epithelial-mesenchymal transition, EMT) will be subject to additional differential analysis, in line with our previously published data. The ultimate goal is to cross-reference the clinical data obtained with our previous experimental results in order to identify therapeutic targets of common interest to both approaches, particularly those related to interactions between the tumor microenvironment and cancer cells. This study could help open up multiple perspectives, both for diagnosis, prognosis, and treatment adaptation, to improve patient care. This study could help open up multiple perspectives, both for diagnosis, prognosis, and treatment adaptation, to improve patient care. This study could help open up multiple perspectives, both for diagnosis, prognosis, and treatment adaptation, to improve patient care. This study could help open up multiple perspectives, both for diagnosis, prognosis, and treatment adaptation, to improve patient care. This study could help open up multiple perspectives, both for diagnosis, prognosis, and treatment adaptation, to improve patient care. This study could help open up multiple perspectives, both for diagnosis, prognosis, and treatment adaptation, to improve patient care. This study could help open up multiple perspectives, both for diagnosis, prognosis, and treatment adaptation, to | Spouse with association | ||
| 2022 | Abdelkader TAIBI | Limoges | Association (AMARAPE) | Rare cancers | Validation of PROs and PREMs questionnaires for patients with peritoneal cancer disease. COMETE II project. BigRenape Group | Quality of life (QoL) plays an important role in patients with peritoneal metastases or primary peritoneal cancer ( peritoneum, PCP). These patients often have a poor QoL from the outset due to the advanced stage of the disease, which can deteriorate further as a result of treatment. High-quality cancer care requires patients to provide information about their feelings/experiences, symptoms, and the effects of chemotherapy or surgery (Patient Reported Outcomes (PRO), PREMs (Patients Reported Experience Measures). Taking PROs and PREMs into account during cancer treatment can improve QoL and patient survival. However, unlike other metastatic sites, the medical community had no specific PRO or PREM questionnaires to assess how patients with PCP felt. To address this issue, between 2020 and 2022, we carried out the COMETE project (Ligue contre le cancer, Bigrenape), which aimed to develop PRO and PREMS questionnaires specific to peritoneal cancer. This was a Franco-Swiss consensus between previously trained patient partners (PELOPS Project) and specialist doctors (oncologists, surgeons, palliative care doctors), which ultimately led to the selection of 8 PROS items and 9 PREMS items. The objective of this COMETE 2 study is to validate these two new PROS and PREMS questionnaires on a population of patients with PCP in real-life situations, and to conduct a parallel qualitative study in the form of semi-structured interviews conducted by a trio consisting of a psychologist, a patient partner, and a health coach. | Spouse with association | ||
| 2022 | Betty GARDIE | Nantes | Associative (VHL) | Von Hippel-Lindau disease | Modeling VHL hemangioblastomas using patient-derived induced pluripotent stem cells | Von Hippel-Lindau disease (VHL) is characterized by the development of multiple benign and malignant tumors richly vascularized in many tissues: hemangioblastomas of the central nervous system (CNS) and retina, renal carcinomas, pheochromocytomas, and neuroendocrine tumors of the pancreas. This disease is caused by mutations in the VHL tumor suppressor gene, which plays a major role in the pathway of adaptation to oxygen deprivation (cell survival, production of red blood cells and blood vessels). It should be noted that certain VHL mutations predispose individuals to the development of polycythemia (overproduction of red blood cells). VHL disease has been studied for decades, but several key questions remain unanswered, particularly regarding the type(s) of cells involved in VHL-associated pathologies. For example, why, when all of a patient's cells carry an inherited VHL mutation, do tumors only develop in certain organs? Why do hemangioblastomas, which are tumors of the blood vessels , appear along the spinal cord? Is there a cell type common to all VHL tumors and polycythemias that could be a single therapeutic target? Here, we hypothesize that all VHL-related diseases result from a single cell type with a common embryonic origin: neural crest cells (NCCs) that migrate along the spinal cord during development and colonize the organs where VHL tumors arise (retina, inner ear, CNS, kidney, adrenal glands, pancreas). The project aims to create a cellular model of VHL disease using these NCS, and more specifically a model of hemangioblastomas, one of the most difficult VHL tumors to study. To do this, we will use an innovative method , namely induced pluripotent stem cells (iPSCs), reprogrammed from blood cells of VHL patients, which will then be cultured to become CCNs. We will characterize these cells, study their intrinsic tumor properties, and also examine the impact of their secreted factors on the formation of the vessels that cause hemangioblastomas. In particular, we will study their effect on vascular cells from VHL patients obtained using iPSCs. We will thus reproduce, for the first time, a unique model of VHL hemangioblastoma, which will be invaluable in identifying new biomarkers and therapeutic targets . | Spouse with association | ||
| 2021 | Alessandro PRIGIONE | Dusseldorf | Associative (AAP AMMi) | Rare neurological diseases | Modeling Leigh syndrome caused by MTFMT mutations using patient- specific neuronal cells | Leigh syndrome (LS) is a rare neurological disorder and the most severe manifestation of mitochondrial disease in children. The disease is caused by mutations in genes associated with the function of the mitochondrial respiratory chain, which is responsible for energy production in cells. Mutations in the MTFMT gene (mitochondrial methionyl-tRNA formyltransferase ) have been associated with LS. MTFMT deficiency has been found to impair mitochondrial protein synthesis, leading to energy defects. The mechanisms by which these defects specifically cause neuronal cell death in patients remain to be studied, as there is a lack of cellular and animal models for MTFMT. We propose to generate induced pluripotent stem cells (iPSCs) from patients carrying MTFMT mutations. We will then differentiate the iPSCs using two approaches: i) conventional neuronal differentiation, ii) brain organoids. Brain organoids are three-dimensional structures that recapitulate the main features of the developing human brain. We aim to uncover the important mechanisms underlying the neuronal pathology caused by MTFMT mutations. Our project Governance and protection of your data. You have the right to access, correct, and object to your data, which you can exercise by contacting the DPO Reference at contact@fondation-maladiesrares.com. could help identify therapeutic targets for LS, which is a rare pediatric disease with very unmet medical needs. | Spouse with association | ||
| 2021 | Amedée RENAND | Nantes | Associative (ALBI) | Rare hepato-gastroenterological diseases | Direct effect of steroid hormone pathways on pathogenic T lymphocytes in autoimmune liver diseases. | - | Autoimmune liver diseases are rare but can be serious. A better understanding of the immune cells involved is crucial for developing new treatments. This study focused on CD4 T cells specific to an autoantigen called Soluble Liver Antigen (SLA) in patients with autoimmune hepatitis with anti-SLA autoantibodies—a more severe form of the disease. Using cutting-edge techniques such as single-cell RNA sequencing, the researchers were able to analyze the detailed molecular profile of these auto-reactive CD4 T cells taken directly from the patients' blood. They compared their gene expression to that of other SLA-nonspecific CD4 T cells from the same patients. Remarkably, a gene expression signature characteristic of auto-reactive CD4 T cells was observed in a conserved manner in all samples, even in the absence of ex vivo restimulation by SLA. This discovery paves the way for the identification of new therapeutic targets to specifically treat these deleterious cells in severe autoimmune hepatitis. | Spouse with association | |
| 2021 | David MICHONNEAU | Paris | Associative (HPN) | Rare non-malignant hematological diseases | Understanding the mechanisms of operational tolerance after hematopoietic stem cell allograft | - | Spouse with association | ||
| 2021 | Guy LENAERS | Angers | Associative (AAP AMMi) | Rare neurological diseases | A pharmacological approach of the Leigh syndrome related to MTFMT recessive variants | Leigh syndrome is a serious neurological disorder linked to mitochondrial (mt) dysfunction, caused by variants in numerous genes, including MTFMT. MTFMT codes for mt methionyl-tRNA formyltransferase, which is necessary for the efficient initiation of translation of mt mRNAs. In fact, MTFMT variants and deletion affect the synthesis of respiratory complex subunits encoded by mt, as well as the assembly of each complex and supercomplexes , leading to a decrease in oxidative phosphorylation. We propose to test three different approaches on two fibroblast cell lines from patients with biallelic variants in MTFMT, each with a strong rationale for hypothesizing that they may improve mitochondrial physiology through different pathways, possibly in a complementary manner: - one is associated with a compound that we have identified as an activator of mitochondrial respiration , - the second is taurine, one of whose properties is to stimulate mitochondrial translation and protein conformation , - the third is vitamin B9, which could potentially promote formylation activity within the mitochondria . The three compounds will be tested individually or in combination on the mitochondrial physiology (6 evaluation criteria) of two lines of fibroblasts mutated in MTFMT and four control fibroblast lines. It should be noted that these three compounds are directly eligible for a clinical trial on patients. The three compounds will be tested individually or in combination on the mitochondrial physiology (6 evaluation criteria) of two lines of fibroblasts mutated in MTFMT and four control fibroblast lines. It should be noted that these three compounds are directly eligible for a clinical trial on patients. | - | Spouse with association | |
| 2021 | Hélène DOLLFUS | Strasbourg | Associative (BBS) | Sensory disorders (rare eye diseases and deafness) | Development of innovative therapies to treat retinopathy pigmentosa associated with Bardet-Biedl Syndrome (collab. Deniz Dalkara) | - | Spouse with association | ||
| 2021 | Ingrid BANOVIC | Rouen | Associative (AAP HPN) | Rare non-malignant hematological diseases | Chronic Fatigue and Cognitive Functioning in Patients with HPN and AM | While fatigue is known to have a significant impact on the quality of life of patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) or Medullary Atrophy (MA), few studies have sought to investigate the specific manifestations of this chronic fatigue. Furthermore, while fatigue is known to affect individuals' cognitive functioning, few studies have highlighted the nature and severity of cognitive impairment in chronic fatigue. The objective of this work is to validate specific scores on the Multidimensional Scale of Chronic Asthenia (EMAC) in patients with HPN or MA. Two studies based on the Stroop paradigm will also be used to study the nature and severity of cognitive deficits in patients suffering from chronic fatigue. Finally, the scores obtained on the EMAC will be linked to those obtained on the Stroop test. This work should provide a better description of chronic fatigue in patients with PNH or MA. It will also provide a tool enabling both patients and caregivers to better understand and describe the different ways in which chronic fatigue manifests itself, thereby making it easier to understand and communicate. Finally, it will provide descriptive data on the degree of fatigue experienced by French patients with HPN and AM. | Spouse with association | ||
| 2021 | Jamila FAIVRE | Villejuif | Associative (ALBI) | Rare hepato-gastroenterological diseases | Immune landscape in human primary sclerosing cholangitis | Chronic inflammatory diseases are characterized by the activation of immune cells in the diseased organ, which create a harmful local microenvironment (inflammatory and fibrotic) and cause/maintain cellular and tissue damage responsible for symptoms of varying severity. In some cases, these diseases can progress to cancer. The project concerns a fibro-inflammatory disease of the bile ducts, primary sclerosing cholangitis (PSC), the cause of which is unknown and the progression unpredictable, preventing the development of effective therapies. As the disease presents in various forms and clinical courses (it is said to be "clinically heterogeneous"), we assume that PBC livers harbor different cellular and immune ecosystems that vary between patients despite the common inflammatory phenotype that characterizes this disease. Our goal is to disentangle the different immune subtypes of PSC in a large cohort of livers from patients who have undergone liver transplantation and to study how different subtypes of infiltrating immune cells may contribute to clinical heterogeneity and tumor development. | Spouse with association | ||
| 2021 | Kevin LE DUC | Lille | Association (APEHDia) | Developmental anomalies and malformation syndromes | Impact of analgesia before intubation and intact cord resuscitation on cardiorespiratory adaptation at birth: study on a CDH newborn lamb's model. | Adaptation at birth and preoperative stabilization of newborns with diaphragmatic hernia are major steps in the care of these babies, as more than 50% of deaths related to this condition occur during the preoperative phase. Intact cord resuscitation is a promising technique that can improve this adaptation; this technique has been tested by our team and is currently being validated through a national randomized multicenter study that we are coordinating. By providing oxygen to the baby during the first minutes of life via the maternal placenta, this technique could also allow us to safely take the time to administer a powerful analgesic to newborns with HCD before performing the intubation that their condition at birth systematically requires. Studies show that intubation itself can have adverse effects on the baby's stress levels and adaptation to birth, and this could be mitigated or eliminated by administering pain relief at birth. The study we wish to conduct aims to evaluate the effect of this approach on the adaptation to birth and the level of stress and discomfort of lambs with diaphragmatic hernia. It will also ensure that there are no side effects associated with this technique. | Spouse with association | ||
| 2021 | Marc BITOUN | Paris | Associative (PACS1) | Developmental anomalies and malformation syndromes | Proof of concept of therapy by allele-specific silencing for the Schuurs-Hoeijmakers Syndrome | - | - | Spouse with association | |
| 2021 | Sandrine CARABEUX | Paris | Associatif (PraderWilli) / IRCEM Corporate Foundation | Developmental anomalies and malformation syndromes | To explore a new mode of social intervention to improve support for people with PWS and other rare and complex disabilities. | - | 1) En pratique : les personnes accompagnées Le dispositif de coordination renforcé expérimenté dans le cadre de la recherche-action Coord+Prader a contribué à la stabilisation et à l’apaisement de 10 PERSONNES parmi les 15 accompagnées. La détermination de la stabilisation et/ou l’apaisement de la situation s'appuie sur un constat général et spontané de l'environnement de la personne. 2) Le dispositif de coordination renforcé Plusieurs raisons nous ont conduit à choisir la dénomination de « dispositif renforcé ». Si le coordonnateur est le seul pilote de l’action au départ, il a pour mission de réunir et mobiliser un collectif d’accompagnement autour de la personne, dont il devra ensuite orchestrer les collaborations. Les termes « dispositif » et « renforcé » se justifient de par la complexité des interactions, la multiplicité des engrenages et la souplesse d’ajustements nécessaire aux variations des besoins. En effet : Le coordonnateur a pour mission de mettre en corrélation de multiples engrenages. Ils appartiennent à différentes familles et sous-familles. Ils sont issus d’environnements différents, et détiennent leur propre culture. Parmi les grandes familles, nous retrouvons notamment : les personnes, les proches, les bénévoles, les institutions, les instances. Elles-mêmes appartiennent à différents champs : sanitaire, médico-social, scolarité,... Le coordonnateur doit intégrer la diversité des sous-systèmes à mettre en articulation et leur spécificité tout en tenant compte d’un grand nombre de paramètres. Parmi ces paramètres nous retrouvons notamment : la réalité des différents acteurs, l’offre du territoire, les besoins spécifiques liés au SPW... Tout au long de l’accompagnement, le coordonnateur devra trouver la juste distance et la juste place. Il devra être soutenant sans prendre la place de celui que l’on soutient. Il devra aussi orchestrer l’articulation de différentes modalités d’accompagnement et d’intensités variables, ajustées aux besoins du moment. Ceci sous-tend une réévaluation permanente et une vigilance accrue pour ne pas être dans le trop, ni dans le trop peu. Pour mener à bien ses missions, le coordonnateur doit tenir compte d’une multiplicité de facteurs en mouvement. 3) Rôles et missions du coordonnateur de dispositif renforcé Le rôle occupé par le coordonnateur de dispositif renforcé évolue dans le temps. Il évolue avec le processus du dispositif. Nous pouvons distinguer 2 PHASES. Pour chacune d’elles, le coordonnateur de dispositif renforcé occupe des rôles et missions spécifiques. Une exploration préalable des besoins de la personne et de ses proches, associée à une analyse de l’environnement, est inhérente. Phase 1 : À l’entrée dans le dispositif. Situation de rupture de parcours, d’impasse, d’épuisement de l’environnement, ... Rôles du coordonnateur de dispositif renforcé •Etre force de mobilisation et de motivation •Apporter des repères et être garant d’un cadre sécurisant pour l’ensemble du système •Insuffler du positif et du possible Missions du coordonnateur de dispositif renforcé •Créer la relation de confiance et la reconnaissance de la légitimité •Ancrer les relations dans une dimension systémique •Faire émerger le projet de la personne •Instaurer le processus d’autodétermination •Rechercher des pistes d’accompagnement cohérentes avec le projet de la personne •Contribuer à la création d’un collectif d’accompagnement autour de la personne Les rôles du coordonnateur cités en phase 1 perdureront tout au long de l’accompagnement. Phase 2 : Soutenir la mobilisation des acteurs du système. Orchestrer un collectif réuni autour de la situation de la personne. Rôles du coordonnateur de dispositif renforcé •Être garant de la mise en lien et de la circulation de l’information •Être garant du respect de la parole et du processus d’autodétermination •Être facilitateur Missions du coordonnateur de dispositif renforcé •Offrir les conditions pour permettre une posture réflexive •Veiller à la cohérence des actions et la cohésion des acteurs •Veiller à ce que l’ensemble des acteurs du système soit associé à la démarche de co- construction 4) La capitalisation des expérimentations positives Dans le cadre de l’accompagnement proposé, le coordonnateur de dispositif renforcé est témoin de la mise en œuvre de pratiques remarquables, notamment de par leur ingéniosité. Pour chaque situation accompagnée, les temps de réflexion organisés avec les acteurs font émerger les observations individuelles et réflexions personnelles que chacun avait souvent gardé pour lui. La synergie du collectif d’accompagnement mis en place favorise ainsi un décalage des pratiques habituelles. Elle autorise à penser l’accompagnement autrement et donne naissance à l’expérimentation d’ajustements. De par sa posture, le coordonnateur de dispositif renforcé a accès à un échantillon significatif de ces pratiques. Par la suite, il a la possibilité de partager et diffuser ces expériences, notamment, dans le cadre des temps de sensibilisation et d’appui aux pratiques. Il s’agit d’un élément clef en termes de diffusion et de capitalisation des savoirs expérientiels. Promouvoir la diffusion et la capitalisation de ces expérimentations est indispensable pour briser l’isolement des acteurs et créer une dynamique vertueuse. Les actions menées peuvent être classées selon 3 CATEGORIES phares : - L’autodétermination de la personne, - L’aménagement de l’environnement, - L’ajustement des postures professionnelles. | Spouse with association | |
| 2021 | Sara LEMOINNE | Paris | Associative (ALBI) | Rare hepato-gastroenterological diseases | Effect of the probiotic Faecalibacterium prausnitzii in primary sclerosing cholangitis | Primary sclerosing cholangitis (PSC) is a rare disease affecting the bile ducts of the liver and can progress to cirrhosis and liver cancer. Currently, the only effective treatment for PSC is liver transplantation , but this treatment is reserved for patients with very advanced disease and cannot always be applied in cases of liver cancer. It is therefore essential to explore other therapeutic avenues. In two-thirds of patients, PSC is associated with chronic inflammatory bowel disease (IBD). Several studies have demonstrated the importance of the gut microbiota in the development of IBD, to the extent that several treatments modulating the gut microbiota are currently being tested for the treatment of IBD. Faecalibacterium prausnitzii (F. prausnitzii) is a commensal bacterium of the gut microbiota with anti-inflammatory properties. Used as a new-generation probiotic, this bacterium has a beneficial effect on IBD in animal models . Several teams around the world, including ours, have shown that the gut microbiota is altered during CSP, with a reduction in certain bacteria, particularly the Faecalibacterium genus . Several data suggest that modulating the gut microbiota to restore its balance could have a beneficial effect on PSC. Thus, the aim of our study is to evaluate the effect of F. prausnitzii on PSC, using a preclinical animal model. Transgenic mice with a knockout ABCB4 gene spontaneously develop a disease of the liver bile ducts that mimics PSC. We will treat these mice with the probiotic F. prausnitzii. We will analyze their gut microbiota before and after administration of the probiotic in order to evaluate the impact of this treatment on the microbiota. We will compare the livers of mice in the PSC model treated with probiotics to the livers of mice in the same model that were not treated (control group) to assess the effect of the probiotic F. prausnitzii on the manifestations of PSC. In addition, we will analyze the gut microbiota of 49 patients with SCD to assess whether there is a correlation between the abundance of F. prausnitzii and the severity of their liver disease . We expect this study to provide proof of concept for a beneficial effect on SCD through modulation of the gut microbiota by a new-generation probiotic (F. prausnitzii). | Spouse with association | ||
| 2021 | Amédée RENAND | Nantes | Foundation For Rare Diseases | AutoImmune Liver Diseases (AILD) | Tracking autoreactive CD4 T cells in rare autoimmune liver diseases | - | GenOmics 2020 | ||
| 2021 | Amélie PITON | Illkirch | Foundation For Rare Diseases | Intellectual diasbility (ID) | Analysis of parental genomes in individuals with intellectual disability without pathogenic mutation identified by solo WGS | - | We carried out a genome sequencing project involving parents of individuals with neurodevelopmental disorders (NDDs) whose solo genome analysis had failed to identify the genetic cause of their condition. Analysis of the parents' genetic information enabled us to develop an effective strategy for detecting genetic variants that occurred only in the affected individual ("de novo" variants, ~80 per individual). It is known that the genetic abnormality responsible for NDD occurs de novo in more than 75% of cases. We first established a strategy to compile a list of de novo variants for each individual while limiting the false positive rate, which enabled us to identify an average of 97 de novo variants per individual. This analysis identified several promising variants, both in known genes and in genes not yet implicated in human pathology. Additional functional analyses will be necessary to confirm the involvement of these new variants and genes in NDDs. | GenOmics 2020 | |
| 2021 | Angela TINGAUD-SEQUEIRA | Bordeaux | Foundation For Rare Diseases | Oculo-Auriculo-vertebral spectrum | Whole-genome sequencing in the complex Oculo-Auriculo-vertebral spectrum: application on whole-exome sequencing negative familial cases versus direct analysis | - | The Oculo-Auriculo-Vertebral spectrum is a complex developmental disorder. It manifests as facial asymmetry linked to hemifacial microsomia, specific abnormalities of the outer ear (microtia, enchondromas) and sometimes of the inner ear. Eye abnormalities (epibulbar dermoids or eyelid colobomas) and/or spinal abnormalities may also be present, and in rarer cases, cardiac or renal abnormalities. The genetic origin of this spectrum remains unexplained in more than 80% of patients, despite research efforts and the development of high-throughput sequencing. Genome sequencing has thus opened up new perspectives with the possibility of exploring regions not covered by older techniques for patients in our cohort. Among the nine families included in our study, access to genome sequencing enabled our team to identify the gene responsible in one case. Studies are still needed to investigate candidate regions in two other cases included. Finally, comprehensive analyses using a bioinformatics approach should still be conducted in order to further analyze the data. | GenOmics 2020 | |
| 2021 | Anne Claude TABET | Paris | Foundation For Rare Diseases | Autism | Characterization of non recurrent duplications by next-generation optical mapping in patients with autism | - | GenOmics 2020 | ||
| 2021 | Clément CARRE | Paris | Foundation For Rare Diseases | Intellectual diasbility (ID) | Lost in translation: RNA methylation controls translation in ID patients mutated in FTSJ1 | - | - | GenOmics 2020 | |
| 2021 | Gilles LAVERNY | Illkirch | Foundation For Rare Diseases | Idiopathic Infantile Hypercalcemia (IIH) | Identification of ZK therapeutic activities for Idiopathic Infantile Hypercalcemia | - | Hypercalcemia induced by high circulating levels of 1,25D3 (CMH) is a characteristic of several rare pediatric diseases caused by loss-of-function variants of Cyp24a1, the enzyme that breaks down vitamin D. Current treatments are ineffective and have a significant impact on children's growth. There is therefore an urgent need to improve clinical management. We have shown that treatment with a molecule that normalizes vitamin D signaling pathways is a promising therapeutic option. In addition, we have demonstrated that intestinal, renal, and bone gene expression is modulated in a similar manner in models of mono- and bi-allelic inactivation of CYP24A1, highlighting the need to monitor patients carrying these variants. | GenOmics 2020 | |
| 2021 | Guilaine BOURSIER | Montpellier | Foundation For Rare Diseases | Amyloidosis of unknown cause (AAx) | Exome sequencing of inflammatory amyloidosis of unknown cause (AAx) | - | AAx amyloidosis is an adult disease resulting from persistent, untreated inflammation, with or without clinical expression, over several years. According to our hypothesis, this recurrent inflammation begins early in life and, when all other possibilities have been ruled out (chronic infections, tumor syndrome, and obesity), a reflection of a monogenic autoinflammatory disease (AID) that has not yet been identified. We therefore sequenced the WES/WGS of 26 adult patients using a solo approach (no relatives available). A single diagnosis of monogenic AID was identified (mevalonate kinase deficiency). Three candidate variants were selected based on correlations between the signaling pathway involved and the clinical features usually found in AIDs associated with this signaling pathway. They are currently undergoing re-evaluation and/or functional testing to determine whether they could be the cause of new monogenic AIDs. We would like to thank the FMR for helping us meet two of the major objectives of our FAI2R network: reducing medical dead ends and reducing medical wandering among patients with autoinflammatory diseases, in our case AAx amyloidosis. | GenOmics 2020 | |
| 2021 | Jean SOULIER | Paris | Foundation For Rare Diseases | Fanconi Anemia | Dysfunctional hematopoietic stem cells and clonal hematopoiesis in Fanconi Anemia: what underlies an attenuated phenotype? | - | Fanconi anemia (FA) is a genetic disorder caused by the presence of a "pathological" gene inherited from both parents. Although it is a rare disease, it is the most common genetic bone marrow failure syndrome (where the bone marrow is unable to produce blood cells). FA is a serious disease because patients develop aplasia (insufficient blood cells) in childhood and then have a high risk of developing leukemia (blood cancer) in adolescence or young adulthood. However, some AF patients have spontaneously "corrected" bone marrow without treatment, allowing for proper blood cell production and a significant reduction in the risk of leukemia. While the correction of bone marrow is understood for some AF patients who have "repaired" the defective causal gene in bone marrow cells (revertant patients), it remains to be elucidated for other so-called attenuated AF patients, in whom the molecular basis for spontaneous improvement in blood cells is still unknown. The aim of the project is to identify acquired genetic events and dysregulated biological pathways in the hematological cells of attenuated AF patients. To do this, we will analyze the bone marrow of AF patients identified as attenuated among all AF patients treated in France at the Center of Reference for Bone Marrow Failure at the St-Louis and Robert Debré Hospitals (Paris) who have signed a consent form for research. By understanding and experimentally modeling attenuation in cellular and mouse AF models, this project could subsequently lead to the identification of new therapies that compensate for bone marrow failure while limiting the progression to blood cancers. | GenOmics 2020 | |
| 2021 | Jean-Yves PICARD | Paris | Foundation For Rare Diseases | Persistent Müllerian duct syndrome (PMDS) | Thinking outside the box: a search for new genes responsible for Müllerian regression | - | For more than 30 years, our team has played a pioneering role in studying the genetic origin of Müllerian duct persistence syndrome, more commonly known as "male uterus" syndrome. This syndrome affects boys who have normal male external genitalia and testicles (often intra-abdominal), but in whom Müllerian duct derivatives, uterus, and/or fallopian tubes are found to be present. In more than 250 cases studied in the laboratory, we have shown that in approximately 90% of cases, the cause was either mutations in the anti-Müllerian hormone (AMH) gene, produced by the fetal testicle, which causes the Müllerian ducts to regress, or mutations in the gene for its receptor, AMHR2. Our goal was to identify the genes responsible in the remaining 10% of patients. With the help of the Rare Diseases Foundation, we were able to show the involvement of two new genes, PPP1R12A, which codes for the regulatory subunit of myosin phosphatase, and ACVR1, which codes for the type 1 receptor for activin A. | GenOmics 2020 | |
| 2021 | Sara BALDASSARRI | Paris | Foundation For Rare Diseases | Focal Cortical Dysplasia (FCD) | Dissection of the genetic etiology of epilepsy with focal cortical dysplasia | - | GenOmics 2020 | ||
| 2021 | Svetlana GOROKHOVA | Marseille | Foundation For Rare Diseases | Early infantile epileptic encephalopathy | Integrating transposable element screening into the diagnostics of patients with rare genetic diseases | - | The majority of patients with rare genetic diseases remain undiagnosed despite extensive testing. Some of these patients may carry a deleterious insertion of a transposable element (TE) that had not been detected previously. Although many cases linked to transposable elements have been reported, patient samples are not systematically screened for transposable element insertions. This is because these mobile elements are difficult to detect due to their repetitive nature. We initially tested a new method for detecting TEs (TE-NGS) and obtained very encouraging preliminary results. The main objective of our GenOmics-funded project was to evaluate the feasibility of integrating the TE-NGS method into the diagnostic process for patients with rare genetic diseases. The secondary objective of our study was to detect possible pathogenic insertions (ETs) in the exomes of nine undiagnosed patients with severe neonatal epilepsy. We analyzed 27 samples from nine families with rare diseases using the TE-NGS method. The number of insertions obtained per sample in the current project was similar to that of the two samples initially analyzed (the NA12878 control sample and one patient sample), indicating that our approach is robust and reproducible. The number of ET insertions obtained was not excessively high, making interpretation possible in a relatively short time. The results of our project therefore show that integrating the TE-NGS approach into the diagnostic process appears feasible. The second part of our project aimed to identify potentially pathogenic ET insertions. We first examined the data to detect the presence of de novo ET insertions in nine epileptic patients. Using the bioinformatics approach followed by manual analysis, we identified two such events, which are currently undergoing experimental confirmation. We then searched for ET insertions present in patients in the heterozygous state. Among 5,291 heterozygous insertions identified, 44 insertions were found in genes known to be responsible for monogenic epilepsies (2-7 per patient). These results will now be used to reanalyze the initial exome sequencing data in search of a pair of potentially pathogenic compound heterozygous variants. Thus, our project has generated data that will be explored by our research team to identify potentially pathogenic ET insertions (second objective). | GenOmics 2020 | |
| 2021 | Audrey LECOUFLE | Lille | Les Ailes Foundation | Developmental anomalies and malformation syndromes | Improving the management of children with esophageal atresia | - | Outside AAP | ||
| 2021 | Betty GARDIE | Nantes | Gift of Mr Fournet | von Hippel-Lindau disease | Study of mutations identified in new exons of the VHL gene associated with polycythemia or VHL disease | - | Outside AAP | ||
| 2021 | Betty GARDIE | Nantes | PGCD donation | von Hippel-Lindau disease | Cellular modeling of pathologies associated with VHL gene mutations | - | Outside AAP | ||
| 2021 | Céline LANCELOT | Angers | Les Ailes Foundation | Rare endocrine disorders | To better understand the social and emotional functioning of girls with Turner syndrome in order to better support them in their daily lives | - | Outside AAP | ||
| 2021 | Clémence VANLERBERGHE | Lille | CIC North West | Developmental anomalies and malformation syndromes | Deciphering The Genetic Basis of Fibular Hypoplasia/ Agenesis - Functional Studies For Non Coding Variants | - | Outside AAP | ||
| 2021 | Fabrice LEJEUNE | Lille | LEJEUNE | Pulmonary rare diseases | Characterization of new nonsense mutation corrector molecules | - | Nonsense mutations affect 10% of patients with genetic diseases, and there is no treatment to specifically correct these mutations, which have a significant impact as they very often lead to the total absence of expression of the mutated gene. Thanks to funding from the Rare Diseases Foundation and the Rotary Club of Bondues, we have undertaken to test 150,000 molecules to detect compounds capable of correcting nonsense mutations. We were able to select 10 molecules and ultimately retain four compounds whose activity has been validated on several cell models carrying a nonsense mutation. These four molecules are currently being characterized to determine their toxicity and mode of action. | Outside AAP | |
| 2021 | Françoise SCHMITT | Angers | Les Ailes Foundation | Rare hepato-gastroenterological diseases | Laparo-DAN Improving the diagnosis and care pathway for children with rare digestive malformations - A prospective study of antenatal diagnostic criteria for digestive complications of laparoschisis | - | Outside AAP | ||
| 2021 | Guy LENAERS | Angers | SODEBO Foundation | Other rare diseases | Interest of micro-nutrition for the treatment of rare diseases | - | Outside AAP | ||
| 2021 | Jérome DINET | Nancy | IRCEM Corporate Foundation | Rare non-malignant hematological diseases | HEMOGAME Co-design of a serious game prototype for children with bleeding disorders, their parents and teachers | Constitutional bleeding disorders (hemophilia and other coagulation factor deficiencies, von Willebrand disease, platelet disorders) are conditions for which physical activity is essential for physical health reasons (e.g., tendon and muscle strengthening) but also for mental health reasons (e.g., self-esteem, educational and social inclusion). Paradoxically, children with these conditions are sometimes excluded from physical and sporting activities due to fears on the part of supervisors and some parents. Although certain specific precautions must be taken when carrying out these activities, the fears of supervisors and parents are mainly based on a distortion of perceived risks and a lack of knowledge of the actual conditions and risk factors. The HEMO-GAME project aims to design a serious game to raise awareness, inform, and convince all those involved in these physical and sporting activities: the sick children themselves, their peers, supervisors (e.g., primary school teachers, sports club leaders), and parents. The goal is to demonstrate that physical activity is a stimulating factor in children's growth and development, beneficial not only physically, but also intellectually and socially. | Outside AAP | ||
| 2021 | Nicoletta DIASIO | Strasbourg | Novo Nordisk | Developmental anomalies and malformation syndromes | The hormonal factory of gender and age: between negotiations and medicalization of body variations - PHARMAGENRE | This sociological study examines the effects of medicalization, which, in the absence of a cure, accompanies patients with genetic anomalies throughout their lives. Through interviews with women of three age groups, and observations in local care centers and an association, we study the individual and social effects of biomedical devices on life courses. This syndrome enables us to analyze a "biotechnical continuum" articulating prenatal screening, hormonal treatments and medically assisted procreation. | Coming soon 10/28/2025 | Outside AAP | |
| 2021 | Pascale QUIGNON | Rennes | Groupama Loire Bretagne | Rare neurological diseases | Genetic research in canine epilepsies as models for human epilepsies | - | Outside AAP | ||
| 2021 | Roland LIBLAU | Toulouse | Patron of the Rare Diseases Foundation | Rare systemic and autoimmune disorders | HUMAN IMMUNE SIGNATURES OF NARCOLEPSY WITH CATAPLEXY (2021) | - | The pathophysiology of type 1 narcolepsy (TN1) remains a mystery, but the combination of particularly telling genetic and environmental factors suggests a strong involvement of the adaptive immune system. Over the past few years, we have built up a unique biobank of blood mononuclear cells from patients with NT1 (idiopathic or post-vaccinal), subjects with other causes of hypersomnia, and cells from healthy subjects carrying the HLA-DQB1*06:02 allele. Thanks to this biological resource, we have defined an initial immunological signature in patients with NT1 (Hartmann et al. J. Exp. Med. 2016; Nguyen et al. J. Autoimmun. 2018). We also studied the TCR and TCR repertoire of memory lymphocytes in patients and healthy subjects matched for age, sex, and HLA-DQB1*06:02 (Beltran, Nguyen et al. J. Autoimmun. 2019). We are currently using a hypothesis-free approach to study the transcriptome of CD4 and CD8 effector or memory T cells in order to identify patient-specific alterations. Using functional approaches, we are analyzing whether patients' T lymphocytes show cross-reactivity between autoantigens from orexinergic neurons and antigens from the implicated vaccine. This is taking place in a competitive international context (Liblau Nature 2018). | Outside AAP | |
| 2021 | Léon KAUTZ | Toulouse | Awards - Alnylam Pharmaceuticals | β-thalassemia | Targeting the hepatokine ERFE-2 to decrease iron overload and improve anemia in β-thalassemia | Beta-thalassemia is a rare genetic disease affecting 1-9 people out of 1 million, caused by a defect in hemoglobin synthesis. The disease is characterized by profound anemia and iron overload, leading to severe, life-threatening clinical complications. Iron is an essential constituent of hemoglobin in red blood cells. Hepcidin is the central regulator of iron homeostasis. In anemia, erythroferrone regulates hepcidin production to ensure iron supply to the bone marrow for erythropoiesis. However, our data indicate that a second factor exerts a similar function. We have identified a novel hepcidin repressor (ERFE-2) whose expression is increased in the liver during repair of anemia or in beta-thalassemia, Our project aims to develop a strategy based on RNA interference (antisense oligonucleotides) to confirm the role of ERFE-2 in hepcidin regulation and the establishment of iron overload in beta-thalassemia, and to assess the therapeutic potential of ERFE-2 inhibition in a mouse model of the disease. The completion of this project will lead to the development of new therapeutic strategies based on the use of antisense oligonucleotides for the treatment of beta-thalassemia, for which current treatments are inappropriate and often ineffective. | Beta-thalassemia is a rare genetic disorder affecting 1-9 people in every million, caused by a defect in hemoglobin synthesis. This condition is characterized by severe anemia and iron overload, leading to serious clinical complications that threaten patients' survival. Iron is an essential component of hemoglobin in red blood cells. Hepcidin is the central regulator of iron homeostasis. In anemia, erythroferrone regulates hepcidin production to ensure iron supply to the bone marrow for erythropoiesis. However, our data indicate that a second factor performs a similar function. We have identified a new hepcidin repressor (ERFE-2) whose expression is increased in the liver during anemia repair or in beta-thalassemia. Our project aims to develop a strategy based on RNA interference (antisense oligonucleotides) to confirm the role of ERFE-2 in the regulation of hepcidin and the development of iron overload in beta-thalassemia and to evaluate the therapeutic potential of ERFE-2 inhibition in a mouse model of the disease. The completion of this project will lead to the development of new therapeutic strategies based on the use of antisense oligonucleotides for the treatment of beta-thalassemia, for which current treatments are inappropriate and often ineffective. | Alnylam Pharmaceuticals 2020 Award | |
| 2021 | Pierre-Louis THARAUX | Paris | Awards - Alnylam Pharmaceuticals | Glomerular Diseases | SILENT COLLAPSE: miRNome of human and experimental collapsing glomerulopathies and therapeutic proof of concept by miR-92a gene silencing | Collapsing glomerulopathy (CGP) is a rare and very serious kidney disease that represents a scientific and medical challenge. CGP causes rapid destruction of the glomeruli, the structures in the kidney that filter blood plasma into urine. It is not possible to prevent this destruction in order to avoid renal failure. An abnormal change in the behavior of glomerular cells, the podocytes, is now recognized as the cause of the disease. Under normal conditions, podocytes are unable to proliferate and retain their differentiated phenotype. During PMC, podocytes revert to a developmental genetic program that includes down-regulation of cell cycle inhibitors and loss of mature cell markers. Our team recently observed that the loss of podocyte quiescence is caused by the appearance of a microRNA, miR-92a, in a CGP model and in patient biopsies. miR-92a inhibits the expression of a potent cell cycle inhibitor, p57, and inhibition of this microRNA limits podocyte proliferation in vitro. This project will study the glomerular expression of miR-92a and its molecular targets in human PMFs and in two mouse PMF models. We will block the action of miR-92a with a laboratory-validated anti-miR strategy to prevent and, more importantly, treat this severe disease. | Alnylam Pharmaceuticals 2020 Award | ||
| 2021 | Brigitte CHABROL | Marseille | IRCEM Corporate Foundation | Rare neurological diseases, Rare inborn errors of metabolism, Rare endocrine diseases, Diaphragmatic hernia, Rare gastroenterological diseases, Rare genetic diseases, Rare anemias, Rare bleeding diseases, Marfan syndrome, Spina bifida, Cystic fibrosis | Ethical reflection on the creation of a Rare Diseases Area dedicated to patients and their families | The Plateforme d'Expertise Maladie Rares (PEMR-APHM), accredited in 2020 by the DGOS, forms a network between AP-HM's 93 accredited rare disease centers and the associations, diagnostic laboratories and research units to which they are attached. Its aim is to encourage cross-functional implementation of patient pathways and support for rare disease centers. It provides for the creation of a meeting place dedicated to rare diseases for patients and their families, similar to the ERI for cancer. The installation of this new space in France for the medico-social support of people suffering from a rare disease and their families is envisaged on the basis of the operation of these ERIs and the medico-social system for rare cancers in Holland. It should encourage listening and exchanges between the PEMR-APHM, patients and relatives at the time of diagnosis, expert patients, partner patients, caregivers, members of associations and other citizens. It will provide information on law and health, and supportive care. We propose to analyze the views of patients, caregivers, associations and healthcare professionals in advance, in order to provide answers to the following questions: How will the system fit into the "disease trajectory" (according to the concept proposed by Pr A. L. Strauss in "La trame de la négociation - Sociologie qualitative et interactionnisme", 1992)? When would this device be used as a recourse (temporality of interest in the device, in particular in relation to the moment of diagnosis)? What would be the benefits and limitations of the device for people? In particular, we'll be looking at the potential relevance of information exchanges between peers (such as patient-patient, parent-parent), the contribution to the care relationship and to empowerment. What kind of communication and organizational arrangements (opening days, resource persons) should be envisaged for the Espace? The research project will be led by Pr Chabrol, in collaboration with Pr Le Coz and his team. Funding from the Fondation Maladies Rares will enable us to recruit a Master 2 student for this study. The results will be used to define the resources and organization of this new space, with the drafting of a best practice guide. | Humanities and social sciences 9 | ||
| 2021 | Christelle DUPREZ | Lille | Foundation For Rare Diseases | Rare systemic and autoimmune diseases / Hereditary angioedemas, Immunological thrombocytopenia | Emotional processes in adult patients with hereditary angioedema: a pilot study coupling self-reported and physiological measures | Hereditary angioedema (HA) is a rare genetic disorder characterized by attacks of swelling. Due to the unpredictable and potentially fatal nature of the symptomatic attacks, particularly of the larynx, the emotional repercussions of the disease are significant (e.g., anxiety, depression, reduced quality of life). Emotions (e.g., fear, anxiety, stress) also play a role in triggering attacks. The clinical observation that HA patients have a somewhat atypical "profile" (minimization of disease severity, disillusioned optimism, detachment, "emotional placidity"), to be confirmed by studies such as the present project, suggests that either these patients activate adapted emotional regulation (ER) mechanisms to anticipate potential symptomatic crises, or they present ER difficulties, which can lead to ER disorders (e.g., difficulty differentiating and expressing emotions, or alexithymia). ER strategies and possible ER difficulties in patients with HA are still poorly studied, but recent data highlight in particular autonomic dysregulation (hyperactivity of the sympathetic system associated with parasympathetic hypoactivity in a stressful situation), compatible with the hypothesis of a specific or deficient ER in patients. The aim of the present project is to determine whether or not patients show an ER deficit, reflected in particular by the presence of alexithymia, using two complementary studies combining self-report measures (questionnaires assessing ER strategies, ER difficulties, alexithymia, anxiety-depression, and quality of life - ANGIORE QUANTI study) and physiological measures more reliable than those used in existing data (measurement of heart rate variability and electrodermal response using an Empatica E4 wristband in a psychological stress task). The results will be used to identify relevant variables that can eventually be taken into account in patient management. The data are intended to be supplemented by studies on larger samples, notably through recruitment via patient associations. | Humanities and social sciences 9 | ||
| 2021 | Estelle LOUET | Paris | Foundation For Rare Diseases | Developmental abnormalities and malformations / Myelomeningocele | In utero surgery for fetal myelomeningocele: mechanisms of decision making and psychological impact of prenatal therapy | Myelomeningocele (MMC) is a congenital malformation of the spinal cord and spine, leading to sensory and motor deficits in the lower limbs, sphincter disorders, and orthopedic and cerebral complications. In utero surgery to repair this malformation has been shown to improve the prognosis of children with MMC, compared with postnatal surgery. To date, very few studies have investigated the psychological impact of choosing in utero surgery on patients and their co-parents. Objectives - The primary objective of our study is to investigate a posteriori the experience of couples who made the choice of fetal surgery for MMC repair. The secondary objectives are as follows: - To identify the factors that contributed to the choice of prenatal surgery rather than postnatal surgery or medical termination of pregnancy. - Evaluate the quality of the information couples received regarding the three options offered in the face of a prenatal diagnosis of CMD: in utero surgery, postnatal surgery and medical termination of pregnancy. - To explore ways of improving support for couples before and after fetal surgery to repair CMD. Methodology - This is a cross-sectional observational study. Our approach will be mixed, qualitative and quantitative. Semi-structured interviews will be conducted with each couple, recorded and transcribed. Analysis will be based on two complementary qualitative methods: thematic analysis (Interpretative Phenomenological Analysis) and discourse analysis. A hetero-questionnaire on decision-making will also be given to the patients and their families, in order to relate its data to the themes obtained by the qualitative analysis. | Humanities and social sciences 9 | ||
| 2021 | Sylvain FEREZ | Montpellier | Foundation For Rare Diseases | Hereditary metabolic diseases | Invisible patients? A study of the reconfiguration of stigma in the school and work environment after lung transplantation in people living with cystic fibrosis | The TransMuco study aims to understand the post-lung transplant experiences of people living with cystic fibrosis. Drawing on the theoretical perspective of the "disability production process" and building on the results of the MQSP-Muco study conducted between October 2016 and December 2018, it will attempt to uncover the major obstacles and facilitators to social participation encountered after lung transplantation within two specific environments, school and the world of work. Its innovative aspects consist in taking into account the interactions between individual and environmental factors in the production of handicap situations, and in the hypothesis that lung transplantation does not necessarily lead to the disappearance of handicap situations experienced by patients, but rather to their transformation. Initially, the study involved ten life-story and practice interviews, repeated at intervals of two or three months, on the individual and daily lives of the people interviewed after transplantation. We would like to propose a quantitative extension, involving the administration of Environmental Quality Measurement questionnaires (MQE Sco and Pro) to all adults with lung transplants of more than 1 year and less than 3 years, followed by the CRCM at Foch Hospital. Three types of results are expected - Identification of environmental factors that hinder or facilitate school and work participation after lung transplantation; - Description of the socio-demographic characteristics of the eligible population followed by the Foch Hospital CRCM, and better characterization of the sample of ten people interviewed as part of the TransMuco study in relation to this group; - Identification of factors outside the school and work environments that may have an impact on the experience of disability in these two environments after transplantation. Patients, their families and associations will be able to support their comments on the defense of rights with the MDPH and other institutions, and propose differentiated systems and aids adapted to patients' specific needs. Finally, some of these results could be transferred to patients with other rare diseases who may require lung transplantation. | Cette enquête par questionnaire étudie les reconfigurations d es sphères de la vie sociale des personnes vivant avec la mucoviscidose après la greffe pulmonaire, avec une attention particulière aux environnements scolaires et professionnels. Elle s’inscrit dans une série d’études, menées par des sociologues et anthro pologues des équipe Sant.E.Si.H. de l’Université de Montpellier et L ViS de l’Université Claude Bernard Lyon 1 en partenariat avec plusieurs CRCM, qui portent sur les obstacles et les facilitateurs à la participation sociale pour les personnes vivant avec la mucoviscidose d’abord l’étude par questionnaires et entretiens MQESP Muco, qui a impliqué une centaine d’adolescents et jeunes adultes de 15 à 26 ans vivant avec la mucoviscidose (pour la quasi totalité non greffés) puis l’étude par entretiens Trans Muco, qui a impliqué le suivi de dix personnes majeures greffées pulmonaires depuis un à trois ans. Toutes ces études ont porté une attention particulière aux interactions que les personnes vivant avec la mucoviscidose nouent au sein de deux environnements aux exigences spécifiques, le monde de l’école et de la formation et le monde du travail, en se focalisant sur deux moments charn ière d’un côté le passage à l âge adulte, avec la conclusion de la scolarité, la possible professionnalisation et les modifi cations du suivi médical et d e l ’autre côté, pour celles et ceux qui sont confrontés à cette expérience, le moment de la greffe pulmonaire. Nous avons adopté la perspective théorique élaborée par le Réseau international sur le Processus de Production du Handicap ( basé au Québec, selon laquelle le handicap n’est pas un attribut individuel mais le résultat de l’interaction entre les caractéristiques des individus et les propriétés des environnements sociaux qu’ils fréquentent. Quand la rencontre en tre ces deux types de facteurs, individuels et environnementaux, produit des situations qui empêchent les individus de s’investir de manière satisfaisante dans les activités et les rôles sociaux qu’ils valorisent, nous parlons de limitations à la participa tion sociale, donc de « situations de handicap ». Cette perspective implique qu’une même personne peut vivre des situations de handicap en certaines circonstances et des situations de participation sociale en d’autres. Notre étude MQESP Muco a montré que l a situation médicale n’était pas le seul facteur qui influençait la participation sociale des adolescents et jeunes adultes concernés, une meilleure santé n’étant pas gage d’une participation sociale satisfaisante. À côté des symptômes de la m ucoviscidose, les caractéristiques des environnements jouent un rôle fondamental l’organisation de l’école et du monde du travail, les caractéristiques matérielles des lieux, les horaires, les règlements, les trajets, et plus spécifiquement l’environne ment humain. En croisant les données d’entretiens et les réponses aux questionnaires, nous nous sommes aperçus que les enqu êtés déployaient des efforts considérables pour contrôler l’information concernant leur mucoviscidose parvena nt à leur s entourage s Cet effort pouvait passer par des stratégies diverses et complexes, d’invisibilisation mais aussi de mise en visibilité, dont la finalité était toujours d’éviter de voir son identité réduite à la maladie, d’être objets de « plainte », de « pitié », d’observations désagréables ou d’être en quelque façon que ce soit stigmatisé La gestion de l’information répondait ainsi à la farouche volonté d’être reconnu, grâce à une égalité de traitement, pour la valeur de son investissement scolai re ou professionnel. L'importance des caractéristiques des environnements nous a finalement conduits à nous interroger sur les possibles évolutions de la participation sociale, et particulièrement de la gestion de l’information dans les environnements sco laires et professionnels, suite à la greffe pulmonaire. Alors que cette dernière permet la restauration rapide de paramètres médicaux qui étaient très dégradés, conduit elle nécessairement à une réduction des obstacles à la participation sociale préalablem ent rencontrés par les individus L’apport des méthodes mixtes Une étude par entretiens approfondis portant sur cette question ( a été achevée en mars 2022. Dans son prolongement, l’objectif de ReconfMQE était de développer une approche quanti tative par questionnaires pour tenter d’élargir les analyses produites en recourant à des méthodes mixtes de recherche. Les questionnaires visaient ici à interroger de manière plus systématique un plus grand nombre de personne greffées, alors que les entre tiens approfondis nous avaient permis d’éclairer des logiques microsociales impossibles à saisir autrement. Le questionnaire utilisé est la Mesure de la Qualité de l’Environnement ( développé par les chercheurs du Réseau International sur le Processu s de Production du Handicap ( dont n ous avons élaboré deux versions centrées l’une sur l’environnement scolaire (MQE Sco), l’autre sur l’environnement professionnel (MQE Pro). Pour mettre en évidence les éve ntuelles différences dans les obstacles dé clarés selon qu’on a été transplanté ou non, nous avons comparé les résultats des réponses au questionnaire d’un groupe de personnes greffés avec ceux obtenus (grâce au même questionnaire) dans le cadre de l’enquête MQESP Muco (qui s’appuyait sur des métho des mixtes) réalisées quatre ans plus t ôt auprès de personnes non greffées. Pour ReconfMQE, le questionnaire a été proposproposé́ aux personnes majeures greffées pulmonaires en raison de leur mucoviscidose depuis plus d’un an et moins de cinq ans suivies par les centres participants ( Marseille, Lyon) et diffusé par l’association Vaincre la Mucoviscidose via différents canaux. Une soixantaine de personnes ont commencé à renseigner un questionnaire Sco ou Pro, mais plusieurs ne l’ont pas complété en totalité. L’enquête a finalement débouché sur un petit nombre de questionnaires exploitables (n= dont les réponses, articulées aux entretiens de l’étude TransMuco et aux entretiens et aux questionnaires de MQESP Muco, nous ont néanmoins permis d’identifier des a xes de résultats et un certai n nombre de pistes pour améliorer le suivi des personnes greffées. Des perceptions de l environnement similaires avant et après la greffe La comparaison des résultats à la MQE entre les enquêtés non greffés et greff és ne montre aucune différence significative concernant la perception d’un certain nombre d’environnements humains, à première vue les plus immédiats, perçus globalement comme facilitateurs (attitudes de la famille, des amis, attitudes des professionnels d u CRCM) la perception d’un certain nombre d’environnements (qui comprennent des environnements humains moins proches, mais pas seulement) perçus globalement comme sans influence (attitudes des voisins, des inconnus, de groupes, les croyances religieuses, les réseaux sociaux, les ressources médicales extérieures, les associations de patients, le printemps, la qualité de l’eau, la faune domestique) la perception d’un certain nombre d’environnements saisonniers et liés à la qualité de l’air, globalement pe rçus comme obstacles ( hiver, été, qualité de l’air). Il apparaît toutefois que « les services du CRCM » sont perçus comme plus facilitateurs pour les personnes non greffées et davantage comme obstac les pour celles greffées, alors que des éléments comme la qualité de l’air et la flore domestique sont davantage perçu s comme des obstacles par les personnes non greffées. L’articulation de ces réponses avec les entretiens des études MQESP Muco et TransMuco nous conduit à interpréter cette différence de perception des ser vices du CRCM comme plus facilitateurs pour les personnes non greffées à partir de deux facteurs 1) D ’un côté, le changement radical du suivi médical après la greffe. En fait, les personnes greffées sont suivies dans des espaces distincts et par des équipes différentes de celles qui les ont suivies pour leur mucoviscidose, parfois pendant de nombreuses années, avant l a greffe. Outre le changement d’équipe, le suivi même est organisé différemment. Les personnes non greffées sont prioritairement suivies par une ou un pneumologue avec qui elles développent une relation de confiance et qui, entouré(e) par les infirmières c oordinatrices et les autres figures du CRCM, devient un point de repère non seulement pour les aspects médicaux mais aussi pour discuter des relations entre ces aspects et les autres aspects de la vie quotidienne. 2) D’un autre côté, les entretiens réalis és avec des personnes non greffées ont fait apparaître l’importance de développer une relation de confiance étroite avec le kinésithérapeute libéral qui les suit quasi quotidiennement. En montrant que les personnels des services des CRCM, comme hors des C RCM, sont perçus comme plus facilitateurs avant la greffe, les résultats de ReconfMQE éclairent ainsi d’une autre manière l’importance de « figures » soignantes clés car rassurantes (pneumologue du CRCM et kinésithérapeute notamment), qui apparaissait clai rement dans les récits des personnes non greffées, et qui semblent faire défaut (et générer une sorte de « manque ») après la greffe. Des difficultés durables d’accès ou de retour à l'emploi Concernant les obstacles rencontrés à la fois hors et dans les environnements de travail, le groupe des enquêtés greffés qui a une activité professionnelle (n= produit finalement des réponses qui sont très proches de celles des enquêtés non greffés qui sont aussi en emploi. Des différences significatives s’observe nt toutefois sur deux facteurs spécifiques l’attitude des supérieurs et le lieu de travail. Alors que les attitudes des supérieurs sont davantage décrites comme facilitantes chez les non greffés, ce facteur est plus variable et incertain chez les personn es greffées. Concernant le lieu de travail, on observe qu’il n’est jamais sans aucune influence pour les personnes greffées interrogées, alors que c’est le cas pour environ 30% des enquêtés non greffés. Les réponses très hétérogènes concernant les environn ements de travail dans le groupe des enquêtés greffés laissent entrevoir des situations professionnelles extr êmement variées (travail à domicile, statut d’autoentrepreneur, etc.). Par ailleurs, la déclaration systématique de la Reconnaissance de la Qualité de Travailleur Handicapé ( pour les enquêtés greffés en emploi laisse à penser que les logiques de gestion de l’information liée à la maladie so nt différentes après la greffe. La perception des attitudes des supérieurs comme plus facilitat rice chez les enquêtés non greffés semble pouvoir être mise en lien avec la tendance, que nous avons relevée chez plusieurs participants aux entretiens de l’étude MQESP Muco (qui a concerné très majoritairement des personnes non greffées), à préférer des a ccords informels avec les enseignants et les supérieurs hiérarchiques plutôt que d’avoir recours aux dispositifs existants (demande de « tiers temps » et Projet d’Accueil Individualisé PAI pour l’environnement scolaire, RQTH pour l’environnement profession nel). Toutefois, si la greffe est systématiquement déclarée aux employeurs, les entretiens réalisé s dans le cadre de l’étude TransMuco montrent qu’elle n’est pas forcément déclarée aux collègues de travail. Ces enjeux d’effacement ou de mise en avant de la greffe serait sans doute à explorer plus en détail auprès d’effectifs plus conséquents ce qui n’e st pas évident dans une période où les transplantations diminuent, depuis l’arrivée du traitement par Kaftrio). Il convient également de souligner le nombre élevé de personnes professionnellement inactives parmi les enquêtés greffées 9 sur 22 Alors que d’un point de vue médical, la greffe est généralement appréhendée comme liée à un changement rapide et brutal, les résultats obtenus montrent que, du point de vue des enquêtés, d’une part il y a peu d’évolutions dans le rapport aux facteurs environnementaux (qu’ils soient obstacles ou facilitateurs), d’autre part il peut y avoir une difficulté durable de réinsertion dans le monde professionnel. De s besoins d’accompagnement au delà de la dimension médicale Le constat des effets complexes de la greffe sur les trajectoires profes sionnelles (et plus généralement sur les trajectoires sociales et les parcours de vie), notamment au regard de la question d e l’emploi, suggère la nécessité de - Mieux suivre l’évolution de la situation des personnes greffées dans la durée, pour mieux les accompagner et pour mieux saisir les obstacles qu’elles peuvent rencontrer dans leurs éventuelles projections professionne lles. Le suivi de cohortes de greffés au delà de cinq ans, et sans doute jusqu’à dix à quinze ans semble donc nécessaire, en introduisant l’attention à un certain nombre de variables concernant les types d’emplois (poste occupé, présence ou non d’aménageme nts, temps de travail effectué, niveau des revenus, obtention de la RQTH, etc.) et sur les types d’employeurs (secteur d’activité et nombre d’employés, entre autres). - Concevoir un accompagnement spécifique sur les dimensions sociales considérant l es projections et les devenirs professionnels des personnes opérées dans les années qui suivent la greffe (au delà de 5 ans), en respectant les désirs et projets de chacun (qui peuvent donner plus ou moins d’importance à la question du travail ou condui re à d’autres choix, qui prennent sens dans des parcours de vie). - Sensibiliser les environnements professionnels susceptibles d’accueillir des personnes qui ont été greffées, notamment en termes de gestion des ressources humaines et de management. | Humanities and social sciences 9 | |
| 2020 | Aloise MABONDZO | Saclay | Associative (Xtra) | Rare neurological diseases | Development of a future drug to treat creatine transporter deficiency | - | 1) Formulation galénique Formulation à base de micelles D'après les données d'absorbance, la solubilité maximale du DCE se situe dans la même fourchette que ce soit dans la Maisine CC à 100 % ou dans la Maisine CC avec 5, 10 ou 15 % de Span 80, soit entre 5 et 15 mg/g. Cependant, les observations effectuées indiquent que le Span 80 en mélange avec les micelles améliore légèrement la solubilisation du DCE. Néanmoins, la solubilité maximale obtenue reste loin de la charge cible de 100 mg/g. La génération de micelles inversées avec ajout de 2 % d'eau semble avoir un effet positif sur la solubilisation du DCE. Cela peut s'expliquer par une meilleure solubilisation/stabilisation du groupe polaire du DCE dans le noyau aqueux. Aucune différence de solubilité n'a été observée entre les deux micelles avec ou sans le Span 80. Un inconvénient potentiel lié à l'ajout d'eau peut être une stabilité chimique réduite du DCE dans la formulation. Il est cependant possible que la formation de micelles, en utilisant par exemple le Span 80, et/ou l'utilisation d'une phase aqueuse acide, puisse avoir un effet positif sur la stabilité chimique du DCE. Microémulsion A l’issue de ces travaux de conception, une formule a été obtenue répondant aux critères suivants : - Solution fluide - à base de lipides et d’excipients « safe » - Concentration importante en DCE et stable dans le temps - pH à 5.5 - Formule sprayable . La solution se présente sous la forme d’un lait blanc opaque, homogène et stable (visuellement) après 1 mois à température ambiante. Le procédé de fabrication comprend 4 étapes : - Phase 1 : Mélange DCE + triglycérides - Phase 2 : Incorporation de polysorbate 80 - Phase 3 : Incorporation d’eau purifiée dans le prémix DCE + triglycérides + Polysorbate 80. Les deux phases sont préalablement chauffées à 40°C pour favoriser l’émulsion. - Phase 4 : Ajustement du pH avec tampon citrate, une fois le mélange refroidi. Cette formule a donc été retenue pour la suite des expérimentations. Les formulations microémulsions avec triglycérides/eau et +/- polysorbate 80 permettent de solubiliser le DCE jusqu'à 50 mg/g. Le polysorbate (surfactant) apparaît comme n'étant pas nécessaire et le DCE jouant très probablement le rôle de surfactant. L'eau a été acidifiée à un pH autour de 4.5 pour essayer de favoriser la stabilité, le pH de la formule finale ne peut pas être mesuré. Il faut rester entre 4.5 et 6.5 pour une utilisation en routine. Les informations principales de stabilité ont été obtenues avec la solution à 20 mg/g et indiquent une dégradation sur 15 jours de 10% en créatinine. La même formulation à 40 mg/g a été préparée et la stabilité sur 7 jours a été testée. La solution est dans les limites de stabilité 95-105 sur 1 semaine. Cette formulation a été utilisé chez le primate non-humain. 2) Etude de toxicité chez le primate non-humain Aucune mortalité n'est survenue au cours de l'étude. Aucun signe clinique lié au candidat médicament n'a été observé à 4 mg/jour (100 μL dans une narine, 3 jours) et à 8 mg/jour (100 μL dans chaque narine, 3 jours). Aucune perte de poids corporel n’a été observée. Par rapport aux valeurs obtenues avant l'administration de la première dose, il n'y a pas eu de changement lié au DCE (CBT101) dans les paramètres hématologiques chez les deux animaux. 3)Etude de biodistribution cérébrale du DCE chez le primate non humain Le DCE (CBT101) ainsi que ses principaux métabolites, la créatine et la créatinine, ont été retrouvés dans les cellules cibles, les neurones, après 28 jours de traitement intranasal. La cinétique plasmatique du DCE (données non montrées) confirme que la voie nasale est la seule voie possible pour délivrer des quantités suffisantes de créatine dans les neurones. Nous démontrons ainsi qu'une prodrogue de créatine peut atteindre le cerveau en utilisant la voie nasale chez des singes cynomolgus. Ces résultats suggèrent que le traitement de maladies cérébrales telle que le déficit en transporteur de la créatine pourrait bénéficier de la combinaison de la stratégie des prodrogues de créatine et de l'administration par voie nasale. 4)Détermination de la fenêtre thérapeutique et recherche de biomarqueurs d’efficacité pharmacologique du DCE pour le suivi de patients atteints du déficit en transporteur de la créatine Pour des raisons de contraintes budgétaires et de contexte sanitaire, les études de détermination de la fenêtre thérapeutique n’ont pu être réalisées. Seules les études visant à identifier les signatures moléculaires caractéristiques du déficit en transporteur de la créatine ont pu être réalisées. Pour ces expériences, le modèle de souris génétiquement modifiées pour mimer le déficit en transporteur de la créatine (KO pour le transporteur de la créatine) a été utilisé. Nous avons pu confirmer les premières observations : à savoir une amélioration des symptômes cognitifs après administration nasale du candidat médicament pendant un mois. De plus, l’analyse protéomique des différentes aires cérébrales des souris sauvages (WT), des souris KO et des souris KO traitées par le DCE a permis d’identifier 14 protéines d’intérêt sur les 5000 protéines analysées. Parmi ces 14 protéines, 2 d’entre elles (KIF1A et PLCB1) sont en lien avec l’amélioration des fonctions cognitives des souris KO traitées par le candidat médicament, le DCE ou CBT101. Nous proposons que la régulation de KIF1A et PLCB1 dans le cervelet est un processus clé pour le maintien de la fonction cognitive médiée par le traitement DCE. Plusieurs études ont rapporté que le cervelet est relié au cortex cérébral par un circuit cortical cortico-cérébelleux-thalamique. Cette boucle facilite la modulation autonome de l'humeur et du comportement ; des études sur les lésions neurologiques ont mis en évidence l'implication du cervelet dans la physiopathologie des troubles psychiatriques tels que la schizophrénie et le syndrome bipolaire, une caractéristique clinique clé du déficit en transporteur de créatine. D'autres études sont nécessaires pour mieux décrire le réseau d'interaction moléculaire possible entre les deux protéines clés impliquées dans la restauration/amélioration des fonctions cognitives médiées par le candidat médicament. | Spouse with association | |
| 2020 | Julien NIZARD | Nantes | Associative (Algo France) | Rare neurological diseases | Towards a better consideration of patients' feelings in complex regional pain syndrome (CRPS): a study mixing quantitative and qualitative approaches to test and make recommendations regarding the use of a Body Perception Disturbances (BPD) assessment tool. | - | Spouse with association | ||
| 2020 | Pedro Henrique DE LIMA PRATA | Paris | Associative (HPN) | Rare non-malignant hematological diseases | Inherited complement regulatory gene mutations in paroxysmal nocturnal hemoglobinuria: an influence in disease presentation and treatment efficacy? | - | Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease that manifests itself mainly through the destruction of red blood cells by the complement system, bone marrow failure, or thrombosis. The most commonly used treatment to date is eculizumab, which inhibits a complement protein, reducing the risk of thrombosis and the need for red blood cell transfusions. However, the effectiveness of individual responses varies greatly, and many patients continue to require transfusions while on this treatment. In this study, we investigated 84 patients diagnosed with PNH. We searched for genetic alterations in the genes regulating the complement system and found that sixteen patients had alterations, including nine in the same gene. Analysis of the response to treatment, particularly transfusion requirements, showed that these alterations were associated with a poorer response to eculizumab. In addition, we found that the frequency of these genetic alterations is higher in patients with PNH than in the general population. The reason for this increased frequency in PNH patients is not yet known. The use of methods such as gene expression profiling has shown that PNH is associated with a specific genetic signature. The reason for this increased frequency in PNH patients is not yet known. The use of molecular biology methods is gradually becoming more accessible in clinical care. Drugs for PNH are expensive. Appropriate treatments could reduce costs and morbidity, thereby improving patients' quality of life. Our results need to be validated and warrant a collaborative study to confirm the impact of genetic alterations in complement regulation genes on the response to PNH treatment. | Spouse with association | |
| 2020 | Simona PAGLIUCA | Cleveland | Associative (HPN) | Rare non-malignant hematological diseases | Immunogenomics of idiopathic bone marrow failure disorders: immune-escape mediated by class I/II HLA somatic mutations | - | Spouse with association | ||
| 2020 | Audrey LECOUFLE | Lille | Without funding | Pediatric feeding disorders | TOP’ LA !: A mobile app for pediatric oral feeding disorders | Pediatric Oral Feeding Disorders (POFD) are characterized by significant feeding difficulties of multifactorial origin. Many children with rare diseases are affected by these disorders, and their families are often unable to help them. TOP'LA is a mobile application designed to support parents on a daily basis and enable progress in their child's feeding, in parallel with medical and paramedical follow-up. | - | E-health 2020 | |
| 2020 | Dan ISTRATE | Compiègne | Foundation For Rare Diseases | Any rare disease | DEDALE : Tool to facilitate access to medico-social assistance by expressing the patient's needs | Patients affected by a rare disabling disease, or their caregivers, are quickly confronted with the complexity and confusion of the various forms of assistance to which they may be entitled. They will, of course, find a wealth of information on various websites (institutional, associative, or even commercial!), but this information will be limited to a description of these forms of assistance. The proposed tool, based on each person's specific needs, will guide them individually through each possible form of assistance. | Since 2005, France has legislated to better accommodate people with disabilities. The law provides for the accessibility of public spaces and establishments open to the public (ERP). The organization of the medical-social care system has been modified with the creation of the Caisse Nationale Solidarité Autonomie (National Solidarity and Autonomy Fund) to manage financial policy at the national level and the Maisons Départementales pour Personnes Handicapées (Departmental Houses for People with Disabilities) to serve as a "single" entry point for benefit applications. The 2005 law marks a change in the recognition and consideration of disability. While there have been notable advances, many shortcomings remain. The legal definition of disability also takes into account disabling health conditions. In order for these to be effectively taken into account, they must be recognized. In the case of rare diseases, this poses an initial bias. Indeed, RARE means little known, often difficult to diagnose... Those affected face many additional difficulties. They are not the only ones impacted; their families are too. Often, loved ones become caregivers. To address their situation, the law provides assistance. Lists are available on government websites as well as on third-party sites. The types of assistance are listed by name along with the conditions for obtaining them (income, age, disability rate, etc.). However, none of them make the connection with the needs of the person concerned. Furthermore, websites provide information where users are looking for guidance and direction. The people for whom the assistance is intended are already facing a complicated situation and no longer have the resources (psychological, technical, or time, etc.) to cope with the ordeal of searching, compiling files, waiting, and discussing the implications of their illness. Yet they have no choice. The ARAMISE association, which came up with the idea, was joined by the Amadys and Tangy Moya-Moya associations, all three of which are members of the BrainTeam network, and by the eBioMed chair team from the BMBI UMR 7338 laboratory at the University of Technology of Compiègne to launch the project. The aim is to create a digital tool that would enable people with a rare disease or their caregivers to identify the assistance available to meet their needs, obtain information about this assistance, and, in particular, find out what steps they need to take. This is how the Dédale project came about. Why this name? It accurately represents what people face when looking for the assistance they need. Dédale, for the number of stakeholders involved: the Primary Health Insurance Fund (CPAM), doctors, the Departmental House for People with Disabilities (MDPH), the Family Allowance Fund (CAF), etc. And we are only mentioning the main and best-known ones. Dédale, to have your situation recognized in the case of a rare disease... To carry out this project, we proceeded in several stages. First, we conducted a state-of-the-art review of existing technologies to build such a tool. We then set our technical constraints (specifications). Finally, we developed our first prototype. This stage was divided into two parts: the first consisted of creating the engine for our solution, which processes the user's questions in order to provide an answer. Finally, we worked on the graphical interface, the part that the person with a rare disease or their caregiver sees and uses to ask their question and where the result will be displayed. | E-health 2020 | |
| 2020 | Ludovic LAUWERS | Lille | Without funding | Dental agenesis | APPLI’DENT: Application for dental agenesis | We want to develop a smartphone (and tablet) app for providing information, education, and follow-up for patients undergoing treatment for tooth agenesis. This cross-functional app should provide patients and their parents with explanations about their care throughout the treatment process, as well as enable the exchange of medical information between the various healthcare professionals involved in the treatment. | - | E-health 2020 | |
| 2020 | Sylvie CAUET | Toulouse | Without funding | Mastocytosis | MASTOGAME: Serious game to improve depression in patients with mastocytosis | Mastocytosis is a rare orphan disease. Depression is associated with more than 50% of patients and can be linked to cognitive symptoms such as memory, attention, and concentration disorders. Therefore, offering these patients the opportunity to project their depressive emotions onto a digital medium could be a way to help them better understand the real world through the virtual world. | - | E-health 2020 | |
| 2020 | Sylvie MANOUVRIER | Lille | Without funding | Any rare disease | E-GEN HDF: Online genetic counseling in Hauts-de-France | Genetic diseases affect more than 5% of the population and patients of all ages. Our original model of e-consultations in hospitals located far from genetics centers allows us to meet the dual imperative of providing care with a high level of centralized expertise and equal access to care with local, in-person support to help manage the psychological impact. | - | E-health 2020 | |
| 2020 | Alexandre FABRE | Marseille | Foundation For Rare Diseases | Congenital Diarrhea Syndrome | Identification of new genes associated with syndromic congenital diarrhea syndrome | - | Funding from the Rare Disease Foundation has enabled the analysis of the genomes of four patients with enteropathies (diarrhea) and multiple organ involvement that could not be diagnosed using standard techniques. Unfortunately, these analyses have not revealed any clear variations responsible for their condition, although there are some leads. Progress will depend on collaboration with other centers. | GenOmics 2019 | |
| 2020 | Benoit ARVEILER | Bordeaux | Foundation For Rare Diseases | Albinism | Search for new albinism genes | - | - | GenOmics 2019 | |
| 2020 | Caroline SCHLUTH-BOLARD | Lyon | Foundation For Rare Diseases | Neurodevelopmental Disorders | Characterization of 3D chromatin architecture disruption in chromosomal rearrangements to identify candidate genes in neurodevelopmental disorders | - | Disruption of the three-dimensional organization of the genome by chromosomal structural rearrangements or structural variations (SVs) can be associated with an abnormal phenotype, including intellectual disability and/or congenital malformations (ID/CM). While current strategies allow SVs to be characterized at the molecular level in more than 90% of cases, 30 to 40% of patients remain undiagnosed. Interpreting the genomic data obtained remains a real challenge, particularly with regard to long-range interactions. The main objective of this study is to investigate chromatin interactions using HiC sequencing in patients with a balanced chromosomal rearrangement associated with intellectual disability that is not or only partially explained by a gene disruption. The identification of aberrant interactions combined with genome and expression (RNA) sequencing data will enable the identification of candidate genes by positional effect. This work will provide a better understanding of the long-range effects of chromosomal rearrangements, their impact on the phenotype, and their role in neurodevelopment. | GenOmics 2019 | |
| 2020 | François-Xavier MAUVAIS | Paris | Foundation For Rare Diseases | Lysosomal Acid Lipase (LAL) deficiency | Identifying the molecular basis underlying the heterogeneity among the spectrum of lysosomal acid lipase deficiency by a proteogenomic approach supported by bioinformatics | - | GenOmics 2019 | ||
| 2020 | Julie STEFFANN | Paris | Foundation For Rare Diseases | Mitochondrial diseases | Does nuclear transfer alter mitochondrial-nuclear crosstalks in the human preimplantation embryo? | - | GenOmics 2019 | ||
| 2020 | Julien BARC | Nantes | Foundation For Rare Diseases | New rare cardiac syndrome associated with an enhancer deletion of chromosome 4q25 | Molecular mechanism of a new syndrome characterized by cardiac electrical and developmental defects and associated with an enhancer deletion of chromosome 4q25 | - | - | GenOmics 2019 | |
| 2020 | Laura MARY | Rennes | Foundation For Rare Diseases | Disorders of sex development (DSD) | Identification of genes involved in syndromic disorders of sex development | - | Sexual development is based on complex mechanisms. Any disruption of these mechanisms can cause variations in sexual development (VDG), either isolated or syndromic. To date, nearly half of affected patients remain undiagnosed, which has a significant impact on their quality of life. The objective of this study was to analyze the entire coding DNA (exome) of 10 fetuses with SDD associated with other malformations in order to identify the genes responsible. The study identified one or more pathogenic variants in six genes, three of which were not previously known to be responsible for SDD. Exome sequencing therefore makes it possible to discover new mechanisms responsible for VDG and thus improve the diagnosis and management of affected individuals. | GenOmics 2019 | |
| 2020 | Marion DELOUS | Lyon | Foundation For Rare Diseases | Idiopathic scoliosis (IS) | Towards the identification of the genetic causes of rare autosomal dominant forms of idiopathic scoliosis | - | GenOmics 2019 | ||
| 2020 | Pierre RONCO | Paris | Foundation For Rare Diseases | PLA2R-Associated Membranous Nephropathy | Whole Genome Sequencing to Unravel the Genetic Mechanisms of PLA2R-Associated Membranous Nephropathy | - | GenOmics 2019 | ||
| 2020 | Pierre-Louis THARAUX | Paris | Foundation For Rare Diseases | Glomerular Diseases | "TRAJHISTORY project: assessing single cell TRAJectories and alterations of cell communication and tissue HISTOry to get causal insights into rare and catastrophic glomerular diseases" | - | GenOmics 2019 | ||
| 2020 | Sylvie MAZOYER | Lyon | Foundation For Rare Diseases | RNU4ATAC-associated rare diseases | A transcriptomic study in zebrafish models of RNU4ATAC-associated rare diseases: connecting U12 splicing defects to developmental abnormalities | - | GenOmics 2019 | ||
| 2020 | Trang HA | Paris | Foundation For Rare Diseases | Congenital Central Hypoventilation Syndrome | Congenital Central Hypoventilation Syndrome - searching causal genes in patients without PHOX2B mutations | - | GenOmics 2019 | ||
| 2020 | Eric DURAND | Marseille | Foundation For Rare Diseases | Cystic Fibrosis | Towards the development of Pseudomonas aeruginosa "virulence blockers" targeting the T6SS nanomachine: A Hits-To-Lead approach | The prognosis of cystic fibrosis is primarily influenced by the pulmonary course of the disease, and especially by chronic bacterial colonization. Pseudomonas aeruginosa, a Gram-negative bacterium, is the most common opportunistic pathogen in cystic fibrosis patients. Primary infection with Pseudomonas aeruginosa in these patients is a crucial stage in the development of the disease and its pulmonary consequences. Infection precipitates lung decline, and may become permanent if not rapidly eradicated. Antibiotic treatment to combat Pseudomonas aeruginosa in patients is increasingly ineffective due to the emergence of multi-resistant strains. There are many different detection methods and treatment regimens available, and there is currently no consensus as to the best course of treatment. We therefore need to develop new therapeutic solutions, such as blocking the development of Pseudomonas aeruginosa virulence at an early stage. The aim of our project is to develop a new therapeutic approach targeting the virulence of Pseudomonas aeruginosa, in particular by blocking the first essential stages in the colonization of patients' lungs. Pseudomonas aeruginosa uses an arsenal of "small molecular weapons" that enable it to colonize humans and develop its pathogenic power. One of these weapons, the "T6SS", enables the "firing" of powerful toxins which, on the one hand, enable Pseudomonas aeruginosa to kill "beneficial" bacteria and thus colonize its site of infection, and, on the other, to enter human lung cells to hide from the immune system, contributing to the chronicity of the infection. The aim of our project is to explore the concept of blocking a virulence factor as a new anti-pyo therapeutic approach. The consortium is expert in the fundamental knowledge of the targeted virulence factor and has already set up a pipeline to identify inhibitors. The project will enable the development of future drug candidates that should limit the virulence of "pyo". The main cause of mortality in cystic fibrosis patients is infection of the lungs by different bacteria, which vary with age. The bacterial composition in patients' lungs is modulated by intense competition between different species vying for resources and space. Pseudomonas aeruginosa appears progressively over the course of a patient's life, and dominates at the end of life. This pathogen possesses a "weapon", the T6SS, which enables it to reign hegemoniously over other bacterial populations, and also to interact with patients' lung tissue. Bacterial infections are usually treated with antibiotics. However, Pseudomonas aeruginosa is becoming multi-resistant to antibiotics, making treatment very difficult and making pulmonary bacterial infections the major cause of mortality in cystic fibrosis patients. Our research project aims to improve the management of bacterial infections in the future by developing new means of combating "pyo", such as anti-T6SS molecules. | - | High throughput screening / Hit to lead 2020 | |
| 2020 | Lucile HOCH | Evry | Foundation For Rare Diseases | Glycogen Storage Disease Type III | Use of pluripotent stem cells to model and treat GSDIII | Glycogen storage disease type III (GSDIII) is a rare genetic disorder (prevalence approx. 1 in 100,000 births) caused by an enzyme deficiency leading to abnormal accumulation of glycogen in the liver and muscles, preventing them from functioning properly. To date, the only treatments available are symptomatic and rely on strict diets to regulate liver abnormalities, but no treatment to improve muscle weakness is currently available. Gene therapy studies have been developed with the aim of replacing the defective gene and treating the disease. However, these therapies are currently unable to simultaneously treat the liver and muscle defects caused by this pathology. The aim of our program is to use pluripotency-induced stem cells (iPSCs) carrying the disease, capable of infinite self-renewal and differentiation into any cell type, to model the muscular damage caused by GSDIII. This study will enable us to gain a better understanding of the molecular mechanisms underlying these pathological defects, as well as to carry out high-throughput screening studies of potentially therapeutic compounds. | Glycogen storage disease type III (GSDIII) is a rare genetic disorder (prevalence of approximately 1 in 100,000 births) caused by an enzyme deficiency that leads to a pathological accumulation of glycogen in the liver and muscles, preventing them from functioning properly. Although the disease manifests itself in childhood through hypoglycemia and impaired liver metabolism, progressive myopathy is the main burden for adult patients with GSDIII, for which no curative treatment is currently available. Our program is based on the use of human induced pluripotent stem cells (hiPSCs), which are capable of infinite self-renewal and differentiation into any cell type, to model the skeletal muscle damage caused by GSDIII. Using the CRISPR/CAS9 genome editing tool on healthy hiPSCs and reprogramming somatic cells from GSDIII patients, we were able to generate five hiPSC lines carrying the GSDIII disease. These cells were then differentiated into skeletal muscle cells to model the muscle damage caused by the disease. A glycogen measurement test was developed and confirmed glycogen accumulation in diseased skeletal muscle cells after a period of glucose deprivation. Ultimately, this test will make it possible to evaluate the therapeutic potential of pharmacological inducers of glycogen degradation for treating GSDIII. | High throughput screening / Hit to lead 2020 | |
| 2020 | Sandrine GULBERTI | Nancy | Foundation For Rare Diseases | Mucopolysaccharidoses | Development of a specific inhibitor of the glycosyltransferase β4GalT7 for substrate reduction therapy in mucopolysaccharidoses: towards the hit to lead stage | Mucopolysaccharidoses (MPS) are rare genetic diseases caused by a defect in the degradation of mucopolysaccharides, large carbohydrate molecules present in the body's tissues. As they are not degraded, they accumulate in cells, producing multiple severe organ damage, particularly in the brain, reducing patients' quality of life and lifespan. The aim of the project is to propose new molecules that could lead to more effective and less burdensome treatments, in particular by improving the neurological symptoms of the disease. We are seeking to develop a small molecule that specifically blocks a step in the synthesis of mucopolysaccharides in order to reduce their accumulation in tissues and their deleterious effects. To this end, we have chosen as our target one of the proteins involved in the early stages of the synthesis process. In the first stage of the project, we tested a large number of chemical compounds for their ability to block the mucopolysaccharide synthesis pathway, and selected the best inhibitor molecules. In this project, we propose to validate the choice of these molecules and, in a second phase, to optimize them to obtain even more effective molecules using complementary approaches combining medicinal chemistry and virtual models generated by software and computer programs developed for these purposes. We hope that this project will provide a new avenue of treatment in the context of mucopolysaccharidoses. | Mucopolysaccharidoses (MPS) are rare genetic diseases caused by a defect in the degradation of mucopolysaccharides, large carbohydrate molecules present in the body's tissues. As they are not degraded, they accumulate in cells, producing multiple severe organ damage, particularly in the brain, reducing patients' quality of life and lifespan. The aim of the project is to propose new molecules that could lead to more effective and less burdensome treatments, in particular by improving the neurological symptoms of the disease. We are seeking to develop a small molecule that specifically blocks a step in the synthesis of mucopolysaccharides in order to reduce their accumulation in tissues and their deleterious effects. To this end, we have chosen as our target one of the proteins involved in the early stages of the synthesis process. In the first stage of the project, we tested a large number of chemical compounds for their ability to block the mucopolysaccharide synthesis pathway, and selected the best inhibitor molecules. In this project, we propose to validate the choice of these molecules and, in a second phase, to optimize them to obtain even more effective molecules using complementary approaches combining medicinal chemistry and virtual models generated by software and computer programs developed for these purposes. We hope that this project will provide a new avenue of treatment in the context of mucopolysaccharidoses. | High throughput screening / Hit to lead 2020 | |
| 2020 | Sophie NICOLE | Montpellier | Foundation For Rare Diseases | Monogenic motor channelopathies | Search for isoform-selective sodium channel modulators to treat monogenic motor channelopathies | Ion channels are proteins which, as their name suggests, transport ions passively and more or less selectively across biological membranes. These proteins play a central role in physiology, being involved in the electrical activity - a process defined as excitability - of a large number of cell types, including neurons, muscle cells and endocrine cells. Considering their central role in major physiological functions such as locomotion, nociception and respiration, mutations in ion channels altering their function induce sometimes severe or even lethal human pathologies, known as channelopathies. In Montpellier, the "Ion channels in neuronal excitability and channelopathies" research team is focusing here on two members of the sodium channel family whose genetic mutations generate rare motor pathologies: the voltage-sensitive sodium channel Nav1.4, expressed exclusively in skeletal muscle, and the leaky sodium channel NALCN, expressed in numerous neurons and endocrine cells. Only expressed in skeletal muscle, loss-of-function mutations in Nav1.4 are responsible for neuromuscular diseases characterized by muscle weakness of varying severity (from lethal at birth in the most severe forms, to transient muscle weakness in response to certain factors in the least severe forms). With a broader tissue expression, loss-of-function or gain-of-function mutations in NALCN are at the origin of clinically complex neurodevelopmental syndromes (CLIFAHDD, IHPRF1) of varying severity, associating several neurological symptoms: hypotonia, facial dysmorphism, global developmental delay and others. Today, there are no drugs that can improve the symptoms of patients suffering from these rare genetic diseases. However, many molecules, both natural and chemical, are capable of modulating ion channel function. The ambition of our project is therefore to identify compounds that modulate Nav1.4 or NALCN activity, by screening libraries of chemical compounds (CNRS chemical compound bank) or natural compounds (spider toxins) using an automated electrophysiological recording screening method (known as "patch clamp") developed by the Therassay platform (Nantes). In particular, we hope to identify Nav1.4 activators and NALCN inhibitors that can then be tested in preclinical models (zebrafish) of these diseases, which the Montpellier team is currently characterizing. | High throughput screening / Hit to lead 2020 | ||
| 2020 | Veronique STOVEN | Paris | Foundation For Rare Diseases | Cystic Fibrosis | New drugs for Cystic Fibrosis based on machine-learning approaches | Cystic fibrosis is caused by mutations in a gene coding for the CFTR protein, whose known function is to transport Cl- ions. In cystic fibrosis, CFTR is absent or no longer performs this function. Drugs to restore its presence and function (known as "CFTR modulators") have become available in recent years, but the precise mechanism of action of these drugs has not yet been established, which is an obstacle to optimizing these treatments. Identifying the mechanism of action of these molecules is an important issue for improving therapies. Our project aims to use artificial intelligence algorithms developed in our team to identify these mechanisms of action, and to validate them experimentally. Knowledge of these mechanisms will enable us to suggest new therapeutic strategies and new drugs to be tested experimentally on respiratory cells from cystic fibrosis patients. We will give priority to opportunities for repositioning known drugs in cystic fibrosis, in order to limit the time required for clinical development. | High throughput screening / Hit to lead 2020 | ||
| 2020 | Cédric BLOUIN | Paris | Foundation For Rare Diseases | Hemophagocytic Lymphohistiocytosis | Development of the first IFN-γ small molecule inhibitors for the treatment of hemophagocytic lymphohistiocytosis | Following our discovery of a molecule capable of inhibiting interferon gamma (IFN-γ), our goal is now to better characterize its action and turn it into an effective therapeutic solution. We hope to improve the treatment of patients suffering from hemophagocytic lymphohistiocytosis (HLH), a rare and serious disease caused by an overproduction of IFN-γ. Since obtaining funding from the Rare Diseases Foundation, we have determined that the solubility of our compound is reduced in an aqueous environment, which may explain the initial results obtained in vivo in a model of acute colic inflammation, which are encouraging but could be greatly improved. Nevertheless, we have been able to develop another formulation (lipid emulsion) with much greater solubility and stability, which would allow for oral administration. This is a good option because it allows our active molecule to be delivered more easily than by injection while maintaining systemic action. At the same time, we are working to better understand its mechanism of action and its specificity with respect to IFN-γ and other interferons, in collaboration with a structural biology team at the Curie Institute. These data will be supplemented by the analysis of quantitative proteomics results by mass spectrometry, as initially planned. All of these future results will strengthen the patent protecting our compounds and constitute a first step in the commercialization of our discovery. We are subsequently considering a collaboration with a pharmaceutical company in the form of a license for the future development of our molecule and potential clinical trials. | High throughput screening / Hit to lead 2020 | ||
| 2020 | Isabelle TALON | Strasbourg | IRCEM Corporate Foundation | Developmental anomalies and malformation syndromes | Improving the Care and Life Course of Children with Congenital Diaphragmatic Hernia | - | We are working to develop an innovative prosthesis for congenital diaphragmatic hernia with mechanical and biointegration characteristics that are superior to what is currently available on the market. This prenatally diagnosed condition is rare and serious. A hole appears in the diaphragm during embryonic life, causing the abdominal organs to rise into the chest and resulting in fatal respiratory distress at birth. Part of the treatment involves closing this hole at birth, and in the most severe cases, this requires the use of a prosthesis. Currently, the prostheses used are far from perfect, and none have been specifically designed for this very specific condition. The prosthesis we are developing could better adapt to the child's growth and may even integrate better. Our work seems to prove this, and our results encourage us to continue our efforts to perhaps finally have an ideal prosthesis. | Outside AAP | |
| 2020 | Marie-Paule GELLE | Reims | IRCEM Corporate Foundation | Rare head and neck malformations | Improving the care pathway for children with rare dental anomalies | - | Outside AAP | ||
| 2020 | Valerie DESQUIRET-DUMAS | Angers | BPGO Foundation | Mitochondrial pathologies | Therapeutic potential of Niclosamide in mitochondrial pathologies (PRINCIPLE) | - | Outside AAP | ||
| 2020 | Valérie DESQUIRET-DUMAS | Angers | Groupama Loire Bretagne | Hereditary metabolic diseases | Targeted-therapeutic approaches to restore oxidative metabolism in rare diseases associated with mitochondrial complex I mutations | - | Outside AAP | ||
| 2020 | Véronique DANEL BRUNAUD | Lille | IRCEM Corporate Foundation | Neuromuscular disorders | Implementation of teleconsultations for patients affected by advanced Amyotrophic Lateral Sclerosis and treated in Hospitalisation à Domicile (HAD) | - | Outside AAP | ||
| 2020 | Alain LOUTE / Jean Philippe COUBBAUT | Lille | Foundation For Rare Diseases | Amyotrophic lateral sclerosis | Evaluation of the ethical and legal stakes of the use of telemedicine in the context of the accompaniment of patients with advanced Amyotrophic Lateral Sclerosis | Diseases on the Amyotrophic Lateral Sclerosis (ALS) spectrum, affecting almost 6,000 people in France, are rare neurodegenerative diseases (incidence 3/100,000) affecting central and peripheral motor neurons in adults, with incidence increasing from the age of 40 onwards. The advanced stage of the disease is a critical period, with a high risk of complex, inadequately controlled symptoms, and hospitalization that can be difficult to cope with. In this context, studies have shown that teleconsultation (TLC) can be useful. TLC is a remote consultation between the hospital doctor and the patient at home. It helps to improve the quality of care in the advanced stages of the disease, right up to death, by limiting hospital admissions, preventing complications and caregiver burnout, and providing access to palliative care. This project continues the evaluation of TLC for advanced ALS patients, but focuses on the question of its ethical and legal impact, which has received little attention in the literature. TLC is not without effect on the patient's living space. Connecting the hospital doctor to the home has the effect of hybridizing the hospital space with that of the home. Conversely, the space of the home can disrupt TLC. Through semi-directive interviews with 40 patients, the project aims to assess the impact of TLC on patient intimacy. Alongside this research objective, the project will also assess the impact of TLC on the quality of the medical relationship. Communication media influence the way we communicate. Using interviews and a questionnaire for ALS Centers, the project will assess how the telemedicine system transforms this relationship. Thanks to this project, it will be possible to better identify the ethical and legal risks associated with the practice of TLC, and how to prevent them. | Humanities and social sciences 8 | ||
| 2020 | Alexandre MATHIEU-FRITZ | Marne-la-Vallée | Foundation For Rare Diseases | Cystic Fibrosis | Sociological study of the support to autonomy in health of adult patients with cystic fibrosis with the help of new technologies and with liberal health professionals | This research project is proposed as an extension of the project entitled "Accompagnement à l' autonomie en santé des patients adultes atteints de mucoviscidose à l'aide des nouvelles technologies et en partenariat avec leur équipe soignante" (AAST-MUCO) which has been selected by the Association Gregory Lemarchal, as part of its 2019 call for projects. The AAST-MUCO project involves setting up a sociological evaluation of the "Assistant de Vie Mucoviscidose" (AVM), a self-monitoring device that aggregates several life data made up of measurements taken via connected objects, as well as feelings and treatments entered manually by patients. The aim of this project is to study the use of MVA in order to assess its impact on patients' experience and participation in the management of their disease, as well as, more generally, on the organization of cystic fibrosis care in hospitals. The study is based on a longitudinal approach, involving several series of semi-structured interviews with members of the CRCM care team at the Foch Hospital in Suresnes, and a panel of 15 patients selected and followed up by them. The present research project completes this sociological study with two main extensions. The first is to include all the other healthcare professionals involved in the organization of cystic fibrosis care, beyond the hospital setting. In fact, this extension to all the liberal professions (physiotherapists, nurses, pharmacists, psychologists and/or coaches, etc.), is essential if we are to grasp the effects of integrating the new self-monitoring tools into the overall organization of cystic fibrosis care. A second extension consists of integrating into this analysis the specific questions that emerge with the new context of care in the Covid-19 era. | Humanities and social sciences 8 | ||
| 2020 | Aurore PELISSIER | Dijon | Foundation For Rare Diseases | Intellectual diasbility (ID) | Helping Configurations and Employment Situations for Caregivers. The case of children with rare diseases and intellectual disabilities. A pilot study. | cCASEPRA Pil is a pilot project designed to initiate research into the configurations of assistance organized around children with rare diseases and intellectual disabilities, and the repercussions of this assistance on the lives of parent carers. The first step is to identify who the caregivers are, and to characterize the nature and intensity of the assistance they provide. This "support network" will be compared with the professional care provided for the person being cared for. The aim is then to analyze the impact of assistance on the employment situation and working life of parent carers. To meet these objectives, the pilot project aims to design the questionnaire survey to be administered to parents nationwide. The project is divided into two phases. The first, qualitative exploratory phase aims to define the subject more precisely. It is based on semi-directive interviews. The second phase, known as the operationalization phase, comprises two stages, with the aim of preparing the survey and developing the questionnaire. CASEPRA Pil is a collaborative project bringing together a team of social science researchers from two disciplines (economics and sociology), two rare disease health networks, a handicaps rares relay team (Bourgogne Franche-Comté branch), UNAPEI and the eNorme network. The aim of the project is to fill a data gap in the field of caregiver analysis for children with disabilities, by producing a targeted survey that will enable the appropriate levers to be activated to meet the needs of family caregivers. Indeed, this research will help identify the specific support needed to best accompany informal caregivers, with the aim of improving their well-being and, ultimately, the care of the person being cared for. | - | Humanities and social sciences 8 | |
| 2020 | Barbara LE DRIANT | Amiens | AG2R La Mondiale | Permanent neonatal hearing impairment | Accompanying parents faced with the diagnosis of permanent neonatal deafness: analysis of difficulties and needs. | Hearing is an essential function for communicating with others. It is not unusual for a newborn to present with a severe hearing anomaly (1 per 1000 births), even though the parents are hearing. Without early diagnosis, hearing loss exposes the child to a risk of delayed development of language, learning and social skills. The decree of April 23, 2012 has systematized the early identification of deafness in newborns, in order to intervene appropriately by ensuring the child's development is as harmonious. as possible. This medical benefit is only optimal if it is coupled with long-term support for parents, and this right from the maternity ward, as the diagnosis often leaves parents very worried and at a loss. Objectives: The aim of this project is to study how each parent experiences the diagnostic process, from screening to caring for their child, and to identify the difficulties encountered and the essential resources for improving the quality of support. Method: Parents with no family history of deafness will be included, whose child born between 2012 and 2017 presents a bilateral, moderate to profound deafness at birth, with no other associated disorder, and whose genetic origin is confirmed. Data collected through interviews and questionnaires will be analyzed both qualitatively and quantitatively. Expected results and impact: A better understanding of parental experiences and needs will enable the development of optimized support programs, by raising awareness and training medical and social staff in existing strengths and limitations. Relevance of the project: As children grow up within their families, it is essential to find ways of supporting them. It is essential to find ways of easing the delicate process of diagnosing deafness by developing and improving support for parents, based on their experiences, needs and expectations. | Hearing is an essential function for communicating with others. However, it is not uncommon for a newborn to have a severe hearing impairment (1 in 1,000 births), even though their parents can hear normally. Without early diagnosis, hearing loss exposes the child to a risk of delayed language development, learning and social skills. The decree of April 23, 2012 systematized the early identification of deafness in newborns, in order to intervene appropriately and ensure their development is as harmonious as possible. This medical benefit is only optimal if it is coupled with long-term support for parents, starting in the maternity ward, as the diagnosis often leaves parents very worried and helpless. The SURGENEA project made it possible to study how each parent experiences this diagnostic journey, from screening to care. The SURGENEA project made it possible to study how each parent experiences this diagnostic journey, from screening to care. The SURGENEA project made it possible to study how each parent experiences this diagnostic journey, from screening to care. The SURGENEA project made it possible to study how each parent experiences this diagnostic journey, from screening to care. The SURGENEA project made it possible to study how each parent experiences this diagnostic journey, from screening to care. The SURGENEA project made it possible to study how each parent experiences this diagnostic journey, from screening to care. The SURGENEA project made it The SURGENEA project has made it possible to study how each parent experiences this diagnostic journey from screening to the care of their child; to identify the difficulties encountered and the essential resources needed to improve the quality of support that should be offered to them. The study conducted among 70 families shows how much the announcement of a deafness diagnosis causes emotional difficulties for parents, who need to be supported as quickly as possible and in a way that takes into account the needs they express. Mothers and fathers do not always experience the same emotions or express the same needs. The support programs offered by medical and social services must therefore take into account the specific needs of each parent. Call for research projects in the humanities and social sciences – Mid-term report 15 The child growing up within their family. It is essential to seek ways to facilitate the delicate process of diagnosing deafness by developing and improving the support provided to parents according to their experiences, needs, and expectations. | Humanities and social sciences 8 | |
| 2020 | Karinne GUENICHE | Paris | Foundation For Rare Diseases | Mayer-Rokitansky-Küster-Hauser syndrome | Evolution of the psychosocial impact of the diagnostic announcement of Rokitansky syndrome: EIPSAMRKH5 | The announcement of an absence of uterus and vagina (MRKH syndrome), usually during adolescence, leads to intense psychological suffering linked to the difficulty of accessing sexual life and motherhood. We recently carried out a large-scale study of the overall and sexual quality of life of 131 MRKH patients who completed validated self-questionnaires (WHOQOL-bref, FSFI, FSDS-R). Among them, 40 benefited from a more in-depth assessment of the psycho-social impact of the diagnosis, using a semi-structured interview and Rorschach and TAT projective tests to evaluate their psychic functioning at a given point in their history. The results showed an alteration in sexual quality of life, with a genuine experience of disability, and unexpectedly, addictive eating disorders (anorexia/bulimia) or sports disorders, and an over-representation of heterosexual orientation compared with the general population. The absence of a uterus led to severe suffering. Projections of access to biological motherhood were essentially focused on GPA. In the light of these data, derived from real encounters with patients, our aim is to assess the evolution of these results, by re-evaluating the psychic functioning of the same 40 young women using the same methods, more than 5 years after the first evaluation. We hope to find an improvement in overall and sexual quality of life, and a disappearance of addictive disorders at a distance from the diagnosis. The desire to have children is likely to be expressed more frequently and more painfully, given the advancing age of young women. The identification of psychosocial prognostic factors should enable us to improve our already multidisciplinary care practices, particularly in the psychological field. This could also benefit other women with rare diseases affecting their sexuality and/or fertility. | Humanities and social sciences 8 | ||
| 2020 | Nathalie ANGEARD | Paris | Foundation For Rare Diseases | Congenital central hypoventilation syndrome | Attentional resources in children with Ondine syndrome | Ondine syndrome is a rare disorder characterized by severe alveolar hypoventilation (hypoxemia and hypercapnia) linked to an anomaly in the central autonomic control of breathing. The disease often reveals itself in the neonatal period, and management may involve lifelong ventilatory assistance. Children with Ondine syndrome nonetheless present significant learning difficulties, despite rehabilitative treatment. Although few studies have focused on cognitive disorders, recent data have highlighted deficits in the attentional sphere. These initial findings are in line with the everyday complaints reported by parents, and could explain the learning difficulties. The aim of this multidisciplinary project is not only to assess the overall attentional capacities of children aged 6 to 16 with Ondine syndrome, but also to study the impact of spontaneous breathing on attentional processes (and vice versa) through a dual-task situation. The study will involve 20 patients aged 6 to 16 with Ondine syndrome at Robert Debré Hospital, and 40 age- and sex-matched control subjects from schools in the Paris region. In the 1st phase, we will evaluate the sustained, divided and selective attention capacities of children with Ondine syndrome, in comparison with the control group. In a 2nd phase, we will place Ondine patients in a situation where they will have to manage their breathing alone or at the same time as performing an attention task. Highlighting the cognitive cost of breathing in dual-task situations in this rare disease will provide a better understanding of the limitations faced by these patients, whether in learning situations at school or in their social interactions. | Humanities and social sciences 8 | ||
| 2020 | Pierre LOMBRAIL | Paris | Foundation For Rare Diseases | Cystic Fibrosis | Patient Experience of the Cystic Fibrosis Pathway during the Covid-19 pandemic | The Covid-19 crisis put healthcare systems to the test, and patients, particularly those with rare and chronic diseases such as cystic fibrosis, may have encountered specific management difficulties during this period. Recent information shows that patients and their families mobilized strongly during the crisis period to avoid infection by Covid-19, by implementing new strategies or reinforcing barrier measures already anchored in the lives of these patients. The ExPaParM-Covid project is a collaborative research project involving patients and parents trained as "co-researchers", clinicians and researchers. It will provide an opportunity to interview patients and parents directly about their experience during the health crisis, in order to understand the specific needs that may have emerged for their care, health and life paths. Based on the analysis of this experience, discussions will be held with teams from specialized cystic fibrosis hospitals. This will also be an opportunity to gather the experience of caregivers during the crisis, identifying problematic or beneficial elements to be maintained outside the crisis period, or to be anticipated in the event of a future health crisis. Finally, this work on the cystic fibrosis community will enable us to engage in a dialogue with the networks and patient associations of other rare diseases, and to make an international comparison of crisis management. ExPaParM- Covid will thus provide an opportunity to cross-reference the experience of patients and caregivers during this exceptional period, with the aim of drawing up scenarios for management in times of health crisis, and identifying effective levers for the future. | Patients and parents emphasized that the organization of CRCMs, particularly structured multidisciplinary teams (Rare Disease Plans and international cystic fibrosis recommendations) with a good understanding of their situations and follow-up needs, made it possible to maintain continuity of care in various ways, despite the upheavals in hospital organization they faced when they had to be hospitalized. Their long-standing relationships with caregivers in the community (nurses, physical therapists, pharmacies) made it possible to negotiate and adapt their home care according to their degree of autonomy. The patients' usual pharmacies ensured the supply of their treatments and masks. The patients' living conditions during the crisis also reflected pre-crisis conditions, in particular individual socio-economic or family factors (small homes making confinement difficult, distance or isolation from their families, working conditions that were more or less flexible depending on their employer) or psychological factors (level of anxiety, sense of control over the disease and risks). Various measures have made it possible to maintain care during this period, both in CRCMs and in towns. Telephone or video consultations (WhatsApp, etc.), sometimes combined with home measurement devices (spirometry, pulse oximeter, scales), as well as remote exchanges with CRCM psychologists and APA coaches, were seen by patients as new opportunities for their future follow-up by the CRCM. Digital tools for remote patient support for respiratory physiotherapy or adapted physical activity were set up in some CRCMs and distributed nationally. Information was made available to patients and families by the associations Vaincre la Mucoviscidose and Etoile des Neiges on their websites, with communication adapted to the different stages of the crisis. Lung transplantation is the only treatment for patients with the most severe cystic fibrosis. In a recent international study, the conditions for access to transplantation in France were identified as the main factor explaining the best median survival rate among developed countries with a single health insurance system. In our country, almost half of the people living with a lung transplant are cystic fibrosis patients. The postponement of transplants during the COVID crisis could have had dramatic consequences for these severely ill patients, who accounted for an average of 100 lung transplants each year between 2011 and 2019. In 2020, this number fell to 53. This could have resulted in a doubling of the number of deaths, which has averaged 50 per year since 2015. However, the number of deaths in 2020 remained at the lowest level of previous years (45). | Humanities and social sciences 8 | |
| 2020 | Yannick LE HENAFF | Ruen | Foundation For Rare Diseases | Congenital diaphragmatic hernia | Engagement in physical activity and sport in adolescents with diaphragmatic dome hernia | cHernia of the Diaphragmatic Cupola (HCD) is a rare congenital condition, most often diagnosed in the ante-natal period, characterized by incomplete or absent formation of the diaphragm during uterine life, enabling abdominal organs to ascend into the thorax. According to several studies, the quality of life and physical capacities of these children, who undergo surgery from birth, appear to be correlated with their level of physical activity and sport, which is also lower in these individuals. Research conducted to date, while leading to this observation, has not investigated the reasons for the low rate of sporting activity among these children. The aim of this research is therefore to assess the level of physical activity in children followed up by the Diaphragmatic Hernia Reference Center, and above all to understand the possible obstacles, when encouraged by the referring physician. After highlighting the obstacles and facilitators (and identifying the underlying mechanisms), a support program will be co-constructed with the APEHDia patient association to support parents and children at every stage of the treatment process. Our hypothesis is that the relationship with physical activity, in addition to objective somatic reasons (cardiac and respiratory), is constructed in relation to CDH and the traumas it can generate, but also in relation to different forms of socialization, which help to define the relationship parents have with their children's bodies and physical activity. The diversity of the experiences of these children and their families is thus partly reflected in the complex combinations of inequalities and life trajectories that will be unravelled. The methods used will be essentially qualitative, based on life-story interviews with 20 parents and 10 teenagers between the ages of 14 and 18. | La hernie de la coupole diaphragmatique (HCD) est une maladie rare congénitale qui touche environ un fœtus sur 3500 (Langham et al., 1996). Elle est généralement diagnostiquée en période anténatale et consiste en une formation incomplète ou absente du diaphragme pendant la vie utérine permettant l’ascension d’organes abdominaux dans le thorax ; ceci peut avoir de graves conséquences sur la survie de l’enfant à sa naissance et sa santé sur le plus long terme, malgré une chirurgie à la naissance. Les enfants opérés d’une HCD sont suivis au long cours par une équipe pluridisciplinaire de centre de référence (Lally et al, 2008 ; Pennaforte et al, 2013). Nous avons tenté dans notre enquête qualitative d’éclairer les logiques d’engagement dans les activités, d’ailleurs très diverses, et leur évolution chez ces enfants atteints d’une HCD. Quel sens est attribuée à l’activité physique : pratique de santé, ou au contraire espace à risque ? Comment, plus largement, l’activité physique de ces adolescent.es est-elle modulée par l’expérience de la maladie ? Ces EOHCD font-ils l’objet d’une attention particulière, voire d’une protection particulière ? 1) Des logiques sociales multiples de mise à distance de l’activité physique 1.1. Les logiques de vulnérabilisation Intéressons-nous dans un premier temps à la manière dont les vulnérabilités physiques de l’enfant sont signifiées au sein de la famille, et conduisent à des logiques d’action associées. « C’est un cérébral » : la naturalisation des vulnérabilités physiques de l’EOHCD Dans de nombreuses familles, on observe des processus de naturalisation du moindre intérêt de l’enfant pour l’AP d’une part, et de moindres dispositions sportives d’autre part ; on le présente alors comme un « cérébral » ; et cela sans questionner la manière dont ce manque d’appétence ou de dispositions pour la pratique physique a pu se construire. Un rapport au corps particulier se construit chez ces enfants. La plupart se considère comme plus fragile. Damien se présente comme « un ficello » et précise qu’il risque de « se faire découper » dans les sports collectifs, intégrant par la même la dangerosité de certaines pratiques sportives. Cette perception de la fragilité s’instruit dans le travail de responsabilisation de l’enfant qu’effectuent les parents à cet égard. L’EOHCD est très tôt sensibilisé au risque, selon un processus de délégation de la surveillance. La mère de Salomé insiste ainsi auprès de sa fille pour qu’elle les contacte immédiatement en cas de maux de ventre – elle a d’ailleurs un téléphone précisément pour cela. Bon nombre de parents, mais aussi d’EOHCD, ont intériorisé cette fragilité. Le sport perçu comme espace à risque : influer sur les activités sportives encadrées Le sport est diversement vécu comme un espace à risque par les familles (voir partie 2). Il n’en reste pas moins que, même lorsque l’enfant est présenté comme « guéri » ou « non malade », les parents gardent un œil vigilant sur les activités sportives encadrées, en particulier aux premiers âges de la vie. Les EHCD ne débutent pas nécessairement plus tard les activités sportives comparativement aux autres membres de la fratrie. Ils font toutefois l’objet d’une attention toute particulière aux risques de contamination, à la fatigue, et plus globalement à leur fragilité. Dans une moitié des familles enquêtées, les choix des activités sportives encadrées sont limités à celles considérées comme les moins brutales et les moins à risques et les formes compétitives sont évitées. Les sports pratiqués par ces enfants enquêtés sont assez éloquents : peu font des sports collectifs – quand bien même la fratrie ou les parents ont pu en faire –, et les filles font beaucoup de danse, et les garçons du tennis de table ou du badminton. Limiter le sport pour se protéger en tant que parent Un aspect que met en lumière cette enquête est le non encouragement de la pratique encadrée comme résultant de la volonté de se ménager en tant que parent. La HCD est pour tous ces parents une épreuve. Sa prise en charge a généré des formes d’épuisement multiples, déjà bien identifiées dans les travaux sur les aidant.es (Le Hénaff et al., 2023 ; Sukik, 2007). Ces parents sont, de fait, impliqués dans le travail de santé, mais s’engagent également dans tout un ensemble de tâches de traduction et de négociations vis-à-vis des crèches, écoles, proches, etc. Les autres activités, comme les activités sportives, peuvent alors être considérées comme secondaires. Certaines familles préfèrent alors se préserver, pour se concentrer sur des aspects qu’ils considèrent comme plus essentiels, dans une situation de choix contraint. Un travail de santé genré qui prime sur les principes éducatifs sportifs L’investissement plus important des mères dans le travail de santé et, plus largement, dans l’éducation des enfants limiterait le poids des pères dans l’un des rares domaines où leur poids est prépondérant, à savoir l’initiation aux pratiques sportives. Le travail de santé des mères est en effet cristallisé par la maladie. Les mères se déclarent, dans leur grande majorité, comme plus anxieuses, plus réticentes aussi à la pratique du sport que les pères. 1.2. Des activités trop peu inclusives : le sport comme expérience négative On peut également faire l’hypothèse que les activités sportives encadrées (en EPS ou en association sportive) sont trop peu inclusives, et donc vectrices d’expériences négatives pour ces familles et ces enfants. Certains ont d’abord fait l’objet de rebuffades dans le système associatif, avant même l’inscription, en raison des difficultés supposées de prise en charge de l’enfant. Le fonctionnement de nombre d’associations sportives, avec entraînements et compétitions, ne correspond pas aux réalités physiques de plusieurs de ces adolescent.es, qui sont amené à manquer régulièrement des entrainements ou à devoir s’arrêter en cours de séance. La trajectoire sportive, en club, de ces EOHCD est d’ailleurs marquée par des abandons multiples. Pour beaucoup, donc, l’activité sportive encadrée est source d’expériences négatives. D’abord car ces EOHCD font, dans ces espaces, l’expérience de leurs limites physiques, voire d’une mise à l’écart. 1.3. Le travail de normalisation au risque de l’activité physique L’une des tensions principales à laquelle font face les parents – et les enfants – est le dilemme de la visibilisation/invisibilisation des difficultés de l’EOHCD. La visibilisation, c’est-à-dire la verbalisation des difficultés physiques de l’enfant, en EPS particulièrement, couve le risque de visibiliser aux yeux de tous une différence. L’invisibilisation au contraire, afin d’éviter la stigmatisation, est vectrice de mise en difficulté. Pour les EOHCD, le sport est un espace à risques car il expose potentiellement la maladie aux yeux des autres. Pour Ewenn, il lui faut prendre de la Ventoline. Ce que l’on souhaitait cacher ou faire oublier est ici visibilisée. Cette logique de la gestion de l’information prend ici une forme particulière en raison de la rareté de l’affection, mal connue et qui implique un délicat travail de traduction, y compris auprès des enseignant.es. La normalisation du quotidien de l’enfant est un objectif pour la totalité des parents rencontrés. Mais, face à l’activité sportive, elle prend des formes très différentes, entre celles et ceux qui tentent de faire du sport pour « normaliser » ou au contraire celles et ceux qui évitent cet espace afin que l’enfant ne soit pas être confronté à ces limitations. 2) Le sport et les principes éducatifs : la maladie comme élément modulateur Si ces EOHCD pratiquent globalement peu de sport encadré, des différences importantes existent entre les familles auxquelles nous tentons de donner sens. Nous distinguons ici trois idéaux-types. 2.1 Le sport comme stratégie éducative centrale Les enfants du premier idéal-type pratiquent, comparativement aux autres EOHCD, plus de sport. Ils sont d’ailleurs les seuls pratiquer deux activités sportives en parallèle, et notamment des sports collectifs (y compris du rugby) ou de force (crossfit). L’activité sportive, en club, est un principe éducatif central, avec un intérêt plus ou moins marqué pour la compétition. Les logiques éducatives de ces parents impliquent d’exposer les enfants à des difficultés voire à des expériences difficiles qu’il s’agit d’apprendre à surmonter. Comme dans les travaux de Mennesson et al. (2016), les parents sont ici eux-mêmes sportifs, voire très sportifs, et ont, ou ont eu, une pratique compétitive, ce qui agit par imprégnation dans l’engagement des EOHCD. Ces parents se démarquent, comparativement au reste de la population d’enquête, par un bagage scolaire relativement important, et se situent dans les catégories supérieures des classes moyennes. Ces caractéristiques sociales ne sont pas sans lien avec leurs capacités à mobiliser des ressources pour faire face aux éventuelles difficultés de leur enfant. 2.2. « On a pas poussé […] on proposait en fait » : les logiques sportives subordonnées au travail de santé Dans ce deuxième idéal-type, l’activité physique des EOHCD se caractérise par une intensité modérée et, à quelques rares exceptions, sans compétition. Ces enfants ont souvent pratiqué plusieurs sports, abandonnant successivement pas manque d’appétence. Pour ces familles, qui constituent la plus grosse part de notre corpus, si le sport est un principe éducatif, il n’apparaît toutefois pas central. Ici, les parents opèrent un guidage important dans les pratiques, notamment pour éviter que l’enfant s’engage dans des pratiques jugées trop risquées. Les sports pratiqués sont d’ailleurs généralement individuels et à contacts limités : badminton, danse, gymnastique, natation, tennis, escalade. Chez beaucoup de ces mères, l’activité physique a principalement une vocation sanitaire (« prendre soin de soi »). Certaines de ces familles ont évolué dans leurs attendus : la pratique sportive pouvait être un attendu qui, peu à peu, s’émousse selon une logique de réajustement. Ces parents ont « lâché du lest » dans les encouragements à l’activité sportive, témoignant d’une forme d’épuisement. 2.3 Le non engagement dans le sport : des familles socialement fragilisées et des logiques de protection prédominantes Dans cette dernière configuration, l’activité sportive n’est pas, ou peu, intégrée dans la palette des pratiques éducatives. Peu de valeurs sociales sont associées à ces activités. Ces EOHCD pratiquent pas ou peu d’activité sportive encadrée. Les parents eux-mêmes ont un passé sportif en club quasiment inexistant. Pour autant, ces familles (et ces enfants) ne sont pas inactifs. Elles privilégient des pratiques physiques informelles, en famille, sous l’œil des parents, dans des espaces considérés comme sécurisés. Ces familles se trouvent parmi les classes les plus populaires de notre corpus. Ce positionnement social fait écho aux grandes enquêtes qui montrent que ces classes sociales investissent moins les pratiques sportives encadrées. Dans trois de ces familles, il faut aussi considérer le contexte social et les configurations familiales qui limitent les engagements extra-scolaires. La mère d’Anne est célibataire, au chômage, avec quatre enfants à charge, dont trois en situation de maladie chronique (en plus d’Anne, on en compte un dysphasique et un autre autiste). Face à ses difficultés diverses, elle estime « vivre au jour le jour ». Ici, c’est l’accumulation du manque de ressources qui rend précaire les engagements. La pratique sportive en association est perçue comme intrinsèquement à risque ; et ces risques ne sont pas contrebalancés par les valeurs/bienfaits associés à ces activités. Dans les premières années de la vie (souvent jusqu’en primaire), ces EOHCD ont connu une limitation importante de leur accès aux jeux d’enfants. | Humanities and social sciences 8 | |
| 2020 | Thierry LEVEILLARD | Paris | Foundation For Rare Diseases | Retinitis pigmentosa | BlindTimee: Reconstruction of the cone-photoreceptor outer segment to recover vison in a large model of retinitis pigmentosa | - | During the BlindThimee program, we developed a genetically dominant porcine model of retinitis pigmentosa using CRISPR/Cas9 technology. This model will be used to study the potential of subretinal injection supplementation with rod-derived cone viability factor (RdCVF) to promote the reconstruction of the outer segments of the cones and thus preserve visual acuity, which depends entirely on the function of the cones, which are predominant in this animal, unlike rodents, which are most often used. | Translational Research 2019 | |
| 2019 | Christelle PEYRON | Lyon | Foundation For Rare Diseases | Narcolepsy type 1 | Development of an hypocretin-KO rat model of narcolepsy type 1 | Narcolepsy type 1 (NT1) is a highly disabling orphan disease that affects 0.025-0.05% of the population and is characterized by daytime hypersomnolence and cataplexy, often associated with hallucinations, sleep paralysis and disturbed night-time sleep. NT1 is a chronic disease that generally appears in adolescence. We have shown that NT1 is due to the death of hypocretin neurons in the hypothalamus. Cataplexy is a major symptom of narcolepsy. It is a loss of muscle tone during wakefulness (causing the patient to fall) which is induced by a positive emotion such as laughter or surprise. There is no cure for this disease, current treatments are only symptomatic and the underlying neurobiological mechanisms are poorly understood. To better understand the activation dynamics between the neuronal populations involved, we will develop an original animal model of narcolepsy. | Narcolepsy type 1 (NT1) is a highly debilitating orphan disease that affects 0.025 to 0.05% of the population and is characterized by daytime hypersomnolence, cataplexy, and disturbed nighttime sleep. Cataplexy is a major symptom of narcolepsy. It is a loss of muscle tone while awake (causing the patient to fall) that is triggered by positive emotions such as laughter or surprise. There is no cure for this disease, and current treatments are only symptomatic. Thanks to the foundation's support, we have created an original animal model of narcolepsy that allows us to study the neurobiological mechanisms that lead to the expression of cataplexy. A better understanding of these mechanisms will enable us to better target and treat them. | Models 2019 | |
| 2019 | Bertrand DIEUSAERT | Hirson | Associatif (AFAF) / IRCEM Corporate Foundation | Rare neurological diseases | COM-ATAXIE Research of innovative solutions to help communication for ataxic people (Friedreich's ataxia and close ataxias) via digital tools | - | - | Spouse with association | |
| 2019 | Jean-Paul LASSERRE | BORDEAUX | Association (BPAN) | Rare neurological diseases | USE OF YEAST FOR THE REPOSITIONING OF THERAPEUTICALLY RELEVANT MOLECULES IN BPAN AND ANALYSIS OF WDR45 VARIANTS | This project focuses on NBIA5 pathology. This human disease is a rare condition caused by mutations in a gene called WDR45. This gene codes for a protein involved in the process of autophagy, a system that cleanses the interior of the cell. The mechanisms linked to this pathology are not yet precisely understood. Furthermore, perhaps because of this lack of knowledge, there is still no specific treatment. The scientific situation is even more critical because, for certain mutations (called variants), we do not know if they are actually responsible for the pathology. To answer these questions, it is now urgent to develop new models. The yeast Saccharomyces cerevisiae represents an interesting alternative model for addressing these various challenges. This organism has a gene that is homologous (equivalent) to the human WDR45 gene. This gene is called ATG18. The three main objectives of this project are therefore: (i) to use yeast as a simplified model to dissect the molecular mechanisms affected by the absence of the Atg18p protein, particularly in mitophagy and the consequences on cellular respiration at the mitochondrial level (where cells respire and produce energy in the form of a molecule called ATP), (ii) This yeast model can also be used to assess the aggressiveness of the different mutations found in patients, (iii) finally, yeast is a good model for identifying molecules that have a positive effect on the disease. Indeed, the absence of the Atg18p protein causes a delay in the growth of the mutant compared to a normal cell. The different molecules in the drug libraries will therefore be selected very simply on the basis of their ability to restore normal growth to cells deficient in the Atg18p protein. One of the main objectives is therefore to aid in the search for chemical compounds with therapeutic potential against NBIA5. As these chemical compounds already have marketing authorization (MA), our approach is part of a therapeutic repositioning strategy. The active drugs found will be validated on patient cells. | I. The respiratory phenotype Under fermentation conditions, when yeast does not use mitochondria, no visible growth delay was observed (Fig. 1). However, on respiratory medium, where functional mitochondria are essential, a growth delay was observed at 36°C (Fig. 1). This growth delay was confirmed in liquid respiratory medium at 36°C by establishing a growth curve for the mutant strain ∆atg18 in comparison with the WT strain (Fig. 1). As our mutant strain has a respiratory phenotype, we can therefore search for pharmacological suppressors. II. Functional homology The results indicate that the presence of the yeast ATG18 gene on a plasmid in the mutated strain (∆atg18 + pATG18 strain) does indeed restore normal growth, as expected, confirming that the growth defect is due to the absence of the Atg18p protein (Fig. 3). Regarding rescue by variants 3 (∆atg18 + pWDR45_Cl3 strain) and 7 (∆atg18 + pWDR45_Cl7 strain) of the human WDR45 gene, the drop test indicates slightly lower growth than that of the wild-type strain (WT + pVide) but higher than that of the mutant strain ∆atg18 + pVide (Fig. 3). This result therefore shows that not only are the yeast ATG18 and human WDR45 genes homologous, as we had hypothesized, but also that there are several isoforms of the WIPI4 protein that are active and functional. These results therefore allow us to conclude, for the first time, that there is functional homology between the yeast ATG18 gene and the human WDR45 gene. In addition, these results can be used to carry out experiments to aid in the diagnosis of the pathogenicity of variants of unknown significance (VUS). III. Screening of molecules The screening results identified 21 molecules that have a positive effect on the growth of the ∆atg18 mutant. A literature search on these molecules shows that many of them have a direct link to either mitochondria, ROS, iron and/or copper, autophagy, or even several of these points. These drugs are currently being confirmed, and among the first to be tested, drugs X and 2 appear to be very promising. The latest results obtained with these two drugs also show efficacy in liquid media, which not only validates their positive activity but also gives an idea of the effective concentration. IV. Autophagy and mitophagy processes Under stress conditions, the persistence of the band corresponding to the GFP-ATG8 fusion protein, as well as the virtual absence of a GFP band alone, seem to reflect the difficulty of the ∆atg18 strain in establishing autophagy, compared to the WT strain. The mutant strain therefore appears to have an altered autophagic flux. The striking difference between the two Western blot profiles strongly suggests, here too, an alteration in mitophagy in the mutant yeast ∆atg18. | Spouse with association | |
| 2019 | Naziha KHEN-DUNLOP | Paris | Association (APEDHia) | Developmental anomalies and malformation syndromes | FETAL LUNG EVALUATION ON BOLD-MRI IN CONGENITAL DIAPHRAGMATIC HERNIA | The BOLD (Blood Oxygen Level Dependent) effect in MRI uses hemoglobin as an endogenous contrast agent. This technique is non-invasive and is studied on T2*-weighted sequences. It uses the natural diamagnetic properties of oxyhemoglobin (weak magnetic effect) as opposed to the paramagnetic properties of deoxyhemoglobin (strong magnetic effect). Pulmonary involvement secondary to diaphragmatic hernia (DH) disrupts fetal lung development, leading to neonatal respiratory failure. Our objective is to demonstrate that the BOLD effect in the fetal lung will differ between fetuses with normal lungs and those with DH. We will use a chemical experimental model in rat fetuses. Imaging will be performed under general anesthesia on a 4.7 T MRI scanner dedicated to small animals (Biospec 47/40 USR, BRUKER, USA). Pulmonary assessment will be based on morphological and histological criteria of the lungs, to enable correlation analyses with the BOLD response. The project has been submitted to the Animal Experimentation Ethics Committee of Paris-Descartes University. Evidence of a correlation between the BOLD response and lung lesions will be a strong argument for evaluating the BOLD effect in pregnant women as a postnatal prognostic factor for lung function in fetuses with HCD. This new parameter could thus complement the solely morphological criterion of lung volume. | Spouse with association | ||
| 2019 | Agnès BLOCH ZUPAN | Strasbourg | Without funding | Rare oral and dental diseases | AI-DENT: A virtual tool to aid in the diagnosis of rare oral diseases | Oral anomalies are often indicative of genetic diseases and have diagnostic or even predictive value. There are clinical signs and imaging techniques that can be used to establish "signatures" recognized by experts in the field. AI-DENT is a virtual diagnostic aid designed to combat diagnostic uncertainty, which remains a major issue for rare diseases with oral manifestations, and to facilitate referral to specialist centers. | - | E-health 2019 | |
| 2019 | David GENEVIEVE | Montpellier | Without funding | Developmental abnormalities | ANDD-E-RARE: A unique, multi-user digital health record | The objective of the project proposed by the AnDDI-Rares network is to develop a mobile application for patients with developmental abnormalities and physicians whose first port of call, to facilitate monitoring and care by breaking down barriers to care through the digitization of national care protocols. The content will be tailored to the patient's age, condition, and specific symptoms. | - | E-health 2019 | |
| 2019 | Géraldine MERRET | Evry | Without funding | Any rare disease | TUTOTEC’H: Development of a platform for aggregating educational video content | The aim is to use an algorithm to find all French-language tutorials covering every aspect of patients' lives and make them available on a platform, sorted by topic. Tutotec'H is a library of approved tutorials on two topics: disability and chronic debilitating illness, accessible online. | - | E-health 2019 | |
| 2019 | Sophie Bernichtein | Paris | Without funding | Rare neurological diseases | QUALVI: Creation of a collaborative database for patients affected by a rare neurological disease. | For rare neurological diseases, molecular, clinical, and therapeutic research efforts are now well recognized by professionals. However, certain crucial data on these often degenerative rare diseases are still lacking in order to fully understand their mechanism of onset and progression. The natural history of the disease, the patient's experience, and their quality of life are valuable sources of data that are too often neglected and not systematically collected. We propose to develop a tool for collecting this metadata, which will be filled out directly by the patient. | - | E-health 2019 | |
| 2019 | Véronique DANEL | Lille | Without funding | Amyotrophic Lateral Sclerosis | Tele-ALS: TeleALS is a project aimed at setting up and evaluating teleconsultations from home for patients with amyotrophic lateral sclerosis (ALS) who are receiving home hospital care, and the medical expert at the ALS reference center. | TéléSLA is a project aimed at setting up and evaluating teleconsultations from home for patients with amyotrophic lateral sclerosis (ALS) who are receiving home hospital care, and the medical expert at the ALS reference center. | Les étapes clés du calendrier prévisionnel ont toutes été réalisées grâce à une collaboration étroite entre le Centre SLA et Santélys lors de toutes les phases du projet. A savoir le cadrage, la planification, la réalisation et l’évaluation de l’expérimentation. Les formations réalisées ont permis l’appropriation des fondamentaux tant au niveau de la prise en charge spécialisée des patients atteints de SLA que des indispensables requis pour la mise en œuvre des téléconsultations dans les meilleures conditions. Le financement obtenu a permis d’accompagner la mise en œuvre du projet d’un point de vue logistique avec l’achats de matériels informatiques adaptés à sa réalisation. (cf Rapport financier) Indicateurs et résultats obtenus entre octobre 2020 et octobre 2021 : Nombre de Téléconsultations SLA planifiées et réalisées : 16 téléconsultations ont été réalisées, 5 ont été annulées, ce qui représente un taux de réalisation de 76% Nombre de TLCS par patient réalisées 16 TLCS ont été réalisées pour un total de 8 patients. Deux d’entre eux ont pu bénéficier de 4 Téléconsultations, deux de 2 téléconsultations, 5 d’une seule téléconsultation. Motif de non-réalisation des TLCS • 3 séances ont été annulées car le patient était décédé (60%) • 2 séances ont été annulées pour un problème technique, résolus grâce à la mise place des clés 4G. Nombre de kms évités au patient + km moyen entre domicile et le Centre SLA 944 kms évités pour les patients et leurs aidants Moyenne de 32kms entre les patients et le CH R.Salengro Min : 2Kms ; Max : 60Kms Nombre de TLCS réalisées en présence d’une personne de l’entourage -100% des téléconsultations ont été réalisées en présence d’un proche - 75% avec la personne de confiance - 50% avec la personne à prévenir - 8% avec une personne de l’entourage (hors personne de confiance ou à prévenir) Taux de souhait de renouvellement de la TLCS (Patient / Aidant) - 100% des patients sont prêt à renouveler la TLCS - 92% des aidants sont prêt à renouveler la TLCS Nombre de contact avec Médecin traitant avant ou après consultation - 50% des séances ont donné lieu à un appel du MT Pour 17%, l’appel était avant la TLCS et 83%, l’appel a eu lieu après. Chaque téléconsultation a fait l’objet d’un compte-rendu écrit adressé au médecin traitant Motif de l’appel au MT 17% des appels étaient pour demander une visite au domicile 83% des appels étaient pour faire un compte-rendu oral de la TLCS L’expérimentation a répondu en grande partie aux objectifs fixés et aux besoins des patients et des équipes. L’adhésion des patients/ aidants à la télémédecine est significative. Les téléconsultations permettent d’améliorer et de maintenir une prise en charge et un suivi par le centre expert SLA. La téléconsultation répond à des problématiques cliniques et rend un véritable service au patient et à son entourage. Bénéfices pour le patient et son entourage - Maintien à domicile avec la mise en place sans délai des préconisations médicales de l’expert qui permet l’anticipation des situations d’urgence - Amélioration du confort du patient en évitant les déplacements - Soutien renforcé au patient et à sa famille grâce au médecin référent du centre expert SLA et aux soignants de l’HAD Impact sur l’organisation des soins - Renforcement des liens ville-hôpital entre professionnels de structures différentes et les médecins traitants - Maintien du lien avec le patient et sa famille -Continuité du parcours de soins La valeur ajoutée de l’expérimentation: la téléconsultation assistée par l’IDE de l’HAD Sa présence et accompagnement permet de lever les freins à l’utilisation du numérique en préparant le matériel informatique et en assistant le patient et/ ou son aidant dans son utilisation L’IDE d’HAD explique également les modalités de la consultation et s’assure du confort, de la qualité d’installation du patient, du lieu approprié au domicile, de la qualité de personnes présentes avec l’accord du patient. Elle place ainsi le patient dans les meilleures conditions possibles afin de faciliter les échanges avec le médecin expert. Elle prépare la consultation médicale avec le patient : liste de symptômes et des plaintes, questions à poser. Enfin au cours de la téléconsultation, elle favorise la compréhension des informations médicales, permet la reformulation des questions et réponses, le signalement d’une expression non verbale. Elle s’assure de l’état clinique et physiologique du patient, et manipule la webcam mobile afin de réaliser des zooms nécessaires à l’observation clinique. En outre les soignants ayant assisté aux téléconsultations spécialisées progressent dans leur pratique et acquiert de l’expertise de la maladie. | E-health 2019 | |
| 2019 | Anne LETESSIER | Paris | Foundation For Rare Diseases | MEIER-GORLIN SYNDROME 1; MGORS1 (MGS; OMIM#224690; ORPHA:2554) | Molecular analysis of Meier-Gorlin Syndrome type 1: consequences of ORC1 mutation on chromatin organization and gene expression. | - | - | GenOmics 2018 - 2 | |
| 2019 | Arnaud DUPUIS | Strasbourg | Foundation For Rare Diseases | Platelet delta storage pool deficiency | Looking for gene(s) responsible for non-syndromic platelet delta storage pool deficiency. | - | - | GenOmics 2018 - 2 | |
| 2019 | Aurélien TRIMOUILLE | Bordeaux | Foundation For Rare Diseases | Oculo-auriculo vertebral spectrum | Further delineation of molecular bases of Oculo-Auriculo-Vertebral Spectrum | - | Thanks to the support of the Rare Diseases Foundation, we were able to explore the genetic causes of a rare disease called oculocutaneous otosclerosis syndrome (OAVS), which affects the development of the face, ears, and spine. By studying the genetic makeup of 23 patients and their families through exome sequencing, we identified several genes responsible for this disease. For example, we discovered abnormalities in two specific genes, ZIC3 and EYA3, which play an important role in the development of the face and ears. These findings were validated through laboratory experiments, including on animal models such as zebrafish, to understand the impact of these mutations. This work has been published in three peer-reviewed scientific journals (Trimouille et al., Clin Genet 2020; Tingaud-Sequeira et al., Hum Genet 2021; Tingaud-Sequeira et al., J Med Genet . 2022). This research has also identified other promising genes that may be involved in similar diseases, thereby strengthening our understanding of the biological mechanisms at play. In addition, it has enabled us to collaborate with European projects to continue these analyses and pave the way for new approaches to help patients and their families. | GenOmics 2018 - 2 | |
| 2019 | Carole ESCARTIN | Fontenay aux Roses | Foundation For Rare Diseases | Huntington's disease | Microglial cells: the third element for mutant Huntingtin clearance in Huntington's disease? | - | GenOmics 2018 - 2 | ||
| 2019 | Caroline MICHOT | Paris | Foundation For Rare Diseases | Myhre syndrome | DISSECTION OF MOLECULAR BASES OF MYHRE SYNDROME : IDENTIFICATION OF NEW GENES IN PRE-SCREENED PATIENTS | - | Myhre syndrome (MS) is a rare disorder characterized by short stature, joint stiffness, muscular appearance, short hands, intellectual disability, and facial features. The only known causative gene to date is SMAD4, but some patients do not have an identified mutation in this gene. The only gene known to date to be responsible is SMAD4, but some patients have no identified mutation in this gene. The aim of the study was to analyze all genes in 10 patients with MS to search for new causes. The results identified: 2 candidate genes, as yet unconfirmed, 2 patients with a variation in FBN1, a gene responsible for conditions similar to MS, and 2 patients with a variation in the WAC gene, responsible for a syndrome with intellectual disability, whose facial morphological features are suggestive of MS. Our study has therefore improved the genetic testing routinely offered to patients with MS by including WAC among the genes tested in the first line. | GenOmics 2018 - 2 | |
| 2019 | Céline GAUCHER | Paris | Foundation For Rare Diseases | amelogenesis imperfecta dentinogenesis imperfecta dentin anomalies | WES for non-syndromic dental hard tissues anomalies: ExoDent | - | Advances in molecular biology, particularly DNA sequencing and analysis, now provide widespread access to personalized genomic medicine. Rare hereditary dental anomalies have long been overlooked in these advances. The EXODENT project is part of a recent initiative to incorporate genetic diagnosis of these abnormalities into the patient pathway by confirming the value of molecular screening in order to rule out a broader pathology (a syndrome) and provide appropriate and accurate genetic counseling to these patients and their families. | GenOmics 2018 - 2 | |
| 2019 | Clémence VANLERBERGHE | Lille | Foundation For Rare Diseases | Fibular hemimelia Fuhrmann syndrome Santos syndrome FATCO (Fibular Aplasia - Tibial Campomelia - Oligosyndactyly) FFU complex (Femur - Fibula - Ulna) | Deciphering the genetic basis of fibular hypoplasia/agenesis | - | GenOmics 2018 - 2 | ||
| 2019 | Isabelle PERRAULT | Paris | Foundation For Rare Diseases | Leber congenital amaurosis (LCA, MIM204000) and other early-onset severe retinal dystrophies (EOSRD) are leading cause of incurable blindness in childhood. Sensorineural hearing loss (SHL) | GENETIC DECIPHERING OF NEW SYNDROME ASSOCIATING EARLY AND SEVERE RETINAL DYSTROPHY AND SENSORINEURAL HEARING LOSS | - | Hereditary retinal diseases are the leading cause of blindness in industrialized countries. The Ophthalmic Genetics Laboratory focuses on the earliest and most severe forms of these diseases. Despite significant advances, the natural history of this disease and the genes involved are only partially understood. Our project aims to fill this knowledge gap in order to improve care for patients and their families, with improved diagnostic and prognostic tools and the identification of therapeutic targets. The Laboratory's integration into the Institute of Genetic Diseases, Imagine, and Necker Hospital, which bring together complementary laboratories and national reference centers, is an asset for the success of this endeavor. We have identified mutations in a gene responsible for deafblindness and have recently shown that this gene may also be responsible for other diseases: ciliary dyskinesias, which are diseases affecting the respiratory tract. The new mutations can cause ciliary dyskinesias with or without neurosensory impairment. | GenOmics 2018 - 2 | |
| 2019 | Michèle STUDER | Nice | Foundation For Rare Diseases | Hereditary congenital facial paresis (HCFP3) (OMIM #614744) | Unravelling the Genetic Pathways Leading to Hereditary Congenital Facial Palsy and Associated Hearing Loss | - | GenOmics 2018 - 2 | ||
| 2019 | Nadine CERF-BENSUSSAN | Paris | Foundation For Rare Diseases | Very early onset inflammatory bowel diseases and congenital diarrheas | Whole genome sequencing in Very Early Onset- IBD and related intestinal disorders | - | GenOmics 2018 - 2 | ||
| 2019 | Piotr TOPILKO | Paris | Foundation For Rare Diseases | Neurofibromatosis type 1 (Recklinghausen disease) | Identification of markers of the cells at the origin of cutaneous Neurofibromatosis type 1 tumours and deciphering the molecular mechanisms responsible for malignant transformation of plexiform neurofibromas | - | GenOmics 2018 - 2 | ||
| 2019 | Sadia SAEED | Lille | Foundation For Rare Diseases | Severe early onset obesity | Identification of new genes and rare variants implicated in monogenic severe obesity in children from a consanguineous population. | - | GenOmics 2018 - 2 | ||
| 2019 | Sandrine BARBAUX | Paris | Foundation For Rare Diseases | The Sertoli Cell Only Syndrome (SCOS). | GENETIC CAUSES OF A RARE FORM OF INFERTILITY, THE SERTOLI CELL ONLY SYNDROME | - | GenOmics 2018 - 2 | ||
| 2019 | Suzanne LESAGE | Paris | Foundation For Rare Diseases | Early-onset Parkinson's disease (Orphanet ORPHA:2828) | Whole genome sequencing in a North African consanguineous family with an early-onset Parkinson's disease | - | GenOmics 2018 - 2 | ||
| 2019 | Cecilia MARELLI | Montpellier | GIRCI SOHO / Fondation Maladies Rares | Friedreich's ataxia | Characterization and study of the role of GAA repeat interruptions in the severity of Friedich's Ataxia Ataxia | - | GIRCI SOHO 2019 | ||
| 2019 | Cyril GOIZET | Bordeaux | GIRCI SOHO / Fondation Maladies Rares | Neurogenetic diseases | The contribution of Oxford Nanopore next-generation high-throughput sequencing to the diagnostic strategy for neurogenetic diseases | - | GIRCI SOHO 2019 | ||
| 2019 | David TOUBOUL | Bordeaux | GIRCI SOHO / Fondation Maladies Rares | Keratoconus, Ectasia | KeratoCone Eye Rub Questionnaire | - | GIRCI SOHO 2019 | ||
| 2019 | Eulalie LASSEAUX | Bordeaux | GIRCI SOHO / Fondation Maladies Rares | Albinism | Implementation of a next-generation sequencing analysis of a panel of genes involved in incomplete forms of albinism. | - | GIRCI SOHO 2019 | ||
| 2019 | Gauthier RATHAT | Montpellier | GIRCI SOHO / Fondation Maladies Rares | Cervical cancer | Validation of the tool for detecting circulating tumor cells released during cervical cancer surgery. | - | GIRCI SOHO 2019 | ||
| 2019 | Guillaume MARTIN-BLONDEL | Toulouse | GIRCI SOHO / Fondation Maladies Rares | Progressive multifocal leukoencephalopathy (PML), infectious diseases, | Lymphocyte expression of immune checkpoint molecules during progressive multifocal leukoencephalopathy (PML). | - | GIRCI SOHO 2019 | ||
| 2019 | Maella SEVERINO-FREIERE | Toulouse | GIRCI SOHO / Fondation Maladies Rares | Cutaneous mastocytosis | Hydroxychloroquine in isolated cutaneous or indolent systemic mastocytosis with associated skin involvement: proof-of-concept study | - | GIRCI SOHO 2019 | ||
| 2019 | Pascal AMEDRO | Montpellier | GIRCI SOHO / Fondation Maladies Rares | Hereditary heart disease | Quality of life and physical activity in children with hereditary rhythmic disease or cardiomyopathy of genetic origin: a multicenter prospective cross-sectional controlled study. | - | GIRCI SOHO 2019 | ||
| 2019 | Yves DULAC | Toulouse | GIRCI SOHO / Fondation Maladies Rares | MARFAN syndrome | Effect on quality of life of a therapeutic education program in patients with Marfan syndrome: an observational, prospective, multicenter study | - | GIRCI SOHO 2019 | ||
| 2019 | Pascale BOMONT | Montpellier | Foundation For Rare Diseases | Giant axonal neuropathy | Hit to Lead discovery for Giant Axonal Neuropathy | - | - | Hit to lead 2019 | |
| 2019 | Yvon TROTTIER | Strasbourg | Foundation For Rare Diseases | Huntington's disease | Hit-to-lead development of amyloid aggregation modulators in Huntington's disease and pioneering a new synergic strategy to potentiate their use in therapy | - | Huntington's disease (HD) is an incurable neurodegenerative disease that affects approximately 6,000 patients in France. It is caused by a protein called huntingtin (HTT) that becomes insoluble and accumulates in the form of aggregates in our tissues, causing, among other things, premature degeneration of the brain. The properties of these aggregates link HD to the vast and devastating family of amyloid diseases such as Alzheimer's and Parkinson's. The case of familial amyloid polyneuropathies shows that using a small molecule as a drug to block the aggregation of an amyloid-like protein can be an effective treatment. This strategy works well in this particular case because the drug fits perfectly into a defined pocket on the surface of the amyloid-like protein responsible for this disease. However, in HD, as in many other amyloidoses, the amyloid protein responsible has a very flexible and poorly defined three-dimensional structure, which explains why no molecule has been found that can bind to it and prevent its aggregation sufficiently effectively. We therefore proposed to develop an innovative combination therapy, in which different inhibitors could act synergistically to prevent HTT aggregation more effectively than when used alone. Such a combination approach has never been developed for amyloid diseases, although it is commonly used for the treatment of AIDS or cancer and is now also being developed for other brain diseases. The Rare Diseases Foundation previously funded an initial project (FONDATION_HTSTM – G201503) that enabled us to screen 7,280 compounds to identify those that inhibit the aggregation of toxic HTT fragments. To do this, we used a dedicated technology that we had previously developed, called SynAggreg. This technology is used to identify compounds that inhibit the aggregation of amyloid-like proteins and is sensitive and accurate enough to determine whether combinations of compounds have a synergistic effect—meaning that low doses of combined compounds are more effective than higher single doses of individual compounds. This initial project enabled us to select 29 primary hits based on their efficacy, their drug potential based on their chemical structure, and the availability of the compounds in quantities compatible with our needs. Based on the success of this first project, the Rare Diseases Foundation funded our current project, the main goal of which was to test combinations of two of these 29 primary hits, corresponding to a total of 406 combinations, in order to discover combinations of compounds that inhibit and act synergistically to inhibit the aggregation of toxic HTT fragments. In addition, this new project has enabled us to screen several other compound libraries (a total of more than 10,000 compounds will have been screened during our two consecutive projects) and also to test structural analogues of these 29 primary hits in order to gain "structure-function" information, i.e., to understand how partial modifications to a compound's structure can affect its effectiveness as an aggregation inhibitor. We obtained excellent results during this project. 1. Primary screening sessions confirmed the high robustness of the technology and enabled us to identify and confirm new aggregation inhibitor compounds, as well as gain structure-function information on certain primary hits. 2. Combinatorial screening enabled us to discover, with a high degree of confidence (high reproducibility of results), 10 pairs of synergistic compounds among the 406 combinations tested. This result shows that it is possible to easily discover such synergistic pairs, as they represent approximately 2.5% of the pairs tested. 3. We even combined up to four compounds and demonstrated that the effectiveness of two-by-two combinations of compounds extends to a larger number of combinations, which is further proof of the robustness and accuracy of our technology, as well as the theoretical potential of a combinatorial strategy targeting the inhibition of amyloid-type protein aggregation. | Hit to lead 2019 | |
| 2019 | Guillaume CANAUD | Paris | IRCEM Corporate Foundation | Hypergrowth syndromes | Hypergrowth syndromes: improving patient outcomes | - | Patients suffering from CLOVES syndrome (Congenital Lipomatous Overgrowth, Vascular Malformation, Epidermal Nevi) or related disorders (PROS, also known as dysharmonious overgrowth syndromes) present with major deformities and vascular swelling due to mutations in a gene called PIK3CA. This gene regulates cell proliferation and growth. When it is overactivated, it causes excessive growth in the parts of the body affected by the mutation. The clinical presentation of patients therefore varies greatly depending on the number of tissues affected, ranging from macrodactyly (isolated finger involvement) to very severe forms affecting the entire body, such as CLOVES syndrome. Due to this variability, the prevalence of these syndromes is unknown. In the most severe forms, there are fatty tissue growths, vascular malformations, scoliosis, skeletal manifestations such as major bone enlargement, and deformities of organs such as the brain or kidneys. Until now, there has been no cure available for these patients, whose prognosis could be serious in the short or medium term and for whom the only treatment options were symptomatic treatments and, in the most severe cases, mutilating surgery to preserve healthy organs or limbs. Finally, these syndromes are frequently associated with chronic pain and have a major impact on patients' quality of life and social life. The PIK3CA gene is mutated in a number of cancers (particularly breast and colon) and is a therapeutic target for the pharmaceutical industry. The PIK3CA mutations in cancers are the same as those found in patients with CLOVES syndrome and related disorders. In 2016, we created the first mouse model of dysharmonious overgrowth syndrome and identified a pharmacological inhibitor of PIK3CA (BYL719, also known as alpelisib) developed by Novartis in breast oncology, demonstrated its effectiveness in our experimental model in preventing and improving malformations, and based on the results obtained in animals, we were authorized to treat 19 patients (aged 4 to 52) with a very severe form of the disease. These authorizations from the French Medicines Agency (ANSM) were exceptional because, at that time, alpelisib was in the final phase of clinical trials in the US for women with breast cancer with PIK3CA mutations. The clinical results in our 19 patients were spectacular, with improvements in quality of life (cessation of bleeding, disappearance of pain, withdrawal from morphine treatments, disappearance of fatigue, return to school, etc.), but were also accompanied by a reduction in the volume of the various malformations. These results were published in the journal Nature (Venot Q... Canaud G. 2018). My clinical department at Necker Enfants Malades Hospital quickly became the global center for the treatment of these pathologies. We have a cohort of nearly 4,000 patients, 155 of whom, aged 6 months to 72 years, are being treated with BYL719 (alpelisib). In partnership with Novartis, we conducted the EPIK-P1 clinical trial (NCT04285723), a real-world trial in the first 57 patients worldwide treated with alpelisib for dysharmonious overgrowth syndrome, the results of which were presented at ESMO 2021 and confirm our initial observations. These data were submitted to the US Food and Drug Administration (FDA) and led to an on-site inspection of our data at Necker. This 15-day FDA inspection confirmed the integrity of our data and, on April 6, 2022, authorized accelerated marketing of alpelisib for patients aged 2 years and older with dysharmonious overgrowth syndrome secondary to PIK3CA gene mutation. At the same time, we continued our fundamental research. With the Foundation's support, we developed new preclinical models that gave us a better understanding of how the disease develops and progresses, and also enabled us to identify blood markers to monitor the progression of these diseases and their response to treatment. These various studies are currently being published in international scientific journals. | Outside AAP | |
| 2019 | Daniel ABERDAM | Paris | Foundation For Rare Diseases | ANIRIDIA; EYE DISEASE | Production of iPSCs derived from patients with aniridia, a rare ocular disease caused by nonsense mutations in the PAX6 gene. | Aniridia is a rare eye disease in which one of the most disabling symptoms is progressive corneal opacification (PCO). There is currently no treatment available. We have modeled ARK on limbal stem cells and identified by high-throughput screening two molecules already used in medicine for severe depression that restore the activity of mutated PAX6. The aim of our project is to validate these two potential drugs for their eventual repositioning. To this end, we aim to derive induced pluripotent stem cells from the blood of 3 KRG patients. This will enable us to validate both molecules in the genomic/epigenetic context of the patients to be treated. As the cornea is easy to target with a topical formulation, the validation of these two molecules should enable the rapid development of a drug applicable in eye drops for the treatment of aniridia. | Congenital aniridia is caused by heterozygous mutations on the PAX6 gene leading to reduced amount of PAX6 protein (haploinsufficiency), abnormal eye development and aniridia-associated keratopathy (AAK). This progressive corneal opacification resembles late-onset limbal stem cell (LSC) deficiency, leading to disrupted corneal epithelial renewal. The factors leading to AAK are not known, and defects in native LSC differentiation and/or features leading to ocular surface dysfunction such as inflammation and loss of innervation could contribute to the development of AAK. Here, we produced induced pluripotent stem cells (hiPSCs) from three AAK patients and examined whether PAX6 haploinsufficiency affects LSC lineage commitment. During LSC differentiation, characterization of the AAK lines showed lowered PAX6 expression as compared to wild type (WT) controls, and expression peak of PAX6 during the early phase of differentiation was detected only in the WT hiPSC lines. Whether this reflects developmental regulation remains to be studied further. Nevertheless, the AAK-hiPSCs successfully differentiated towards LSC lineage, in line with the presence of LSCs in young patients before cell loss later in life. In addition, patient-specific LSCs showed similar wound healing capacity as WT cells. However, extensive batch-related variation in the LSC marker expression and wound healing efficacy was detected without clear correlation to AAK. As development and maintenance of corneal epithelium involves an interplay between LSCs and their environment, the AAK-hiPSCs generated here can be further used to study the crosstalk between LSCs and limbal niche including e.g. corneal immune cells, stroma cells, and neurons. | Models 2019 | |
| 2019 | Fabrice ANTIGNY | Le Plessis Robinson | Foundation For Rare Diseases | PULMONARY ARTERIAL HYPERTENSION | Role of Orai1 in the pathogenesis of pulmonary arterial hypertension | Pulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary artery (PA) blood pressure, ultimately leading to right ventricular failure. It involves functional abnormalities of PA smooth muscle and endothelial cells, as well as cardiac cells. Our preliminary results indicate that Orai1 calcium channels contribute to pulmonary artery smooth muscle cell dysfunction. We aim to generate a rat strain smooth muscle cells unable to produce a functional Orai1 protein. This animal model will enable us to study precisely the role of Orai1 in the pulmonary circulation, and provide evidence for the involvement of this Orai1 channel in the development of PAH. Ultimately, we aim to identify new therapeutic targets in PAH. | - | Models 2019 | |
| 2019 | Frederic RELAIX | Creteil | Foundation For Rare Diseases | Duchenne Muscular Dystrophy | Accurate preclinical modeling and treatment proof-of-principle for Duchenne Muscular Dystrophy | Duchenne muscular dystrophy (DMD) is a rare neuromuscular pathology that mainly affects boys, resulting in the loss of dystrophin. Patients present with progressive muscle weakness, lose the ability to walk by the age of 10-12 and die of cardiorespiratory failure in the second or third decade of life. Persistent failures to transfer preclinical research in mice to humans demonstrate the need for laboratory animal models that faithfully mimic the disease state in humans. The preclinical models of Duchenne muscular dystrophy we aim to develop correspond to frequent human mutations and will enable us to design personalized genome-editing strategies integrated with our ambitious ongoing research program on preclinical therapeutic development. | La dystrophie musculaire de Duchenne (DMD) est une maladie neuromusculaire rare qui touche principalement les garçons. Elle est due à une mutation du gène DMD (sur le chromosome X) entraînant une perte de la dystrophine. La DMD est la myopathie héréditaire la plus répandue chez les enfants, avec une incidence de 1 pour 3 300 naissances masculines vivantes (référence ORPHANET ORPHA:98896). Les patients présentent une faiblesse musculaire progressive qui commence dès le plus jeune âge et perdent leur mobilité vers l'âge de 10-12 ans. Les personnes atteintes de DMD présentent également une cardiomyopathie à apparition tardive et meurent d'une insuffisance cardiorespiratoire au cours de la deuxième ou troisième décennie de leur vie. Malheureusement, il n'existe aucune option thérapeutique pour guérir la cause de la maladie, et les tentatives d'essais cliniques n'ont pas donné de résultats concluants. En l'absence de thérapies appropriées pour la DMD, les patients sont généralement traités par corticostéroïdes, ce qui retarde légèrement l'évolution de la maladie et amène les patients à un besoin d’utilisation d’appareillage tel le fauteuil roulant. Depuis les années 1990, le recours croissant à l'assistance respiratoire et cardiaque a permis d'allonger la durée de vie des patients, de la fin de l'adolescence jusqu'au milieu de la trentaine. Cependant, ces interventions ne permettent aucune amélioration de la fonction musculaire. La protéine perdue, la dystrophine, est exprimée dans les muscles squelettiques et cardiaques, mais aussi dans les muscles lisses et le système nerveux central. Elle a une structure permettant dans le muscle squelettique de stabiliser les complexes moléculaires permettant la contraction musculaire. Les mutations de la dystrophine altèrent donc le complexe multiprotéique associé à la dystrophine au niveau de la membrane de la cellule, ce qui entraîne une fragilité des fibres musculaires et donc des dommages induits par la contraction. Bien que les cellules abimées se régénèren, les multiples cycles de nécrose-régénération conduisent avec le temps à une altération de cette capacité de régénération. Les muscles dystrophiques sont progressivement remplacés par une fibrose étendue et un dépôt de tissu adipeux. Le gène DMD est le plus grand gène trouvé dans la nature, représentant près de 0,07 % du génome humain total. Il existe plusieurs formes, exprimées dans les tissus musculaires et non musculaires. La très grande taille du locus explique probablement la diversité élevée de mutations spontanées de la maladie. Actuellement incurable, la DMD est un candidat de choix pour les approches de thérapie génique. Le gène DMD comprend de nombreux domaines structurels, dont certains sont redondants et pourraient être inutiles à la fonction de la dystrophine. La majorité (60 %) des mutations génétiques du gène DMD trouvées chez les patients atteints de DMD sont de grandes délétions ou insertions qui décalent le cadre de lecture du code génétique de la protéine dystrophine, provoquant des défauts de structure. Des duplications, de petites insertions ou délétions et des mutations ponctuelles ont également été documentées. Les mutations de la dystrophine se trouvent principalement dans les zones proximales (plutôt des duplications) ou distales (plutôt des délétions), représentant plus de 60 % des mutations chez les patients atteints de DMD. Il est important de noter que les mutations de la DMD qui ne perturbent pas le cadre de lecture du code génétique entraînent la production d'une protéine dystrophine tronquée, mais partiellement fonctionnelle, et transforment le phénotype de la DMD en une maladie moins grave, la dystrophie musculaire de Becker (BMD). Les patients atteints de BMD présentent un large spectre d'évolution de la maladie, mais en général, ils sont moins affectés, conservent leur capacité à marcher et vivent plus longtemps que les patients atteints de DMD. Des patients atteints de BMD auxquels il manque plus de la moitié de la séquence codante de la protéine dystrophine ont été documentés, parfois associés à des cas extrêmement légers de BMD. L'existence de ces patients atteints de BMD fournit une preuve de principe que l'expression d'une protéine de dystrophine tronquée pourrait être utilisée pour traiter les patients atteints de DMD avec des variantes de protéines de dystrophine plus petites. La DMD est un candidat de choix pour les approches de thérapie génique à l'aide d'un virus adéno- associé (AAV). Les progrès récents dans les stratégies d'édition du génome ont été associés au développement du système d'édition génomique CRISPR (clustered regularly interspaced short palindromic repeats):Cas9 (CRISPR associated protein). Ce système est très polyvalent et ouvre de nouvelles possibilités pour effectuer des mutations ou des délétions génomiques efficaces et dirigées vers un site. Des études réalisées sur des lignées cellulaires ont démontré la faisabilité de cette stratégie pour les patients atteints de DMD. De plus, la restauration de l'expression de la dystrophine a été démontrée dans un modèle canin de DMD. En outre, la faisabilité du transfert vers des essais cliniques n'a pas été évaluée et il n'existe pas actuellement de procédure générale de transfert des études précliniques vers une utilisation thérapeutique qui puisse être appliquée à la plupart des troubles neuromusculaires et des maladies génétiques. De plus, d'importantes questions demeurent. Par exemple, comment concevoir des stratégies de délétion appropriées ? Comment évaluer la fonction de la dystrophine tronquée ? Quelle serait l'efficacité d'une thérapie à base de cellules souches pour la dystrophine ? Nous proposons de répondre à toutes ces questions. À cette fin, nous avons établis des modèles précliniques dont nous évaluons la pertinence quant aux caractéristiques de la maladie. Nous avons généré un modèle de rat ayant une duplication de la DMD (R-DMDdup10-17) pour fournir une preuve de principe de la réparation complète du gène de la dystrophine. Notre laboratoire est en train d’évaluer les fonctions musculaires, cardiaques et respiratoires de ces animaux au cours du temps afin de valider ce modèle. Ainsi, nous pourrons par la suite tester des traitements qui bénéficieraient aux patients afin de retarder voire soigner la maladie. | Models 2019 | |
| 2019 | Grégoire MICHAUX | Rennes | Foundation For Rare Diseases | Microvillus Inclusion Disease Familial hemophagocytic lymphohistiocytosis type 5 | Role of V0-ATPase in intestinal absorption and Microvillus Inclusion Disease | Congenital diseases of intestinal absorption can lead to diarrhea that affects the survival of newborn infants. Microvillous inclusion disease is one such condition that can only be treated by total parenteral nutrition or intestinal transplantation. To better understand the origins of this pathology, we propose to create a new model using the nematode C. elegans, whose genome is easily modifiable and whose transparency allows direct, non-invasive observation of the intestine. By combining CRISPR/Cas9 genome editing and super-resolution microscopy, we will develop an animal model that will initially enable us to better monitor the onset of the disease. Ultimately, we aim to use this model for high-throughput screening of small molecule libraries to identify potential new therapeutic approaches. | - | Models 2019 | |
| 2019 | Hamid-Reza REZVANI | Bordeaux | Foundation For Rare Diseases | Xeroderma pigmentosum type C (XP-C) | Modelling of Pigmentary abnormalities in xeroderma pigmentosum type C | Rare diseases such as those linked to abnormalities in nucleotide excision repair (NER) are useful models for understanding complex diseases and developing new therapeutic strategies. The absence or dysfunction of the NER system leads to diseases such as xeroderma pigmentosum (XP). XP type C (XPC) is one of the most common forms in Europe, the USA and Japan. Homozygous individuals have a severe, early-onset sensitivity to the sun, which damages the skin and eyes. The term XP refers to the phenotype which includes the two clinical signs: xerosis and hyperpigmentation. However, hyperpigmentation in XP patients has been neglected until now due to the lack of a relevant model. We propose to investigate the role of XPC in pigmentation using the Xenopus model, which offers a unique opportunity to study melanocyte homeostasis. | Our project, through the production of XPC-deficient embryos, should enable us to better understand the alterations induced in the epidermis as a result of this deficiency. In addition, using the Xenopus embryonic model, we will be able to gain a better understanding of the cellular and molecular mechanisms that lead to the pigmentary disturbances observed in patients. | Models 2019 | |
| 2019 | Laurence LEGEAI-MALLET | Paris | Foundation For Rare Diseases | X linked hypophosphatemia rare bone diseases | Zebrafish model of X-linked hypophosphatemia | Mutations in the PHEX gene (phosphate regulating gene with homologies to endopeptidases on the X chromosome) are responsible for X-linked hypophosphatemia, resulting in abnormalities of the appendicular and craniofacial skeleton. The role of PHEX in craniofacial ossification is currently poorly understood. The establishment of a zebrafish line expressing a loss-of-function loss-of-function mutation will provide a better understanding of the skeletal abnormalities induced by this mutation. The zebrafish is a model of choice for the study of craniofacial skeletal development, due to its many homologies with mammals. This model will also enable us to identify new therapeutic approaches, the zebrafish being an excellent model for screening molecules. Current treatments are very restrictive and do not allow us to treat all symptoms. | Models 2019 | ||
| 2019 | Marc BAUD'HUIN | Nantes | Foundation For Rare Diseases | Spondyloepimetaphyseal dysplasia SEMD | RIBObone | Ribosomes are the cell's protein "factories", and their biogenesis and function are highly regulated. Certain disorders of these "factories", most of which are genetic in origin, lead to pathologies known as ribosomopathies. Our team has identified a new form of ribosomopathy ribosomopathy responsible for a rare bone development disease: spondyloepimetaphyseal dysplasia. It is caused by mutation of a protein in the large subunit of the ribosome. Affected patients suffer from short stature, limb deformity and spinal deformity. The generation of a mouse model will reveal the pathophysiological mechanisms and better characterize the events leading to this rare disease. The RIBObone project will provide further insights into the production by ribosomes of essential factors for bone growth, and is part of a growing body of innovative research in this field. | We have identified de novo variants in the gene encoding RPL13, a protein in the large subunit of the ribosome, a complex involved in the translation of messenger RNAs into proteins. These variants are responsible for the development of spondyloepimetaphyseal dysplasia in patients with various clinical signs (short stature, genu varum, scoliosis, etc.). One approach to understanding the pathophysiology of the disease is to study an animal model carrying the variant. We therefore generated a mouse model using CRISPR/Cas9 by inserting the selected human intronic region at the end of exon 5 of the murine Rpl13 gene. The study of this model revealed that, in the homozygous state, expression of the variant did not lead to growth retardation. However, the study of bone parameters at the epiphysis of the proximal tibia, determined by microtomography (microCT), revealed that second-generation homozygous double mutant animals had a transient phenotype. These animals, derived from the crossbreeding of homozygous mutants, had a higher bone volume fraction (BV/TV) at 3 weeks, suggesting early entry into a more advanced stage of growth. Immunohistochemical analyses showed that these differences were not due to variations in osteoblastic and osteoclastic activity, suggesting an alteration in the chondrocytes of the growth plate. Studies are still ongoing on this model, in particular to evaluate the effects of mechanical activity on bone development. | Models 2019 | |
| 2019 | Massimo MANTEGAZZA | Nice | Foundation For Rare Diseases | Autism, Intellectual Disability, Epileptic Encephalopathies, Neurodevelopmental Disorders | Knock-in mouse model for studying and treating negative dominant SCN2A mutations: a novel pathological mechanism specific of autism mutants. | The SCN2A gene codes for Nav1.2 sodium channels, which are essential for neuronal excitability. Mutations in this gene are responsible for neurodevelopmental diseases such as autism. The genotype-phenotype relationships and pathological mechanisms have yet to be elucidated. Our preliminary in vitro results show for the first time that the SCN2A mutations responsible for autism induce a negative dominance effect that is not observed in any other disease. We have identified the region of the channel involved in this mechanism and are developing strategies to counteract the effect of the mutations. We propose to develop a mouse model carrying an SCN2A autistic mutation, with the aim of validating our study in an integrated system to reveal a pathological mechanism specific to autistic mutations, and to test in vivo therapeutic approaches currently under development in vitro. | - | Models 2019 | |
| 2019 | Nadia BAHI-BUISSON | Paris | Foundation For Rare Diseases | Spinal Muscular Atrophy with Lower Limb predominance Motor Neuron diseases | Investigating the cellular basis of DYNC1H1 related malformations of cortical development and spinal muscular Atrophy with lower limb predominance using targeted differentiation of human iPS cells | The formation of neuronal circuits depends in part on axonal transport, which ensures essential communication between the tip and the cell body. In humans, dynein is a major player in this transport. DYNC1H1 mutations encoding dynein are responsible for a spectrum of diseases ranging from cerebral malformations (MCD) to a form of spinal muscular atrophy predominating in the lower limbs (SMALED). This diversity of disease expression would be linked to the variable consequences of mutations on dynein functions. We propose to study the impact of DYNC1H1 mutations in the principal clinical forms (MCD and SMALED; fetal and minor forms) of the disease using patient fibroblasts harvested for IPSC formation. Our approaches will enable us to study the impact of mutations on the development of neural progenitors, motor neurons and on the development of cerebral organoids generated in our team. | Models 2019 | ||
| 2019 | Olivier GOUREAU | Paris | Foundation For Rare Diseases | Inherited retinal dystrophies (Retinitis Pigmentosa) | Modeling retinitis pigmentosa using retinal organoids derived from patient-specific induced pluripotent stem cells | Recent technological innovations have made it possible to manufacture pseudo-organs, or "organoids", from human cells transformed into stem cells (iPS cells). These in vitro models can be used to reproduce and study the cellular and molecular processes leading to specifically human diseases such as neurodegenerative diseases, particularly those affecting the retina. Our project consists in making 3D mini-retinas from cells of patients suffering from retinitis pigmentosa due to mutations in the Rhodopsin gene, to understand the development of this form of degeneration. These human iPS cell models are of major interest for understanding human diseases and designing new therapeutic strategies. | Hereditary retinal dystrophies, such as retinitis pigmentosa (RP) associated with the loss of photosensitive neurons, photoreceptors, are the leading cause of blindness or visual impairment in young adults. There is an urgent need to develop strategies for prevention and visual restoration. While the retinas of animal models of RP can be used to study certain aspects of the disease pathology, they do not exhibit all the characteristics of the human disease. Recent technological innovations have made it possible to manufacture pseudo-organs called "organoids" from human cells transformed into stem cells (iPS cells). These in vitro models make it possible to reproduce and study the cellular and molecular processes leading to neurodegenerative diseases affecting the retina, such as pigmentary retinopathies. Our project involves creating mini-retinas from cells taken from patients with RP in order to understand the development of this form of degeneration. We are interested in one of the main genes responsible for RP, rhodopsin, which codes for the light-absorbing molecule that triggers the cascade of signal transmission in photoreceptors. Our goal is to model RP caused by three specific RHO mutations by generating iPS cells from RP patients carrying RHO mutations and correcting each of the mutations through genome editing (DNA scissors: CRISPR/Cas9). We will then use well-established protocols in our team to direct the differentiation of iPS cells into retinal organoids in order to try to identify the molecular and cellular mechanisms underlying RP. These human iPS cell models are also of major interest for the validation of new therapeutic strategies based on gene correction using innovative genome editing strategies involving DNA scissors, CRISPR/Cas9. | Models 2019 | |
| 2019 | Philippe LORY | Montpellier | Foundation For Rare Diseases | Childhood Cerebellar Atrophy (ChCA) | A mouse model of Childhood Cerebellar Atrophy (ChCA) is required to decipher the pathogenic mechanism and to design a therapeutic option | Our team studies neurological diseases such as epilepsy and ataxia linked to ion channel mutations. We have just characterized new mutations in the gene coding for the Cav3.1 calcium channel, which are responsible for an extremely deleterious neurodevelopmental disease (infantile cerebellar atrophy, ChCA). These mutations are inherited in a dominant de novo fashion, are "gain of function" and most likely lead to massive neuronal death explaining the cerebellar atrophy. We aim to develop an animal model of ChCA to study the mechanism of the pathology, and to determine whether selective Cav3.1 channel blockers are capable of preventing or even treating the cerebral abnormalities caused by the Cav3.1 mutation. We have chosen to develop a mouse model, the most widely used preclinical model for which we have solid experience in exploring functions, including those of the cerebellum. | - | Models 2019 | |
| 2019 | Thierry BIENVENU | Paris | Foundation For Rare Diseases | Anorexia nervosa | Development of a new mouse model of anorexia nervosa, a knock-in mice model carrying a missense variant in the cholecystokinin A receptor (CCKAR) | Anorexia nervosa (AN) is a complex psychiatric illness whose etiology remains uncertain. Recently, an association study identified the cholecystokinin type A receptor (CCKAR), expressed in peripheral tissues and the brain. Exome analysis in a familial form of AN has identified a new variant co-segregating with AN. This p.Cys387Tyr variant is located in the C-terminal cytoplasmic region of CCKAR in the S-palmitoylation site, involved in receptor internalization. Our project consists in introducing this variant into the corresponding position of the mouse CCKAR protein in order to reproduce a human model of AN. The study will investigate the consequences of the mutation on measures of peripheral and central metabolic components associated with reward abnormalities and on behavior, and test therapeutic strategies using CCKAR antagonists. | Models 2019 | ||
| 2019 | Thomas BOULIN | Lyon | Foundation For Rare Diseases | Mutations in Neurobeachin have only very recently been identified as causing a spectrum of neurodevelopmental deficits (autism, neurodevelopmental disorders, ataxia, epilepsy, dysarthria). It is not yet identified as a specific disease. | Modeling disease-causing mutations of Neurobeachin/NBEA in the nematode Caenorhabditis elegans | Neurobeachin/NBEA is a brain protein involved in vesicular trafficking and the function and structure of synapses. Mutations in NBEA cause neurological disorders (autism, epilepsy, ataxia, dysarthria, neurodevelopmental disorders). The majority of mutations identified to date invalidate NBEA. However, direction-changing mutations whose impact is impossible to predict are also known. are also known. However, to date, there is no model system in which this type of mutation can be rapidly characterized. Confirmation of the pathogenic effect of such a variant is a key step in the "diagnostic odyssey" of rare disease patients. The aim of this project is therefore to use the powerful genetic tools available in the nematode C. elegans (e.g. genome editing by CRISPR/Cas9) to study the effect of genetic variants of Neurobeachin, and to understand the molecular and cellular processes affected by these mutations. | Neurobeachin/NBEA is a brain protein involved in vesicular trafficking, synaptic function, and structure. NBEA mutations cause a rare neurodevelopmental syndrome called NEDEGE. Most of the mutations identified to date invalidate NBEA. However, missense mutations whose impact cannot be predicted in silico are also known. We have developed approaches to validate these variants by combining CRISPR/Cas9 genome editing techniques with in vivo functional tests in the model nematode C. elegans to demonstrate the pathogenicity of these patient missense variants, thereby contributing to the diagnosis of this new rare disease. | Models 2019 | |
| 2019 | Valérie DUPE | Rennes | Foundation For Rare Diseases | Holoprosencephaly | ASSESSMENT OF FUNCTIONAL RELEVANCE OF SYNONYMOUS VARIANTS IN SHH IDENTIFIED IN PATIENTS WITH HOLOPROSENCEPHALY | Holoprosencephaly is a genetic developmental disorder characterized by cerebral and craniofacial anomalies of varying severity, the most severe form of which is cyclopia. In milder cases, the disease manifests itself as a single median incisor, close-set eyes and cleft lip and palate. The genetic causes are still poorly understood; our latest results strongly suggest that mutations known as synonyms, which have long been ignored in medicine, are involved in the development of this pathology. To test the relevance of our results, we need to determine the impact of these mutations on the development of a mammalian model, in this case the mouse. This is why we are asking the Rare Disease Foundation for the financial resources needed to generate this unique model. | In this study, we attempt to demonstrate the contribution of synonymous variants in the SHH gene. When altered, this gene causes a brain development abnormality called holoprosencephaly. Until now, synonymous variants have been systematically overlooked in clinical studies, mainly because of the large number of these variants normally present in each individual's genome. Genetic screening carried out by our team revealed that patients with holoprosencephaly were carriers of synonymous variants in the SHH gene. Our previous cell tests showed that five of these synonymous variants lead to a significant reduction in the amount of SHH protein. Our main objective in this call is to create a mouse model that will allow us to determine the relevance of these synonymous variants on the SHH protein translation program. This mouse will be a new model of the disease and will be used to determine whether a synonymous variant has clinical relevance in the onset of rare diseases. This will therefore improve the diagnostic yield of holoprosencephaly and possibly other rare developmental disorders. In collaboration with the Clinical Mouse Institute (ICS, Strasbourg), we used a classical approach based on homologous recombination to generate this mouse model. Among the synonymous variants tested in vitro, the c.921C>T p.Ser307Ser variant (879C>T in mice) was selected as the most appropriate candidate variant. In the numerous hypomorphic mouse models for Shh, abnormalities have previously been observed in the brain and craniofacial bones. The same abnormalities will be studied in the mouse model generated in this project. The presence of such a phenotype in animals carrying the 879C>T variant will validate the impact of a synonymous variant on the disease. This result will increase pathophysiological knowledge of the disease and have a direct impact on public health. | Models 2019 | |
| 2019 | Agnès DUMAS | Paris | FE IRCEM | Systemic lupus erythematosus, Juvenile idiopathic arthritis | Transition of care and well-being for young adults with juvenile idiopathic arthritis and systemic lupus erythematosus (Transcare) | Adolescence and early adulthood represent an important period for young people suffering from rare systemic inflammatory rheumatic and autoimmune diseases (RAISE): they must prepare to assume responsibility for their health independently and cope with the consequences of the disease and its treatment, while also facing the psychological and social challenges typical of adolescence. The few existing studies on the fate of RAISE patients following the transition transition show that a significant proportion are lost to follow-up or experience increased disease activity. Ultimately, little is known about the factors that promote transition in these young people. The main aim of our research is to quantify and understand the individual and organizational factors influencing the successful transition of care for these young patients, and to identify the psychosocial difficulties associated with this period. In addition, we wish to integrate the point of view of young patients, their caregivers and professionals. The research will use mixed methods (questionnaires and interviews). The quantitative component will focus on 120 young people aged 18 to 23, referred to adult services, with juvenile idiopathic arthritis or systemic lupus, followed up in the participating centers. A component of the study will also involve the parents of these young people. Several variables relating to the outcome of the transition will be quantitatively measured, both subjectively (notably the establishment of a relationship of trust with the adult physician) and objectively (through medical record data), and individual (clinical and social) and organizational (practices around the transition) factors will be analyzed. Several questionnaires will be used to collect data from young people, their parents and clinicians. | Contexte : L'adolescence et le début de l'âge adulte correspondent à une période de développement importante pour tous les jeunes. Cette période est d’autant plus importante pour les jeunes adolescents souffrant de maladie chronique comme les rhumatismes inflammatoires et les pathologies systémiques auto-immunes, telles que l'arthrite juvénile idiopathique (AJI) et le lupus systémique. En effet, au moins la moitié des jeunes atteints a une maladie active ou développe des poussées de maladie à l'âge adulte, nécessitant un suivi médical régulier. Le passage vers les services pour adultes est une période à risque qui peut être marquée par une augmentation de l’activité de la maladie, avec parfois des complications à risque vital. Or, les études étrangères sur le devenir des patients suite à la transition vers les services pour adultes montrent qu’une part importante des patients présente des ruptures dans le suivi, voire est perdue de vue (30% à 50%). Ces études ne se sont pas intéressées aux facteurs qui favorisent la transition de ces jeunes. Plus généralement, les travaux sur la transition adoptent principalement un point de vue quantitativiste et clinique et peu d’entre elles intègrent le point de vue des jeunes malades et de leurs aidants. Objectifs : L’objectif principal de notre recherche était de comprendre les facteurs agissant sur la réussite de la transition des soins, y compris du point de vue subjectif de patients et de parents ayant déjà passé l’étape du transfert vers la médecine pour adultes. Méthodes : Au total, 125 patients ayant été transférés vers les services pour adultes entre 2017 et 2020 ont été identifiés au travers de 5 centres pédiatriques situés en région parisienne, en région Auvergne-Rhône Alpes, dans l’Est et le Nord. Il s’agissait d’une recherche par méthodes mixtes croisant plusieurs sources de données. Des données médicales d’abord, recueillies dans les centres de pédiatrie et dans les centres pour adultes où les jeunes ont été adressés suite à la transition. Des données recueillies par questionnaires et entretiens approfondis ensuite, adressés et menés avec des parents et des patients en 2021-2022. Résultats : Parmi les 125 patients identifiés et pour lesquels des données cliniques ont pu être collectées dans les dossiers médicaux, les adresses de 109 patients et de 109 parents ont pu être retrouvées et 37 parents (34%) et 32 patients (29%) ont répondu au questionnaire. Au total, nous avons réalisé 38 entretiens avec 40 personnes, qui ont tous répondu au questionnaire : 18 entretiens avec des patients et 20 entretiens avec des parents, dont 2 entretiens de couple. Données des dossiers médicaux Sur les 125 participants, 4 patients ont été perdus de vus sur le plan clinique (pas de dossier retrouvé dans l’hôpital vers lequel le transfert était prévu, pas de consultation en rhumatologie dans l’hôpital vers lequel le transfert était prévu ou plus de nouvelles après la première consultation en rhumatologie). Au moment de la consultation des dossiers, les patients étaient suivis en moyenne depuis 1 an et demi et ont eu en moyenne 2 consultations en médecine adulte sur cette période. La majorité d’entre eux n’a pas fait de poussée pendant cette période, un quart a fait une poussée ou plus. Résultats des questionnaires Parmi les répondants au questionnaire patients (n=32), la majorité assistait aux consultations avec leur parents la dernière année avant le transfert (93%). Concernant la préparation à la médecine pour adultes, 40% des patients considéraient avoir été tout à fait bien préparés. Cinq patients (15%) ont éprouvé la nécessité de revoir leur pédiatre après le transfert, et le même effectif déclarait une expérience médiocre ou mauvaise de transition. Au total, 87%des patients faisaient confiance à leur médecin pour adultes. Parmi les répondants, 2 ont déclaré avoir connu une période sans aucun suivi médical en post-transfert de 12 mois ou plus ; quatre ont eu besoin de recourir à des services d’urgences médicales depuis le transfert. Enfin, les répondants déclaraient des conséquences de la maladie sur leur vie sociale (discrimination (28%, n=8), et un impact sur les études (20%, n=6). Parmi les parents répondant au questionnaire (n=37), la majorité était des mères (94%). Une minorité n’avait pas assisté aux dernières consultations en médecine pédiatrique (3%) ou aux premières consultations de médecine adulte (11%), tous pour des raisons de disponibilités. Parmi les parents ayant accompagné leur enfant en médecine adulte, seulement 6% déclarent avoir reçu un accueil inadapté et 11% déclaraient avoir mal vécu le transfert et rapportaient un sentiment de rupture dans la prise en charge. Résultats des entretiens Une errance diagnostique a été rapportée dans la moitié des cas (23/38 entretiens) et a parfois été suivie par une « errance thérapeutique ». Outre les enjeux médicaux liés à cette errance, les entretiens ont permis de mettre en évidence les effets pervers de cette errance, en particulier pour les patients porteurs d'AJI. En effet, dans plusieurs cas, les parents, les enseignants ou les camarades de classe pensaient parfois que l'enfant/adolescent mentait sur la douleur, ce qui a pu à la fois susciter une détresse psychologique importante chez les patients au moment de l’enfance et/ou de l’adolescence, mais également, a posteriori, un sentiment de culpabilité chez les parents. Les résultats des entretiens ont permis de nuancer les résultats issus des dossiers médicaux. En effet, 6 cas de rupture médicale ont été décrits par 5 patients et 1 parent, soit en raison d’une impossibilité à prendre rendez-vous avec le médecin pour adultes, soit par l’échec de la mise en place d’une relation thérapeutique satisfaisante avec le médecin d’adultes, entraînant la recherche d’un autre soignant, parfois pendant plusieurs mois, aboutissant parfois à un recours au secteur privé. Les patients et les parents interrogés ont insisté, dans les entretiens, sur l’importance de la qualité de la relation s’établissant avec le médecin pour adultes pour qualifier la réussite de la transition. Cette « qualité de la relation » se caractérisait par le temps et l’écoute accordée par le soignant au discours du patient, et était de manière très frappante principalement évoquée par des patients ou des parents ayant rapporté une errance diagnostique dans l’enfance ou l’adolescence (15/18 personnes), montrant l’importance redoublée de la prise en compte du discours des patients et l’effet que pouvait avoir cette absence de prise en compte à l’âge adulte. Conclusion et intérêt de l’étude D’après les dossiers médicaux, le taux de perdus de vue est faible dans la deuxième année de suivi en post transfert. La prise en charge médicamenteuse et l’activité de la maladie est relativement stable chez les patients non perdus de vus. Ces données plus rassurantes que celles de la littérature peuvent s’expliquer par la force du réseau établi dans ces centres grâce à la structuration mise en place au sein des filières de Santé Maladies Rares. Les données des entretiens ont permis de nuancer ces résultats en montrant que s’il n’y avait pas beaucoup de perdus de vue, il y avait tout du moins des cas de ruptures médicales. Les facteurs associés à une transition « réussie » rapportés par les patients et les parents incluaient des éléments déjà pointés par la littérature scientifique, mais les entretiens ont permis de mettre en relief l’importance de la qualité de la relation avec le médecin pour adultes, en particulier pour les patients et/ou les parents ayant connu une forme d’errance, sans doute en raison de la prépondérance de l’invisibilité des douleurs dans ces pathologies, en particulier pour l’AJI. Surtout, les entretiens ont permis de comprendre plus précisément ce qui était en jeu derrière la qualité de la relation, à savoir la confiance accordée au discours des patients, cette confiance étant basée sur le temps et l’écoute des professionnels du secteur adulte. Ces résultats, qui sont probablement valables dans d’autres contextes cliniques caractérisés par une invisibilité des symptômes, amènent à l’idée que ce qu’il serait nécessaire d’intégrer cette dimension sur la qualité de la relation soignant/soigné dans les outils d’évaluation de la transition, que ces outils soient utilisés dans le cadre du soin ou de la recherche. | Humanities and social sciences 7 | |
| 2019 | Alexandra FOUBERT-SAMIER | Bordeaux | CNSA | Multi System Atrophy | Quality of life for patients with multisystem atrophy and their caregivers | Multisystem atrophy (MSA) is a rare, progressive neurological disease caused by the loss of neurons (atrophy) in several brain regions (several systems=multisystem). Occurring between the ages of 50 and 70, it is characterized by a combination of motor disorders causing gait problems associated with genito-urinary disorders, malaise due to a fall in blood pressure (orthostatic hypotension), and speech and swallowing disorders. To date, this pathology is incurable, and its very severe prognosis leads to significant disability in 4 to 5 years, with an average lifespan of 8 to 9 years. As with other neurodegenerative diseases, the absence of curative treatment and the rapid progression of AMS patients mean that the family and especially the caregiver are at the heart of their care. The quality of life of both patient and carer is rapidly affected. In this context, the rare disease reference center for AMS wishes to assess whether targeted medico-psycho-social support tailored to the concerns of the patient and caregiver could improve the couple's emotional and social quality of life. To this end, we will adapt a program developed by Prof. Mittelman, the New York University Caregiver Intervention (NYUCI), which is recognized for its support of caregivers and their families in other pathologies. This program consists in identifying the needs of the patient-caregiver couple, with a view to improving day-to-day management by involving those around them. A total of 72 couples will be included, half of whom will receive the intervention immediately and the other half with a 6-month delay. We will evaluate whether, at 6 months, the quality of life of the intervention group has improved. The ARAMISE association will accompany us in this program, and will be able to provide support to families as a relay to the intervention. | Humanities and social sciences 7 | ||
| 2019 | Amélie ROCHET-CAPELLAN | Grenoble | CNSA | Angelman syndrome | ParticipAACtion: A participatory corpus of Augmentative and Alternative Communication for people with rare neurogenetic syndromes to understand and improve it | Certain rare genetic diseases affect the functioning of the brain as a whole, altering the person's perceptual-motor and intellectual capacities to varying degrees. These multiple difficulties mean that speech is often impossible or severely restricted, as in the case of Angelman syndrome (AS). Yet caregivers' testimonies and research into Augmentative and Alternative Communication (AAC, i.e. means of communication other than speech such as manual gestures, images, tablet software, etc.) show that these people have communicative skills and needs like everyone else. Some caregivers use AAC to support their loved one's or patient's communication, while a majority of others are unable to express themselves to the extent of their skills, or to develop their communicative potential. This is partly due to the fact that very little research has been carried out into the communication of people with this type of disorder, and that conventional methods of communication research are not adapted to these people. In order to overcome these limitations, the ParticipAACtion project proposes a participatory and interdisciplinary approach consisting in creating and analyzing an audio-visual corpus of the communication of people affected, filmed in their daily lives by their relatives. The project involves researchers in language and communication sciences, a French association of families with Angelman syndrome, the DéfiScience rare disease health network and the Handéo association, as well as caregivers who will take part in collecting and analyzing the recordings and interpreting the results. The results should make it possible to identify the tools and contexts that promote communication, enhance the skills of the people concerned, and contribute to the development of the use of AAC. | - | Humanities and social sciences 7 | |
| 2019 | Jean-Pierre POULAIN | Toulouse | CNSA / Fondation Maladies Rares | Prader-Willi syndrome | Socialization of the Feeding Practices of Children with Prader-Willi Syndrome - SoPAP | Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder linked to a gene expression defect. People with PWS present somatic, cognitive and behavioral disorders. Throughout development, the disease is characterized by "severe eating disorders" with consequences for the child's health and social life, as well as for the family environment. In this pathology, the biological and psychological dimensions of eating are described, while the socio-cultural dimensions are only mentioned. What's more, our knowledge of eating behaviours is mainly based on what people with PWS and their parents have to say, or on observations made in care settings. Using an interdisciplinary approach, this research aims to understand the (de)socialization of children with PWS into ordinary life by describing and analyzing the construction of eating practices and parental management of these practices, which are described as problematic. Survey data will be collected using 3 methodological devices: individual interviews, observations of family meals (at home and in experimental situations) and telephone questionnaires with a larger number of families. Analysis of the data will enable us to simultaneously construct a typology of food neophobia, describing and explaining the individual, family, health and social issues facing this population. Finally, this work aims to update and develop concrete applications (information and support tools) co-constructed "by" and "for" the family, associative and professional players present on a daily basis, and could serve as a reference for other pathologies with neurodevelopmental disorders. | In biomedical literature, eating "disorders" during development in people with Prader-Willi syndrome are generally presented by their unique progression over the course of a lifetime: infants exhibit anorexic behavior, while children and adults exhibit hyperphagic behavior with a major interest in or preoccupation with food. To date, there is no drug treatment available. Early, multidisciplinary management is based on dietary control, which is mainly implemented in the home by parents. Parents must anticipate strict control of access to food in order to prevent severe obesity. Research has studied the ways in which families manage food for children with PW syndrome and the impact of this syndrome on food socialization (social learning, foods consumed, table manners, etc.). It highlights the mental burden on parents from the first months of their child's life, with inter-individual and family differences. It also highlights the value of sharing best practices from successful parental experiences in the form of therapeutic education days. | Humanities and social sciences 7 | |
| 2019 | Marcela GARGIULO | Paris | CNSA | Spinal Muscular Atrophy | Project: PARENTALITY and Spinal Muscular Atrophy. Multidimensional study of parental overload Franco-Chilean study | SMA is the 2nd rare disease of genetic origin (approximately 1/10,000 births). It is characterized by progressive muscular atrophy leading to disability. Parenting a sick child with a severe disability is an ordeal that can disrupt the experience of parenthood. The involvement of parents in daily long-term care, the medicalization of the relationship and their participation in sometimes dilemmatic therapeutic decisions can modify the exercise, practice and experience of parenthood. Objective: to study the specificity of representations of parenthood, to evaluate and analyze the feeling of parental overload, including the search for risk and protective factors. Partners: this is an interdisciplinary collaboration, with 3 neuropediatric consultations (Trousseau, I-Motion and Raymond Poincaré hospitals) and the AFM's regional services. Population: 60 parents of children with SMA (types 1, 2 and 3), recruited through the 3 consultations. Methodology: mixed methodology, using qualitative and quantitative tools. Innovative aspects: first study carried out in France. The expected results could have a high degree of transferability to other serious genetic diseases of children. The mixed methodology will enable us to identify parental representations and the determinants of parental overload, with a view to developing intervention programs. Comparison of our results with those of the Chilean team will enable us to determine whether the health and inclusion policies of the two countries are determinants of parental overload. | Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease that affects the motor skills of children from the first months of life. Long considered a Long considered an incurable disease, SMA has undergone a radical transformation in recent years with the arrival of innovative new therapies, such as gene therapy and SMN2 modulators. These treatments now offer improved clinical prospects and even change the natural history of the disease. In this context of therapeutic upheaval, families are faced with unprecedented challenges: while children can now benefit from prolonged care and a relative improvement in their health, the daily demands of care remain heavy. It is the parents who bear the brunt of this burden. However, their experiences, their adaptation, and the consequences of this reality on their parenting experience are still poorly understood. This research sought to better understand the impact of SMA on the parenting experience, particularly in this context of therapeutic innovation. We surveyed 55 parents of children with SMA type 1, 2, or 3, using an in-depth questionnaire aimed at documenting: their family, professional, and social situation; the organization of care and available assistance; their subjective feelings about parenting, their perceptions of themselves and their child; their perception of the burden associated with care and the impact on their quality of life. The aim was to give families a voice, to highlight their daily reality, and to produce data that would enable support mechanisms to be better tailored to their needs. The results show that, despite therapeutic advances, the daily lives 66 Call for research projects in the humanities and social sciences – Final report of families remain deeply affected by the disease. Parents must cope with demanding multidisciplinary care: respiratory care, physical therapy, orthopedics, nutrition, occupational therapy, psychomotor therapy, speech therapy, etc. For many children, this care is provided on a daily basis, often at home, and requires specialized medical equipment (wheelchairs, respiratory devices, standing frames, etc.). This arrangement gradually transforms the family home into a care facility. This "medicalization of daily life" has profound consequences: it changes the relationship to time, space, and the role of parenting itself. Parents must be caregivers, logisticians, helpers, administrative managers, and educators all at once. For some, this situation is experienced as an overload, not only physically and mentally, but also existentially: the ordinary aspects of family life, consisting of spontaneity, play, and moments of respite, tend to fade away in favor of a form of parenting marked by the demand for performance in care. The results also show that mothers are heavily involved in all of these responsibilities, highlighting a persistent gendered division of labor. Spousal support varies depending on the form of the illness and the type of care provided. By highlighting this reality, our research sheds light on key public health issues : the need to recognize the central role of families in care systems, to provide more active support to parents (psychological support, home help, reduction of administrative procedures), and to consider forms of organization that preserve family balance and the uniqueness of each child, beyond the disease. This study thus provides a basis for developing health policies that are responsive to the realities experienced by families affected by SMA. | Humanities and social sciences 7 | |
| 2019 | Nathalie ANGEARD | Paris | CNSA | Myotonic dystrophy type 1 (DM1) | Theory of Mind Training in Virtual Reality in the infantile form of Myotonic Dystrophy Type 1 (DM1) | The infantile form of Myotonic Dystrophy type 1 (DM1) is a rare disease, little-known by doctors and even by the families concerned, as its presentation differs markedly from the congenital form (in its severity) and from the adult form. Affected children show few muscular signs, yet frequently have learning and social difficulties. These difficulties may stem from a disturbance in their Theory of Mind (ToM) skills, notably in their ability to recognize emotions and understand the intentions, desires or beliefs of others (mental states). Given this observation, it seems crucial to create a Virtual Reality (VR) training protocol focusing on emotional processing and theory of mind, and to offer it to children with DM1. The interest of this innovative environment lies not only in its ecological and attractive character, but also in the possibility of adjusting the complexity of social interactions between the different avatars according to the specific difficulties encountered by the participant. The program will be offered to 35 children/adolescents with DM1 aged between 5 and 16. 6 training sessions will be held in environments reproducing familiar contexts such as a classroom, a playground or a camping camp. Participants will be able to virtually navigate through the environment, exploring settings, faces and understanding the mental states of different characters (e.g., saying the wrong thing and understanding the emotional impact on others) thanks to explanations provided by the experimenter. Ultimately, we expect to see an improvement in the ability to recognize and understand emotions. These pioneering results should eventually enable the creation of a serious game on a tablet that can be used at home. | Humanities and social sciences 7 | ||
| 2019 | Pascal ANTOINE | Lille | MGEFI / Fondation Maladies Rares | Huntington's disease, Huntington's chorea | Dyade: Couple dynamics in Huntington's disease | Taking into account and integrating the patient's family and friends is a major factor in improving the quality of patient care. A growing number of studies are focusing on the experiences of caregivers confronted with Huntington's disease, demonstrating the importance of considering the physical and emotional impact on those around them, and the support they can receive. Huntington's disease is a rare genetic disorder that affects young people, with serious consequences for those around them, especially couples. The issues specific to the different stages of the disease are likely to call into question the balance of this affective system and its protective role for each individual. Studies have highlighted the difficulties faced by each partner in isolation. Research is needed, however, to understand the difficulties of both partners, their experiences as a function of the stage of the disease, how both partners adjust (or fail to adjust) to symptoms and care, and to each other. Overall, dyadic functioning is poorly documented. As a result, as yet underdeveloped support systems are unable to integrate this essential dimension of quality of life and care. Our aim, therefore, is to understand the functioning of couples confronted with illness, in order to identify the processes that deteriorate the quality of life of both spouses and those that contribute to their resilience. Thirty couples and fifteen spouses-caregivers will be asked to talk about their experiences. These interviews will be recorded, transcribed and qualitatively analyzed to identify dyadic processes and understand the evolution of interactions during the illness. The results will serve as a clinical basis for identifying and supporting people in difficulty. | Le contexte de la recherche La maladie de Huntington (MH) est une maladie neurodégénérative héréditaire autosomale dominante qui entraîne des symptômes moteurs, cognitifs et comportementaux. Il s’agit d’une maladie rare qui débute le plus souvent entre 35 et 45 ans. Le traitement est actuellement uniquement symptomatique : traitements pharmacologiques, rééducatifs et mise en place d’un cadre médico- social approprié5. Dans les premiers stades, les symptômes sont peu prononcés et la personne continue à mener une vie familiale et/ou professionnelle sans grande difficulté. A un stade intermédiaire, la personne ne peut plus travailler et a besoin de beaucoup de supervision pour la gestion des affaires financières. Elle accomplit les activités de la vie quotidienne avec quelques difficultés et un peu d'aide. Aux stades tardifs de la maladie, les limitations physiques et fonctionnelles s’accentuent. La personne ne peut plus accomplir seule les activités de la vie quotidienne, elle peut encore vivre chez elle uniquement si elle bénéficie du soutien de ses proches et/ou de services d’aide à domicile. Les caractéristiques génétiques, et les symptômes neuropsychiatriques d’une maladie neurodégénérative touchant en majorité des adultes jeunes sont autant d’aspects dont il faut tenir compte pour aborder le vécu des proches-aidants. La MH affecte des personnes jeunes, souvent en activité et avec des enfants à charge. L’entourage va devoir s'adapter à des difficultés croissantes et prendre en charge de plus en plus de tâches du quotidien. La famille peut être confrontée à des préoccupations financières liées à une réduction des ressources de la personne malade et de l’aidant pour se rendre disponible. Les symptômes associés à la MH peuvent entrainer un rejet par le réseau social préexistant et au final un isolement. La nature héréditaire de la MH, associée à l’expérience de la maladie dans les générations précédentes, entraine des conséquences sur la famille avec des phénomènes de rupture et de tabou, parfois un isolement renforcé par un manque de soutien de la famille élargie. Ces éléments sont sources de détresse chez les aidants qui expriment leur inquiétude et certains rapportent leur détresse face au manque de services appropriés, impliquant la nécessité de recherches sur les besoins des proches-aidants. Dans la MH, le proche aidant est le plus souvent le conjoint. La perte d’autonomie et la diminution des activités vont diminuer non seulement la qualité de vie de chacun mais également bouleverser le quotidien à deux, le relationnel et l’intimité du couple. Les enjeux et les objectifs Intégrer l’entourage de la personne malade et en tenir compte est indispensable pour l’amélioration de la qualité de prise en soin du patient. Si des travaux ont mis en évidence les difficultés de chaque partenaire isolément, des recherches sont nécessaires pour appréhender leurs difficultés en tant que couple, leur vécu en fonction du stade d’évolution de la maladie, leur adaptation aux symptômes et aux soins, ainsi que l’évolution de leur relation. On en sait peu sur le fonctionnement du couple dans ce contexte et les dispositifs d’accompagnement sont encore peu développés. L’objectif du projet de recherche était de comprendre le fonctionnement des couples confrontés à différents stades de cette maladie afin d’identifier les processus qui détériorent la qualité de vie des deux conjoints mais aussi ceux qui contribuent à leur résilience. Aperçu des moyens et méthodes Une étude collaborative associant chercheurs, soignants et association, a été menée sur plus de trois années. 15 couples et 30 conjoints-aidants ont témoigné de leur expérience, de leur quotidien. Ces entretiens ont été ensuite retranscrits et analysés pour identifier les différents processus et comprendre les implications et la nature des interactions au sein du foyer. Appel à projets de recherche en Sciences Humaines et Sociales – Rapport final 14 Les principaux résultats Dans un premier temps, il est apparu que les couples au stade intermédiaire de la maladie étaient trop en difficulté pour communiquer, en particulier le conjoint malade. Les difficultés sont essentiellement dues à la charge cognitive et émotionnelle. Nous avons donc revu notre objectif pour ce stade en interrogeant principalement des conjoints-aidants plutôt que les deux membres du couple. Concernant les retours d’expérience des conjoints-aidants, au stade débutant, les niveaux de détresse et de souffrance sont marquants. Ils verbalisent le sentiment d’être totalement happés par une spirale, dans laquelle ils ont le quotidien à gérer avec des symptômes intenses, de l’agitation, des difficultés de comportement. Parallèlement, ils ont aussi le sentiment d’être seuls à être garant du bien-être de leur conjoint malade. Aux stades plus avancés, nous nous attendions à une souffrance encore plus importante mais les résultats sont plus subtils : avec le temps, et probablement du fait de la perte d’autonomie plus marquée, les situations vécues au quotidien semblent moins intenses avec moins de troubles du comportement. Le conjoint-aidant acquiert aussi de l’expérience, il sait comment interagir avec son conjoint pour l’apaiser et gérer le quotidien. Le conjoint-aidant se vit cependant plus aidant que conjoint. Il relate le sentiment que le lien se délite au profit d’un relationnel quotidien bien plus marqué par l’aidance que la conjugalité. Concernant les témoignages de couples, au stade débutant dans cette recherche, le sentiment d’être de plus en plus seul face à la maladie est largement partagé. Plusieurs couples rapportent un écart entre d’une part leur vécu de la maladie ou leurs attentes de soutien et d’autre part les réactions de l’entourage décrites en termes d’indifférence, de rejet ou de peur. Ce phénomène peut entrainer un repli des couples sur eux-mêmes avec un recentrage et un enfermement dans le quotidien avec la maladie. L’interdépendance entre les partenaires est marquante, dès l’installation de la maladie. Dans ce contexte, deux tendances relationnelles sont notables dans les témoignages recueillis : Plusieurs couples en ont commun de s’inscrire dans la continuité d’une relation positive et de vouloir la préserver. Ils se situent entre le choc émotionnel de la survenue des premiers symptômes et la perspective des aménagements qui seront nécessaires pour s’adapter au futur handicap. Dans cette période d’incertitude, propice aux planifications mais aussi aux ruminations, ils s’efforcent en couple de se centrer sur le moment présent. La recherche d’équilibre nécessite des efforts et peut être comprise sur le plan relationnel entre les deux partenaires, mais aussi sur le plan individuel face aux dilemmes intérieurs. Par ailleurs, pour d’autres couples, les partenaires constatent que la maladie accentue des discordances préexistantes et les partenaires en viennent à mener deux vies parallèles. Le quotidien est marqué par les divergences d’organisation entre les partenaires, liées à l’emprise des symptômes ou à des désaccords. Par exemple la proactivité des conjoints-aidants qui luttent contre le déclin de la relation et de l’identité de leur partenaire peut s’opposer à la difficulté de ce dernier pour se mobiliser. En dépit de ces difficultés, le conjoint, qui est parfois l’unique ressource de la personne malade, reste présent préservant la qualité de vie du partenaire et plus globalement l’équilibre de la famille. Les retombées de cette recherche L’objectif de ce travail inédit était de comprendre le fonctionnement du couple dans le contexte de cette maladie. Toute la chaine de soin et d’accompagnement psychosocial est susceptible de tirer profit des résultats générés par cette recherche. L'évolution de la maladie nécessite des ajustements à différents niveaux. Le couple est amené à modifier son organisation et à prendre des décisions plus ou moins conjointes ou partagées concernant les soins et le quotidien qui engagent les deux partenaires. Pour les professionnels, il est important de comprendre ces implications, leurs évolutions et la nature des interactions au sein du foyer afin d’apporter des informations adaptées, en temps utiles, compréhensibles par chacun des partenaires. Ce projet avait pour ambition de permettre de saisir les enjeux pour différents bénéficiaires : pour la personne qui vit avec la maladie - concernée en premier lieu ; pour le conjoint - à la fois proche et aidant, garant à terme du maintien à domicile et susceptible de devoir bénéficier d’aide pour lui-même ; et pour le couple, dont les décisions prises à deux et la qualité de vie, résultent d’interactions complexes qui ne se résument pas à la somme de la Appel à projets de recherche en Sciences Humaines et Sociales – Rapport final 15 subjectivité de l’un et de l’autre. De plus les résultats de ce travail serviront de socle pour créer des outils cliniques de repérage des personnes en difficulté et construire des stratégies et des contenus d’accompagnement adaptés aux différents vécus identifiés face à cette la maladie. Pour illustrer cette dernière perspective on peut anticiper, par exemple, concernant les couples au début de la maladie, de proposer des accompagnements dyadiques pour préserver la qualité de la relation le plus longtemps possible. Et puis, dès lors que les dynamiques de communication sont trop affectées et/ou les symptômes très envahissants au quotidien, des accompagnements indépendants pourront être centrés sur les besoins de chacun | Humanities and social sciences 7 | |
| 2018 | Anne PHILIPPE | Paris | Foundation For Rare Diseases | Non syndromic autism spectrum disorders | Whole exome sequencing in non-syndromic autism spectrum disorders | - | The objective of our study was to investigate the genetic origin of autism spectrum disorder in two boys from two families who presented with a similar atypical clinical course, i.e., the onset of compulsive motor disorders from the age of 11-12 years, based on the hypothesis of pathogenic variants in a gene common to these two families. Exome sequencing revealed two variants in a new candidate gene according to an autosomal recessive pattern in the boy from the first family, but only one variant inherited from the mother in the boy from the second family. We continued with genome sequencing for this second family, which did not reveal the second variant. We did not find any other subjects with the same phenotype via the Gene Matcher platform. | GenOmics 2018 - 1 | |
| 2018 | Caroline KANNENGIESSER | Paris | Foundation For Rare Diseases | Pleuroparenchymal fibroelastosis Pulmonary fibrosis | Identification of new genes implicated in Pleuroparenchymal fibroelastosis | - | - | GenOmics 2018 - 1 | |
| 2018 | Clement CARRE | Paris | Foundation For Rare Diseases | Intellectual Disability (ID) Non-syndromic X-linked Intellectual Disability (NSXLID) | tRNA Fragments & RNA methylation detection for functional diagnostic in Intellectual Disability | - | - | GenOmics 2018 - 1 | |
| 2018 | Florent SOUBRIER | Paris | Foundation For Rare Diseases | Precapillary Pulmonary arterial hypertension | Search for new genes in familial pulmonary hypertension by Whole Genome Sequencing | - | GenOmics 2018 - 1 | ||
| 2018 | Frederique MAGDINIER | Marseille | Foundation For Rare Diseases | Facio Scapulo Humeral Dystrophy (FSHD) Bosma Arhinia and microphthalmia (BAMS) | Identification of genes and regions regulated by the SMCHD1 chromatin-associated factor in Facio-Scapulo-Humeral Dystrophy (FSHD) and Bosma Arhinia and Microphtalmia Syndrome (BAMS) | - | La dystrophie facio-scapulo-humérale (FSHD), une maladie autosomique dominante, est la troisième dystrophie musculaire la plus fréquente. Elle est caractérisée par un affaiblissement progressif et asymétrique de certains muscles, avec un début au cours de la deuxième décennie et une sévérité ou une pénétrance variable. Chez 95% des patients (FSHD1), elle est liée au locus 4q35 et implique une réduction du nombre de macrosatellites D4Z4, riches en GC. Les patients FSHD1 sont porteurs d'une contraction pathogène (<10 D4Z4), associée à une hypométhylation (40-65%) et à la présence en cis d'un haplotype de type qA. La FSHD de type 2 (FSHD2, 5% des patients), n'est pas liée à la réduction du nombre de D4Z4 mais, dans 80% des cas, à une mutation du gène SMCHD1, entraînant une hypométhylation des D4Z4 (<40%). De plus, le gène SMCHD1 est muté dans un syndrome développemental rare, sans lien avec la FSHD, le syndrome d'arhinie et microphtalmie de Bosma (BAMS). De nombreuses questions demeurent sur le rôle de SMCHD1 dans la régulation de la chromatine dans les cellules humaines et la façon dont des mutations de ce gène conduisent à deux syndromes distincts. Beaucoup de ces questions ne peuvent pas être abordées sur la base des modèles disponibles, les laissant sans réponse. Nous avons produit des modèles cellulaires à partir de cellules souches pluripotentes induites pour la modélisation de ces pathologies. Par une approche de RNA Seq dans les cellules musculaires, spécifiques de la FSHD ou les cellules de la crête neurale, spécifiques du syndrome BAMS, nous avons montré une atteinte sarcomérique dans le FSHD et un défaut de migration des cellules de la crête neurale dans le BAMS. Par une analyse chromatinienne à l'échelle du génome, nous avons également montré que SMCHD1 est impliqué dans la déposition de la marque chromatinienne répressive H3K27me3, en particulier au niveau des enhancers spécifiques de tissus. | GenOmics 2018 - 1 | |
| 2018 | Helene PUCCIO | Illkirch | Foundation For Rare Diseases | Friedreich Ataxia | Identification of pathological mechanisms underlying proprioceptive neurons dysfunction and cell death in Friedreich Ataxia | - | GenOmics 2018 - 1 | ||
| 2018 | Marie-Christine CHABOISSIER | Nice | Foundation For Rare Diseases | Frasier syndrome | Identification of the Genetic Network Leading to Frasier Syndrome and other Disorders of Sexual Development | - | Sexual development disorders (SDDs) are rare heterogeneous diseases. Despite intensive research over the past 30 years, only about 50% of SDDs can be explained at the molecular level to date. This highlights our ignorance of the mechanisms that control sex determination. DSD causes a variety of conditions ranging from intersexuality with dysfunctional genitalia to infertility and hormonal imbalance, all of which cause severe psychological and social distress for the affected individual. In addition, patients often have a high risk of developing gonadal cancers. Understanding normal and defective gonadal development has therefore become a key research issue, as it may have a significant impact on future diagnoses for sex assignment and surgery. This knowledge is valuable for medical counseling to families in their decision for or against gonadectomy for their children with these conditions. Frasier syndrome is an ADS that leads to malformations of the urogenital system, kidney disorders, and gonadal dysgenesis with the appearance of nephro- and gonado-blastomas. Our study identified the causes of these developmental abnormalities through single-cell RNA sequencing. We discovered that this pathology is due to the abnormally high expression of a variant of the Wilms tumor suppressor, Wt1. This variant is the main regulator of ovarian differentiation, and our work has identified for the first time the molecular mechanism that initiates ovarian differentiation. Furthermore, this gives us a starting point for identifying the factors responsible for developmental pathologies in this organ. These new factors will help clarify the etiology of sexual development abnormalities and provide new tools for better diagnosis and anticipation of the consequences on an individual's development. | GenOmics 2018 - 1 | |
| 2018 | Mireille COSSEE | Montpellier | Foundation For Rare Diseases | Myopathies and Muscular dystrophies | Evaluation of a Whole Genome and RNA-sequencing strategy to identify the molecular bases of unsolved myopathies and muscular dystrophies | - | Myopathies and muscular dystrophies constitute a group of genetically and phenotypically heterogeneous diseases. Despite the power of whole exome sequencing (WES) and whole genome sequencing (WGS) approaches, the diagnosis rate is less than 50%. One pitfall of WGS is the large number of variants of unknown significance (VUS) identified, particularly in non-coding regions. One approach to assess the impact of these variants on transcription and splicing is to combine WGS with transcriptome analysis of affected tissues. In this project, we wanted to implement a WGS strategy coupled with RNA-Seq on muscle transcripts in patients with myopathies. We selected two families with autosomal dominant myopathy and a sporadic case (trio) with a phenotype suggesting recessive titinopathy, where a single variant had been previously identified. In addition, two positive controls carrying mutations in the DMD gene and another in the titin (TTN) gene, for which the consequences of intronic variants on splicing had already been characterized by RT-PCR Sanger sequencing, were included in this study. The data analyses were the subject of a Master's 2 internship in bioinformatics and made it possible to 1) initiate the implementation of a pipeline for analyzing variants from WGS, 2) develop a pipeline for analyzing RNAseq data, and 3) demonstrate that RNAseq transcript analyses are essential in myopathies due to variants in the titin gene, a large and highly complex gene in which the laboratory has expertise. These results led to a publication, a Master's thesis, and a poster presentation. The expertise acquired through this project is a first step toward further improvements. Given the lack of a reliable and routinely usable strategy for RNAseq data analysis, we have established and are actively participating in national projects bringing together several laboratories working on this topic. | GenOmics 2018 - 1 | |
| 2018 | Stanislas LYONNET | Paris | Foundation For Rare Diseases | Mayer-Rokitansky-Kuster-Hauser syndrome | Deciphering the molecular mechanisms leading to Mayer-Rokitansky-Kuster-Hauser syndrome | - | GenOmics 2018 - 1 | ||
| 2018 | Stephane BEZIEAU | Nantes | Foundation For Rare Diseases | Intellectual disability | Trio-based whole-genome sequencing of patients with syndromic and non-syndromic moderate or severe intellectual disability | - | Intellectual disability (ID) has a prevalence of 1 to 2% in the general population. Genetic diagnosis enables genetic counseling to be provided to families, for example by offering access to prenatal or preimplantation diagnosis, improving medical care, and advancing knowledge of the pathophysiology of these diseases. The aim of this project was to sequence the entire genome of 33 patients with ID and their parents (trios). These patients were in diagnostic limbo after a negative exome analysis. We were able to provide a diagnostic answer for 16 patients (48%). This high diagnostic rate was achieved by identifying variants that were not detectable by the techniques used to date, such as balanced structural variations, but also by applying complementary techniques such as high-throughput RNA analysis (RNA-Seg) and optical genome mapping. We also identified a new gene responsible for ID by collaborating with international teams. These results provide a better understanding of the role of genome sequencing in the diagnosis of ID. | GenOmics 2018 - 1 | |
| 2018 | Stephane VIVILLE | Strasbourg | Foundation For Rare Diseases | Female infertility | Exome sequencing in consanguinous families in the quest of genes implicated in oocyte maturation arrest | - | GenOmics 2018 - 1 | ||
| 2018 | Caroline LE GUINER | Nantes | Foundation For Rare Diseases | Duchenne Muscular Dystrophy | Gene therapy for the cardiac disease in Duchenne Muscular Dystrophy: Definition of the optimal mode of delivery to transduce the heart of nonhuman primates using a rAAV9 vector | - | Translational Research 2017 | ||
| 2018 | Gabriel RAHMI | Paris | Foundation For Rare Diseases | Esophageal atresia Anastomotic fistulas | Fistula therapy by extracellular vesicles into thermoreversible hydrogels: tackling a complication of esophageal atresia reparative surgery | - | In this study, we evaluated several types of regenerative therapy (human AdSCs, EVs derived from human AdSCs alone or combined with Pluronic F127 gel) in a rat model of esophagogastric fistulas. The EVs were produced at high yield using a methodology that can be implemented in bioreactors compatible with future GMP (Good Manufacturing Practice) production, and all therapies were administered percutaneously. In the pig model, treatment groups were selected for testing. The results obtained in the porcine model validated those of the rat model. The proposed approach allows for the screening of several candidate therapies. Based on this approach, we demonstrated that local administration of EVs derived from human AdSCs reduces gastro-cutaneous fistula flow, fibrosis, and inflammation compared to control groups. This study highlighted the therapeutic potential of EVs administered locally and in a heat-resistant hydrogel for the management of difficult-to-treat post-surgical esophagogastric fistulas as part of a minimally invasive "subcellular" strategy. | Translational Research 2017 | |
| 2018 | Laurent STORME | Lille | Foundation For Rare Diseases | Congenital diaphragmatic hernia | Optimization of intact cord resuscitation in newborn lambs with congenital diaphragmatic hernia | - | Translational Research 2017 | ||
| 2018 | Laurent TIRET | Paris | Foundation For Rare Diseases | Centronuclear myopathies, Myotubular myopathies, Fiber-size disproportion myopathies, Mitochondrial myopathies | Establishment and characterization of a humanized canine DNM2 colony dedicated to validate efficient treatments in mice | - | Translational Research 2017 | ||
| 2018 | Bruno QUINTARD | Bordeaux | Foundation For Rare Diseases | Albinism | Biopsychosocial determinants of dyadic adjustment to illness in albino subjects and their close circle: a mixed qualitative and quantitative approach ALBIPSY | Background Oculocutaneous Albinism [OCA] is a rare disease with various symptoms (depigmentation, visual deficit, sun exposure disorders). This displaying disease has social (stigmatization, withdrawal) and psychological consequences for the AOC subject and those around him/her (adaptation disorders, altered quality of life [QoL]). To date, no study has jointly explored the experience of COA in the subject and his or her close caregivers (family and non-family). Aims - To explore the psychosocial impact (stigmatization, QoL, emotional state) of albinism on the AOC subject and his/her close relative (parent or spouse); - To compare the way in which the AOC subject and his/her close relative (parent or spouse) experience the disease, and to see whether or not there is convergence in this experience; - at the level of non-family caregivers (caregivers, GENESPOIR albinism association), assess the relevance of the proposed interventions, given the specific needs of the AOC patient and his/her relative. Method - 150 pairs (AOC subject + parent or spouse) recruited by GENESPOIR and the skin CRMRs of Bordeaux, Necker and Strasbourg. Protocol evaluating : - various contextual, medical and personal factors associated with: QoL, emotional state and degree of perceived stigma ; - 30 interviews with family pairs (AOC subject/spouse or parent) and 30 interviews with non-family carers (15 carers; 15 GENESPOIR members), to explore representations of the disease, its consequences and needs in terms of medical and associative support. Conclusion This study is original in that it combines an approach focused partly on the discourse of the AOC subject, but also on that of his or her relatives. It should enable us to gain a better understanding of the complexity of interactions between the various partners involved in COA, and to better adapt medical and associative intervention methods to the specific needs of patients and their relatives (parents or spouses). | Humanities and social sciences 6 | ||
| 2018 | Carolina BAEZA-VELASCO | Paris | Foundation For Rare Diseases | Hypermobile Ehlers-Danlos syndrome | Activity patterns of individuals with hypermobile Ehlers-Danlos syndrome: associated factors and decision-making: ACTI-SEDh | Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue disorders. Hypermobile EDS (hEDS) is the most common form, accounting for 80-90% of cases of SED. The manifestations of hEDS are multi-systemic due to the wide distribution of collagen in the body. Pain is nevertheless the most frequent symptom. The variety and accumulation of pain and their long duration make hEDS a potentially very disabling pathology. Studies show severe functional impairment in hEDS, determined mainly by pain and fatigue. This leads to a reduction in patients' ability to hold down gainful employment, perform household chores and engage in social activities. In this sense, it is necessary to identify the factors contributing to functional decline in hEDS to manage the personal and economic impact that generates this pathology. One of the key factors in the overall functioning of chronic pain patients is their relationship to activity (activities of daily living and the way they carry them out). Three major patterns of activity have been observed: avoidance, persistence and modulation. These patterns may be responsible for perpetuating pain and disability. They have been studied in a variety of pain-related pathologies, enabling us to propose appropriate treatments to help restore patients' function by promoting the right mix of activities. However, no study has explored the relationship between activity and people with hEDS. This study explores patients' dysfunctional activity patterns, associated factors, the link between patterns and functional outcome, and patients' decision-making processes regarding activity. The results will help to better target rehabilitation strategies. | Contexte Le syndrome d’Ehlers-Danlos hypermobile (SEDh) est considéré comme la pathologie héréditaire du tissu conjonctif la plus courante. Les personnes atteintes par le SEDh peuvent présenter un ensemble de symptômes très variés tels que des douleurs chroniques, de la fatigue, de l’anxiété, etc. Le traitement de ce syndrome est à ce jour symptomatique et doit être pluridisciplinaire (médecins, kinésithérapeutes, psychologues, etc.) pour aider la personne au mieux dans son quotidien. Même si les symptômes du SEDh n'entraînent pas de risque vital direct pour la personne, l’accumulation de symptômes peut entraîner une perte d’autonomie, des répercussions psychosociales importantes (dépression, isolement, difficultés d’emploi, etc.). Des approches comportementales se sont intéressées à la manière dont les personnes souffrant de douleur chronique ou de fatigue chronique géraient leurs activités au quotidien. La manière de gérer l’activité étant perçue comme un facteur protecteur ou au contraire aggravant les répercussions de la maladie. Ainsi, trois patterns d’activité principaux ont été décrits : On parle de pattern évitant lorsque la personne évite systématiquement toute activité, que ce soit dans le but de réduire les douleurs ou d’économiser de l’énergie par exemple. Bien que cette stratégie puisse être adaptée à court terme, le fait d’éviter l’activité sur le long terme finit par déconditionner la personne, entraîner des conséquences psychologiques (dépression) et finalement aggraver les symptômes en retour. A l’extrême inverse, le pattern persistant consiste à poursuivre les activités de manière excessive et sans prise en compte de leurs répercussions. A terme, cette stratégie peut également entraîner une aggravation de la symptomatologie car elle entraîne l’épuisement, la blessure, l’augmentation des douleurs et donc finalement une atteinte de l’autonomie. Enfin, le pattern modulant consiste à se placer entre l’évitement et la persistance excessive de l’activité en adaptant l’activité en fonction des symptômes. Cette stratégie est généralement considérée comme plus adaptée sur le long terme pour limiter les répercussions de la maladie et avoir un fonctionnement optimal. Objectifs : L’objectif de l’étude présentée ici était d’explorer les patterns d’activité des personnes atteintes de SEDh, de voir si certains patterns étaient liés à un meilleur fonctionnement et si l’on pouvait prédire les patterns d’activité en fonction d’autres dimensions (dépression, anxiété, peur du mouvement, tendance aux pensées catastrophistes concernant la maladie, etc.). Des entretiens ont également été réalisés afin d’explorer les dimensions subjectives (motivations, valeurs, etc.) en lien avec ces différents patterns d’activité. Résultats obtenus Les résultats de notre étude révèlent que les patterns d'activité évitant et modulant sont associés à un moins bon niveau de fonctionnement global, à une réduction de l'activité physique et à une augmentation des difficultés liées à des problèmes physiques. Ces conclusions soulignent l'importance de ces deux patterns d'activité comme prédicteurs clés du retentissement fonctionnel chez les individus atteints de SEDh. L'analyse a montré que le pattern d'activité évitant est fortement lié à plusieurs variables sociodémographiques et cliniques. Notamment, ce pattern est associé à l'absence d'activité professionnelle ou étudiante. De plus, les scores élevés d'évitement sont prédits par des niveaux plus élevés de dépression, de catastrophisme, de peur du mouvement (kinésiophobie), de fatigue et de troubles du sommeil. Ces associations suggèrent que les personnes utilisant un pattern évitant sont non seulement moins actives, mais également plus susceptibles de souffrir de divers troubles psychologiques et physiques, aggravant ainsi leur qualité de vie globale. Le pattern modulant, quant à lui, présente des similitudes et des différences avec le pattern évitant. Comme pour le pattern évitant, l'absence d'activité professionnelle ou étudiante est un facteur prédictif. En outre, la fatigue et les troubles du sommeil sont également fortement associés au pattern modulant, ce qui pourrait indiquer que ces personnes modifient leur niveau d'activité en fonction de leurs capacités physiques fluctuantes. Cependant, contrairement au pattern évitant, les niveaux de dépression et de catastrophisme ne sont pas des variables associées au pattern modulant. Cela suggère que bien que ces individus ajustent leurs activités en réponse à la fatigue et aux troubles du sommeil, ils ne présentent pas nécessairement les mêmes niveaux élevés de détresse psychologique que ceux observés chez les individus avec un pattern évitant. L’analyse du discours des participants lors des entretiens a permis d’identifier cinq grandes thématiques, chacune associée préférentiellement à un des trois patterns d’activité. Le pattern d’activité modulant était associé aux troisième et quatrième classes. La troisième classe se concentrait sur la gestion des relations sociales. Elle était caractérisée par des expressions suggérant des limitations dans les activités sociales en raison de symptômes tels que la douleur et la fatigue. Les participants de cette classe décrivaient souvent une réduction des activités sociales ou un temps passé à l'extérieur moins important lorsqu'ils ressentaient de la fatigue, ce qui avait des répercussions notables sur leur vie sociale. Il est intéressant de noter que la réduction des interactions sociales est parfois perçue comme une stratégie d'adaptation délibérée pour gérer efficacement la fatigue. La quatrième classe se concentrait sur la gestion nuancée des activités en fonction du niveau de douleur et de fatigue perçu chez les individus atteints de SEDh. Cette classe était caractérisée par des stratégies visant à éviter de dépasser ses limites et à anticiper les conséquences potentielles des activités. Les participants de cette classe mettaient l'accent sur l'importance d'écouter leur corps et de fixer des limites pour éviter l'aggravation des symptômes. Ils exprimaient une approche pragmatique de la gestion des activités, reconnaissant la nécessité de faire une pause ou d'arrêter en cas de douleur ou de fatigue pour éviter une détérioration de leur état. De plus, la décision de s'engager dans une activité était souvent basée sur une évaluation minutieuse du plaisir tiré de l'activité par rapport aux conséquences potentielles, qu'elles soient vécues ou anticipées. Le pattern évitant était associé au thème de la gestion et l'organisation de la vie quotidienne. Elle tournait autour des routines et des responsabilités envers la famille, les amis et les animaux de compagnie. Il y avait un sens du devoir et de l'obligation envers les proches et les tâches ménagères, comme l'illustrent les déclarations sur le soin apporté aux membres de la famille, l'entretien de la maison et du jardin, et la prise en charge des animaux. L'évitement peut alors être considéré comme une stratégie visant à limiter la plupart des activités pour conserver de l'énergie pour des activités perçues comme plus importantes (par exemple, les tâches ménagères ou l'éducation des enfants). La persistance de l'activité était associée au thème de la recherche de solutions pour faire face aux défis quotidiens. Les segments de cette classe exprimaient une approche proactive de la vie, cherchant à trouver des solutions malgré les obstacles. Ils se concentraient sur l'amélioration et l'adaptabilité, même face à l'adversité. Le plaisir et la jouissance des activités étaient également des thèmes centraux, bien que souvent tempérés par des considérations pratiques comme la capacité physique ou la nécessité d'environnements calmes. La persistant était également associée à un thème faisant référence aux activités physiques et à leurs conséquences potentielles sur des parties spécifiques du corps. Ce thème soulignait l'idée que certaines activités physiques ont un impact direct sur le corps et sont perçues comme risquées ou dangereuses. L'axe 1 semble représenter un continuum allant d'une description objective de l'impact des activités physiques à une description personnalisée de la gestion des symptômes. Intérêt social de ces résultats Ces résultats soulignent l'importance d'une approche individualisée dans la gestion des patients atteints de SEDh, en tenant compte des patterns d'activité spécifiques et de leurs déterminants pour améliorer leur qualité de vie et leur fonctionnement quotidien. | Humanities and social sciences 6 | |
| 2018 | Celine LANCELOT | Angers | Foundation For Rare Diseases | Turner syndrome | Impact of social and affective cognition skills on relationship and social adjustment difficulties in adolescent girls with Turner syndrome CAST | Turner syndrome (TS) is a rare chromosomal disorder linked to the complete or partial absence of an X chromosome. of an X chromosome, affecting around one in every 2,000 female newborns. While the medical consequences are well described and benefit from appropriate treatment, understanding of the cognitive and socio-cognitive specificities associated with complaints about establishing or maintaining harmonious social relationships is less well developed, particularly in children and adolescents. Some girls with TS may complain of difficulties in making friends, understanding the emotions and intentions of others, and controlling their own emotions. These difficulties in social and affective cognition can contribute to the emergence of social withdrawal, which can have repercussions on their psycho-emotional well-being. The aim of this project is to identify functional and dysfunctional cognitive and social-cognitive abilities in girls with TS that may account for the difficulties in social interaction and adjustment reported by some of them. To this end, 35 participants with TS aged between 10 and 16 years 11 months and 35 control participants matched according to age and parents' level of education will undergo clinical and experimental tests evaluating cognitive functioning, social cognition and affective cognition, as well as questionnaires exploring psycho-affective aspects and social skills. In order to examine the specificity of the cognitive, social and affective profile of patients with ST, a second control group consisting of children and adolescents with idiopathic isolated growth hormone deficiency with normal cranial MRI will be created. We assume that complaints concerning social functioning will be explained mainly by difficulties in affective cognition. | Humanities and social sciences 6 | ||
| 2018 | Charlotte JACQUEMOT | Paris | Foundation For Rare Diseases | Hungtington | Using language as a marker for Huntington's disease to improve management and follow-up LanguageHungtington | Huntington's disease is an incurable genetic and neurodegenerative disorder. It affects young adults (aged 35-45) and causes motor, cognitive and psychiatric disorders. Although little-known, language disorders are among the first cognitive problems to appear. They reduce patients' ability to communicate, have a major impact on their personal and professional lives, and gradually lead to social exclusion. To date, there is no standardized protocol for assessing language disorders in Huntington's disease. However, the assessment stage is crucial to proposing appropriate treatment and rehabilitation. It enables us to set rehabilitation objectives and determine the therapeutic approaches best suited to the patient. To remedy this shortcoming, our project is to characterize patients' language disorders and develop a language assessment protocol to improve and propose effective rehabilitation. We will focus on three essential parameters of communication which, when deficient, are highly disabling for patients: intelligibility (phonetics), words (lexicon), and the ability to use humor and irony (pragmatics). For each parameter, we will obtain a score indicating whether or not a deficit exists. The secondary objective is to use these different scores to detect the first signs of the disease as early as possible. Indeed, treatments are more likely to be effective if delivered at the very beginning of the disease, and it is therefore crucial to have "markers" of this phase. This project will be carried out in collaboration with the Huntington France Association, and will involve researchers from the "Language" team of the NeuroPsychologie Interventionnelle laboratory, experts in the cognitive disorders of Huntington's disease. | - | Humanities and social sciences 6 | |
| 2018 | Delphine HERON | Paris | Foundation For Rare Diseases | Isolated corpus callosum agenesis | Decision-making processes of couples facing prenatal diagnosis of isolated agenesis of the corpus callosum ACCED | The aims of the study are: (1) to study and describe the effects of decision-making in couples faced with major uncertainty about the child's future (risk of disability) during pregnancy; (2) to study the experience and psychological impact of couples regarding their decision to continue or terminate pregnancy; (3) to identify the needs of those concerned, in order to reassess practices and improve the care pathway currently on offer. We have chosen as an example the case of prenatal diagnosis of agenesis of the corpus callosum of isolated appearance, which constitutes a paradigm of this situation of uncertainty, since for the same anomaly (ACC), 75% of children will have normal development and 25% will have a neurological handicap (severe in 5 to 10% of cases), leading parents to make a decision based on statistics. We propose to meet 50 couples divided into 2 groups: (G1) 25 who have decided to continue the pregnancy and (G2) 25 who have decided to stop it. The proposal to enter this research protocol will be made a few months after the birth (whatever the outcome), in order to better identify the factors involved in this decision, their feelings about it, and the couples' experiences afterwards. The interviews will also be accompanied by the use of scales to take into account the emotional state of each individual, as well as the conjugal bond and its particularities. and its particularities. This research will lead to a better understanding of the factors that lead parents to make decision to continue or terminate a pregnancy, and can then be extended to other situations of prenatal uncertainty. These factors will lead to the implementation of better support for these couples, to better meet their needs and support them in their decision-making process, through concrete measures applicable to the care offered. | L’immense majorité des grossesses se déroulent simplement. Mais lorsqu’est dépisté une anomalie à l’échographie, les projections du couple sur le déroulement de la grossesse, leur parentalité en construction et leur enfant à venir sont bouleversées. Ces diagnostics prénatals ont un impact important sur le « devenir parent » et sur les liens parents-enfant par la suite, lorsque la poursuite de la grossesse est décidée. L’évolution des technologies génère des situations d’incertitude pronostique, comme dans le cas de l’anomalie du corps calleux isolée – ACCi –assez paradigmatique. Cette situation confronte les médecins qui annoncent à transmettre une information incertaine à des couples qui ne s’y attendent pas et à les accompagner dans un processus de réflexion pour décider de la poursuite ou de l’interruption médicale de la grossesse (IMG). En effet, l’agénésie du corps calleux – ACC – est la malformation cérébrale la plus fréquente identifiée en prénatal. Elle est détectée généralement à la 2ème échographie (5ème mois de la grossesse) et parfois à la 3ème échographie (7ème mois de la grossesse). Les couples confrontés à cette situation bénéficient alors d’un parcours de soin spécifique comprenant plusieurs échographies, des consultations en neuropédiatrie, des examens génétiques sur liquide amniotique dont le but est essentiellement de trouver la cause en vue d’affiner le pronostic, et enfin une IRM fœtale et une IRM parentale sont généralement réalisées (Heide, 2020). Lorsque l’ACC est isolée, c’est-à-dire en l’absence d’autres malformations associées et d’anomalie génétique, le pronostic est considéré comme plutôt favorable. Toutefois, une part d’incertitude demeure : environ 80 % des enfants nés avec une ACCi ont un développement considéré comme normal, tandis que 20% présentent une déficience intellectuelle de gravité variable (Moutard et al., 2012). Ainsi, pour les couples ayant reçu une annonce d’ACCi, l’enjeu majeur réside dans la décision de poursuivre ou d’interrompre la grossesse, une décision à prendre dans un contexte d’incertitude pronostique quant au développement de leur enfant. Les équipes cliniques de génétique, neuropédiatrie et de médecine fœtale de APHP Sorbonne Université se sont réunies pour partager leurs interrogations quant à l’accompagnement à apporter aux couples confrontés à cette situation et ont souhaité construire un projet de recherche (ACCED) qui puisse apporter des éléments de réponse à ce sujet. Les objectifs de ce travail sont de décrire les enjeux du processus décisionnel au sein du couple, d’analyser les effets psychologiques liés à la décision de poursuivre ou d’arrêter la grossesse, et d’améliorer les pratiques ainsi que l’accompagnement des couples en prénatal et en postnatal. Cette recherche s’adresse à des couples qui ont eu une annonce d’ACCi en prénatal, au cours d’une consultation de suivi, à partir de 3 mois après l’accouchement et jusqu’à 10 ans après la fin de la grossesse. Elle s’appuie sur des échelles d’anxiété, de dépression, d’impact traumatique de l’évènement, d’harmonie dans le couple, de sentiment de soulagement/regret quant à la décision et un entretien semi-structuré, qui vise à entendre le vécu du processus de décision au sein du couple. Résultats retenus Au final 22 entretiens ont eu lieu, dont 12 étaient avec des couples et 10 avec des femmes seules, soit un total de 34 participants, dont 30 ont poursuivi la grossesse et 4 ont eu recours à une IMG. Cette recherche, centrée sur les processus décisionnels des couples confrontés à une anomalie isolée du corps calleux en prénatal, met en lumière les enjeux psychologiques que soulève l’annonce d’un diagnostic médical incertain pendant la grossesse. L’étude met en avant que l’annonce d’ACCi a une portée traumatique pour les couples qui y sont confrontés qui les bascule dans un espace-temps particulier et constitue une blessure intime, car cela remet en question pour beaucoup la capacité qu’ils ont de créer un enfant qui va bien et leur impose une forme de perte de l’enfant imaginaire qu’ils avaient construit et rêvé pour cette grossesse. Ensuite, le caractère incertain de ce diagnostic a des implications particulières. Les couples cherchent une représentation de ce qui va se passer et beaucoup ont recours à des images de handicap grave pour essayer de penser ce que cela leur ferait vivre. Cette difficulté à se représenter les implications du diagnostic du fait de l’incertitude pronostique a pour effet de les faire fluctuer dans leur façon d’investir la grossesse, certains ont le sentiment d’arrêter de l’investir comme si la grossesse n’avait pas réellement lieu (arrêter de toucher le ventre, arrêter les achats pour le bébé à venir, arrêter de sentir les symptômes de la grossesse totalement ou partiellement), d’autres ont le sentiment de la surinvestir pour essayer de protéger le futur bébé d’éventuels dommages (par ex. en mangeant des brocolis pour protéger le développement du cerveau et en projetant de faire de la rééducation au bébé après la naissance pour compenser d’éventuels retards). Le rapport au pourcentage indiqué par les médecins (20% des enfants nés qui présentent des particularités dans le développement et 80% qui suivent un développement normal) est complexe, à la fois il donne un peu de consistance au flou et en même temps il est décorrélé de la binarité du risque : malade ou non. Les couples ont oscillé dans leur rapport à leur entourage entre un besoin de partager leur douleur à la recherche de moyen de penser ce qu’ils vivent et un une mise à distance de l’entourage pour penser par soi-même. Le vécu de la décision sur l’issue de la grossesse est en lien avec la façon dont les couples avaient investi initialement la grossesse et le fœtus, leur rapport individuel et de couple à l’incertitude en général, ce qu’ils ont compris du discours médical et leur interprétation de la perception qu’ont les médecins du pronostic (des médecins très inquiets renforçaient leur inquiétude quant à la gravité possible), le choix de la poursuite de la grossesse a été décrit souvent en négatif : comme une impossibilité d’avoir recours à l’IMG. Le choix d’IMG a été présenté par les participants comme une décision proposée par les soignants et soutenue par la collégialité de la décision. Ainsi le choix de l’IMG est impossible pour les couples à porter seuls. Par ailleurs, de nombreux hommes ont énoncé leur place particulière et différente des femmes dans ce temps-là car à la fois leur avis est sollicité et en même temps la grossesse n’a pas lieu dans leur corps , ils ne sont pas légalement responsables de la décision. Ainsi alors il est parfois complexe pour eux de trouver leur place dans ce temps-là. Cela milite pour une attention, dans les entretiens d’annonce et de réflexion en prénatal, centrée sur les deux membres du couple individuellement mais aussi sur la dynamique du couple en tant que telle. L’incertitude pronostique laisse des traces en post-natal. Les couples témoignent souvent de leur besoin de s’assurer que leur enfant se développe bien après la naissance, de façon plus ou moins envahissante et consciente, en cochant des cases développementales qui peuvent parfois couper les jeunes parents d’une certaine rêverie sur leur enfant, la possibilité du handicap plane dans la construction des liens parents-enfant. Le fait d’avoir envisagé en prénatal d’avoir recours à une IMG a pu teinter pour de nombreux participants le lien à l’enfant, générer une culpabilité voire une certaine honte. La question de ce qui est racontée à l’enfant ensuite de son histoire prénatale est délicate car les parents ont des difficultés à la fois à raconter ce flou de l’incertitude pronostique avec des mots simples et ils ont en même temps peur que raconter cette histoire à leur enfant ait un effet de prédiction de handicap sur son avenir : « si on lui dit alors à la moindre difficulté il se dira que c’est son ACCi qui lui cause ça et il s’enfermera dedans ». Pour les couples qui ont eu recours à l’IMG se pose aussi la question plus ou moins consciemment pour eux : seront-ils jamais sûrs d’avoir la bonne décision quant au handicap incertain du fœtus ? Dans les deux cas la décision dans un contexte d’incertitude continue de travailler les couples et de s’actualiser. Enfin quant au discours médical, les couples s’appuient beaucoup sur les médecins pour prendre leur décision de poursuite ou d’interruption de la grossesse et sont à l’affût pour essayer d’interpréter le vécu intime et personnel des soignants de cette incertitude. Ils s’appuient notamment sur ces éléments pour orienter la décision. De plus, nous avons noté que les couples entretenaient un rapport ambivalent quant au regard des médecins sur le développement de leur enfant en post natal : à la fois ils ont besoin que les soignants les assurent de la normalité du développement de leur enfant, comme une réparation de l’histoire prénatale, et en même temps ils ont extrêmement peur de ce regard qui pourrait signer un retard de développement et annoncer un handicap certain. Ces résultats contribuent à améliorer l’accompagnement des couples à travers la formation des professionnels de santé et de l’accompagnement périnatal, en favorisant une posture plus empathique, plus sensible à la complexité du vécu parental, et respectueuse de l’autonomie des familles. Il semble essentiel que les consultations de prénatal puissent aussi être un espace pour ces couples de commencer à amorcer une reflexion, de poser les enjeux de ce choix difficile. Cette compréhension des dynamiques décisionnelles permet également de renforcer les dispositifs de soutien psychologique, d’accompagner les souffrances et de prévenir des répercussions sur la santé mentale conjugale et familiale à long terme. Au-delà du soin, cette recherche alimente les réflexions bioéthiques et sociétales autour du dépistage prénatal, en donnant une voix aux parents, souvent absents des débats publics. Elle invite à une approche plus humaine et contextualisée des choix liés à la naissance, dans une société où les possibilités techniques dépassent parfois les cadres de pensée et de soutien existants. Les résultats de notre recherche ont un degré de transférabilité important pour d’autres diagnostics prénatals incertains, qui se développent avec les progrès techniques de la médecine fœtale et de la génétique. Les résultats aideront les professionnels impliqués dans l’accompagnement des familles à réfléchir à leur accompagnement autour de l’annonce et à développer des programmes d’intervention pour améliorer leur bien-être. En soutenant cette recherche, la Fondation Maladie Rare a contribué ainsi à une cause à la fois éthique, sociale et profondément humaine, en faveur d’une médecine plus consciente des réalités vécues par les familles et plus à l’écoute de leurs besoins. | Humanities and social sciences 6 | |
| 2017 | Anne DEBANT | Montpellier | Foundation For Rare Diseases | neurodevelopmental disorders Intellectual disability (ID) | Contribution of de novo mutations in the trio gene in intellectual disability: development of a trio knock-in mouse model mimicking the human disease | The integrity of synaptic activity is essential for proper brain function. Alterations in synaptic function are implicated in diseases such as autism and mental retardation. Recent data have revealed new mutations in these patients, which could alter the function of the affected genes and thus contribute to the development of the disease. We are working on the RhoGEF Trio, which plays a fundamental role in neuronal development. Mutations in this gene have been identified in patients suffering from autism and mental retardation. The aim of the project is to understand how mutations in this gene affect its function and how they cause mental retardation. We aim to develop a mouse model that mimics the mental retardation caused by mutations in the trio gene, to better understand the pathophysiology of the disease and lead in the long term to the identification of therapeutic targets. | - | Mouse models 2016 | |
| 2017 | Dominique BONNEAU | Angers | Foundation For Rare Diseases | Rare Intellectual disabilities | Omics for Improving the Diagnosis of Rare Intellectual Disabilities | Background Genetic factors play a major role in intellectual disability (ID), but the underlying cause is far from always being determined. This project is a continuation of the HUGODIMS inter-regional project, in which we performed exomic sequencing of 69 carefully selected trios including a single child with ID and both parents. The genetic cause of ID was determined or strongly suspected in 48 cases (69.5%), and 7 new ID genes were identified. Hypotheses We hypothesize that an approach combining genomics with transcriptomic, metabolomic and morphological analyses performed on neuronal cells derived from induced pluripotent stem cells (iPSCs), could improve the diagnosis and understanding of ID. The aim of this project is to demonstrate that this "multi-omics" approach is relevant and effective. Materials and methods Ten people with ID whose exomic sequencing did not lead to a diagnosis will be included. The study design is as follows: 1. Whole genome sequencing for the 10 negative trios (Nantes) 2. Bioinformatics analysis 3. For 3 negative cases after genome sequencing, as well as for 3 positive controls carrying a mutation in the CAMK2a gene (identified by HUGODIMS) and 3 healthy negative controls: a) Derivation of neural progenitors from iPSCs (Nantes platform) b) Targeted and non-targeted metabolomic analyses of 9 neuronal cell lines (Angers) c) Transcriptomic analysis of the 9 cell lines (Rennes) d) Morphological analysis of neural cells obtained from affected subjects and positive positive controls carrying CAMK2a mutations (Tours) e) Integration and validation of multi-omics and morphological data. Expected results and impact We expect this multi-omics approach to improve diagnosis and understanding of ID. | The objective of the MIDRID study was to demonstrate the proof of concept that a multi-omic approach would prove effective and relevant in improving the diagnosis of genetic intellectual disabilities (ID). In order to identify the causes of intellectual disability, it was necessary to have a cellular model adapted to the brain, which is the organ affected by the pathology. Blood samples were therefore taken from patients with undiagnosed ID and from patients with ID resulting from a variant found in the CAMK2A gene (positive controls). The blood cells from these samples were dedifferentiated into induced pluripotent stem cells (iPSCs) before being reprogrammed into neural stem cells (NSCs). After the presence of specific neuronal markers was confirmed, the progenitors were characterized by microscopy. The specific morphology of the neuronal cells was confirmed, in particular through the observation of neurites enabling neuronal communication. These neurites were described as being of normal size in negative controls without ID. However, in all patients with ID, both positive controls and patients without a diagnosis, the size of the neurites was found to be reduced. Neurites are structural elements that are crucial for the proper functioning of the brain. Their reduced size could therefore be an argument in favor of cerebral dysfunction. The metabolomic analyses conducted in parallel aimed to standardize this approach and define the optimal preanalytical conditions for obtaining the most robust results. A standardized protocol was thus established. Further analyses will be necessary to obtain the metabolic profiles of patients with ID and compare them with those of patients without ID. In the future, differential profiles should make it possible to identify potential markers of ID, and their analysis should determine any potential impacts on neuronal function. Finally, transcriptomic analyses found specific signatures of the NSCs obtained, confirming the correct cellular phenotype and demonstrating their ability to multiply and then differentiate into neurons over time, regardless of the profile of patients with or without the disorder. Further work is needed to analyze the differences in transcriptomic profiles and identify the cellular pathways likely to be impacted in affected patients. Identifying the effectors of these pathways will be essential to understanding the causes of ID before any therapeutic interventions can be attempted in the future. The MIDRID study has demonstrated that it is possible, from a simple blood sample, to obtain a model for investigating the causes of genetic intellectual disabilities. Now that the techniques have been developed and the initial results obtained, it is necessary to increase the number of patients in order to obtain more discriminating and robust data, and to continue the efforts already underway to better understand the origin of ID and improve its diagnosis, before we can hope to identify potential therapeutic targets in the coming years. | GCS HUGO 2016 | |
| 2017 | Jean-Baptiste GOURRAUD | Nantes | Foundation For Rare Diseases | long QT syndrome, idiopathic ventricular fibrillation | CIQTP prolongation: role and mechanism in sudden cardiac death | Malgré les progrès importants du dépistage clinique et génétique, la majorité des morts subites survenant chez des sujets jeunes (<45ans) demeurent inexpliquées. L’identification des mécanismes conduisant à ces arrêts cardiaques est pourtant primordiale pour prévenir et traiter les arythmies à risque de mort subite. Nous avons récemment mis en évidence un nouveau syndrome héréditaire caractérisé par un électrocardiogramme normal au repos mais présentant lors d’un stress mental un allongement de l’intervalle QT responsable de morts subites. L’objectif de notre étude est de mieux comprendre le mécanisme et l’importance de ce syndrome dans la mort subite du sujet jeune. A cette fin nous commencerons par réaliser, en plus du dépistage conventionnel, un test de stress mental lors du dépistage de familles atteintes de mort subite inexpliquée ou de syndrome du QT long (arythmie héréditaire présentant un allongement de l’intervalle QT au repos avec risque de mort subite). Cette partie de l’étude, réalisée dans les CHU de Brest, Nantes, Rennes et Tours permettra d’identifier de nouveaux patients atteints par ce syndrome et de préciser sa présentation clinique en comparant les anomalies observées au repos et lors des tests de dépistage pour ce syndrome et le syndrome du QT long. L’étude se poursuivra par une analyse génétique de 4 familles afin d’identifier les gènes responsables de ce syndrome. Parmi ces quatre mêmes familles, des cellules cardiaques seront générées à partir de 3 patients appartenant à chacune d’entre elles ce qui offrira la possibilité de rechercher les modifications d’expression des gènes et de courants ioniques à l’origine de ce syndrome. | Malgré les progrès importants du dépistage clinique et génétique, la majorité des morts subites survenant chez des sujets jeunes (<45ans) demeurent inexpliquées. Du fait d’un caractère héréditaire, l’identification des mécanismes conduisant à ces arrêts cardiaques est pourtant primordiale pour prévenir et traiter les arythmies à risque de mort subite. Nous avons récemment mis en évidence un nouveau syndrome héréditaire (catecholamine-induced QT prolongation; CIQTP) caractérisé par un électrocardiogramme (ECG) normal au repos mais présentant lors d’un stress mental un allongement de l’intervalle QT responsable de morts subites. L’objectif de l’étude était de mieux définir ce syndrome et d’explorer les mécanismes qui pourraient être impliqués dans celui-ci pour permettre à terme une meilleure prise en charge des patients. Cette étude a débuté par la réalisation dans le grand ouest d’un bilan exhaustif systématique chez les apparentés d’un individu ayant présenté une mort subite prématurée et inexpliquée. Nous avons pour cela utilisé un test de stress mental que nous avons mis au point dans les familles déjà identifiées et qui permet, par le stress induit, de démasquer sur l’ECG l’aspect pathologique qui demeure aujourd’hui le seul moyen d’établir un diagnostic. Après la mort subite inexpliquée d’un de leur proche, nous avons ainsi pu identifié 169 apparentés répondant au critère de ce syndrome. Ces apparentés se répartissent au sein de 82 familles. Au-delà de l’importance de ces données pour la recherche en constituant la première base de données mondiale dans ce nouveau syndrome, cette identification a permis de prendre en charge ces patients et ces familles avant la survenue d’autres morts subites. En parallèle, nous avons essayé d’utiliser le test de stress mental dans le dépistage d’une autre arythmie cardiaque héréditaire à risque de mort subite, le syndrome du QT long. Ce syndrome se caractérise par un allongement permanent de l’intervalle QT mais avec une variabilité interindividuelle rendant le diagnostic difficile. On a ainsi souvent recourt à différents tests de provocation pour renforcer l’aspect sur l’ECG. Ces tests nécessitent le plus souvent une hospitalisation. L’utilisation du test de stress mental, utilisable lors d’une simple consultation, a permis de démontrer une bonne efficacité dans le dépistage du syndrome du QT long et ouvre la voie à une simplification de celui-ci. Ces données ont été publiées dans une revue internationale à comité de lecture. Sur le plan l’identification des mécanismes conduisant au CIQTP nous avons choisi, afin de maximiser nos chances d’identification de réaliser une double approche, génétique et fonctionnelle. L’analyse génétique a été réalisée dans des grandes familles sélectionnées permettant ainsi de comparer les variations génétiques du génome des individus sains et atteints. Nous avons identifié 3 gènes candidats dont le mécanisme moléculaire pourrait passer par une régulation extra cardiaque des systèmes de stress (système nerveux ou système hormonale). Ces résultats sont en phase avec le phénotype des patients sensibles au stress mental. Cependant, avant d’affirmer la participation de ces gènes dans le syndrome, des analyses fonctionnelles vont être réalisées pour confirmer ces données. L’analyse fonctionnelle a été réalisée à partir de cellules souches pluripotentes de patients atteints. A partir des cellules du patient nous pouvons effectivement reprogrammer les cellules en cellules souches pour les redifférencier en cardiomyocytes isolés. Cette technique a l’avantage de pouvoir étudier des cellules cardiaques du patient, en essayant, sans poser d’hypothèse préalable, de mettre en évidence des anomalies de fonctionnement. - Les résultats obtenus suggèrent que les hiPS-CMs permettent de modéliser le phénotype clinique du CIQTP. L’analyse du fonctionnement des gènes a permis de démontrer une signature dite transcriptomique spécifique aux patients atteints. Ces anomalies de fonctionnement de la cellule semblent toucher le fonctionnement des gènes impliqués dans la réponse au stress (signalisation β-adrénergique), ce qui pourrait donc expliquer le développement d’un phénotype anormal en condition de stress. L’analyse électrique des cellules retrouve des anomalies concordantes avec des modifications n’apparaissant que lors d’un stress. Notre étude a donc permis sur le plan clinique d’identifier de nouveau patient atteint par le CIQTP confirmant ainsi l’implication de celui-ci dans la mort subite du sujet jeune. Les premières pistes physiopathologiques nous orientent vers une exagération de la réponse au stress qui pourrait expliquée la survenue de la mort subite. En réponse, des médicaments déjà utilisé en pratique courante et ciblant spécifiquement le système neurohormonal du stress sont introduit chez les patients atteints les plus à risque avec des résultats qui semblent prometteur. | GCS HUGO 2016 | |
| 2017 | Laurent PLANTIER | Towers | Foundation For Rare Diseases | Idiopathic Pulmonary Fibrosis | Acoustic Waves and Helium/oxygen for Aerosol Treatment of Idiopathic Pulmonary Fibrosis (IPF) | Idiopathic pulmonary fibrosis (IPF) is a rare disease with a very poor prognosis. Innovative inhalation (aerosol) treatments for IPF are currently being developed in our laboratory. To date, the use of aerosols for the treatment of IPF has been limited by the fact that they are mainly deposited in the best-ventilated, i.e. least diseased, regions of the lung. The aim of this project is to develop a method to overcome this limitation. In the laboratory, we will use a device that models healthy and diseased regions of the respiratory tract to determine whether the application of acoustic waves of different frequencies, the use of a helium/oxygen mixture (Heliox®), the application of continuous positive airway pressure (CPAP), or the performance of maneuvers simulating deep inspirations (IP), increase the deposition of a medicated aerosol (salbutamol) in the affected regions. Effective interventions will then be combined to identify an optimal aerosolization protocol. Next, we will conduct a clinical study in IPF patients to determine whether the optimal protocol delivers enhanced deposition of a model aerosol, compared with the conventional technique (without acoustic waves, helium/oxygen, CPAP, or IP). To precisely quantify deposition in diseased and healthy regions of the patient's lung, we will combine CT images, which enable fine analysis of lung structures, with single-photon emission computed tomography (SPECT) images, which enable three-dimensional visualization of aerosol deposition traced by a radioelement, 99mTechnetium. The safety of the aerosolization protocol will be verified by repeated measurements of respiratory function and symptom questionnaires. This project will be developed by a multidisciplinary team including physicians and engineers specialized in IPF, aerosol generation and medical image analysis. | GCS HUGO 2016 | ||
| 2017 | Brahim BELBELLAA | Illkirch | Foundation For Rare Diseases | Freidreich Ataxia associated cardiomyopathy | Multisystem approach analysis of friedreich ataxia cardiomyopathy in frataxin-deficient mice models and hIPS-derived cardiomyocytes for the elucidation of pathophysiological mechanisms and identification biomarkers. | Friedreich's ataxia is a rare and incurable hereditary mitochondrial disease accompanied by lethal cardiomyopathy. The main objective of this study is to identify the main transcriptional and metabolic dysregulations occurring at the onset of the disease and shortly after the rescue of mitochondrial function following in vivo gene therapy. We will perform a comprehensive RNAseq analysis of transcriptional dysregulation of mRNA and RNA, using two mouse models with partial or total reduction of frataxin, the protein responsible for the disease. Metabolic and molecular analyses will also be performed and correlated with these data. Finally, we will cross-validate our results on patient plasma samples and iPS-derived cardiomyocytes. | - | GenOmics 2017 - 1 | |
| 2017 | Capucine TROLLET | Paris | Foundation For Rare Diseases | Oculopharyngeal muscular dystrophy | Long and small non coding RNA in oculopharyngeal muscular dystrophy | - | GenOmics 2017 - 1 | ||
| 2017 | Caroline NAVA | Paris | Foundation For Rare Diseases | Epilepsy Dravet syndrome | Identification of novel genes responsible for Dravet syndrome | - | - | GenOmics 2017 - 1 | |
| 2017 | Cecile JEANPIERRE | Paris | Foundation For Rare Diseases | Congenital anomalies of the kidney and urinary tract (CAKUT) Renal hypodysplasia (RHD) | Identification of novel genes and mutational mechanisms for renal hypodysplasia | - | GenOmics 2017 - 1 | ||
| 2017 | Claire FRANCASTEL | Paris | Foundation For Rare Diseases | ICF syndrome: Immunodeficiency Centromeric instability Facial anomalies | GenOmics of the ICF syndrome: when studying a rare disease also sheds new light on the "old" field of DNA methylation | - | GenOmics 2017 - 1 | ||
| 2017 | FRANCIS COUTURAUD | Brest | Foundation For Rare Diseases | Idiopathic venous thromboembolism | EXTENDING IDENTIFICATION OF NEW INHERITED THROMBOPHILIA IN SELECTED FAMILIES | - | - | GenOmics 2017 - 1 | |
| 2017 | François VIALARD | Paris | Foundation For Rare Diseases | Azoospermia | Identification and characterization of gene alterations in patients with a spermatogenesis maturation arrest | - | GenOmics 2017 - 1 | ||
| 2017 | Genevieve de SAINT BASILE | Paris | Foundation For Rare Diseases | X-Linked thrombocytopenia, Woodhouse Sakatti, IgA nephropathy, Severe Immune disorder, Vasculopathy | Genetic basis of various phenotypes segregating in a large inbred family | - | GenOmics 2017 - 1 | ||
| 2017 | Martine COHEN-SALMON | Paris | Foundation For Rare Diseases | Megalencephalic leukoencephalopathy with subcortical cysts | Deciphering the gliovascular functions of MLC1 underlying megalencephalic leukoencephalopathy | - | Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy (MLC, OMIM 604004). Patients present with macrocephaly, cysts, and vacuolization of the white matter, leading to motor and cognitive disorders. To date, there is no treatment for MLC. Moreover, the pathophysiology of the disease is poorly understood. In most patients, the disease is due to mutations in the MLC1 gene (MIM #605908). Our exploration of a mouse model of MLC deleted for the MLC1 gene allowed us to determine that this pathology is primed by a molecular and functional defect of the interface between the astrocytes, which are the main glial cells of the brain, and the cerebrovascular system. This early gliovascular component of the disease was unknown and may represent a new therapeutic perspective for patients. | GenOmics 2017 - 1 | |
| 2017 | Sandrine MARLIN | Paris | Foundation For Rare Diseases | Non syndromic hearing impairment with enlarged vestibular aqueducts | Identification of the second gene responsible for isolated hearing impairment with enlarged vestibular aqueducts | - | GenOmics 2017 - 1 | ||
| 2017 | Stephane SAVARY | Dijon | Foundation For Rare Diseases | X-linked adrenoleukodystrophy and Acyl-CoA Oxidase deficiency (peroxisomal leukodystrophies) | Novel CRISPR-mediated mutant microglial cell models to better understand the physiopathogenesis of peroxisomal leukodystrophies and identify novel therapeutic targets by NGS RNAseq | - | - | GenOmics 2017 - 1 | |
| 2017 | Stephane VIVILLE | Strasbourg | Foundation For Rare Diseases | Spontaneous ovarian hyperstimulation syndrome (sOHSS) | Exome sequencing in a consanguineous family with spontaneous ovarian hyperstimulation cases with unknown triggers | - | GenOmics 2017 - 1 | ||
| 2017 | Veronique PAQUIS-FLUCKLINGER | Nice | Foundation For Rare Diseases | Mitochondrial disorders | Identification of new genes and possible de novo mutations in early-onset mitochondrial disorders | - | - | GenOmics 2017 - 1 | |
| 2017 | Veronique PINGAULT | Paris | Foundation For Rare Diseases | Waardenburg syndrome type 2 | Molecular bases of Waardenburg syndrome type 2 | - | GenOmics 2017 - 1 | ||
| 2017 | Virginie CARMIGNAC | Dijon | Foundation For Rare Diseases | CLOVES: Congenital Lipomatous Overgrowth, Vascular Malformations and Epidermal Nevi syndrome MCAP: Megalencephaly-Capillary Malformation-Polymicrogyria syndrome KTS: Klippel Trenaunay Syndrome | Unraveling the genetic basis of mutation-negative mosaic overgrowth syndromes through deep whole exome sequencing | "Postzygotic activating mutations in PIK3CA are responsible for a large number of patients with CLOVES syndrome and related disorders. However, in approximately 40% of patients with the correct phenotype, deep sequencing has failed to detect PIK3CA mutations. Our goal is to identify the causal postzygotic mutation in a cohort of 41 patients with mosaic overgrowth without an identified mutation. The absence of mutations in these patients may result from the involvement of another gene, inadequate tissue sampling, or insufficient NGS sensitivity for the detection of weak mosaics. Therefore, as a first step, we collected additional samples of affected tissue from patients and sequenced other candidate genes, which remain negative. In a second step, when the results remain negative, we will compare the deep ESW technique (200X) on the affected skin with the conventional deep ESW technique (80X) on each patient's blood. We hope to find de novo postzygotic mutations in new responsible genes, which could lead to new therapeutic targets." | GenOmics 2017 - 1 | ||
| 2017 | Alexandre BACQ | Paris | Foundation For Rare Diseases | Epilepsy | Identification of novel pathogenic mechanisms involved in DEPDC5-related epilepsy and SUDEP. | - | - | GenOmics 2017 - 2 | |
| 2017 | Arthur SORLIN | Dijon | Foundation For Rare Diseases | Hypomelanosis of Ito, Linear Whorled Nevoid Hypermelanosis, and other mosaic development disorders with skin pigmentary anomalies | Deciphering the genetic basis of mosaic development disorders with skin pigmentary anomalies | - | GenOmics 2017 - 2 | ||
| 2017 | Arturo LONDONO-VALLEJO | Paris | Foundation For Rare Diseases | Hoyeraal-Hreidarsson syndrome Primary pulmonary fibrosis Dyskeratosis congenita | RNA partitioning in RTEL1-associated Hoyeraal-Hreidarsson syndrome | - | RTEL1 is an essential gene, and mutations in this gene are responsible for severe diseases that affect bone marrow function in particular, but also the functioning of other systems. It is generally accepted that these problems are the result of a telomeric defect (telomeres that are too short) that prevents cell renewal. However, experimental results suggest that in severe forms of the disease, certain manifestations may be due to dysfunctions in RNA trafficking between the nucleus and the cytoplasm. This project attempted to highlight these defects by adopting a comprehensive, unbiased approach, analyzing the distribution between the nucleus and cytoplasm and the alternative splicing variants of all transcripts detectable by massive sequencing. Our results did not demonstrate any obvious defects affecting RNA trafficking or structure. Furthermore, our results suggest that there may be defects in the release of RNA from chromatin affecting specific regions of the genome. Although very preliminary, these observations could justify further, more direct analysis. The question of whether these defects contribute to clinical manifestations not explained by short telomeres remains open. | GenOmics 2017 - 2 | |
| 2017 | Betty GARDIE | Nantes | Fondation Les Ailes / Kiwanis | Hereditary erythrocytosis (HE) | Whole genome sequencing of patients with hereditary erythrocytosis | - | - | GenOmics 2017 - 2 | |
| 2017 | Gaetan LESCA | Lyon | Foundation For Rare Diseases | Epilepsy West syndrome | Searching for the genetic basis of West syndrome with favorable outcome | - | GenOmics 2017 - 2 | ||
| 2017 | Jean MULLER | Strasbourg | Foundation For Rare Diseases | Bardet-Biedl syndrome Ciliopathy | Identification of genes and pathways implicated in families affected with a ciliopathy. | - | - | GenOmics 2017 - 2 | |
| 2017 | Nadine CERF-BENSUSSAN | Paris | Foundation For Rare Diseases | Monogenic Intestinal disorders | HIGH-TROUGHPUT SCREENING FOR IDENTIFICATION OF MENDELIAN CAUSES OF INTESTINAL INFLAMMATION | - | GenOmics 2017 - 2 | ||
| 2017 | Nicolas CHASSAING | Toulouse | Foundation For Rare Diseases | Microphthalmia/anophthalmia | ANALYSIS OF REGULATORY GENE SEQUENCES IN MICROPHTHALMIA/ANOPHTHALMIA | - | Microphthalmia (small eyes) and anophthalmia (absence of eyes) are severe eye malformations. Mutations in numerous genes have been identified in patients, but a cause has been identified in less than half of patients. We hypothesized that mutations not usually sought (because they are located outside the areas directly coding for proteins that are usually explored) could explain the ophthalmological involvement in some patients with no known cause. We therefore explored the entire genome in nine patients with microphthalmia/anophthalmia in previously identified mutations in known genes. This approach enabled us to describe the presence of mutations in a new gene not previously associated with a human disease, thereby increasing our knowledge of the genes involved in these eye development defects. We were unable to identify any causal non-coding mutations in the samples explored. However, such mutations have since been identified in a few patients, thus validating our initial research hypothesis. | GenOmics 2017 - 2 | |
| 2017 | Nicolas RAMOZ | Paris | Foundation For Rare Diseases | Anorexia nervosa dominant form, eating disorders, psychiatric disorders | COMBINING HIGH THROUGHPUT SEQUENCING APPROACHES TO DEFINE THE GENETIC BASES OF DOMINANT FAMILIAL FORMS OF ANOREXIA NERVOSA | - | GenOmics 2017 - 2 | ||
| 2017 | Pascale QUIGNON | Rennes | Foundation For Rare Diseases | Epilespy | Whole genome sequencing of dogs affected by idiopathic epilepsy as genetic models for human epilepsies | - | GenOmics 2017 - 2 | ||
| 2017 | Pauline ARNAUD | Paris | Foundation For Rare Diseases | Marfan syndrome Familial Thoracic Aortic Aneurysm and Dissection | Identification of new genes involved in Marfan syndrome and Familial Thoracic Aneurysm and Dissection by WES and WGS approaches | - | GenOmics 2017 - 2 | ||
| 2017 | SANDRINE PASSEMARD | Paris | Foundation For Rare Diseases | Primary microcephalies: MicroCephaly Primary Hereditary, microcephalic dwarfism (Seckel syndrome / MOPD / Meyer Gorlin syndrome), microcephaly and chorioretinopathy | MICRO-WGS: Identifying genes responsible for primary microcephaly | - | GenOmics 2017 - 2 | ||
| 2017 | Veronique PAQUIS-FLUCKLINGER | Nice | Foundation For Rare Diseases | Mitochondrial diseases | Identification of new genes responsible of mitochondrial disorders by RNA sequencing | - | GenOmics 2017 - 2 | ||
| 2017 | Jean-Jacques FEIGE | Grenoble | Foundation For Rare Diseases | HHT: Hereditary Haemorrhagic Telangiectasia (Rendu-Osler-Weber disease) PAH: Pulmonary Arterial Hypertension | HHTreat: new drugs for the treatment of HHT patients | Rendu-Osler disease is a rare genetic disorder characterized by vascular fragility leading to profuse nosebleeds, telangiectasias (small pockets of blood on the mucous membranes) and, at a more advanced stage, arteriovenous malformations responsible for heart failure. Only surgical or palliative treatments currently exist for this disabling disease. In 90% of cases, patients carry a mutation in the ACVRL1 or ENG genes, which code for receptors present in vascular cells. Our team has identified the physiological ligands of these receptors (BMP9 and BMP10) and developed cell-based assays to characterize the functional consequences of these mutations. Building on this work, we now aim to identify new drug candidates for this disease by screening a bank of pharmaceutical compounds already on the market for other indications. | High throughput screening 2017 | ||
| 2017 | Johann BOHM | Illkirch | Foundation For Rare Diseases | Tubular aggregate myopathy (TAM) | A high-throughput screen to identify compounds antagonizing tubular aggregate myopathy | Muscle diseases affect children and adults in all populations, and are potentially lethal. There is no therapy for a majority of these myopathies, which represents a considerable burden for patients and their families. Our team has identified the genetic causes of tubular aggregate myopathy (TAM), which involves muscle weakness, cramps and pain, and we have discovered that this disease stems from a calcium imbalance in the muscle. Calcium plays a vital role in normal muscle function, and aberrant calcium homeostasis is observed in various muscle diseases. We aim to test the potential of approved drugs to reverse cellular alterations and - in perspective - restore muscle function in an animal model of TAM. Through this project, we aim to pave the way for the development of a pharmacological treatment for TAM and other calcium-related myopathies. | High throughput screening 2017 | ||
| 2017 | Marie-Odile FAUVARQUE MARRAS | Grenoble | Foundation For Rare Diseases | Cushing's disease | Targeting USP8 in Cushing's disease | Cushing's disease is a rare disorder in which pituitary micro-tumors produce excess adrenocorticotropic hormone (ACTH) and consequent hypercortisolism. This can lead to obesity, brittle skin, cardiovascular disease, depression and reduced fertility. depression and reduced fertility. The first-line treatment is transphenoidal surgery, which results in a high remission rate for 64-90% of patients. However, a significant percentage of pituitary adenomas recur, and not all tumors are operable. Recently, mutations in the USP8 protease have been found in patient micro-tumors. These mutations cause constitutive enzyme activity and increased ACTH secretion. The project aims to provide specific USP8 inhibitors with satisfactory medicinal properties in order to develop a personalized treatment for Cushing's disease. | High throughput screening 2017 | ||
| 2017 | Benoit MIOTTO | Paris | Foundation For Rare Diseases | Meier-Gorlin Syndrome | Study of a mouse model of Meier-Gorlin Syndrome based on a mutation in the conserved BAH domain of ORC1 | Meier-Gorlin syndrome is a rare disorder characterized by growth failure from the earliest stages of development in utero. Patients are small in stature, with underdeveloped ears and kneecaps. Mutations in several genes encoding factors essential for the initiation DNA replication are responsible for the syndrome. Mutations causing the most severe phenotype alter the function of the ORC1 gene. The most recurrent ORC1 mutation results in the substitution of glutamine for arginine 105 at the protein level. We propose to build a mouse model containing this mutation. This model will enable us to study the developmental processes affected by the ORC1 mutation, such as signaling pathways and various molecular processes. Taken together, these data will provide a better understanding of the events leading to the disease, and enable us to propose possible therapeutic targets in the future. | - | Mouse models 2016 | |
| 2017 | Denis HERVE | Paris | Foundation For Rare Diseases | ADCY5-related dyskinesia | A mouse model for studying pathophysiological mechanisms of ADCY5-related dyskinesia | Paroxysmal dyskinesias are rare diseases characterized by episodes of involuntary abnormal movements, which are very disabling in some patients. Recently, geneticists have found that the disease results from mutations in a gene called ADCY5 in certain patients. This discovery led to the creation of a group of ADCY5-associated dyskinesia sufferers, around one of the first patients to be diagnosed (Adcy5.org website). The functions of the ADCY5 gene are well known to scientists, but the consequences of its mutations are still unknown. The aim of the project is to create a mouse with a mutation exactly equivalent to that found in patients heavily affected by the disease, in order to discover the altered biological mechanisms in neurons. We will investigate whether mutant mice show movement disorders similar to those of patients, and we will test drugs likely to reduce motor abnormalities. | Mouse models 2016 | ||
| 2017 | Jacques YOUNG | Paris | Foundation For Rare Diseases | Severe hyperandrogenism and oligomenorrhea | KI mouse model as a proof of concept for human hyperandrogenism, anovulation associated with activating LHCGR mutation | Ovarian and testicular function requires stimulation by two hormones, the gonadotropins (FSH and LH) secreted by a gland at the base of the brain, the pituitary gland. They act via receptors located in testicular and ovarian cells. In healthy individuals, these receptors do not function until puberty. Genetic abnormalities in the receptor genes can disrupt their function. In a patient with masculinization and high testosterone, we have discovered a very rare mutation which enables the receptor to function without the intervention of LH. We will reproduce this mutation in a female mouse to induce the same type of disease and gain a better cognitive understanding of ovarian function. This will enable us to demonstrate the responsibility of the mutation we have discovered, and to avoid confusing this disease with others with similar symptoms. | Mouse models 2016 | ||
| 2017 | Jean-Jacques BOFFA | Paris | Foundation For Rare Diseases | Idiopathic nephrotic syndrome | Pathophysiological role of Isthmin-1 in idiopathic nephrotic syndrome | Idiopathic nephrotic syndrome (INS) is a kidney disease that affects both children and adults. unknown mechanisms. We have discovered the involvement of isthmine-1 (ISM-1), whose role in renal in renal pathophysiology. We have shown physiological expression in podocytes (renal cells and target of NIS), but above all strong de novo expression by circulating leukocytes of adults and children suffering from NIS. Our aim is to develop a strain of transgenic mice to study the pathophysiological role of ISM-1 in INS. We hypothesize that circulating ISM-1 acts as a permeability factor and induces proteinuria. These mice would overexpress ISM-1 in leukocytes and mimic human INS. Our results have already led to the filing of a patent, and we are looking forward to identifying a therapeutic target for SNI. | Mouse models 2016 | ||
| 2017 | Jean-Vianney BARNIER | Paris | Foundation For Rare Diseases | Intellectual disability | First mutation in the auto-inhibitory domain of the PAK3 gene associated with ID. | Advances in human genetics have made a decisive contribution to our understanding of psychiatric neurodevelopmental disorders. However, mutations in the same gene can lead to different different pathologies, without the reason being understood. Understanding the relationship between a mutation, its functional effects and clinical signs is essential for proposing therapeutic strategies. We have identified a new mutation associated with mental retardation in a gene coding for a kinase, a mutation which does not destroy enzymatic activity. We aim to understand the biochemical defects induced by this mutation in vitro and in cells. We would like to have the corresponding mouse model to link these dysfunctions to behavioral and memory abnormalities, as well as to synaptic defects and clinical signs in patients. The results obtained should enable us to propose therapeutic strategies. | Mouse models 2016 | ||
| 2017 | Juliette GODIN | Illkirch | Foundation For Rare Diseases | Malformation of cortical development - microcephaly - intellectual disabilities | Understanding the roles of tRNAs modifications in cerebral corticogenesis through the investigation of an ADAT3 knock-in model | Transfer RNAs (tRNAs) are key molecules in protein synthesis. In order to be functional, these tRNAs undergo a dozen or so modifications. We have recently established a link between the presence of certain modifications and the ability of neural stem cells to generate neurons. In addition, mutations in several modifying enzymes have been associated with neurodevelopmental pathologies in humans. How do mutations in these enzymes lead to brain malformations? We will take a candidate approach and characterize the developmental functions of a tRNA-modifying enzyme, ADAT3, which, when mutated, leads to microcephaly (smaller brain size). We will evaluate the functions of ADAT3 altered by the mutations found in patients. This study will lead to a better understanding of the fundamental causes of neurodevelopmental disorders, and to the discovery of new therapeutic targets. | Transfer RNAs (tRNAs) are key molecules for protein synthesis. In order to be functional, these tRNAs undergo around ten modifications. Mutations in several modifying enzymes have been linked to neurodevelopmental disorders in humans. How do mutations in these enzymes cause brain malformations? We adopted a candidate-based approach and characterized the developmental functions of a tRNA modification enzyme, ADAT3, which, when mutated, leads to microcephaly (smaller brain). We successfully generated the Knock-in ADAT3 p.V128M model. We validated the model and observed a 75% decrease in protein levels, consistent with what has been observed in fibroblasts from patients carrying the mutation in the ADAT3 gene. Complete characterization (histology from E14.5 to P60) of the model showed no severe brain abnormalities. At the molecular level, we sequenced tRNAs from isolated cortexe from this mouse and showed an absence of phenotype. Overall, the data obtained with this mouse model indicate that, in mice, there are compensatory mechanisms that are not at play in humans, as shown by the severe brain abnormalities in humans. These results prompted us to study phenotypes specific to humans and, in parallel, to study compensatory mechanisms in mice. These projects are still ongoing. | Mouse models 2016 | |
| 2017 | Laurent SCHAEFFER | Lyon | Foundation For Rare Diseases | Neuromuscular disorders affecting the neuromuscular junction | Light up the neuromuscular junction to monitor muscle innervation | Neuromuscular diseases encompass a wide range of pathologies affecting muscles, the motor neurons that control them and/or their meeting point, the neuromuscular junction (NMJ). Loss of motor neurons inevitably results in impaired muscle contraction. Unfortunately, assessing the state of communication between neurons and muscles in mice models of neuromuscular disease is difficult and requires specialized electrophysiological and pathological methods. To circumvent these difficulties, we propose to develop a mouse that will greatly simplify and standardize the state of nerve-muscle communication by introducing a fluorescent sensor of this communication into the muscle. This will greatly facilitate quantitative analysis and monitoring of the innervation status of an entire muscle. | Mouse models 2016 | ||
| 2017 | Metodi METODIEV | Paris | Foundation For Rare Diseases | mitochondrial diseases; Leigh syndrome including French-Canadian Variant (LSFC). | A mouse model to understand the pathophysiology and tissue-specificity of mitochondrial disease caused by mutations in the RNA stability factor LRPPRC. | Mitochondrial diseases are incurable, often very severe, and affect 1 in 5000 individuals. They are caused by mutations in different genes and lead to a wide variety of clinical symptoms. To better understand and treat these diseases, we need to create better models to study disease progression and tissue specificity. We will create mice expressing a deleterious mutation in the LRPPRC gene, involved in mitochondrial RNA metabolism. This gene has already been associated with lactic acidosis, and sometimes liver disease and (cardio)myopathy. In-depth studies in different tissues will enable us to better understand how mutations in the LRPPRC gene lead to mitochondrial diseases in humans. Mouse models will also be used to develop new treatments for this and other severe diseases caused by mitochondrial dysfunction. | Mouse models 2016 | ||
| 2017 | Miria RICCHETTI | Paris | Foundation For Rare Diseases | Cockayne syndrome | A mouse model for Cockayne syndrome | Cockayne syndrome (CS) is a rare disease characterized, like other syndromes, by sensitivity to light (UV rays), but also by premature aging and neurodegeneration. The mouse model of mutation of the same proteins as in humans (CSA and CSB) does not recapitulate the disease, except for UV sensitivity. We have recently discovered a specific defect in SC, which is independent of UV sensitivity, and consists in the degradation of an important protein in mitochondria, the energy-producing organelles of cells. This results from overexpression of the protease, HTRA3, which degrades other proteins. We have reversed the altered parameters in the cells of CS patients, opening up therapeutic strategies that do not currently exist. Our project is to over-express HTRA3 in mice to trigger premature aging and neural degeneration, in order to study them and test treatments. | The mechanisms governing aging, a multifactorial process, remain unresolved and constitute a fundamental question in cellular and organismal biology. Understanding these mechanisms is essential for implementing prevention or improvement strategies with significant potential medical and societal impact. Exceptionally, in certain rare genetic diseases such as Cockayne syndrome (CS), aging is greatly accelerated. Understanding the molecular alterations responsible for these premature aging diseases is crucial for developing treatments that are sorely lacking, but also for elucidating the mechanisms underlying physiological aging. CS is characterized by sensitivity to light (UV rays), but also by premature aging and neurodegeneration. The life expectancy of these patients, mainly young children, is greatly reduced and accompanied by progressive and dramatic physical and cognitive degeneration. We have recently discovered a specific defect in the cells of CS patients, which is independent of UV sensitivity and consists of the degradation of an important protein in the mitochondria, the organelles that produce energy for cells. This results from the overexpression of the protease HTRA3, which degrades other proteins, including the one responsible for mitochondrial DNA replication. We believe that this new mechanism of mitochondrial alterations, which have already been associated with aging, could explain the accelerated aging observed in CS. Our project is to generate a new line of transgenic mice that inducibly overexpress the HTRA3 protein to trigger premature aging and neurodegeneration in order to characterize them and test treatments. Using a targeted transgenesis strategy, we inserted the human HTRA3 gene into the genome of mouse embryonic stem (ES) cells so that we could activate this gene at the desired time by adding an antibiotic. After functional testing (HTRA3 overexpression) and genotyping, these ES cells were implanted into the blastocysts of pregnant mice to generate chimeric mice, which, after crossing, allowed us to obtain mice that inducibly overexpress the HTRA3 protease. We expect to generate a mouse model for premature aging and neurodegeneration in Cockayne syndrome (a model that does not currently exist), which will allow us to study the disease in a robust experimental model, something that is not possible in humans, and should enable the analysis of new medical strategies to counteract cell and organism deterioration in this disease. We also expect our results to reveal fundamental aspects of the molecular dysfunctions leading to physiological and pathological aging. | Mouse models 2016 | |
| 2017 | Pascal HOUILLIER | Paris | Foundation For Rare Diseases | Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC) | A Claudin 16-knock-in mouse as a model of Familial hypomagnesemia with hypercalciuria and nephrocalcinosis | A very rare genetic disease of recent discovery, "familial hypomagnesemia with hypercalciuria hypomagnesemia with hypercalciuria and nephrocalcinosis" (FHHNC), results in decreased blood magnesium concentration Calcification of the kidneys and renal failure may lead to dialysis. There is currently no specific treatment for this disease. It is linked to the loss of function of a protein (claudin 16) which serves as a cell-cell junction in a part of the kidney specifically involved in the reabsorption of magnesium and calcium. The mouse model used to study this disease is not fully representative of human pathology. We therefore aim to create a genetically modified mouse model, carrying a human genetic mutation for this disease, enabling us to better understand it and test new treatments. | Mouse models 2016 | ||
| 2017 | Stephane NEDELEC | Paris | Foundation For Rare Diseases | Spinal muscular atrophy, lower extremity-predominant, 2, AD SMALED2 | Development and characterization of preclinical Human and Mouse models of Spinal Muscular Atrophy to determine the mechanisms of selective motor neuron impairments | Spinal muscular atrophies are rare neurodevelopmental genetic diseases characterized by selective degeneration of certain neurons, leading to paralysis and sometimes death. Understanding the mechanisms that protect certain neurons could lead to the discovery of new therapeutic avenues. We are therefore studying the cellular and molecular bases underlying the resistance or sensitivity of particular groups of motor neurons in a severe infantile case associated with the BICD2 gene and characterized by selective damage to neurons innervating the legs. We have succeeded in generating these lumbar neurons in vitro from patient biopsies. We will study their characteristics in detail to determine what makes them more fragile than other neuronal populations. The study of a mouse mimicking the patients' genetic defect will be essential to complete our in vitro data. | Mouse models 2016 | ||
| 2017 | Agnes DUMAS | Paris | Foundation For Rare Diseases | Congenital adrenal hyperplasia, Isolated anorectal malformations or syndromic, Crohn's disease, Juvenile idiopathic arthritis, Mucoviscidosis | Transition Platforms: Understanding the Expectations of Parents of Young People with Rare Diseases | Context: Young patients are faced with the transition of care from pediatrics to adult wards. Scientific recommendations all agree on the need for upstream preparation for the transition and the need to involve adolescents and their parents. In this respect, several hospitals have recently built "transition platforms". These platforms are designed to meet the needs of young patients first and foremost. There is currently no intervention aimed at parents. To improve care provision, it is essential to know what difficulties and expectations parents of young patients face. Objectives: -Characterize, in different medical and social contexts, the experience of transition, from the point of view of parents of young people with rare diseases; -Identify parents' expectations of their child's care within a transition platform. Methods: This is a qualitative study based on interviews with a sample of parents of young people cared for in the transition platforms of two hospitals in the Paris region. Interviews will also be conducted with representatives of associations involved in the platforms to benefit from their expertise. Observations will also be carried out in the platforms to understand how they operate. Expected results: The research will lead to a better matching of care and support provision to the specificities of of rare diseases, and to the development of interventions entirely dedicated to parents. This will have a major impact not only on the two platforms involved in the project, but also on platforms under construction in other locations. | The results of the study highlight two notable elements: one concerns the socially differentiated ways in which parents perceive their place in adult medical services, and the other concerns the conflict of norms and values they experience during the transition, between the desire to care for their child and the desire to make them independent. Indeed, the results show that the ability to negotiate the place granted in the adult sector is not equitably distributed according to the social background of the parents, echoing the work of S. Fainzang (2015). In our study, the transition was perceived as abrupt or even violent by parents who believed (wrongly) that exclusion from adult consultations was non-negotiable, and who were most often mothers from working-class backgrounds. For these mothers, the transition sometimes amounted to a denial of the knowledge they had acquired over the years, or even the loss of a symbolic place and a renunciation of part of their identity, particularly when they had interrupted their professional activity to care for their child. Their "work" of providing support (Corbin & Strauss 1988) and their investment was thus called into question at the time of the transition, leading some mothers to a profound upheaval in their identity, resulting in a form of second "biographical rupture" (Bury, 1982), after the first rupture caused by the arrival of their child. Beyond differences between social classes, the results show that the gender categorizations to which mothers may have been assigned in the history of their child's care also play a role in their experience of the transition. Mothers described as having excessive concerns at the time of diagnosis seem to be subsequently prevented from asserting their place in the adult sector, thus establishing a repetition of symbolic violence. For parents, the transition is part of a broader conflict of norms between the desire to "care" and the desire to empower the adolescent. While this conflict of norms arises for all parents during adolescence, it is more complex for parents of sick children, primarily due to the effort to normalize the illness (Mougel, 2009), which runs counter to the process of empowerment. This conflict between the norms of care and those of empowerment becomes even more acute when young people stop following their treatment or neglect their medical follow-up despite the risk of complications. In this context, some mothers feel that no longer attending consultations prevents them from protecting their children: without access to doctors or the necessary information about treatments, they can no longer perform their supervisory and alerting duties to caregivers (Young et al., 2002; Harden, 2005). This conflict of norms is compounded by a conflict of timing between the medical transition, which begins at age 18 with the transition to legal adulthood and the right to manage one's own health, and the timing of the transition to adulthood, which is occurring later and later in contemporary Western societies (the average age of leaving the parental home is 23 in France, and access to stable employment occurs on average at 27 (INSEE, 2018). In fact, at age 18, young people are still "dependent" on their parents, who have a financial but above all a moral responsibility towards their children and their children's health, which can cause significant tension when young people live with their parents. This study had limitations, as parents experiencing difficulties may have been more inclined to participate in the study. However, this did not constitute a bias as such, since the qualitative approach does not seek to quantify problems but to explain them. Furthermore, the conditions included were far from representing all rare diseases, while being very diverse from one another. Despite this diversity, we were able to analyze the effects of social background and gender on the ways in which parents approached the transition and thus highlight reflections that are relevant to all parents of adolescents with rare diseases. | Humanities and social sciences 5 | |
| 2017 | Lionel DANY | Marseille | Foundation For Rare Diseases | Systemic lupus erythematosus | Psychosocial consequences of systemic lupus erythematosus: a study of patients and their spouses | Systemic lupus erythematosus (SLE) is a rare chronic autoimmune disease (1/2000 population) which progresses in relapses interspersed with periods of remission. Most sufferers are young women of childbearing age. SLE has an impact on both married and family life (financial, emotional, relational and sexual conditions). What's more, the disease and its treatments can hamper the possibility of building a family project (pregnancy). The aim of the Psy-LUP study is to investigate the repercussions of SLE on patients' social participation, i.e. on their ability to get involved in the various areas of daily life. The more active the lupus disease, and the more severe its complications, such as kidney damage, the greater the impact. Our aim is to study how people with lupus and those close to them (spouses in particular) perceive lupus disease, how it fits into their life history, how they have adapted to the disease and what impact it has had on their social participation, social support and life as a couple. The Psy-LUP study will be carried out in various care services, and by telephone interviews at home, with two main thrusts: (1) a questionnaire study with patients; (2) a qualitative research interview study with patients and their spouses. All the data collected will be used to target interventions with 1) patients and their families, in terms of therapeutic education, psychosocial support and support groups (associations); 2) carers caring for people with SLE, so that they can integrate the challenges of patients' experiences into their care practice and their thinking about therapeutic strategies. | - | Humanities and social sciences 5 | |
| 2017 | Maria POPA-ROCH | Strasbourg | Foundation For Rare Diseases | Ehlers-Danlos syndrome, Ondine syndrome Juvenile arthritis | Rare Invisible Disease and Schooling of Children | The aim of this research program is to promote school inclusion for children with Ehlers-Danlos, Ondine and juvenile arthritis syndromes. Indeed, parents who are members of partner associations and clinicians who see these children in consultation have told us about the difficulties the children encounter, which are barriers to their development at school. Very often, the testimonies reveal resistance on the part of the teaching staff and attitudes that could be detrimental to learning: as the disability is not visible and the difficulties unrecognized, teachers find themselves worried and feel uncomfortable when faced with these different pupils. This program, conducted in collaboration with parents, doctors and psychology researchers, aims to show how the success of young people with these syndromes can depend on teachers. We will measure teachers' attitudes (conscious or unconscious) and the cognitive abilities of students with these rare diseases and their non-diseased peers. Our hypothesis is that if these young people do less well at school than other pupils, it's not a question of their objective level of intelligence and reasoning, but depends on how they are perceived by their teachers. These results will enable us to develop a specific training program for teachers in order to reduce their resistance and a priori attitudes towards pupils with rare and little-known diseases. This training will be tested experimentally before being included in the training program for future teachers to improve the benefits of school inclusion for children with invisible disabilities. | Three important findings are worth noting. First, the results of this study revealed no significant differences between the group of children with JIA and the control group, both in terms of comprehensive neuropsychological assessment and academic performance estimation tasks. Our research indicates that children with JIA are therefore likely to progress positively in their academic careers. Second, children with JIA rate themselves more favorably on the competence dimension than their peers without the condition. We interpret these results as reflecting the need to occupy a valued place among their peers. However, we would like to mention the characteristics of the sample, i.e., families recruited on a voluntary basis, on the one hand, and from privileged socioeconomic backgrounds with strong involvement and significant support for their children's academic progress, on the other. This study highlights the importance of studying the self of people with invisible disabilities, as they seem to develop unique strategies in response to the social perception of disability. The results are encouraging because they point to the importance of supporting students with invisible disabilities in their academic careers, both by their families and, above all, by their teachers. Thirdly, the results concerning teachers show the importance of factors that can be modified through training, i.e., attitudes, self-efficacy, and well-being. Studies suggest that teachers are not sufficiently trained to perform their role in inclusive schools. Inadequate training creates a context conducive to negative perceptions of children with disabilities, stress, and poor relationships with them. Targeted training on the inclusion of children with invisible disabilities appears to be the preferred and crucial means of ensuring the successful schooling of these children. | Humanities and social sciences 5 | |
| 2017 | Pierre ANCET | Dijon | Foundation For Rare Diseases | Congenital Giant Naevus | Study Congenital Giant Naevus: Psychology, Info-Com, Health, Transdisciplinary, Ethics | Giant congenital nevus is a rare skin malformation characterized by giant moles on the body and/or face. They vary in complexion from reddish-brown to black, and may be smooth or covered with hairs or bumps. Repeated plastic surgery is generally proposed to prevent serious cancers, which occur in 5% of affected children, but to date there is no way of knowing how effective it is, or whether the benefits outweigh the risks. Thus, this research project focuses on the psychosocial consequences and ways to improve their repercussions. We will study the challenges faced by: 1. parents: how did they feel when the nevus was discovered at birth? Were they well informed by the medical teams? How long did their diagnostic wandering last, and what was the effect on their relationship with the baby or the doctors? 2. children, teenagers and adults with a nevus: how do they feel about themselves and other people, whether face-to-face or on social networks? Our approach will involve doctors, researchers in the human sciences (philosophy, psychology, communication) and professional representatives of French family associations. This interdisciplinary team will collaborate with another association whose aim is to offer workshops for people with aesthetic disabilities, in particular giant nevi, using cognitive and behavioral compensation techniques already successfully tested for burns and other malformations. A comic strip featuring a heroine visibly affected by a giant nevus will be one of the tools, and information will be disseminated via social networks and associations. Interviews and other analyses will be carried out before and after the workshops to assess their effectiveness. | Notre étude a confirmé que les conséquences psychiques de la différence physique visible dans la construction de soi varient dans des proportions surprenantes pour des atteintes très proches, ce qui rejoint des revues de littérature à ce sujet (Billaud Feragen, 2012, p. 365 ; Masnari, 2019). De même, nous avons relevé le fait que pouvoir cacher sa différence sous des vêtements ou l’étendue de celle-ci sont de mauvais prédicteurs de la difficulté à vivre avec elle (même après une chirurgie, d’autant que celle-ci laisse des traces de greffe de peau comme chez les grands brûlés). Des personnes semble-t-il très peu touchées peuvent souffrir bien davantage du regard porté sur elles que d’autres dont l’atteinte est plus étendue et plus grave sur le plan fonctionnel. Nous avons décidé de réaliser des entretiens avec des personnes qui ont eu une capacité d’adaptation (coping) précoce, des personnes souvent présentes sur les réseaux sociaux ou au sein des associations qui souhaitent partager leur expérience notamment en direction des plus jeunes. L’idée n’est certainement pas d’inciter les plus jeunes à se montrer avec leur particularité sur les réseaux sociaux, ce qui les expose à une possible violence ou à du harcèlement. Aussi avons-nous enquêté également sur cet aspect de l’exposition en ligne avec nos collègues d’info-com, ce qui nous a conduits aux résultats suivants : - il est possible d’avoir de vraies relations, très intimes, à distance : la relation par l’intermédiaire de moyens dits virtuels n’est pas une « relation virtuelle ». Les groupes fermés sont une manière efficace de rencontrer des personnes qui partagent un vécu lié à une atteinte rare malgré la distance géographique. Ce mode de communication est à préférer à la présentation de soi en ligne devant le grand public qui suppose beaucoup de recul par rapport aux commentaires (le cyberharcèlement est même plus pénible encore que le harcèlement ordinaire) - Ies pratiques de pairémulation sont pertinentes, y compris en ligne. Il convient toutefois de souligner que des influenceurs et influenceuses, à partir d’un certain degré de notoriété, ne sont plus exactement des pairs, puisqu’ils ou elles ont fait de leur spécificité une ressource, y compris financière puisque notre équipe a repéré du placement de produit et une dérive commerciale dans la mise en scène de soi - Les personnes plus âgées (jeunes adultes) restant des pairs ont évoqué toute une série d’adaptations personnelles pour pallier les difficultés par exemple le « fake it to make it » (que l’on peut traduire par : « fais semblant jusqu’à le devenir vraiment ») n’a rien d’illégitime lorsque l’enjeu est seulement une question d’apparence. Cette approche a été défendue par une personne qui a pratiqué le théâtre depuis l’âge de 4 ans, ce qui l’a habituée au regard des autres malgré un naevus étendu sur le visage. - Beaucoup de personnes interrogées ont rapporté l’importance d’activités comme le théâtre, le chant, la danse, le sport ou toute autre pratique développant l’efficience du corps et une conscience du corps vécu plutôt qu’une focalisation sur l’apparence du corps. Cela permet une habitude de la visibilité assumée, ce sont des moyens repérés comme très efficaces par les adultes interrogés à propos de leur parcours. Cela ne permet pas de supprimer la difficulté sociale, mais d’en faire suffisamment l’expérience par l’exposition publique pour savoir la déjouer habilement, surtout lorsque ces activités sont pratiquées depuis le plus jeune âge. - Loin de devoir protéger les enfants de leur exposition ou de leur permettre de se contenter du repli sur eux-mêmes, il apparaît donc important de susciter en eux l’envie de jouer avec le regard et des bases pour se projeter à sa façon en tant qu’acteur du quotidien. Apprendre à jouer un personnage, avoir les capacités d’agir pour paraître quelqu’un de confiant jusqu’à pouvoir le devenir est essentiel pour faire face. Cela permet de souligner un paradoxe concernant la position de l’acteur : ce qui n’est au départ qu’un simple jeu indépendant d’une recherche identitaire va donner du jeu dans le rapport à ses multiples identités, et permettre par exemple de se dessaisir d’une de ses identités de victime ou de malade au profit d’une facette de ses identités qui sans ce jeu n’aurait pas pu s’affirmer. - Le dialogue et le jeu n’ont pas lieu qu’avec les autres : ils favorisent également le dialogue avec soi-même et sa propre image, contre l’empreinte du stigmate qui rigidifie le rapport à soi et limite l’évolution positive de l’image de soi. Reprendre ce dialogue au sein d’activités apparemment anodines, se concentrer sur les sensations de son propre corps dans un espace intime, octroie une possibilité de dialogue avec soi-même et de redécouverte sensorielle. - Réinvestir son corps par la sensorialité tactile, la proprioception en les articulant à la visibilité du corps a été une démarche également souvent citée par nos enquêtés. Elle donne le droit de s’aimer et d’apprécier son corps en instaurant un dialogue entre l’image de son corps et la sensation de celui-ci. Cette renarcissisation passe par la conscience du corps tout autant que par sa visibilité. Cette assise sensorielle peut se suffire à elle-même ou aider à se lancer dans des pratiques esthétiques qui ne vont pas de soi pour les personnes marquées par un stigmate. Prendre soin de soi contribue à restaurer une image de soi fragilisée et très valorisante pour nos enquêtées. Ce principe, valorisé par la socio-esthétique qui combine travail sur l’image de soi et l’apparence y compris pour des personnes semble-t-il très peu valorisables, permet d’encourager les individus à s’apprécier et leur permet de se sentir plus légitimes à entreprendre des pratiques esthétiques ou de contrôle de leur corps. - En écho à la sensorialité corporelle, parmi les ressources évoquées par les enquêtés se trouve l’attention au présent, la préservation de moments privilégiés permettant d’échapper à la menace d’envahissement psychique par l’obsession de son apparence. La conscience du présent vise à se concentrer sur ce qui est en train d’être ou d’être fait pour réduire le « bruit » mental associé à la spécificité d’apparence. - Différents moments cruciaux de la construction de soi peuvent être identifiés, depuis la découverte de la maladie (touchant d’abord les parents et la sphère familiale), jusqu’à l’entrée dans le monde du travail et aux relations sociales adultes, en passant par l’épreuve scolaire (le rapport aux enseignants et aux autres), la relation aux autres à l’adolescence et durant les phases de séduction. Tous ces moments peuvent être considérés comme des formes d’épreuves, variables en fonction du contexte social. Mais cette notion d’épreuve ne doit pas être envisagée seulement péjorativement : il apparaît possible de se forger par l’épreuve (Martucelli, 2006) dans la mesure où l’on dispose de ressources personnelles et d’appuis sociaux, familiaux, économiques et culturels suffisants. Par l’entraînement à l’exposition réitérée, certains sujets parviennent à déjouer les rôles sociaux imposés, comme ont pu le souligner un certain nombre des personnes interrogées. Cela va tout à fait dans le sens du programme d’ETP que notre équipe a contribué à créer, visant à l’apprentissage du coping face au regard des autres et à ses effets comme l’auto-dépréciation de soi et de son image. | Humanities and social sciences 5 | |
| 2017 | Sebastien RUFFIE | Pointe-à-Pitre | Foundation For Rare Diseases | Sickle cell disease | Sickle cell disease, neurocognitive disorders and social participation | Sickle cell disease is the most common genetic disorder in France. to reduce morbidity and mortality. In Guadeloupe, systematic screening from birth encourages early medical care, combined with psychological and social follow-up. Sickle-cell anemia in children can lead to neurological complications, including stroke, which can develop with or without clinical signs. A major risk associated with these strokes is the impact on general intellectual functioning and neuropsychological disorders affecting intellectual functioning, executive and attentional functions. The aim of this project is to study the influence of these neurocognitive disorders on the participation of children and adolescents with sickle cell disease (aged 6 to 16) in Guadeloupe. neurocognitive disorders on social participation not previously explored, in contrast to the well-documented well-documented negative impact of sickle cell disease on quality of life. The results of social participation assessments will be analyzed according to the nature of neuropsychological disorders, using a transdisciplinary approach. Neuropsychological disorders will be investigated by the clinical psychologists and neuropsychologists regularly involved in the care of these patients, using the usual appropriate tests. To assess their social participation, methods adapted to detect the obstacles and facilitators involved in the social integration of individuals will be used (MHAVIE and MQ,). Semi-structured interviews will complete the qualitative data collection. Expected results include understanding the impact of neurocognitive disorders on the personal and/or environmental difficulties encountered by these patients in their social participation. | La drépanocytose, maladie génétique affectant l’hémoglobine, est la pathologie la plus fréquente en France. En Guadeloupe, où elle est une priorité de santé publique, un dépistage systématique dès la naissance favorise la prise en charge médicale précoce associée à un suivi psychologique et social. Les enfants drépanocytaires, du fait de leur anémie importante, peuvent présenter des complications neurologiques incluant des accidents vasculaires cérébraux (AVC) se développant avec ou sans signes cliniques. Un risque majeur associé à ces AVC concerne une atteinte des fonctions exécutives et attentionnelles. La maladie entraîne également des conséquences psychosociales sur l’enfant et sa famille, dans une gestion d’un quotidien marqué par les contraintes (variations de température, exposition solaire, effort lors des activités...). Entre stigmatisation de la maladie et restrictions d’activités, l’enfant peut ainsi rencontrer des situations dans lesquelles il ne réalise pas pleinement ses habitudes quotidiennes et ses rôles sociaux. Ces éléments sont regroupés sous la notion de participation sociale, conceptualisée par le modèle systémique du Processus de Production du Handicap (PPH). Objectifs et méthode : L’objectif de ce projet était d’étudier la participation sociale d’enfants et adolescents drépanocytaires (6 à 16 ans) suivis en Guadeloupe, pouvant présenter des troubles neurocognitifs. Ce champ d’investigation est neuf, contrairement à l’impact négatif bien documenté de la drépanocytose sur la qualité de vie. Les résultats des évaluations de la participation sociale ont été analysés en fonction de la nature des troubles neuropsychologiques à partir d’une approche transdisciplinaire, combinant des données médicales, neuropsychologiques, et sociologiques. Sur le plan méthodologique, l’échantillon était composé d’un groupe de 81 drépanocytaires (sur une cohorte totale de 102 sujets) et d’un groupe contrôle composé de 45 individus sains ayant des caractéristiques socio-démographiques similaires. Les troubles neuropsychologiques ont été recherchés par les psychologues et neuropsychologues cliniciens régulièrement impliqués dans la prise en charge de ces patients avec des tests d’évaluation des fonctions exécutives (i.e., WISC5, BRIEF, Figure de Rey, NEPSY-II). Pour évaluer la participation sociale, une échelle permettant l’évaluation du degré de réalisation, des aides et difficultés dans l’accomplissement des habitudes de vie a été utilisée (MHAVIE). Un second outil (MQE) a permis d’identifier les obstacles et les facilitateurs engagés dans l’intégration sociale des individus. Enfin, des entretiens semi-directifs ont complété le recueil quantitatif de données. Les résultats portent sur la compréhension de l’impact des troubles neurocognitifs sur les difficultés personnelles et/ou relevant de l’environnement, rencontrées par ces patients dans leur participation sociale. Principaux résultats obtenus Dans le cadre de l’évaluation clinique et psychologique, 76 drépanocytaires ont réalisé la totalité des tests psychométriques et neuropsychologiques. Quinze ne présentaient aucun des déficits recherchés. Les analyses portent sur les enfants restants. Près de 75% des enfants ne présentent aucun des troubles neurocognitifs testés. Ils se situent dans la zone moyenne et moyenne forte. Des dysfonctionnements sont toutefois mis en évidence, les fonctions cognitives les plus atteintes étant l’inhibition, l’attention sélective, l’efficience globale. La grande majorité des parents relèvent peu de perturbations exécutives à l’indice exécutif global, en métacognition et en régulation comportementale. Dans cette population d’enfants ayant un suivi homogène, le taux d’accident ischémique cérébral est faible (1.4% tous âges confondus). Cela est probablement en lien avec le dépistage précoce de la vasculopathie cérébrale et la mise en place de traitement intensifié. Sur le plan sociologique, une première analyse porte sur la comparaison des groupes quant aux résultats liés à la participation sociale (i.e., scores de la Mhavie : global, lié aux activités quotidiennes, aux rôles sociaux, et aux catégories composant chaque sous-score). Tout d’abord, les données liées aux caractéristiques socio-démographiques montrent des différences significatives : ainsi, le fait d’être drépanocytaire semble être corrélé avec des configurations familiales voire géographiques particulières : les drépanocytaires sont concentrés dans ce qu’on a qualifié de zone centrale de l’île (urbanisée), peut-être pour des raisons de proximité des soins et d’accès à l’hôpital. Mais l’échantillon n’est pas assez important pour le dire avec certitude. D’autre part, sur le plan familial, la situation de parent isolé (la mère dans la majorité des cas) est surreprésentée chez les drépanocytaires. On peut également noter la différence liée à la CSP maternelle, les catégories inférieures (comprenant les ouvrières et les employées) et inactives (femmes en recherche d’emploi ou sans activité professionnelle) étant surreprésentées chez les drépanocytaires. La pathologie des enfants induit des ruptures de carrière, des pertes d’emploi du fait des absences répétées, voire parfois l’impossibilité de maintenir une activité professionnelle lorsque la maladie est particulièrement symptomatique et que les conséquences (en termes de crises, d’hospitalisations et de problèmes de santé) sont importantes. Une part importante des drépanocytaires n’a pas renseigné la CSP paternelle. Dans de nombreux cas, les répondants ont précisé oralement n’avoir plus aucun contact avec leur père et ne pas connaître sa situation professionnelle actuelle. Ces éléments sont conformes à la littérature, qui montre l’impact de la drépanocytose sur la cellule familiale. La survenue, puis le vécu de la maladie conduisent à un éclatement du noyau parental ; la mère est souvent le seul parent à gérer le quotidien de l’enfant drépanocytaire. Conformément à nos hypothèses, les scores de participation sociale globale, et de réalisation des activités courantes et des rôles sociaux, sont significativement plus faibles chez les sujets drépanocytaires, attestant qu’ils rencontrent des restrictions dans l’accomplissement de leurs habitudes de vie, à l’exception de la catégorie Travail que nous avons considérée comme habitude de vie non pertinente, et des Relations Interpersonnelles. Pour cette dernière, les groupes ne se distinguent pas sur le plan des relations entretenues au sein de la cellule familiale et amicale proche, mais le passage d’une sociabilité « interne » à une sociabilité « externe » est plus problématique. Les jeunes drépanocytaires évoluent dans une diversité d’environnements et une multitude de cadres de socialisation, constituant des freins ou, au contraire, contribuant à faciliter leur participation sociale. Une deuxième analyse visait à répondre à la question suivante : Comment ces jeunes drépanocytaires perçoivent-ils ces environnements physiques et sociaux comparativement à des jeunes du même âge ? Comment facilitent-ils ou au contraire rendent-ils plus difficile leur participation sociale ? Tous les facteurs environnementaux composant la MQE sont perçus plus négativement par les jeunes drépanocytaires que par leurs pairs, à l’exception des facteurs renvoyant aux services socio-sanitaires (perçus comme des facilitateurs) et liés aux systèmes politiques (perçus comme des obstacles) pour lesquels les groupes ne se différencient pas. Dans le micro-environnement, le soutien familial apparait comme un facteur environnemental facilitateur, tout comme le soutien amical bien que de façon moins saillante que chez les pairs. La sphère scolaire est un environnement dans lequel les drépanocytaires rencontrent davantage de difficultés ; de plus l’appui des camarades, et le soutien des enseignants et plus largement les services éducatifs constituent des ressources, mais moins saillantes pour les sujets malades. A l’échelle macro-environnementale, les orientations et politiques publiques entravent également la participation de ces jeunes et font l’objet de représentations négatives, bien que comparables à celles de leurs pairs. S’ils ne sont pas décrits comme des obstacles, les facteurs contextuels renvoyant aux offres et activités culturelles, sportives et de loisirs constituent des facilitateurs moins importants qu’ils ne le sont chez leurs homologues sains. Une partie de nos analyses a porté plus spécifiquement sur l’environnement familial et les impacts de la maladie sur la structuration familiale. La situation monoparentale affecte sélectivement la participation sociale des répondants drépanocytaires, alors que la situation d’un foyer autour d’un couple contribue à l’améliorer. Dans les familles isolées, les mères, car ce sont le plus souvent elles qui ont la charge de l’enfant, sont fragilisés par les conséquences sociales et économiques de la maladie, et ne disposent pas toujours des ressources pour pouvoir accompagner leurs enfants à participer socialement, comme semble l’indiquer les écarts liés à la CSP familiale. Il y a ainsi, chez le groupe des enfants drépanocytaires, une moindre participation globale et de réalisation des rôles sociaux quand les parents sont inactifs que lorsqu’ils appartiennent aux professions intermédiaires-supérieurs. Le cumul de la monoparentalité et des difficultés économiques fragilise donc davantage leur participation sociale. Intérêt social des résultats : A partir de la perspective offerte par un cadre d’analyse systémique, intégrant des facteurs internes et externes à l’individu, cette étude a permis une meilleure connaissance de l’expérience et des difficultés des jeunes malades mais également de leur entourage. En plus de nourrir la réflexion des chercheurs, d’alimenter l’intérêt et questionner les pratiques des professionnels et des acteurs locaux qui agissent à différents niveaux et dans diverses sphères du jeune drépanocytaire : personnels médicaux, scolaires et parascolaire, associations locales, décideurs politiques, institutions pertinentes (MDPH, Rectorat). D’un point de vue social, comme médical, le projet a permis de discuter avec l’institution Rectorale, et particulièrement l’inspectrice ASH, afin d’améliorer la participation scolaire de ces jeunes, par une évolution du dispositif PAI, et un guide d’accueil et d’accompagnement scolaire des jeunes drépanocytaires. Par ailleurs, ce projet a également permis aux médecins de signaler objectivement aux parents, grâce aux tests effectués, les difficultés que vivent leurs enfants en leur expliquant les problèmes, entre autres cognitifs qu’ils peuvent vivre. Il a favorisé également la mise en place de remédiations cognitives spécifiques et individualisées à plus grande échelle. Enfin, un travail de vulgarisation de nos connaissances a permis de restituer ces résultats aux patients, leurs parents, les associations, les professionnels et les institutions. | Humanities and social sciences 5 | |
| 2017 | Stephanie MAZZA | Lyon | Foundation For Rare Diseases | Narcolepsy type 1 | Study of the academic and professional path of narcoleptic patients | Type 1 narcolepsy is a rare, disabling chronic sleep disorder characterized by abnormal sleepiness and emotion-related muscle tone dips (cataplexy). It begins in childhood or young adulthood. Its symptoms are responsible for significant disability, and are often poorly understood by those around them. Other conditions are often associated with narcolepsy (depression, anxiety, obesity). Few studies have examined the impact of narcolepsy on patients' educational and professional careers. Little is known about the handicap factors associated with the characteristics of the disease, and the determinants of patients' integration into society, even though this information could be used to inform patients, guide them in their choices of orientation, and act on certain critical factors. The aim of the NarcoScol/NarcoVitae study is to take stock of the academic and professional career paths of narcolepsy patients in a large national population, and to analyze the determinants of these paths. Patients will be recruited from reference/competence centers treating adults and children suffering from narcolepsy. They will be offered questionnaires as part of their usual follow-up, as well as to related or unrelated control subjects. The following will be assessed: educational and professional background, use of available aids, quality of life, depression, sleepiness and, for patients, the severity of the disease. The study will also assess the financial impact of the disease on patients and society. The NarcoScol/NarcoVitae study will 1) provide patients with better information to help them choose their career path, train and keep their jobs 2) set up specific actions to help them integrate into school and the workplace. | Contexte : La narcolepsie de type 1 est une maladie neurologique chronique du sommeil, rare, invalidante, caractérisée par une somnolence anormale et des chutes du tonus musculaire liées aux émotions (cataplexies). Elle débute souvent dans l’enfance ou chez l’adulte jeune. Les symptômes de la narcolepsie sont responsables d’un handicap important au quotidien et restent souvent mal compris par l’entourage. De plus, de nombreuses autres affections sont associées à la narcolepsie, telles que la dépression, l’anxiété, ou l’obésité. Pertinence : Peu d’études se sont intéressées à l’impact de la narcolepsie sur le parcours scolaire et professionnel des patients. En particulier les facteurs de handicap liés aux caractéristiques de la maladie et les déterminants de l’insertion des patients restent mal connus. Une meilleure connaissance de ces déterminants permettrait d’informer les patients, de les guider dans leurs choix d’orientation et d’agir sur certains facteurs critiques. Objectifs : L’objectif de l’étude NarcoScol/NarcoVitae était de dresser un état des lieux du parcours scolaire et professionnel des personnes atteintes de narcolepsie dans une vaste population nationale et d’en analyser les déterminants. Méthodes : Des personnes adultes atteintes de NT1 et des « contrôles » (personnes de leur entourage, appariées pour le sexe et l’âge, ne souffrant pas de narcolepsie) ont été sollicitées par les médecins du centre de compétence/référence narcolepsies-hypersomnies rares où elles étaient suivies habituellement. Il leur a été proposé de répondre à un questionnaire en ligne sur leur parcours scolaire et professionnel ainsi qu’à différentes échelles (somnolence, dépression, symptômes psycho-comportementaux, échelle de déséquilibre effort/récompense au travail, qualité de vie). Résultats : - Au total, 235 patient.e.s (63,8% de femmes, 36,4±14,7 ans) ont participé, ainsi que 166 contrôles (69,9% de femmes, 40,3±14,4 ans). Les personnes atteintes de NT1 étaient moins souvent en couple et avaient moins d’enfants. Elles rapportaient moins de temps libre, et pratiquaient moins d’activité physique que les témoins. Les symptômes dépressifs et la somnolence diurne excessive étaient plus fréquents et la qualité de vie moindre, avec des difficultés dans les relations amicales et professionnelles. - Concernant le parcours scolaire, Les niveaux de diplômes obtenus ne différaient pas entre les patients atteints de NT1 et les témoins, mais les patients rapportaient davantage d’interruptions de la scolarité (20 % contre 8,5 %) et percevaient leur parcours comme plus difficile. Ils évoquaient plus Appel à projets de recherche en Sciences Humaines et Sociales – Rapport final 18 fréquemment des problèmes d’attention, d’absentéisme et de retard en cours, surtout lorsque la maladie avait débuté dans l’enfance. Parmi les élèves dont la maladie avait été diagnostiquée dans l’enfance, environ 60 % avaient bénéficié de soutiens spécifiques, principalement du temps supplémentaire pour les examens. - Les patients atteints de NT1 présentaient des parcours professionnels globalement comparables aux témoins en termes de taux d’emploi (69,5 % vs 77,0 %), de catégories socio-professionnelles et de périodes de chômage. Cependant, leurs carrières étaient marquées par davantage de travail à temps partiel (38,9 % vs 25,3 %), de changements de poste non souhaités et des difficultés à obtenir des promotions. Les patients rapportaient un déséquilibre effort/récompense accru lié à un niveau de récompense perçu comme plus faible, à des contraintes professionnelles et à un sentiment d’instabilité de leur emploi. En termes d’adaptations, 21 % des patients bénéficiaient d’aménagements professionnels (horaires flexibles, siestes, télétravail). Malgré ces aides, 16 % se sentaient incompris ou perçus comme paresseux, tandis que 59,2 % citaient la somnolence comme leur principal handicap au travail. Sur le plan économique, les revenus mensuels des patients étaient inférieurs à ceux des témoins ; ceci était plus marqué lorsque la maladie avait été diagnostiquée tardivement. - Enfin, la dépression et les troubles de l’attention étaient identifiés comme des facteurs associés à un parcours professionnel plus difficile, alors que le fait d’avoir fait l’expérience de la maladie pendant la scolarité était associé à un pronostic plus favorable. Discussion: Les résultats de l’étude NarcoScol NarcoVitae suggèrent que la plupart des patients atteints de NT1 pris en charge dans des centres spécialisés parviennent à atteindre leurs objectifs professionnels, mais que le prix à payer en termes d'efforts quotidiens, de concessions sur d'autres aspects de leur vie (familiale, amicale) et de charge psychologique est élevé par rapport à la récompense obtenue, avec notamment moins de perspectives de promotions et un impact financier négatif de la maladie. Davantage que les symptômes liés au sommeil, généralement bien pris en charge par les traitements existants, les comorbidités de la maladie telles que les troubles cognitifs (attention) et la dépression jouent un rôle essentiel dans le pronostic éducatif et professionnel des patients. De manière intéressante, l'expérience de la narcolepsie pendant la scolarité est associée à un meilleur pronostic professionnel. Cela suggère que la période scolaire pourrait servir de période critique d'ajustement en faciliter le développement de stratégies d'adaptation. Conclusion Ces résultats renforcent la nécessité d'une prise en charge globale des personnes souffrant de narcolepsie, incluant les dimensions psycho-cognitivo-sociales. Des études prospectives seront nécessaires pour évaluer quelles mesures (traitement pharmacologique ou non pharmacologique, soutien psychologique, développement des compétences psychosociales, adaptation de l'environnement...) sont susceptibles de réduire le fardeau scolaire et professionnel associé à la maladie. | Humanities and social sciences 5 | |
| 2017 | Virginie POSTAL | Bordeaux | Foundation For Rare Diseases | Prader Willi syndrome | Communication in Prader-Willi syndrome: study of emotional control related to behavioural disorders, their daily repercussions and examination of innovative therapies | Prader Willi syndrome (PWS) is a rare (1 in 25,000 births) and complex genetic disease characterized by mild to moderate intellectual retardation, obesity and behavioral problems. behavioral problems. It leads to difficulties in social integration, first at school and then at work (only 4% of PW adults in France live alone). Integration into the mainstream or into a work-based support service, as well as day-to-day management by families, is difficult due to frequent behavioral problems. Over 80% of PWS patients suffer from temper tantrums. In view of these difficulties, and their repercussions on families and carers (stress, burden, etc.), identifying the factors that explain these disorders would enable us to gain a better understanding of the syndrome as a whole, and to tailor treatment more effectively. Proposing new therapeutic avenues is a major challenge in this syndrome, for which there is currently no drug treatment. The aim of the PRACOM (PraderWilli Communication) project is to identify and characterize emotional functioning disorders, in particular those linked to anger, and their behavioral consequences; to situate them in their environmental contexts (frequency, cause, consequences on well-being and parental, school or professional relationships); and to propose innovative therapeutic approaches aimed at improving these behavioral disorders. Various questionnaires and semi-directive interviews will be administered to children and adults with PWS, their families and professionals working in care facilities. At the end of these assessments, 3 innovative approaches will be evaluated to offer new therapeutic avenues, which could be extended to pathologies with similar disorders. | Le syndrome de Prader-Willi (SPW) est une maladie génétique rare et complexe causée par l’absence d’expression des gènes de la région q11-q13 du chromosome 15 paternel, et impliquant une diversité de symptômes cliniques, comportementaux et cognitifs handicapants le quotidien. Sa prévalence est estimée à 1 sur 20000 à 1 sur 25000 (Whittington et al., 2004). Concernant l’étiologie génétique, on observe majoritairement (70 à 75% des cas) une délétion totale (type I) ou partielle (type II) du chromosome 15 paternel. Dans 25 à 30%, il s’agit d’une disomie uniparentale maternelle. Et enfin, dans moins de 5% des cas, la pathologie est causée par d’autres mécanismes tels qu’une mutation ou une anomalie du chromosome. Le SPW est principalement caractérisé par une hyperphagie avec obsession de la nourriture, menant bien souvent à une obésité précoce. Les personnes atteintes de la pathologie ne ressentent pas le sentiment de satiété, et la plupart de leurs problèmes comportementaux sont reliés à cette caractéristique (Jauregi, Laurier, Copet, Tauber, & Thuilleaux, 2013) ce qui représente un obstacle majeur à leur intégration sociale. En effet, la majorité des patients (83 à 97 %, Rice & Einfield, 2015) sont sujets à des épisodes de crises de colère, voire des comportements agressifs (Woodcock, Oliver, & Humphreys, 2011). En règle générale, les patients ont des difficultés à s’adapter au quotidien ; ils montrent peu d’autonomie et présentent une mauvaise gestion émotionnelle des situations sociales. Sur le plan cognitif, les patients ont un quotient intellectuel autour de 60 en moyenne (Ho & Dimitropoulos, 2010) et on note un ralentissement général du traitement de l’information (Chevalère, 2014). Les chercheurs mettent en avant un déficit des fonctions exécutives (Chevalère et al., 2013 ; 2020, 2021, Jauregi et al., 2007). Chez les personnes atteintes du SPW des difficultés à interpréter les informations sociales et à lire et transmettre les informations émotionnelles nécessaires ont été montrés. On note par exemple des difficultés dans la reconnaissance des émotions faciales (Whittington & Holland, 2011, Debladis et al., 2019 ; Famelart et al., 2019). Ces différentes limitations, cognitives et comportementales constituent des freins à l’intégration sociale des patients atteints de SPW tant au niveau scolaire que professionnelle (seulement 4% d’entre eux vivent seuls, Laurier et al., 2015, et 1/3 sont sans emploi, Waters et al., 1990). Le SPW a également des répercussions au niveau familial en termes de bien-être et de qualité de vie. D’une part, des études ont rapporté que les parents d'enfants PW ont un manque d'informations important sur la maladie. Ce manque a comme conséquences une baisse de la qualité de vie avec un sentiment de perte de contrôle ou des symptômes dépressifs et anxieux (Mazaheri et al., 2013; Thomson, Glasson, Roberts, & Bittles, 2016; Van den Borne et al., 1999) ainsi que des restrictions dans les activités quotidiennes (Reilly, Murtagh & Senior, 2015). L’objectif du projet PRACOM était d’identifier et de caractériser les troubles émotionnelles et comportementaux associés au syndrome de Prader-Willi pouvant faire obstacle à la communication et rendant difficile l’intégration des patients dans le système scolaire ou professionnel et proposer des prises en charge innovantes visant à répondre à ces difficultés. La partie pédiatrique du projet (PRACOM 1) a permis d’objectiver une plus grande labilité émotionnelle des enfants atteints du SPW par rapport à la moyenne, ainsi qu’une irritabilité et des difficultés d’attention soutenue. Concernant les troubles du comportement, de façon générale, nous avons observé un retrait social, des problèmes de pensées, d’attention et d’agressivité mais avons constaté des variations interindividuelles importantes pouvant faire écho aux difficultés de prises en charge du syndrome. Cette variabilité se traduit également au niveau des crises de colère des enfants, dans leur fréquence, leur intensité et leur durée. La partie adulte du projet (PRACOM 2) confirme le même tableau clinique avec une labilité et une irritabilité plus importantes que la moyenne. Les études corrélationnaires menées dans cette partie ont permis montrer un lien entre l’anxiété-dépression, la colère et l’irritabilité et l’importance de l’hyperphagie. De même ; nous avons montré un lien entre les difficultés de contrôle de la labilité émotionnelle, l’irritabilité et la fréquence, la durée et l’intensité des crises de colère. Sachant que l’expression des crises de colère fait souvent obstacle à l’intégration sociale et professionnelle des patients, cela souligne l’intérêt de pouvoir améliorer la gestion du contrôle émotionnel chez les patients atteints du SPW. La labilité émotionnelle est également un facteur important sur le bien-être des parents. Les entretiens réalisés avec les parents et aidants professionnels des enfants et avec les parents des adultes PW mettent en exergue les préoccupations principales qui concernent ; les besoins des enfants et adultes (professionnels et occupationnels ainsi que besoins familiaux et sociaux), les besoins en termes de diagnostic et de prise en charge (à la fois pour les enfants et les parents) et de façon plus marquée pour les enfants, les difficultés liées à la gestion des crises de colère et de la déficience intellectuelle (par les professionnel. Ces différents éléments pris ensemble confirment l’intérêt pour les prises en charge thérapeutique, notamment celles visant à réguler le traitement des émotions. Trois prises en charge thérapeutiques ont été proposées (la t-VNS pour les enfants, un programme psychothérapeutique et la t-DCS pour les adultes) afin d’en évaluer la faisabilité et les premiers effets. Les trois programmes se sont avérés bien tolérés par les patients (parmi ceux présentant les troubles du comportement les plus importants), sans évènements indésirables graves et permettant d’observer de façon exploratoire (pas de groupe contrôle) des effets positifs. Chez les enfants, bien que le dispositif de t-NVS ne se soit pas avéré très adapté à la morphologie des enfants, entrainant des difficultés de maintien du dispositif et des abandons assez importants, les résultats ont montré grande préoccupation pour les sentiments des autres, une augmentation des comportements affectueux (câlins) ou une meilleure verbalisation de l'anxiété. Chez les adultes, le programme psychoéducatif a permis de constater une baisse de l’hyperphagie et de façon plus surprenante une augmentation des conduites anti-sociales que nous avons mis en lien avec une plus grande facilité pour les patients à exprimer leurs émotions à l’issue de la prise en charge. Enfin la t-DCS a permis, suite à une prise en charge relativement courte (20 minutes pendant 10 jours) d’observer une diminution des troubles de l’humeur, une meilleure régulation émotionnelle mais également une augmentation de la labilité émotionnelle. Ces études exploratoires méritent d’être confirmées par des études menées en aveugle et avec groupe contrôle mais compte-tenu des liens que nous avons mis en évidence entre la régulation émotionnelle, les troubles du comportements (dont l’agressivité ou l’hyperphagie) et le retentissement sur la sphère familiale (bien-être et fardeau), elles constituent une réponse aux difficultés d’intégration et de communication des patients atteints du syndrome Prader Willi. | Humanities and social sciences 5 | |
| 2016 | Albertina DE SARIO | Montpellier | Foundation For Rare Diseases | Cystic Fibrosis | DNA methylation and pulmonary disease in cystic fibrosis patients | - | GenOmics 2016 - 1 | ||
| 2016 | Alice HADCHOUEL | Paris | Foundation For Rare Diseases | Pulmonary alveolar proteinosis | Identification of a new gene in a familial form of pulmonary alveolar proteinosis | - | GenOmics 2016 - 1 | ||
| 2016 | Amelie PITON | Strasbourg | Foundation For Rare Diseases | intellectual disability autism | Evaluation of RNA-sequencing strategies to better diagnose intellectual disability | - | - | GenOmics 2016 - 1 | |
| 2016 | Angela TINGAUD-SEQUEIRA | Bordeaux | Foundation For Rare Diseases | Goldenhar syndrome Oculo-auriculo-vertebral spectrum | Exome sequencing to find new candidate genes involved in Goldenhar Syndrome and Oculo-Auriculo-Vertebral Spectrum | - | GenOmics 2016 - 1 | ||
| 2016 | Caroline MICHOT | Paris | Foundation For Rare Diseases | Cornelia de Lange syndrome | Dissection of molecular bases of Cornelia de Lange syndrome: identification of new genes in pre-screened patients | - | GenOmics 2016 - 1 | ||
| 2016 | Celia CRÉTOLLE | Paris | Foundation For Rare Diseases | Currarino Syndrome (non mutated for MNX1 gene) Syndromic caudal dysgenesis: Ano-rectal malformation associated with partial sacral agenesis and occult dysraphism and pre sacral tumor | Genotype-endophenotype correlation study in patients with a MNX1 gene non mutated Currarino syndrome | - | GenOmics 2016 - 1 | ||
| 2016 | Christel DEPIENNE | Strasbourg | Foundation For Rare Diseases | Familial cortical myoclonic tremor and epilepsy (FCMTE) | Identification of the unconventional genetic basis for familial cortical myoclonic tremor and epilepsy | - | GenOmics 2016 - 1 | ||
| 2016 | Christian PINSET | Paris | Foundation For Rare Diseases | Duchenne muscular dystrophy (DMD) | Studying myogenesis and the onset of Duchenne muscular dystrophy (DMD) in human pluripotent stem cells to identify early disease markers and potential therapeutic targets | - | GenOmics 2016 - 1 | ||
| 2016 | Eric LE GUERN | Paris | Foundation For Rare Diseases | Genetic generalized epilepsy | IDENTIFICATION OF NEW GENES FOR FAMILIAL FORMS OF GENERALIZED EPILEPSIES | - | GenOmics 2016 - 1 | ||
| 2016 | Genevieve BAUJAT | Paris | Foundation For Rare Diseases | Klippel Feil syndrome | Molecular basis dissection of isolated Klippel Feil syndrome: identification of new genes | - | GenOmics 2016 - 1 | ||
| 2016 | Guy LENAERS | Angers | Foundation For Rare Diseases | Mitochondrial Inherited Optic Neuropathies Dominant Optic Atrophy Kjer disease | Genetic analysis of dominant optic atrophy | - | - | GenOmics 2016 - 1 | |
| 2016 | Jean MULLER | Strasbourg | Foundation For Rare Diseases | Bardet-Biedl Syndrome | Identification of novel genes underlying Bardet-Biedl Syndrome using Next Generation Sequencing | - | - | GenOmics 2016 - 1 | |
| 2016 | Pascale GUICHENEY | Paris | Foundation For Rare Diseases | Long QT syndrome (LQTS) Catecholergic polymorphic ventricular tachycardia (CPVT) | Elucidation of the molecular variants responsible for sudden cardiac death in two large families | - | GenOmics 2016 - 1 | ||
| 2016 | Sandrine VUILLAUMIER-BARROT | Paris | Foundation For Rare Diseases | CDG syndrome, glycosylation defect, coagulation defect | Identification of a gene underlying same coagulation factors abnormalities and CDG II profile in two unrelated families with anticipated dominant transmission. | - | GenOmics 2016 - 1 | ||
| 2016 | Stephane BÉZIEAU | Nantes | Foundation For Rare Diseases | Syndromic and non-syndromic severe intellectual disability (IQ<50) | Trio-based whole-genome sequencing of patients with syndromic and non-syndromic severe intellectual disability | - | GenOmics 2016 - 1 | ||
| 2016 | Yanick CROW | Paris | Foundation For Rare Diseases | Aicardi-Goutieres syndrome Type I interferonopathies Familial chilblain lupus | Whole genome sequencing in Aicardi-Goutieres syndrome and related type I interferonopathies | - | GenOmics 2016 - 1 | ||
| 2016 | AGNES ROTIG | Paris | Foundation For Rare Diseases | Mitochondrial diseases | IDENTIFICATION OF NUCLEAR GENES OF MITOCHONDRIAL DISEASES WITH NEUROLOGICAL INVOLVEMENT | - | GenOmics 2016 - 2 | ||
| 2016 | Alexandre FABRE | Marseille | Foundation For Rare Diseases | Waldmann's disease or Primary intestinal lymphangiectasia | GENETIC BASES OF PRIMARY INTESTINAL LYMPHANGIECTASIA | - | GenOmics 2016 - 2 | ||
| 2016 | Ange-Line BRUEL | Dijon | Foundation For Rare Diseases | Oral-facial-digital syndromes | IDENTIFICATION OF NEW GENES IMPLICATED IN ORAL-FACIAL-DIGITAL SYNDROMES, IN EXOME-NEGATIVE PATIENTS | - | - | GenOmics 2016 - 2 | |
| 2016 | Anne JOUTEL | Paris | Foundation For Rare Diseases | Hereditary cerebral small vessel disease | DISSECTING MOLECULAR PATHWAYS INVOLVED IN COL4A1-RELATED INTRACEREBRAL HEMORRHAGE | - | GenOmics 2016 - 2 | ||
| 2016 | Christel THAUVIN | Dijon | Foundation For Rare Diseases | Developmental anomalies | IDENTIFICATION OF NEW GENES IMPLICATED IN UNDIAGNOSED DEVELOPMENTAL ANOMALIES FOLLOWING A GENOTYPE-FIRST APPROACH USING GENOME SEQUENCING, IN TRIO-EXOME-NEGATIVE PATIENTS | - | GenOmics 2016 - 2 | ||
| 2016 | Delphine HERON | Paris | Foundation For Rare Diseases | Agenesis of the corpus callosum | IDENTIFICATION OF GENES FOR ISOLATED AGENESIS OF THE CORPUS CALLOSUM WITHOUT INTELLECTUAL DEFICIENCY | - | GenOmics 2016 - 2 | ||
| 2016 | Herve MOINE | Strasbourg | Foundation For Rare Diseases | Fragile X syndrome | IDENTIFICATION OF THE FMRP BINDING SITE ON ITS NEURONAL MRNA TARGETS BY CLIP-SEQ IN THE FMR1-KO MOUSE MODEL OF THE FRAGILE X SYNDROME | - | - | GenOmics 2016 - 2 | |
| 2016 | Jocelyn LAPORTE | Strasbourg | Foundation For Rare Diseases | Muscular dystrophy Congenital myopathy | COMBINING HIGH THROUGHPUT SEQUENCING APPROACHES TO DEFINE THE GENETIC BASES OF MYOPATHIES | - | - | GenOmics 2016 - 2 | |
| 2016 | Louise BENARROCH | Paris | Foundation For Rare Diseases | Marfan syndrome Familial Thoracic Aortic Aneurysm and Dissection | IDENTIFICATION OF NEW GENES INVOLVED IN MARFAN SYNDROME AND FAMILIAL THORACIC AORTIC ANEURYSM AND DISSECTION | - | GenOmics 2016 - 2 | ||
| 2016 | Marie-Christine ALESSI | Marseille | Foundation For Rare Diseases | ETV6-related thrombocytopenia | UNRAVELING MOLECULAR MECHANISMS OF ETV6-RELATED THROMBOCYTOPENIA | - | GenOmics 2016 - 2 | ||
| 2016 | Mathieu BARBIER | Paris | Foundation For Rare Diseases | Frontotemporal-Lobar Dementia (FTLD) | IN SEARCH OF GENETIC MODIFIERS TO PREDICT THE AGE AT ONSET IN FRONTOTEMPORAL-LOBAR DEMENTIA | - | GenOmics 2016 - 2 | ||
| 2016 | Roland LIBLAU | Toulouse | Foundation For Rare Diseases | Narcolepsy with cataplexy | HUMAN IMMUNE SIGNATURES OF NARCOLEPSY WITH CATAPLEXY | - | GenOmics 2016 - 2 | ||
| 2016 | Valerie CORMIER-DAIRE | Paris | Foundation For Rare Diseases | Genochondromatosis | IDENTIFICATION OF THE MOLECULAR BASIS OF GENOCHONDROMATOSIS | - | GenOmics 2016 - 2 | ||
| 2016 | Mathieu RODERO | Paris | Foundation For Rare Diseases | STING-associated vasculopathy with onset in infancy (SAVI) | Identification of molecules able to control interferon beta transcription in patients with gain-of-function mutations in TMEM173. | We have discovered that genetic modifications affecting the STING molecule create a rare genetic disease that is generally very severe, and can affect the skin, lungs and blood vessels. Patients with this disease have bodies that behave as if perpetually infected by a virus. They produce large quantities of antiviral molecules called "interferon". Unfortunately, these molecules are toxic if produced in excessive quantities. Two INSTITUT IMAGINE teams specializing in the study of interferon-related diseases have joined forces to develop a strategy for the identification, optimization and therapeutic use of molecules capable of blocking interferon production in these children. | High throughput screening 2016 | ||
| 2016 | Michel FONTES | Marseille | Foundation For Rare Diseases | X-linked Charcot-Marie-Tooth disorder (CMTX) | HTS screening to identify molecules correcting connexon activity in CMTX disorder. | We have created transgenic mouse lines expressing the protein mutated in the disease and showing a locomotor deficit. This involves Calmodulin Kinase type II, and inhibitors of this enzyme correct the phenotype of the cells and halt the degradation of locomotor abilities. Finally, we were able to show that cells from CMTX patients displayed the same abnormalities. This has enabled us to develop a screen for the disease's primary deficit, connexon activity. We propose to use these tools to identify molecules capable of restoring normal connexon activity. Chemical libraries will be screened on the PICBS platform in Strasbourg. Molecules identified in this way will be validated using cells from CMTX patients. We thus hope to define drug candidates that could be used in clinical trials on patients. | High throughput screening 2016 | ||
| 2016 | Sylvie FOURNEL-GIGLEUX | Nancy | Foundation For Rare Diseases | Mucopolysaccharidoses | Search for inhibitors of the galactosyltransferase β4GalT7 by High Throughput Screening: towards a specific substrate reduction therapy in mucopolysaccharidoses | Mucopolysaccharidoses (MPS) are rare genetic diseases caused by a deficiency in the enzymes that break down glycosaminoglycans (GAGs) or mucopolysaccharides. They accumulate in cells, leading to serious multi-organ damage, particularly in the brain, and shortening life expectancy. Objective-Develop less burdensome treatments to improve neurocognitive symptoms. We will search for a small molecule that specifically inhibits an enzyme that constructs GAGs in order to reduce their accumulation and deleterious effects. To this end, we will screen a large number of molecules at high molecules. We have patented a fluorescence assay which will be miniaturized and robotized on a dedicated platform, in order to discover molecules blocking the activity of the target enzyme, which will then be validated on MPS patient cells. As most of the molecules screened are already on the market, we hope to quickly come up with a new treatment for MPS. | High throughput screening 2016 | ||
| 2016 | Valerie DESQUIRET-DUMAS | Angers | Foundation For Rare Diseases | Mitochondrial complex I deficiency | Screening of pharmacological molecules to restore oxidative metabolism in rare diseases associated with mitochondrial complex I mutations. | Complex I deficiencies account for up to 30% of mitochondrial diseases. These devastating pathologies, linked to a defect in energy production, have no curative treatment. Our results show, in fibroblasts from patients with complex I structural defects, a blockade of substrate entry into the mitochondria. of substrates into the mitochondria and glycolytic metabolism, leading to severely slowed cell growth. The aim of this project is to screen for molecules that can improve cell growth by overcoming the blockage of mitochondrial energy synthesis. This parameter will enable an initial simple screening; hits will then be validated by more detailed analyses of mitochondrial metabolism. The identification of molecules capable of overcoming the metabolic blockage induced by structural defects in complex I could lead to the wider treatment of other rare diseases linked to alterations in mitochondrial function. | - | High throughput screening 2016 | |
| 2016 | Aziz EL-AMRAOUI | Paris | Foundation For Rare Diseases | Usher syndrome type I (USH1), retinopathies | Modeling the Usher syndrome type I (USH1) retinopathy in pig: physiopathology and gene therapy | - | Usher syndrome (USH) is the leading cause of deafness and blindness in humans (50% of cases). Today, there is good care available for patients with hearing disorders, but there is no treatment that can halt the progression of retinitis pigmentosa, which is usually discovered around puberty. Through the study of already identified USH genes, the properties of the proteins for which they code, the identification of their key partners, and the characterization of corresponding Usher models, major advances have been made, particularly with regard to the origin of sensory deficits and the implementation of genetic diagnostic tests for early screening. Today, with access to new Usher models in large animals, it will be possible to better define the natural history of the disease and to evaluate the effectiveness of treatment on a model closer to humans. Due to the promising results obtained in preclinical Usher models, there is a lot of hope for gene therapy, also because of the recent success of this type of therapy for hereditary retinal dystrophies, such as Leber congenital amaurosis associated with the RPE65 gene. However, the therapeutic strategy adopted may differ depending on the form of Usher syndrome and the stage of the disease (before or after the onset of the first symptoms), and the approach chosen will also need to be adapted according to the size of the gene involved and the nature of the mutation (genetic variation) causing the disease. Various approaches based on whole gene replacement or direct correction of the mutation within the genome are currently being explored. The aim is to prove their effectiveness in vivo (on the whole organism) and demonstrate their safety before future clinical transfer. | Translational Research 2016 | |
| 2016 | Gerard LAMBEAU | Valbonne | Foundation For Rare Diseases | Rare kidney diseases Rare systemic and autoimmune disorders, idiopathic Membranous Nephropathy | Membranous nephropathy, a rare autoimmune kidney disease: establishing the first model in non-human primates | - | Translational Research 2016 | ||
| 2016 | Olivier GOUREAU | Paris | Foundation For Rare Diseases | Sensory disorders (rare eye diseases and deafness), Rod-cone dystrophies (retinitis pigmentosa), Cone-rod dystrophies | Preclinical validation of a stem cell-derived Retinal Pigmented Epithelium (RPE) in non-human primates | - | Diseases affecting the retinal pigment epithelium, including age-related macular degeneration (the most common form of blindness in Western countries) and pigmentary retinopathies (30 to 40,000 people in France), cause severe and rapid vision loss leading to blindness. Despite significant scientific advances, there is no treatment available for these diseases. We have therefore developed a tissue engineering product consisting of retinal pigment epithelial cells, derived from human embryonic stem cells, polarized in a monolayer on a biocompatible substrate, enabling the formation of a functional 3D pigment epithelium that can be used for transplantation. After validating the proof of concept in a rat model of retinitis pigmentosa, we demonstrated the safety and feasibility of this approach in macaques, whose eyes are anatomically similar to human eyes and where the surgical procedure is identical to that performed in humans. Based on these results, a Phase I/II clinical trial for certain patients with retinitis pigmentosa (a cohort of twelve patients) began in the fall of 2019. | Translational Research 2016 | |
| 2016 | Pierre CATTAN | Paris | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes, esophageal atresia, esophageal carcinoma, esophageal caustic injury | Full thickness circumferential esophageal replacement by a tissue engineered construct in a porcine model. | - | The Rare Diseases Foundation provided our research team with significant financial support to conduct our research into the development of a substitute for esophageal replacement in the treatment of esophageal atresia. This funding enabled us to establish that mesenchymal stem cells play an active role in the creation of a new esophagus when implanted on an extracellular matrix used to replace a segment of the esophagus in large animals. These results have given us a better understanding of the mechanisms of tissue regeneration in this context and have enabled us to make significant progress in our project. As a result, our team has obtained funding from the PHRC 2021 to initiate the first clinical trial of esophageal replacement using tissue engineering. | Translational Research 2016 | |
| 2016 | Caroline DESOMBRE | Lille | Foundation For Rare Diseases | Rare non-malignant hematological diseases | How to restore equality of opportunity for students with hemophilia? / Élèves touchés par l'hémoPHILie et autres maladies hémorragiques familiales : cOmMENt rétablir l'Egalité des chances à l'école | The aim of this research program is to combat the discrimination suffered by children with hemophilia by raising awareness among their parents, teachers and peers, in order to re-establish equal opportunities. The aim is to highlight the fact that the negative image of the haemorrhagic disease that these children carry excludes them from some of the experiences they should be having. This exclusion can lead to a spiral of failure, with less success at school and less ambitious life choices. Indeed, a body of work in social psychology indicates that success at school is largely a reflection of how parents and teachers believe their children can succeed. In turn, the child will adopt the adults' position and feel able or unable to succeed at school. In order to verify that this insidious phenomenon can have an impact on the academic success of a certain number of children with hemophilia, we will begin by analyzing the discourse conveyed about the disease. We will interview young people aged between 6 and 19, and compare their representations with those of their parents and teachers. We will then show how these representations can constitute a threat and a stress that handicap these children when they are faced with school tests. These results should enable us, in the third phase, to propose concrete actions to restore equal opportunities for pupils affected by hemophilia: we will develop a pedagogical game on a digital environment by involving the various participants in this research. We will also be offering training courses for teachers. Finally, AFH will distribute a brochure and offer training courses for families to counteract these effects. | Funding for our PHILOMENE project from the Ircem Corporate Foundation and support from the Foundation has enabled the launch of a vast, unprecedented research program in the humanities and social sciences dedicated to studying representations of hemorrhagic diseases—particularly hemophilia—and their impact on the educational experiences of children with these rare diseases. These conditions present a paradox. While they benefit from active medical research and increasingly effective treatments, they still suffer from many subjective representations that impact children's daily lives and their social and educational inclusion. By investigating the beliefs of parents and teachers, we have been able to highlight a shared, still very medical conception of the disease, of living with it, and of the precautions it requires. Children are perceived first and foremost as sick before being seen as students with plans for the future. These perceptions have an effect on behavior towards children and thus influence their academic success and career choices. This project was very stimulating in that the theoretical frameworks in social psychology fully met the concerns of the doctors at the Lille University Hospital. The Rare Disease Foundation provided relevant support for this project by facilitating meetings between social science researchers and doctors. The social science research team wishes to continue its work on rare diseases. | Humanities and social sciences 4 | |
| 2016 | Delphine DELLACHERIE | Lille | Foundation For Rare Diseases | Developmental anomalies and malformation syndromes | Dance as a new tool for remediation in rare cerebellar developmental pathologies / TEMps et DANse comme outil de remédiation du fonctionnement dans les anomalies de développement du CErvelet | The main aim of this research project is to promote the social integration and academic success of children with a rare developmental pathology of the cerebellum, using dance as a new remediation tool. The cerebellum is a "little brain" located at the back of the brain and comprising 50% of our neurons. Children with cerebellar disorders present cognitive deficits that are the source of complex handicap situations, and for which there are no specific means of compensation. The processing of time, crucial to everyday life, seems to be affected in these patients, particularly the natural ability to move in rhythm with sounds or music. Recent research suggests that this universal ability, also known as "sensory-motor synchronization", has a strong influence on cognition, learning and social interaction. The aim is therefore to test a new dance program designed to stimulate sensory-motor synchronization and, in so doing, improve patient functioning. In order to verify the benefits of dance, we will conduct a study on twelve patients aged 8 to 12 with congenital cerebellar anomalies. We will first analyze the deficits present before the start of the dance program. Then, the children will follow dance sessions twice a week for one month. Finally, we will evaluate the children's progress by comparing pre versus post intervention results in the temporal, motor, cognitive and social spheres. In the long term, this project should provide solutions to the social and therapeutic isolation of children with developmental abnormalities of the cerebellum, as well as contributing to the management of other neurodevelopmental pathologies linked to the cerebellum and which can lead to temporal cognition disorders, as is the case, for example, in dyslexia. | Cette étude interventionnelle a exploré l'effet d'un protocole d'entraînement à la danse chez les enfants atteints d'anomalie développementale du cervelet. Il s’agit d’une première étude réalisée auprès d’un petit effectif de patients. Sept patients ont participé à quatorze cours de danse sur une période de sept semaines. Avant et après l'entraînement, nous avons testé la motricité, les capacités sensorimotrices et cognitives, ainsi que les fonctions sociales et affectives des enfants atteints d'anomalie développementale du cervelet. Les résultats ont montré une amélioration des aptitudes sensorimotrices rythmiques (taping avec un métronome et de la musique), motrices (équilibre), cognitives (flexibilité cognitive) et sociales (cognition sociale) chez la plupart des patients. Nous avons comparé ces changements avec l'évolution des performances de participants témoins appariés en âge évalués avant et après une période de durée équivalente. Cela a confirmé que l'amélioration ne reflétait pas simplement ce que l'on pouvait attendre d'une évolution normale du développement ou d'un effet test-retest. Étant donné la rareté de l’anomalie développementale du cervelet et la complexité du protocole de recherche, un petit nombre de participants a été inclus dans cette étude. Nous avons utilisé des analyses de cas unique avec un design à lignes de bases multiples pour comparer les performances de chaque patient avant et après l’entraînement. Les difficultés des enfants atteints d’anomalie développementale du cervelet dans la synchronisation sensori-motrice étaient manifestes : six patients sur sept présentaient une performance plus variable que les témoins lorsqu'ils tapaient sur le rythme d'un métronome ou d'une musique. À notre connaissance, c'est la première fois que des difficultés rythmiques sont signalées dans des anomalies de développement affectant le cervelet. Ce résultat souligne le rôle important joué par le cervelet dans la synchronisation, déjà suggéré par des études montrant des déficits rythmiques dans les dysfonctionnements cérébelleux acquis (Provasi et al., 2014). Des preuves récentes en neuroimagerie vont également à l’appui du rôle du cervelet dans la détection neurale du rythme et la pulsation (Nozaradan, Schwartze, Obermeier, & Kotz, 2017 ; Paquette et al., 2017 ; Schwartze et al., 2016). Cependant, ce résultat contraste avec ceux obtenus dans d'autres études chez des patients présentant des lésions cérébelleuses acquises qui présentaient des difficultés de perception des durées mais pas de traitement du rythme lié à une pulsation (Breska & Ivry, 2016, 2018 ; Grube, Cooper, Chinnery, & Griffiths, 2010) bien que le fait que le traitement rythmique soit préservé chez les patients présentant des lésions acquises du cervelet n'exclut pas l'implication du cervelet dans le développement des capacités rythmiques. Après le protocole d'entraînement à la danse, la plupart des patients ont eu des performances de synchronisation sensori-motrice comparables à celles des témoins alors que leurs performances étaient déficitaires avant l’entraînement. En effet, par rapport à la période de ligne de base, la variabilité motrice des patients lors de la synchronisation avec un métronome ou de la musique a diminué (c'est-à-dire que la performance a été améliorée). Cette étude est la première à montrer que les compétences en matière de synchronisation sensori-motrice peuvent être améliorées chez les enfants atteints d'anomalie développementale du cervelet. Cela confirme l'hypothèse selon laquelle la danse, qui améliore les fonctions sensorimotrices chez d'autres populations (Jin et al., 2019 ; Karpati et al., 2016), pourrait stimuler ces fonctions dans les troubles cérébelleux. Ce résultat pourrait indiquer que le fonctionnement du réseau cérébral sous-tendant la synchronisation sensori-motrice a été partiellement amélioré après l'entraînement. Le cervelet fait partie de ce réseau cérébral qui implique également les ganglions de la base, ainsi que les cortex moteurs et prémoteurs (Breska & Ivry, 2016 ; Coull & Nobre, 2008 ; Coull, Cheng, & Meck, 2011 ; Grahn, 2009 ; Grahn & Brett, 2007 ; Kotz & Schwartze, 2011). La danse est une activité complexe qui recrute un vaste éventail de régions du cerveau, y compris les réseaux cérébello-corticaux et cortico-basaux (c'est-à-dire l'aire motrice supplémentaire, le cortex moteur, les ganglions de la base et le cervelet ; Bachrach et al. 2016 ; Brown et al. 2006 ; Cross et al. 2006, 2009 ; Giacosa et al. 2016 ; Karpati et al. 2015). Le recrutement de ces régions par la danse est peut-être à l'origine des améliorations observées après l’entraînement de danse. Une question ouverte est de savoir si l’entraînement a eu un effet direct sur le cervelet. L'amélioration observée peut également être expliquée par des mécanismes cérébraux compensatoires des circuits cérébelleux affectés impliquant d'autres structures telles que les ganglions de la base. Les mécanismes cérébraux compensatoires ont été mis en avant pour expliquer l'effet des protocoles d'entraînement rythmique dans la maladie de Parkinson (Benoit et al., 2014a ; Cochen De Cock et al., 2018 ; Dalla Bella, 2020 ; Dalla Bella et al., 2015 ; Nombela, Hughes, Owen, & Grahn, 2013). La maladie de Parkinson sert de modèle de dysfonctionnement des ganglions de la base car, contrairement aux anomalies cérébelleuses, elle affecte principalement les ganglions de la base alors que le cervelet est relativement épargné (Breska & Ivry, 2018 ; Wu & Hallett, 2013). L'hyperactivation dans le réseau cérébello-cortical pourrait agir comme un mécanisme compensatoire pour les ganglions de la base qui dysfonctionnent (Benoit et al., 2014 ; Cochen De Cock et al., 2018 ; Dalla Bella, 2020 ; Dalla Bella et al., 2015 ; Nombela et al., 2013 ; Wu & Hallett, 2013). Le schéma inverse, à savoir le recrutement du réseau cortico-basal pour compenser les altérations des voies cérébello-corticales, pourrait sous-tendre l'effet de l'entraînement sensorimoteur par la danse. D'autres études impliquant la neuroimagerie sont nécessaires pour confirmer cette hypothèse. Les réseaux cérébello-corticaux et cortico- basaux qui sous-tendent la synchronisation sensori-motrice sont également impliqués dans diverses compétences motrices (Bengtsson, Ehrsson, Forssberg et Ullén, 2005 ; Dalla Bella, Benoit, Farrugia, Schwartze et Kotz, 2015 ; Lang et al., 2017), cognitives (Murdoch, 2010 ; Kotz et Schwartze, 2010 ; Schwartze et Kotz, 2013) et sociales (Van Overwalle et al., 2019). Il n'est donc pas surprenant que l'effet de la danse s'étende à d'autres compétences, ce qui confirme l'idée que l'entraînement sensorimoteur peut avoir un impact positif sur d'autres capacités. Par exemple, l'équilibre implique des structures du réseau cérébral de la synchronisation sensori-motrice telles que le cervelet et les ganglions de la base (Surgent, Dadalko, Pickett et Travers, 2019). L'effet de la danse sur l'équilibre pourrait être directement lié à l'amélioration des compétences en matière de synchronisation sensori-motrice. Néanmoins, même si l'effet de l'entraînement à la danse peut être médiatisé par la synchronisation sensori-motrice, les changements ne se limitent pas nécessairement aux réseaux cérébraux de la synchronisation sensori-motrice. La danse implique un entraînement à l'équilibre et stimule plusieurs structures cérébrales associées à l'équilibre mais pas à la synchronisation sensori-motrice, comme le cortex frontal, temporal et pariétal et le thalamus (Brown et al., 2006 ; Karpati et al., 2015 ; Surgent et al., 2019). Ces régions pourraient également être stimulées par le protocole d'entraînement à la danse et soutenir l'amélioration de l'équilibre. Les compétences cognitives (flexibilité cognitive) ont également été améliorées par l'entraînement à la danse. Cela peut sembler surprenant à première vue, car la danse est une activité physique qui implique principalement des compétences motrices et de synchronisation sensori-motrice. La flexibilité cognitive est soutenue par un réseau fronto-pariétal (Dajani & Uddin, 2015 ; Mogadam et al., 2018) qui n'est généralement pas associé à la motricité et à la synchronisation sensori-motrice. Il est toutefois important de noter que la flexibilité cognitive est une capacité complexe qui implique différents sous-domaines tels que l'inhibition, la mémoire de travail et le changement d’activité (Dajani & Uddin, 2015). Des études récentes ont montré que ces capacités sont corrélées avec les aptitudes de synchronisation sensori-motrice chez les enfants (Puyjarinet et al., 2017 ; Tierney & Kraus, 2013 ; Bégel et al, en cours de révision). On ne peut donc pas exclure que le gain en flexibilité cognitive soit lié à l'entraînement à la synchronisation sensori-motrice, même s'il peut aussi s'expliquer par d'autres facteurs. Dans une revue des interventions visant à aider les fonctions exécutives chez les enfants, Diamond & Lee (2011) ont conclu qu'il était plus efficace de s'intéresser au développement émotionnel, social et physique de l’enfant que de se concentrer uniquement sur les fonctions exécutives (Diamond & Lee, 2011). En outre, la flexibilité cognitive est liée à la créativité (De Dreu et al., 2011). Par conséquent, avec ses composantes sociales, physiques et créatives, la danse apparaît comme un candidat idéal pour stimuler les fonctions exécutives, et plus particulièrement la flexibilité cognitive. Il est à noter qu'une étude précédente a rapporté l'effet de la danse sur la flexibilité cognitive au cours du vieillissement (Coubard et al., 2011). Cela suggère que l'effet de la danse sur la flexibilité cognitive ne se limite pas au protocole et aux patients de l'étude présentée ici. L'amélioration observée après l'entraînement s’étend aux compétences sociales. Plus précisément, les parents ont fait état d'une amélioration de la cognition sociale et de la théorie de l'esprit de leurs enfants, comme la capacité à exprimer ses propres émotions, à adapter son comportement aux autres dans un contexte social et à déduire les états mentaux des autres. Le protocole d'entraînement collectif proposé dans cette étude peut avoir contribué à développer les compétences sociales des enfants en stimulant leur capacité à anticiper le mouvement des autres. Il a été précédamment démontré que la synchronisation motrice entre les individus conduit à un comportement pro-social accru (Hove & Risen, 2009 ; Cirelli, Einarson & Trainor, 2014 ; Wiltermuth & Heath, 2009), De plus, la synchronisation interpersonnelle impliquée dans la danse augmente le sentiment de connexion avec les partenaires (Himberg, Laroche, Bigé, Buchkowski, & Bachrach, 2018). La danse favorise également l'attention portée aux états cognitifs et mentaux des autres (Joufflineau et al., 2018), et l'entraînement à la danse est lié à des capacités empathiques accrues (Gujing et al., 2019). La flexibilité cognitive est notamment importante pour le comportement social, en particulier pour la capacité à adapter le comportement au contexte social (Turner, Oakes, Haslam et McGarty, 1994). La flexibilité cognitive est également corrélée avec les mesures de l'empathie (Grattan, & Eslinger, 1989 ; Milders, Ietswaart, Crawford, & Currie, 2008). En revanche, d'autres aptitudes cognitives, telles que la mémoire, la vitesse de traitement ou l'attention, jouent un rôle limité dans le comportement social (Milders, Ietswaart, Crawford et Currie, 2008). Par conséquent, l'amélioration simultanée de la synchronisation, des compétences sociales et de la flexibilité cognitive n'est pas surprenante. Toutefois, les relations de cause à effet entre ces différentes compétences restent à explorer. Les fonctions qui ont été améliorées à la suite de l’entraînement de danse sont cruciales pour les activités de la vie quotidienne. Cet effet de transfert peut à son tour améliorer considérablement la qualité de vie des patients. Notamment, l'effet constaté sur un test comportemental de flexibilité cognitive est corroboré par l'évaluation des parents, ce qui signifie que l'effet dans la vie quotidienne a été remarqué par les parents. La flexibilité cognitive sous-tend les modifications exécutives et c comportementales en réponse à l'environnement. Elle est particulièrement importante pour différentes aptitudes telles que les mathématiques (Verschaffel, Torbeyns, De Smedt, Luwel et Van Dooren, 2007), le langage (Deák, 2004) et la planification (Snow, 1992). L'amélioration de la flexibilité cognitive est un bon moyen d'améliorer la qualité de vie des patients et de stimuler leurs résultats scolaires. En général, les fonctions exécutives sont un bon indicateur de la réussite scolaire (Becker, Miao, Duncan et McClelland, 2014). En outre, les réponses des parents au questionnaire sur les compétences sociales indiquent un effet positif du protocole d'entraînement à la danse sur les compétences sociales des enfants. Les compétences sociales sont également un bon indicateur de la réussite scolaire (Agostin & Bain, 1997 ; Bramlett, Scott, & Rowell, 2000). Le fait que les compétences en matière de motricité et d'équilibre aient également été améliorées par le protocole d'entraînement à la danse impacte également positivement la vie quotidienne des patients. En raison de leurs difficultés, les enfants atteints d’anomalies développementales du cervelet ne peuvent pas participer à la plupart des activités physiques extrascolaires avec des enfants de leur âge. Cela réduit leurs chances de progresser. Ainsi, en plus de l'absence de traitement ou de rééducation spécifique disponible pour les anomalies développementales du cervelet (Brenna, 2014), il existe un choix limité d'activités pour ces enfants. Certains types de danse peuvent être trop difficiles, mais les résultats de cette étude confirment que la danse peut être proposée aux patients atteints d'anomalie développementale du cervelet. Le protocole d'entraînement à la danse que nous avons proposé est prometteur car il est adapté aux compétences de chaque enfant. Les enfants présentant divers troubles et symptômes peuvent participer au même cours de danse. De plus, il n'y a pas de compétition et aucun jugement sur la production esthétique des enfants, ce qui laisse de la place pour un entraînement dans un environnement de confiance. La danse est également une activité qui peut être adaptée aux besoins spécifiques des participants. Le protocole d’entraînement peut donc être adapté à différentes populations, comme les adolescents ou les adultes atteints d'anomalies cérébelleuses en utilisant différents types de danse. Le protocole pourra également être adaptée à d’autres populations développementales présentant des déficits rythmiques associés ou non à des anomalies du cervelet, comme par exemple le TDAH (Trouble Déficitaire de l’Attention avec ou sans Hyperactivité). En résumé, des améliorations sensorimotrices, motrices, cognitives et sociales très encourageantes ont été constatées chez les enfants atteints d'anomalies développementales du cervelet à la suite d'un protocole d'entraînement à la danse. Le cervelet est une structure clé du système nerveux central et son rôle dans diverses fonctions motrices (Bastian, 2006 ; Manto et al., 2012 ; Therrien & Bastian, 2019), cognitives (Murdoch, 2010 ; Schmahmann, 2004 ; Schmahmann, Guell, Stoodley, & Halko, 2019) ainsi que sociales (Van Overwalle et al., 2019) et affectives est bien connu. Par conséquent, tout ou partie de ces domaines sont affectés chez les patients atteints d'anomalie développementale du cervelet. Développer des interventions pour améliorer les compétences motrices, cognitives et sociales des patients atteints d’anomalie du cervelet est un défi que nous avons relevé en utilisant la danse dans cette étude. La danse est une activité qui stimule différents aspects du comportement, en particulier les fonctions sensorimotrices. L'effet bénéfique de la danse est probablement dû en partie à une activité accrue dans les voies sensorimotrices cortico-cérébello-striatales. Il s’agit d’une première étude auprès d’un petit échantillon. Cette recherche ouvre la voie à des études à plus grande échelle sur la danse en tant qu'outil de rééducation des dysfonctionnements cérébelleux. | Humanities and social sciences 4 | |
| 2016 | Helene AMIEVA | Bordeaux | Foundation For Rare Diseases | Fronto-Temporal Lobar Degenerations | Personalized and multidisciplinary care on behavioral disorders of Fronto-Temporal Lobar Degenerations / Prise en charge pluridisciplinaire et personnalisée des troubles du comportement dans la Dégénérescence Lobaire Fronto-Temporale | Fronto-Temporal Lobar Degeneration (FTLD) is a serious, neurodegenerative disease that falls into 3 categories: Fronto-Temporal Dementia, Primary Progressive Aphasia and Semantic Dementia. This degeneration, which is related to Alzheimer's disease, generally occurs early, between the ages of 55 and 65, and is characterized by the appearance of significant behavioral and personality disorders, which vary from patient to patient, and are particularly difficult to manage. Because DLFT is not recognized by mainstream healthcare services, the healthcare system does not meet the expectations and needs of these patients and their families. Thus, people with DLFT and their carers need the healthcare system to identify and recognize them, and to provide them with appropriate support and follow-up through specific, personalized actions carried out by a multidisciplinary professional team trained in these pathologies. The aim of the present project is to evaluate the usefulness of personalized multidisciplinary home-based intervention in the management of behavioral disorders in DLFT sufferers, followed up by in Aquitaine, and the support of their family carers, in comparison with usual care. It will aim to provide them with health, social and/or psychological responses that are as close as possible to their needs, and will promote patients' social participation, notably through the use of compensatory strategies put in place by their family carers, and by strengthening recourse to and coordination with the social support network. Finally, one of the major spin-offs of this study will be to help raise awareness of DLFT, which is still under-appreciated, and to develop a psychosocial care strategy based on the skills of professionals from not only the health field, but also the medico-social and voluntary sectors. | - | Humanities and social sciences 4 | |
| 2016 | Benjamin DEHAY | Bordeaux | Foundation For Rare Diseases | Kufor-Rakeb Syndrome Neuronal Ceroid Lipofuscinosis | PHYSIOPATHOLOGICAL CHARACTERIZATION OF A RAT MODEL OF KUFOR-RAKEB SYNDROME | Mutations in the ATP13A2 gene are associated with both Kufor-Rakeb syndrome and neuronal ceroid-lipofuscinosis. The clinical manifestations are progressive motor and cognitive disorders with visual impairment. The course of the disease is invariably fatal. To date, there is no treatment available to halt or slow down the degenerative process. Two murine animal models have recently have recently been developed, showing modest motor dysfunction without any neuronal loss, which is a feature of human pathology. To overcome this blockage, we propose to develop a rat model of the disease. The rat is a model of choice for biomedical research. The possibility of studying two different diseases by analyzing a single gene, ATP13A2, makes this approach promising, and will contribute to understanding these hitherto little-studied pathologies. | Small animal models 2016 | ||
| 2016 | Brigitte LELONGT | Paris | Foundation For Rare Diseases | Nephronophtisis | IMPACT OF ANKS3 HUMAN MUTATION IN RAT MODEL | Nephronophthisis is a chronic tubulointerstitial disease, i.e. an abnormality initially localized in the renal tubules and the interstitial tissue surrounding these tubules. There are three clinical forms, depending on the age of onset of the disease. It is a rare disease, affecting 1/100,000-1/50,000 people, and is the leading cause of end-stage renal failure in childhood. The disease is both clinically and genetically heterogeneous. Although 20 genes responsible for the disease have been identified, the genetic cause has yet to be determined in 50% of patients. S. Saunier's group has recently identified a new gene, ANKS3, responsible for the disease in humans. The aim of this project is to provide an animal model that will enable us to detail the expression, function and interactions of ANKS3 with other partners, thereby providing new information on this disease. | Small animal models 2016 | ||
| 2016 | Bruno DELLA GASPERA | Paris | Foundation For Rare Diseases | Spinal muscular atrophy with respiratory distress (SMARD1) also called autosomal recessive distal spinal muscular atrophy-1 (DSMA1) | XENOPUS TROPICALIS MODEL OF SPINAL MUSCULAR ATROPHY WITH RESPIRATORY DISTRESS (SMARD1) | Distal spinal muscular atrophy type 1 (SMARD1) is a genetic disorder caused by mutation of the IGHMBP2 gene. This pediatric disease is characterized by loss of motor neurons, leading to distal muscle weakness and respiratory distress. Life expectancy is around 1 year, and there is no treatment to date. The aim of this project is to create a new animal model of this disease, based on the amphibian xenopus, which has the advantage of being completely external in development, and can be studied and modified easily using current techniques. This transgenic model will enable us to better understand this disease and easily test drugs for therapeutic purposes. | Small animal models 2016 | ||
| 2016 | Charles-Henry COTTART | Paris | Foundation For Rare Diseases | Cystic fibrosis | A NEW RAT MODEL FOR CYSTIC FIBROSIS CARRYING THE F508DEL MUTATION IN THE CFTR GENE | Cystic fibrosis is the most common of rare diseases. It is a fatal genetic disease that mainly affects the lungs, but also other organs. In cystic fibrosis, the CFTR protein is either not produced or abnormal. 80% of sufferers carry the F508del mutation. Promising corrective molecules have been synthesized to correct the effects of this F508del mutation. Mouse models are used in preclinical studies, but they poorly mimic lung pathology. A rat model that does not express the CFTR protein has shown the presence of lung damage that is not seen in mice, but it does not allow us to test molecules that correct the F508del mutation. The aim of this work is to develop a rat model with the F508del mutation, which should enable us to evaluate corrective molecules and in particular their protective effects on cystic fibrosis lung damage. | Mouse, pig, and ferret models of cystic fibrosis either poorly mimic the disease or are extremely difficult to use. In this context, the creation of a rat model carrying the F508del mutation, which is present in more than 80% of patients in France, seemed relevant. The creation and characterization of homozygous 3-month-old rats carrying the F508del mutation was carried out. The results show abnormalities related to cystic fibrosis similar to those observed in KO rats (which do not express the protein). Our rats show significant mortality at weaning, which can be counteracted by appropriate nutritional and drug management. These rats also show growth retardation, intestinal obstruction, dental abnormalities, and abnormalities in ion transport in tissues characteristic of cystic fibrosis. The severity of the phenotype is lower than that of KO rats. We have also succeeded in producing primary cultures of nasal cells from these rats, which should enable us to test the effect of candidate corrective molecules or the effects of combining several targeted molecules. We are continuing the characterization in older rats to look for spontaneous lung damage. The F508del rat model is a new and relevant model for exploring certain aspects of the pathophysiology of cystic fibrosis. | Small animal models 2016 | |
| 2016 | Christophe SIRAC | Limoges | Foundation For Rare Diseases | AL amyloidosis | EESTABLISHMENT OF A RAT MODEL FOR AL AMYLOIDOSIS | When plasma cells (antibody-secreting cells) proliferate, abnormal antibodies can aggregate and deposit in various organs, leading to their destruction. The study of these pathologies requires the use of reliable experimental models, which not only provide a better understanding of the disease, but also enable the testing of innovative therapeutic strategies. For many years now, our laboratory has been developing transgenic mouse models to reproduce these pathologies, but these animals appear to be resistant to AL amyloidosis, one of the most serious diseases that can result from these antibody deposits. However, the rat model appears to be a credible alternative for reproducing this pathology in a physiological model close to humans. Our aim is to develop a transgenic rat model expressing an abnormal human antibody, in order to reproduce AL amyloidosis and test innovative therapeutic approaches. | Small animal models 2016 | ||
| 2016 | Gilles MILLAT | Lyon | Foundation For Rare Diseases | Endocardial Fibroelastosis Dilated Cardiomyopathy | PRKAG2 MUTATIONS AS A MOLECULAR EXPLANATION ON PATIENTS WITH DILATED CARDIOMYOPATHY AND ENDOCARDIAL FIBROELASTOSIS? | Endomyocardial fibroelastosis is a common cause of unexplained heart failure in children. It results from diffuse thickening of the endocardium, leading to dilated cardiomyopathy in most cases. cases. The incidence has been estimated at 1 in 5000 births. Endomyocardial fibroelastosis is diagnosed between 3 and 6 months of age in most cases. Approximately 10% of cases are familial, but the molecular aspects associated with this type of cardiomyopathy remain poorly understood. Sequencing of a panel of over 40 genes involved in cardiomyopathies identified a homozygous PRKAG2 truncating mutation in an infant who died at 2 months of cardiogenic failure, and whose autopsy showed endomyocardial fibroelastosis. The aim of creating this zebrafish PRKAG2 ko model is therefore to confirm that PRKAG2 truncating mutations, in an autosomal recessive mode, can lead to cases of endomyocardial fibroelastosis. | - | Small animal models 2016 | |
| 2016 | Laurence LEGEAI-MALLET | Paris | Foundation For Rare Diseases | FGFR3-related osteochondrodysplasias (chondrodysplasias and craniosynostoses) | ZEBRAFISH MODEL OF FGFR3-RELATED SKELETAL DISORDERS | Mutations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene are responsible for the most common forms of dwarfism both the most common forms of dwarfism, achondroplasia, and craniostenosis, Muenke's syndrome. Muenke syndrome. The mechanisms controlling craniofacial ossification and axial skeleton formation are poorly understood. The establishment of zebrafish lines expressing respectively a mutation responsible for dwarfism or craniostenosis, respectively, will enable us to better understand the skeletal anomalies induced by these mutations. Indeed, the zebrafish is a model of choice for the study of craniofacial skeletal development, due to its many homologies with mammals. These models will also enable us to identify new therapeutic approaches, the zebrafish being an excellent model for screening molecules. | Small animal models 2016 | ||
| 2016 | Sylvie MAZOYER | Lyon | Foundation For Rare Diseases | MICROCEPHALIC OSTEODYSPLASTIC PRIMORDIAL DWARFISM, TYPE I; MOPD1 ROIFMAN SYNDROME; RFMN | STUDY OF THE PHYSIOPATHOLOGY OF RNU4ATAC-ASSOCIATED DISEASES | Several steps are necessary before our genes can be expressed in our cells. One of these is splicing, which removes unnecessary material from messenger RNAs, leaving only that required for protein production. We have shown that a defect in a component of the splicing machinery, U4atac, is responsible for the TALS syndrome, which results in numerous malformations (including severe brain malformations), intellectual disability and death before the age of 2-3 years. Our aim is to identify the consequences of the U4atac defect at the cellular level and on the scale of an animal model, the zebrafish, in order to discover new genes necessary for the proper development of the organism, in particular the brain, and to better understand its various stages. Our study will enable better clinical management of TALS patients and, more generally, of patients with cerebral malformations and their families. | Small animal models 2016 | ||
| 2016 | Yann AUDIC | Rennes | Foundation For Rare Diseases | Epidermolysis bullosa | XENOPUS EPIDERMIS DEVELOPMENT IN THE SEARCH FOR MODIFIER GENES OF EPIDERMOLYSIS BULLOSA | Epidermolysis bullosa is caused by mutations in genes encoding components of the dermal-epidermal junctions. There is considerable variability in disease severity between patients from the same sibling. This variability is thought to be due to the existence of modifier genes that make patients more or less ill. Inactivation of the RNA-binding protein Ptbp1, highly expressed in the skin, leads to the development of epidermal blisters in the xenopus embryo. We have identified itga6 and tp63 as 2 major players in epidermal differentiation whose splicing is controlled by Ptbp1. We will block expression of epithelial forms of itga6 and tp63 to study the phenotype of the phenotype of treated embryos. We will generate animals with one copy of the gene modified and study whether Ptbp1 inactivation of the other copy alters the phenotype, making Ptbp1 a modifier gene. | Small animal models 2016 | ||
| 2015 | Alain HOVNANIAN | Paris | Foundation For Rare Diseases | Recessive Dystrophic Epidermolysis Bullosa | Generation of a humanized mouse model for Recessive Dystrophic Epidermolysis Bullosa harbouring a recurrent COL7A1 mutation | Epidermolysis bullosa recessiva (EBDR) is a rare and severe genetic disease of children and adults, responsible for skin and mucous membrane detachments from birth. The disease is due to mutations in the COL7A1 gene encoding collagen VII, which is essential for the adhesion of the superficial layer of the skin to the middle layer. There is currently no specific treatment for EBD, and skin cancer is the most frequent cause of death in these young patients. This research project aims to develop a new mouse model carrying the mutated human version of the COL7A1 gene to the exclusion of the mouse version of the gene. The mutation introduced into the human gene is a mutation very frequently found in patients. These mice are expected to develop signs of the disease and will be studied in great detail. In the future, they will be used to test the feasibility and in vivo efficacy of new gene therapy approaches based on DNA double-strand cutting and nuclease repair. | Mouse models 2014 | ||
| 2015 | Pascale BOMONT | Montpellier | Foundation For Rare Diseases | Giant Axonal Neuropathy (GAN) | Reversing motor deficits in GIant Axonal Neuropathy | Giant Axon Neuropathy (GAN) is a neurodegenerative disease that begins in childhood and leads to a fatal outcome in young adulthood. No treatment is available to prevent or ameliorate the severe symptoms, which induce progressive loss of walking, sensation and severe deficits in the brain. While research is advancing into the mechanisms responsible for this disease, no laboratory has been able to create a mouse model reproducing the pathology. We have now developed the 1st animal model for NAG, reproducing the severe neurological disorders found in patients, and propose to implement it for the benefit of patients, in the search for new treatments. To this end, we propose to undertake the 1st pharmacological mass screening for NAG. This study will enable us to identify molecules active against NAG and thus envisage future preclinical development for patients. | High-throughput screening 2014 | ||
| 2015 | Vincent GACHE | Lyon | Foundation For Rare Diseases | Centronuclear Myopathies (CNM) | Rescue myonuclear domains establishment in centronuclear myopathies with chemical compounds | Centronucleated myopathies (CNM) are muscle diseases characterized by the persistent abnormal positioning of nuclei in muscle fibers. During muscle formation, specialized cells fuse to form multi-nucleated cells which, after maturation, become muscle fibers. The nuclei of these fibers are first positioned in the center, then migrate to the periphery to shape the nuclear domains of each fiber. Poor positioning of the nuclei in the early phases of fiber formation is correlated with a defect in the formation of these nuclear domains, which are responsible for the functional integrity of the fibers. Our preliminary data have identified an early defect in the localization of nuclei in fibers in a mouse model of CNM. The aim of this study is to identify new molecules that will restore the correct localization of nuclei in CNM muscle fibers. Ultimately, this study will enable us to identify new therapeutic targets in the context of developing and diseased muscle. | High-throughput screening 2014 | ||
| 2015 | Yvon TROTTIER | Strasbourg | Foundation For Rare Diseases | Huntington's disease | High Throughput screening for the identification of amyloid aggregation modulators in Huntington's disease | Huntington's disease (HD) is a neurodegenerative disorder with no known cure. HD, like Alzheimer's, Parkinson's and other diseases, is characterized by the accumulation in the brain of protein aggregates known as "amyloid". Although inhibiting amyloid aggregation has been shown to be effective in treating familial amyloid polyneuropathy, there is as yet no effective inhibitor for HD. Our research team has developed an innovative technology, called SynAggreg, designed to identify amyloid aggregation inhibitors from screens of large chemical compound libraries. In this project, we intend to adapt and use SynAggreg to identify specific inhibitors of the amyloid responsible for HD. These inhibitors will then be tested in animal models of HD to establish their potential to prevent disease symptoms, a necessary step prior to clinical applications. | High-throughput screening 2014 | ||
| 2015 | Alexandre FABRE | Marseille | Foundation For Rare Diseases | Syndromic diarrhea/tricho-hepato-enteric syndrom | Identification of new genes associated with syndromic diarrhea/ tricho-hepato-enteric syndrom | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Christina ZEITZ | Paris | Foundation For Rare Diseases | Retinitis pigmentosa (RP) | Identification of novel gene defects underlying retinitis pigmentosa in France by whole exome sequencing | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Isabelle AUDO | Paris | Foundation For Rare Diseases | Retinitis pigmentosa (RP) | Gene defect identification in X-linked retinitis pigmentosa cases excluded for currently known gene defects | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Jamel CHELLY | Strasbourg | Foundation For Rare Diseases | Focal cortical dysplasia - Epilepsy | Genetics of Focal Cortical Dysplasias | - | - | High throughput sequencing 2015 - 1 | |
| 2015 | Nadia BAHI-BUISSON | Paris | Foundation For Rare Diseases | Periventricular Nodular Heterotopia | Investigating novel modular basis for Periventricular Nodular Heterotopia | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Nadia CERF-BENSUSSAN | Paris | Foundation For Rare Diseases | Early onset inflammatory intestinal diseases | Determination of mendelian causes of intestinal inflammation | - | - | High throughput sequencing 2015 - 1 | |
| 2015 | Nathalie ROUX-BUISSON | Grenoble | Foundation For Rare Diseases | Exertional Heat Stroke syndrome (EHS) | Identification of new genes in Exertional Heat Stroke syndrome (EHS) with positive in vitro contracture test and no mutation in RYR1 gene | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Nicolas CHASSAING | Toulouse | Foundation For Rare Diseases | Anophthalmia - microphthalmia | Analysis of regulatory elements sequences in microphthalmia/anophthalmia | - | - | High throughput sequencing 2015 - 1 | |
| 2015 | Patrick CALLIER | Dijon | Foundation For Rare Diseases | Pai syndrome | Identification of the gene for Pai syndrome through Whole Genome Sequencing | - | - | High throughput sequencing 2015 - 1 | |
| 2015 | Pauline ARNAUD | Paris | Foundation For Rare Diseases | Marfan Syndrome and related disorders, Familial Thoracic Aneurysm and Dissection (FTAAD) | Identification of new genes involved in Marfan Syndrome and Familial Thoracic Aneurysm and Dissection (FTAAD) | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Sandrine MARLIN | Paris | Foundation For Rare Diseases | Cochlear nerve Aplasia | Identification of the molecular basis of cochlear nerve aplasia | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Sophie NAUDION | Bordeaux | Foundation For Rare Diseases | A new entity (glomerular disease-lymphoedema-hypotrophy-developmental delay-immune deficiency) | Identification of the molecular bases of a new phenotype of multiple malformations in a multiplex family | - | - | High throughput sequencing 2015 - 1 | |
| 2015 | Stephane VIVILLE | Strasbourg | Foundation For Rare Diseases | Infertility | Genetics of male infertility: genes implicated in non-obstructive azoospermia | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Stephanie BAULAC | Paris | Foundation For Rare Diseases | Epilepsy | Identification of new genes for autosomal dominant focal epilepsies | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Sylvain LATOUR | Paris | Foundation For Rare Diseases | Rare primary immunodeficiencies | Molecular identification of novel forms of inherited lymphoproliferation syndromes associated with a susceptibility to EBV infection | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Valerie MALAN | Paris | Foundation For Rare Diseases | Intellectual disability and congenital malformations | Unmasking of a recessive mutation: what role in the incomplete penetrance of CNVs | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Veronique PAQUIS-FLUCKINGER | Nice | Foundation For Rare Diseases | Mitochondrial diseases | Identification of new genes responsible for mitochondrial disorders by exome sequencing | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Vincent CANTAGREL | Paris | Foundation For Rare Diseases | Cerebellar atrophy associated with intellectual disability | Genetic basis of childhood-onset cerebellar atrophy associated with intellectual disability | - | High throughput sequencing 2015 - 1 | ||
| 2015 | Agnes RÖTIG | Paris | Foundation For Rare Diseases | Mitochondrial disease with neurological involvement | Identification of nuclear genes responsible of abnormal respiratory chain assembly | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Alain CALENDER | Lyon | Foundation For Rare Diseases | Sarcoidosis (Besnier-Boeck-Schaumann disease) | Identification of genes involved in familial forms of sarcoidosis | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Caroline ROORYCK-THAMBO | Bordeaux | Foundation For Rare Diseases | Right ventricular hypoplasia | Identification of a gene involved in familial right ventricular hypoplasia | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Caroline MICHOT | Paris | Foundation For Rare Diseases | Microcephalic osteodysplastic primordial dwarfisms | Dissection of molecular bases of microcephalic osteodysplastic primordial dwarfisms: identification of new genes in pre-screened patients | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Celine HUBER | Paris | Foundation For Rare Diseases | Asphyxiating Thoracic Dysplasia or Jeune syndrome | Identification of the molecular basis of the Asphyxiating Thoracic Dysplasia | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Christine BELLANNÉ-CHANTELOT | Paris | Foundation For Rare Diseases | Congenital neutropenia | Identification of new genes in congenital neutropenia | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Laurent PASQUIER | Rennes | Foundation For Rare Diseases | Rhombencephalosynapsis | Identification of a gene involved in rhombencephalosynapsis | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Marie-Christine ALESSI | Marseille | Foundation For Rare Diseases | Platelet dysfunction | Identification of new genes involved in platelet dysfunction | - | - | High throughput sequencing 2015 - 2 | |
| 2015 | Megana PRASAD | Strasbourg | Foundation For Rare Diseases | Bardet-Biedl and Bardet-Biedl-like syndromes | Identification of novel genes underlying Bardet-Biedl and Bardet-Biedl-like syndromes | - | - | High throughput sequencing 2015 - 2 | |
| 2015 | Muriel GIRARD | Paris | Foundation For Rare Diseases | Biliary atresia | Identification of a common signaling pathway involved in biliary atresia | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Pascale DELONLAY | Paris | Foundation For Rare Diseases | Rhabdomyolysis and Reye syndrome | Identification of the gene(s) responsible for recessive rhabdomyolysis and Reye syndrome in 3 patients from 2 families presenting the same phenotype | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Pierre RAY | Grenoble | Foundation For Rare Diseases | Non-obstructive azoospermia | Identification of genetic causes of human non-obstructive azoospermia | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Veronique PAQUIS-FLUCKLINGER | Nice | Foundation For Rare Diseases | Mitochondrial diseases | Progressive external ophthalmoplegia with multiple mitochondrial DNA deletions: identification of new genes | - | High throughput sequencing 2015 - 2 | ||
| 2015 | Vincent LAUGEL | Strasbourg | Foundation For Rare Diseases | Cockayne syndrome | Investigating novel molecular basis for Cockayne syndrome | - | The diagnostic rate for exomes funded by the FMR is 25%. In-depth study of patients with mutations in the MED20 gene will enable better clinical and molecular characterization of this rare and poorly understood condition, which is now included in the differential diagnosis of Cockayne syndrome. In this regard, it is particularly interesting to note the clinical overlap between the loss of function of the MED20 gene, which is involved in the initiation of transcription, and the loss of function of the CSA or CSB genes, which are involved in transcription-coupled DNA repair. This discovery paves the way for more comprehensive research into mediator pathologies. | High throughput sequencing 2015 - 2 | |
| 2015 | Carine LE GOFF | Paris | Foundation For Rare Diseases | Myhre syndrome (MS) | SMAD4 and Myhre syndrome | Myhre syndrome (MS) is a developmental disease characterized by short stature, short extremities and joint stiffness. It is also associated with complications such as arterial hypertension, bronchopulmonary insufficiency and obesity leading to early death. We have identified mutations in the SMAD4 gene in 30 MS patients. In cells from MS patients, deregulation of the TGFβ pathway was observed. SMAD4 is also known to be a tumor suppressor. However, to date, MS patients have not developed cancer. MS is a unique model that can allow us to study both bone and cartilage development. Our aim is therefore to study the function of SMAD4 in these processes. To do this, we want to develop a mouse model that mimics the MS. Secondly, we will study the functional consequences associated with mutations in the SMAD4 gene. This project will enable us to discover new target molecules with potential spin-offs for the treatment of SMAD4-related cancers. | Mouse models 2014 | ||
| 2015 | Christian HAMEL | Montpellier | Foundation For Rare Diseases | Vitelliform macular dystrophies (VMD) | Impg1 gene Knock-Out, a mouse model for human vitelliform macular dystrophy and retinitis pigmentosa | The human retina is made up of different cell types essential for vision, including photoreceptors and retinal pigment epithelial (RPE) cells. Photoreceptors and RPE are separated by a very thin layer, the interphotoreceptor matrix (IPM). This IPM enables the retina to adhere and function properly within the eye. We have discovered that mutations in two major components of this ILM, the SPACR and SPACRCAN proteins, are responsible for vitelliform macular dystrophy and retinitis pigmentosa. These diseases are hereditary degenerative disorders of the retina, leading to blindness in the most severe forms. The concept that PIM is an important player in lipofuscin accumulation is novel. Lipofuscin is a cellular pigment composed of debris molecules which is characteristic of vitelliform macular dystrophy and, more generally, of numerous retinal pathologies such as AMD, the leading cause of blindness in France. The development of mice that do not express these two proteins will enable us to gain a better understanding of the pathophysiological mechanisms of the disease and the development of innovative therapies. | Mouse models 2014 | ||
| 2015 | Delphine MEYNARD | Toulouse | Foundation For Rare Diseases | Iron Refractory Iron Deficiency Anemia (IRIDA) | Is matriptase-2 involved in iron homeostasis regulation and anemia exclusively through the hepatocytes? | IRIDA syndrome is an inherited disorder characterized by severe anemia that can only be partially corrected by iron supplementation. The disease is due to a defect in the expression of the matriptase-2 protein. It is currently accepted that the absence of matriptase-2 in the liver leads to increased expression of hepcidin, thus blocking the entry of iron into the body. However, the severity of the anemia observed is disproportionate to the level of hepcidin. Furthermore, erythropoietin injections in IRIDA patients have no effect on their anemia. This suggests that matriptase-2 may have a role in erythropoiesis, independent of hepcidin through an extrahepatic function. To investigate this possibility, we propose to produce mice expressing no matriptase-2 in the liver only, and to assess their degree of anemia. Full characterization of matriptase-2 function will improve our understanding of IRIDA syndrome and anemia in general. This may help in the development of new therapies to correct anemia in IRIDA patients. | Mouse models 2014 | ||
| 2015 | Frederic RIEUX-LAUCAT | Paris | Foundation For Rare Diseases | Primary immunodeficiency with autoimmunity | Role of LRBA in the control of the immune response: implication in primary immunodeficiencies | Several international teams, including our own, have identified a deficiency of the LRBA gene in pediatric patients with susceptibility to infections and autoimmune manifestations. To date, little is known about the role of this molecule, and the mechanisms of the pathology remain to be discovered in order to provide these patients with specific therapeutics. Our aim is to generate a mouse deficient in the LRBA gene, in order to study the functions of this gene in the immune response and to provide a model for studying human pathology. | Mouse models 2014 | ||
| 2015 | Frederique RENE | Strasbourg | Foundation For Rare Diseases | Amyotrophic Lateral Sclerosis (ALS) | Generation of an ALS-FTD mouse model based on a conditional CHMP2B intron 5 mutant Knock-In | Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. Between 10% and 20% of ALS patients also develop behavioral disorders due to fronto-temporal dementia (FTD). To date, there is no curative treatment for this pathology, and the mechanisms leading to neuronal death have not been fully elucidated. Mutations in the CHMP2B gene have been identified in patients with ALS, ALS-FTD and FTD. Recent data have shown that the intron5 mutation is capable of inducing neuronal death in vitro. Moreover, transgenic mice overexpressing this mutant develop certain aspects of the pathology. In this project, we propose to generate a mouse that will conditionally express this mutant in one or 2 alleles of the Chmp2B gene. These mice, which will closely mimic the genetic changes described in humans, will enable us to study the cellular and molecular mechanisms that lead to the pathology, and to propose new therapeutic avenues. | Mouse models 2014 | ||
| 2015 | Helene DOLLFUS | Strasbourg | Foundation For Rare Diseases | Ciliopathy-like phenotype associating kidney alteration and retinal degeneration | Mouse modeling of a missense mutation in the essential gene PIK3R4 (VPS15) responsible for a ciliopathy-like disease | A sequencing analysis of the coding parts of the genome of various members (diseased or not) of a family presenting a clinical picture suggestive of ciliopathy (renal impairment, retinal degeneration) revealed a missense mutation in the PIK3R4 gene (VPS15). This gene codes for a protein essential for the synthesis of a lipid, PI3P, a key component of membranes. The name of the VPS15 gene comes from the baker's yeast in which it was discovered and named Vps15 for "vacuolar protein sorting 15". Studies in zebrafish and baker's yeast show that the pathological mutation VPS15R998Q is responsible for cellular defects linked to cilium function (fish) and vesicular trafficking (yeast). A mouse mimicking the human mutation in the VPS15 gene (VPS15R998Q knock-in mouse) is essential on a pathophysiological level in order to link clinical manifestations to ciliary dysfunctions. From a fundamental point of view, this knock-in mouse will enable many laboratories around the world to gain a better understanding of the PI3P synthesis pathway and its role in the cell. The scientific interest is complemented by a potential therapeutic interest, as numerous studies are underway to modulate these lipid synthesis pathways in order to act in various fields of medicine (neurology, myopathy, cancer, infectious diseases). | - | Mouse models 2014 | |
| 2015 | Jamel CHELLY | Illkirch | Foundation For Rare Diseases | Malformations of Cortical Development - Periventricular Nodular Heterotopia (PVNH) | Understanding NEDD4L-related MCD (Malformations of Cortical Development) through investigations of a Knock-In mouse model | Our recent work using the WES approach in MDC patients has led to the identification of mutations in a set of genes encoding proteins involved in the regulation of protein ubiquitination. Among these genes is NEDD4L, which codes for a protein containing an E3 ubiquitin ligase domain. Further targeted analysis of NEDD4L identified two additional mutations associated with periventricular nodular heterotopias (PVHN) clinically characterized by ID and epilepsy. Our main objective is to better characterize the neurodevelopmental abnormalities associated with NEDD4L mutations. We therefore propose to develop a KI mouse model carrying the mutation, Nedd4l - p.R897Q, identified in a patient whose MRI revealed PVNH, and to carry out studies: - behavior and susceptibility to epilepsy - neurodevelopmental processes, with a focus on progenitor proliferation, neuronal polarization and migration - molecular networks disrupted by Nedd4l dysfunction, by undertaking expression studies and proteomic analysis. The results of these studies should contribute to a better understanding of the pathophysiological mechanisms involved in MCDs, and could also help identify potential targets that could be exploited to modulate epilepsy severity. | - | Mouse models 2014 | |
| 2015 | Johann BOHM | Illkirch | Foundation For Rare Diseases | Tubular aggregate myopathy and Stormorken syndrome | First mammalian model for tubular aggregate myopathy and Stormorken syndrome | Muscle diseases affect children and adults in all populations, but their molecular basis is poorly understood. Without detailed knowledge of the pathomechanisms of these rare diseases, it is very difficult to develop therapeutic approaches. Our team recently identified the first gene (STIM1) associated with tubular aggregate myopathy, and demonstrated that this muscle disease is due to a muscle calcium imbalance. Calcium induces contraction and is a key factor in muscle function. As many muscle diseases are the consequence of a muscle calcium imbalance, tubular aggregate myopathy represents an excellent model to study the correlation between calcium homeostasis and muscle weakness. We propose to generate a mouse model carrying the most recurrent and severe STIM1 mutation, associated with a multi-system phenotype described as Stormorken syndrome, in order to study in detail the development of the disease and test initial therapeutic strategies in preclinical settings. | - | Mouse models 2014 | |
| 2015 | Julie DUMONCEAUX | Paris | Foundation For Rare Diseases | FacioScapuloHumeral Dystrophy (FSHD) | FacioScapuloHumeral Dystrophy (FSHD): targeting two alternative Fat1 exons with one mouse | FacioScapuloHumeral Dystrophy (FSHD) is one of the most common muscular diseases for which there is no palliative or curative treatment. It is mainly characterized by atrophy of the shoulder, face and arm muscles. Although the genetic cause is known (loss of a piece of chromosome 4 in the vast majority of patients), the molecular and cellular mechanisms that lead to the disease's symptoms are not yet clearly understood. We have recently demonstrated the involvement of a new gene (called FAT1) in the onset/progression of this pathology. Until now, however, no-one had realized the importance of this gene in muscle physiology. Studying this gene is tricky, because at DNA level, it is very large and gives rise to several different proteins. The aim of our project is to create a mouse model in which some of these alternative forms of FAT1 protein will be eliminated. Such mice will make it possible (i) to identify the form of FAT1 required for proper muscle function and (ii) to develop a therapeutic approach for FSHD. | Mouse models 2014 | ||
| 2015 | Pascale BOMONT | Montpellier | Foundation For Rare Diseases | Giant axonal neuropathy | Development of an In vivo model for Giant Axonal Neuropathy | Giant Axon Neuropathy (GAN) is a rare, fatal neurodegenerative disease of young adults for which there is currently no cure. Extremely severe, NAG leads to a loss of mobility and sensitivity in young children, and then targets the central nervous system, causing intellectual, vision and language disorders. In order to study the neurodegenerative mechanisms in NAG and develop new methodologies for clinicians/geneticists and patients, our laboratory has identified the NAG gene, generated diagnostic tools, and created cellular and animal models of the pathology. In particular, we have generated a mouse model of NAG, but this does not reproduce the severity of the human disease and thus considerably limits the pre-clinical trials needed to develop therapy in patients. This project aims to generate a new type of mouse model reproducing NAG pathology, which will enable us not only to dissect the mechanisms of death in NAG but also to test and validate new therapeutic approaches for this fatal and incurable pathology. | - | Mouse models 2014 | |
| 2015 | Sebastien LACROIX-DESMAZES | Paris | Foundation For Rare Diseases | Hemophilia A | Generation of a novel mouse model of hemophilia A constituted of mice transgenic for a human T cell receptor specific for therapeutic factor VIII | Treating hemophilia A patients with therapeutic factor VIII induces an immune response that renders the treatment ineffective. This makes it very difficult to treat bleeding patients. Our aim is to develop a new murine model of hemophilia A using transgenic mice in which the majority of T cells are specific for factor VIII. Unlike existing animal models, in which only a tiny proportion of T cells recognize factor VIII, this new model will enable us to study in great detail the cellular and molecular interactions that characterize the development of the immune response against therapeutic factor VIII. These mice will be an unrivalled tool for dissecting this immune response, for testing the safety of new genetically engineered therapeutic factor VIII, and for monitoring the innate immune response in hemophilia A patients throughout their lives. The development of this model should ultimately improve the management of hemophilia A patients. | Mouse models 2014 | ||
| 2015 | Veronique PAQUIS-FLUCKINGER | Nice | Foundation For Rare Diseases | Motor neuron disease and ataxia | CHCHD10S59L mouse model: how mitochondrial dysfunction promotes motor neuron disease? | Amyotrophic lateral sclerosis (ALS), also known as Charcot's disease, is a neurodegenerative disease that affects the motor neurons, leading to death within 3 to 5 years of diagnosis. There is no cure for this terrible disease, which is mostly accidental but can run in families in 5 to 10% of cases. We have recently identified a new gene, CHCHD10, responsible for ALS but also for other pathologies that include motor neuron damage. This gene encodes a mitochondrial protein whose function we have begun to study. To understand how mitochondrial dysfunction leads to motor neuron death, we need a mouse model which is as close as possible to the human disease, and which will also enable us to test new therapeutic strategies. | Mouse models 2014 | ||
| 2015 | Anne MARCELLINI | Montpellier | Foundation For Rare Diseases | Down syndrome, 22q11 deletion, Williams-Beuren syndrome | Becoming an adult with developmental anomalies: obstacles and facilitators | The term "developmental anomalies" covers a wide variety of "rare diseases" that can lead to delays in intellectual development, more or less associated with behavioral disorders. In our society, these two types of difficulties are the ones that produce the most serious handicap situations for the people concerned. The aim of this research is to understand how people affected by these developmental anomalies can achieve a satisfying adult life. The study will focus on a population of adolescents and young adults (aged 16-25) affected by three rare diseases - trisomy 21, 22q11 deletion and Williams and Beuren syndrome - diversifying the profiles according to criteria of level of behavioral disorders, family and social situation, schooling and social participation. In-depth interviews will be conducted separately with the young people, their parents and possibly their siblings, in order to understand the recurring obstacles and facilitators encountered by the young people in their educational, professional, leisure and access to emotional and sexual life trajectories. The expected results will shed light on the practices and questions of professionals in the field and families concerning the educational and professional orientation of these young people, their support in social and affective life, the management of information concerning medical labeling and the analysis of its affective, identity, family and social consequences. The aim is to improve the quality of support for these people as they move towards independent adulthood. | Prémisses méthodologiques La discussion des résultats demande quelques précisions préliminaires. La plupart des familles participantes ont été recrutées via le Centre de Référence, qui a relayé notre appel à témoignages aux familles des patients qui pouvaient rentrer dans le champ de l’étude. Dans la plupart des cas nous avons rencontré ces familles au CHU de Montpellier, quand elles venaient pour la consultation annuelle dans le cadre du suivi en génétique (quelques fois ils sont venus exprès pour la recherche). Cette modalité de recrutement nous a permis de rencontrer plusieurs familles qui n’auraient pas répondu favorablement à notre appel à témoignages s’il n’était pas venu des médecins. Comme il arrive pour toute recherche qualitative, nous avons recueilli des récits coproduits dans un contexte spécifique qui d’un côté en a permis la production, et d’autre côté a contribué à déterminer le contenu des échanges et à les encadrer. Par ailleurs, spécialement dans les cas où les entretiens ont été réalisés avec les parents et les jeunes ensemble en raison des difficultés d’expression de ces derniers, la dynamique des échanges a demandé une réflexion critique sur la manière dont les représentations sur les personnes ayant des limitations de capacités intellectuelles pouvaient influencer les normes d’interaction et participer de la construction et de la reproduction de situations de handicap10. Les difficultés du devenir adulte Pour la plupart des individus de notre société le passage à la majorité comporte un changement de statut face aux institutions. Autour de ce passage se développe une série d’interrogations concernant le devenir professionnel et affectif. Pour les jeunes porteurs d’anomalies chromosomiques ce passage n’implique pas dans tous les cas l’acquisition du droit à l’autodétermination. Il s’accompagne, parfois, d’une série d’interrogations et préoccupations différentes. Du point de vue médical, il y aura le passage des dispositifs de prise en charge consacrés à l’enfance vers les dispositifs pour les adultes. D’un point de vue plus général, il s’agira de conclure la scolarité et d’entreprendre éventuellement une vie professionnelle. Les jeunes qui fréquentent des établissements médico-sociaux devront effectuer le passage vers des institutions pour adultes (même s’ils peuvent reporter cette transition jusqu’à l’âge de 20 ans). Pour certains parents, cette phase de la vie de leurs enfants comporte des préoccupations d’ordre financier et organisationnel liées au maintien de leur bien-être quand ils ne seront plus là pour s’en occuper. - L’inclusion scolaire. Même si tous les parents n’utilisent pas le mot inclusion, il apparaît clairement que la plupart préféreraient que leurs enfants fréquentent l’école ordinaire, ou du moins perçoivent une injonction à la préférer11. Le modèle de l’école inclusive devenant de plus en plus normatif12, la permanence dans le milieu ordinaire peut apparaître comme une réussite, avec par conséquent un sentiment d’échec ou de culpabilité chez certains parents dont les enfants n’ont pas pu y être maintenus. Ceux- ci peuvent avoir le sentiment de ne pas s’être battus convenablement, de ne pas avoir suffisamment stimulé leurs enfants pendant la petite enfance, ou bien que le regard des autres parents leur impose de se justifier13, même si parfois la stimulation précoce n’a pas été possible à cause de problèmes médicaux (malformations cardiaques, maladies intestinales) qui mettaient en question le pronostic vital des enfants. Toutefois, les cas des familles qui ont finalement préféré inscrire leurs enfants dans des écoles spécialisées confirment que la présence d’un individu dans le milieu ordinaire n’implique pas forcément une participation sociale effective et satisfaisante (Barreyre et al. 2008, Garel 2010). - La valeur symbolique du travail Les combats pour la scolarité se rejouent au moment de l’entrée éventuelle dans la vie professionnelle. Pour les parents, l'accès de leurs enfants au travail est motivé par le désir de leur donner une place sociale qui n'est plus assurée par la scolarité qui donnait le statut d’élève. Là où trouver une école, c'est trouver une place d'enfant, trouver un travail c'est trouver une place d'adulte aux significations symboliques multiples : être utile, avoir un salaire, faire comme ses frères et sœurs, être indépendant financièrement14. Nous constatons qu'il est très difficile de laisser émerger un projet exprimé par le jeune lui-même dans un contexte qui restreint les possibles, c’est pourquoi les parents s’efforcent parfois de cadrer les désirs de jeunes, et ce, dans leur perspective, afin de leur éviter des frustrations trop douloureuses. Par exemple, dans des cas où le jeune a été encouragé à expliciter ses désirs d’activité professionnelle, une forte frustration a pu naître de l’impossibilité de trouver une place correspondante. À l’inverse on voit des cas où des jeunes ont pu découvrir des activités différentes tant en milieu ordinaire qu’en milieu protégé lors de stages, parfois cherchés par les parents, et où les jeunes ont pu effectuer un choix. La possibilité d'expérimenter les différentes modalités de travail à travers des stages semble ainsi importante dans la réalisation d'un choix éclairé. L’idéal de l’inclusion en milieu ordinaire pèse sur les familles, dont certaines craignent l’irréversibilité des choix qui leur sont demandés : peut-on revenir vers le milieu ordinaire après une expérience douloureuse en milieu protégé et vice versa ? C’est la question des passages, du décloisonnement entre les types d’environnement qui est souvent posée. En fait, même quand certains adolescents ont pu rester longtemps dans l’école ordinaire, les enseignants ont suggéré à la famille de les faire passer par le parcours IME/IMPro15 au moins vers la fin de la scolarité, de manière à pouvoir bénéficier des passerelles vers le travail en milieu protégé, qui leur resterait autrement fermé. - La désirabilité du milieu ordinaire et la sélection à l’entrée des ESAT Cette question, déjà critique pour la scolarité, l’est aussi à l’égard du travail. Si le travail en milieu ordinaire apparaît comme l’idéal, des personnes trisomiques ou leurs familles ont préféré le travail dans des établissements médico-sociaux en raison d’une plus grande facilité de tisser des liens. Les ESAT, toutefois, sont devenus plus sélectifs qu’ils ne l’étaient au moment de leur création en 1957 (Velche, 2009). Par exemple, l’un des acquis demandés par plusieurs de ces établissements est que la personne soit capable de se déplacer seule avec les transports en commun, ce que peu des jeunes rencontrés savent faire. En plus, il est évoqué dans l’enquête que certains ESAT refusent a priori les personnes trisomiques. Là où celles-ci sont admises, les contraintes horaires et les rythmes du travail peuvent être à l’origine de fatigue ou de frictions avec les encadrants. Les personnes ayant le syndrome de Williams et Beuren ont des difficultés similaires, ce qui fait que leurs options sont limitées et ne correspondent pas forcément à leurs aspirations. Parfois ces jeunes sont très demandeurs de métiers riches en contacts personnels, mais il leur arrive d’être considérés comme inadaptés aux tâches professionnelles qui leur permettraient de rencontrer des gens (accueil, vente...). - Le non-travail Il apparaît difficile pour les parents d'envisager le « non-travail » comme une éventualité non stigmatisante. Quand le jeune ne peut pas travailler parce qu’aucun environnement professionnel ne l’accueille – ni en milieu ordinaire, ni en milieu spécialisé dans les ESAT – on observe un très fort ressenti de culpabilité ou d’échec chez les parents. L'accès au travail est mis en exergue comme une réussite, ce qui crée une sorte de hiérarchisation implicite entre les jeunes. Dans cette configuration, rejoindre un ATO est vécu comme une solution de dernier recours particulièrement douloureuse pour la famille. Ces configurations sont aussi celles dans lesquelles il est plus difficile de connaître et comprendre le vécu des jeunes, du fait de leurs difficultés d’expression. Les parents ne semblent toutefois pas relever chez leurs enfants la même souffrance que celle qu’ils ressentent en tant que parent, à l’égard de leur impossibilité d’accéder au statut de travailleur. En conclusion, nous observons qu’à la fin de la scolarité la plupart des familles sont confrontées à de nouveaux obstacles et refus, et doivent s’engager dans de nouveaux combats. Les parents ayant le plus de capital culturel et social, et particulièrement ceux qui sont professionnalisés dans le domaine du travail social, de la santé ou de l’éducation, ont plus de facilité à appréhender les complexités bureaucratiques des dispositifs de prise en charge et sont plus facilement en mesure de comparer plusieurs options. Dans les cadres des dispositifs et des règlements existants, ils arrivent à pousser les institutions à adopter des solutions plus proches des besoins de leurs enfants comme par exemple l’emploi à temps partiel en ESAT, qui permet aux jeunes adultes de travailler tout en gardant des temps de récupération et des énergies psychophysiques pour des activités de loisir. Dans plusieurs cas, ces parents sont ou ont été parmi les membres les plus actifs des associations de parents. Partir du domicile familial, se mettre en couple Comme l’ont très bien montré Barreyre et al. (2008) mais aussi Desjardins (2002), les adultes ayant des limitations en termes de capacités mentales ou de capacités de contrôle comportemental peuvent être caractérisés par la plus grande ambivalence à l’égard du statut de personne handicapée. En effet ce statut est à la fois refusé par eux pour sa dimension stigmatisante, mais dans le même temps accepté voire recherché pour sa dimension de protection. De la même manière, dans les relations familiales, les jeunes concernés par une vie en milieu ordinaire adressent à leurs familles des demandes d’aides qui constituent un « mélange complexe de rapprochement et d’émancipation ». Ces différents travaux montrent en outre que le « coût » de la participation sociale en milieu ordinaire des personnes ayant des incapacités mentales peut être extrêmement élevé en termes de sentiment de solitude, d’isolement et de souffrance affective. Les activités de sport et de loisir, en milieu ordinaire ou adapté, contribuent à éviter l’isolement et offrent des opportunités pour diversifier les rencontres. Les activités en milieu protégé (associations de parents et sport adapté) offrent tout particulièrement un cadre protecteur où les jeunes peuvent expérimenter moins de frustrations et être reconnus pour leurs capacités16. Les entretiens réalisés dans le cadre de la présente étude montrent que, de la part des parents, une dialectique complexe entre protection et contrôle s’établit, où le fait de pouvoir exercer quelque forme de surveillance sur la vie des jeunes (accompagnement par des éducateurs, vie en foyer collectif, prise des transports en commun avec un téléphone portable à la main) favorise les expériences en dehors de la maison parentale. La capacité et la disponibilité des jeunes à demander de l’aide favorisent ultérieurement la confiance des parents. De la part des jeunes nous constatons aussi des sentiments partagés entre le besoin de protection et le désir de jouir d’espaces de liberté (voir aussi Marcellini 2005). Les frères et sœurs constituent un modèle et une source de motivation importante, qu’ils souhaitent imiter et par rapport auxquels ils ressentent à la fois de la gratitude et de la pression. Le départ des frères et sœurs de la maison peut contribuer à stimuler le désir d’aller vivre ailleurs que chez les parents et l’envie de montrer qu’on a les capacités pour franchir cette étape. Nous retrouvons la dialectique entre protection et contrôle déjà prégnante au sujet de la vie affective des jeunes. Une relation amoureuse peut constituer un espace d’affirmation de soi, mais en plusieurs cas les rencontres entre les deux amoureux sont rendues possibles par la collaboration des parents. Accompagner son enfant chez l’ami ou l’amie permet aussi de rencontrer l’autre famille et de veiller à l’évolution de la relation17. Une question particulièrement délicate est posée par le désir que peuvent avoir ces jeunes de se marier comme le font une grande partie des couples, et aussi d’avoir des enfants. Le mariage des frères et des sœurs, ou la naissance des neveux ou des nièces peuvent être les moments où les jeunes se posent la question de leur propre mariage et de leur propre maternité ou paternité. Tous les parents de jeunes qui ont des syndromes génétiques ne sont pas favorables à ce que leurs enfants se marient ou à ce qu’ils aient des enfants18. À part le risque de la transmission de l’anomalie chromosomique, ils ne sont pas sûrs que les jeunes sauraient s’occuper de leurs enfants et, pour certains, ils craignent de devoir s’en occuper eux-mêmes. Dans ces cas, ils cherchent à les dissuader de devenir parent en mettant en avant le risque de la transmission de l’anomalie chromosomique, mais aussi en les mettant face aux difficultés de prendre soin des enfants en bas âge lorsqu’ils ont l’occasion de rencontrer les petits neveux ou petites nièces, ou les bébés d’autres personnes connues de la famille. | Humanities and social sciences 3 | |
| 2015 | Dominique FARGE | Paris | Foundation For Rare Diseases | Systemic sclerosis, Lupus | Establishment of a collaborative e-platform to identify and characterize the handicaps of patients with rare autoimmune diseases within the cell therapy or biotherapy | To improve care and support for patients with disabilities linked to a rare autoimmune disease (AID), we need to know how the disease impacts their daily lives, by listening to them talk about their life course. Research in the human and social sciences (SHS) on this theme is based on what these patients experience, as they invent solutions to preserve their quality of life, their health and their very lives. E-FORM-Innov proposes to bring together 3 research teams (patients, SHS researchers, medical and care teams) who will work together to produce knowledge in this field. Patient volunteers are considered as co-researchers, in view of the questions they ask and the solutions they propose, after a short research training course. By creating a virtual community of 36 patients suffering from a rare IAD (systemic scleroderma or lupus), the aim is to invite them to transform their knowledge into organized knowledge about what they experience on a daily basis, the strategies they invent and the solutions they find to overcome their disability. These patients are invited to tell their life story in front of a third party, to describe and analyze what they do, how they do it and how they transform themselves to pursue their personal development despite their illness. They have a surplus of daily tasks "in the service of keeping themselves alive", which far exceeds their therapeutic obligations. They may have to choose between their care priorities and their quality of life. To generate knowledge, we propose to mobilize "collective intelligence", bringing together individual intelligences to create a dynamic of cooperation, thanks to a "collaborative virtual platform" on a dedicated website. Digital tools (virtual lounges, chatrooms, etc.) will be made available to patient-users to facilitate their exchanges with each other, with other researchers and with the community manager (CM). The CM will lead the exchanges, with the aim of answering the question: how can we identify and characterize the disabilities of patients suffering from a rare IAM requiring cell therapy or biotherapy? | L’analyse des récits et témoignages des co-chercheurs atteints de sclérodermie ou de lupus a permis de mettre en évidence les éléments suivants : 1- L’ensemble des récits des co-chercheurs fait état d’une forme d’errance diagnostique et thérapeutique qui va de quelques semaines à plusieurs années. La difficulté ainsi éprouvée à trouver rapidement les compétences et les traitements médicaux adaptés entraîne des préjudices sur différents plans : au niveau médical, la maladie continue à progresser ; au niveau psychique, l’incertitude dans laquelle se trouvent les patients est génératrice d’angoisse ; en termes de qualité de vie et de rapports sociaux, les différents symptômes sont physiquement incapacitants et sont susceptibles de provoquer dans l’entourage personnel comme dans le milieu professionnel des réactions nuisant à l’estime de soi. 2- Le diagnostic de la maladie et sa prise en charge dans un Centre de Référence Maladies Rares marquent une sortie de l’errance thérapeutique et la possibilité pour les co-chercheurs de se mobiliser positivement face à la maladie. À ce stade, ils se disent bien informés, en confiance, bénéficiant le plus souvent d’une prise en charge (à l’hôpital Saint-Louis pour les patients atteints de sclérodermie) qui les aide à affronter les difficultés. 3- La période de la greffe, tant dans sa préparation que dans sa mise en œuvre et ses suites à court ou moyen terme, est un moment crucial pour les co-chercheurs. Elle cristallise les espoirs et les attentes quant à une évolution positive du cours de la maladie et au retour à une meilleure qualité de vie. Par ailleurs, au-delà des contraintes imposées par le soin, cette période peut être vécue comme particulièrement difficile en raison de la durée d’hospitalisation qu’impose l’opération et de l’isolement qu’elle provoque par rapport à l’entourage familial lorsque le domicile des patients est éloigné de l’hôpital. D’où le besoin d’ouverture sur l’extérieur, de contacts et de relations dont font état nombre d’entre eux. 4- C’est surtout après la greffe, ou lorsqu’un traitement médical semble ajusté que les co-chercheurs mentionnent une reconfiguration de leur vie qui les amène à s’adapter à leur nouvelle « condition physique » et à rechercher un nouvel équilibre de vie. Ils font état alors d’importantes difficultés à faire reconnaître les contraintes et limitations imposées par la maladie, qu’il s’agisse de l’obtention d’indemnités, d’adaptation de leur poste de travail, de formation, d’adaptation du logement, etc. Ils manquent d’informations, sont confrontés à la lourdeur des démarches administratives à accomplir et quelquefois à la méconnaissance et à l’inertie des organismes sociaux ou des milieux professionnels. Les associations n’ont jamais été mentionnées comme présentes dans cette étape de la vie des co- chercheurs, ce qui laisse supposer un manque d’information sur l’existence de ces associations ou sur le soutien qu’elles peuvent apporter. 5- Les récits des co-chercheurs font apparaître différentes étapes dans l’expérience vécue de la maladie, qui vont souvent dans le sens d’une accommodation les amenant à « vivre avec » la maladie et àdévelopper des stratégies de « santé-dans-la-maladie ». La difficulté est souvent ressentie d’inscrire la maladie dans un parcours d’existence et de donner du sens à cette expérience, d’autant plus inédite qu’il s’agit de maladies rares. S’appuyant sur la recherche à laquelle ils ont participé et sur la production et le partage de récits auquel elle a donné lieu, de nombreux co-chercheurs expriment le désir, pour eux- mêmes et pour l’ensemble des patients, de pouvoir accéder à des récits d’expérience variés de malades qui pourraient les aider à rompre leur sentiment d’isolement, à mettre en commun leurs difficultés et leurs efforts, à subjectiver leur parcours. Ils font état également de leur souhait de mieux connaître et de partager des pratiques et des exercices (hygiène de vie, alimentation, respiration, méditation, etc.) complémentaires des soins proprement médicaux et permettant d’améliorer les conditions physiques et mentales de la vie au quotidien. Si l’on récapitule le sens et les finalités donnés par les co-chercheurs à leur participation à la recherche, il se dégage les points suivants : – rompre la solitude, l’isolement en partageant le récit de leurs expériences : trouver du même malgré les différences – renforcer et partager les savoirs, les connaissances sur la maladie vécue de l’intérieur – échanger des techniques et des pratiques visant à apaiser et à mieux supporter la douleur, à améliorer la qualité de la vie – renforcer la formation des soignants concernant les maladies auto-immunes de manière à éviter les errances thérapeutiques des malades – inciter les associations à élargir leurs actions d’information (tant auprès des malades que des organismes sociaux et professionnels) et à développer des activités de soutien et d’aide aux malades – faire mieux reconnaître socialement et professionnellement les maladies auto-immunes et les empêchements et limitations qu’elles entraînent – constituer un réseau d’information, de partage et d’échanges, sous la forme de plateformes collaboratives, de forums, etc. Il se dégage aussi des données recueillies un certain nombre de ressources utilisées et d’apprentissages réalisés par les co-chercheurs pour vivre avec leur maladie. Ceux-ci sont de l’ordre du mental (apprentissage de la patience, du courage, d’une attitude positive et d’un ancrage dans le présent), de la gestion des émotions et de la douleur (respiration, sophrologie, autohypnose, méditation, relativiser), du soin du corps (écoute des symptômes, respect des limites, pratique du sport, alimentation, relaxation, traitement). Mais les apprentissages concernent aussi l’espace interrelationnel (prendre du recul, s’appuyer sur des valeurs telles que la tolérance, la patience, l’humilité, mais aussi s’affirmer) et professionnel quand la maladie amène à une reconversion ou à un bilan de compétences permettant de se découvrir. Les apprentissages tournés vers la maladie sont variables : certains co-chercheurs considèrent qu’ils doivent en avoir la meilleure connaissance possible (reconnaissance des symptômes, évolution possible de la maladie), d’autres au contraire ne le souhaitent pas ou choisissent soigneusement leur source d’information (plusieurs co-chercheurs mentionnent leur méfiance vis-à-vis d’Internet et une conscience de la singularité de leur cas). Un nombre important de co-chercheurs mentionnent aussi l’appui qu’ils trouvent dans des formes de spiritualité et le développement de cette dimension spirituelle dans le cours de la maladie. | Humanities and social sciences 3 | |
| 2015 | Gregoire MERCIER | Montpellier | Foundation For Rare Diseases | Lymphedema | The LYMPHO-RAC study: analyzing out-of-pocket payments of primary lymphedema patients in France | Primary lymphedema is a rare, chronic and debilitating disease that causes swelling and pain in a part of the body. Primary lymphedema (prevalence 1 to 5 per 10,000) is caused by a failure of the lymphatic system during childhood or adolescence, affecting both children and adults, and leading to functional disability. It is responsible for serious infectious complications that profoundly alter patients' future quality of life, with a sometimes very significant economic impact on the family. Its treatment relies on medical devices that are poorly reimbursed, resulting in a cost to the patient known as Reste à Charge (RAC). This RAC threatens equity of access to care. The main aim of the LmyphoRAC study is to estimate the RAC for adults and families of children suffering from primary lymphedema. It is a prospective study of usual care in several French cities. Associations, doctors and other healthcare professionals working in the field of lymphedema in several locations in France have committed themselves to motivating the participation of patients and their families. The LymphoRAC data collection system is innovative. It relies heavily on the commitment of patients to connect via the Internet to anonymous electronic questionnaires and to fill them in. The data collected will not be able to identify patients, and will be accessible only to the study's principal investigator. From a collective point of view, this study will provide a better understanding of the cost of lymphedema management, the amount of out-of-pocket expenses for patients, and the degree of equity in the distribution of out-of-pocket expenses in the population and in access to appropriate care for patients. | Dans notre étude le Lymphœdème primaire est une pathologie qui a une forte implication pour les professionnels de santé et patients dans tout le pays. La plupart de notre échantillon est composé de femmes âgées de 50 ans, touchées par un lymphœdème primaire diagnostiqué pendant l’enfance ou il y a plus de 10 ans. Le lymphœdème primaire est fréquemment localisé aux membres inférieurs ; sans prise en charge il peut évoluer aux stades plus sévères de la maladie, entrainant une diminution des capacités fonctionnelles importantes et des complications infectieuses graves. Les soins spécifiques reposent sur le drainage lymphatique manuel (DLM) et l’utilisation des dispositifs médicaux (DM). La limitation de l’évolution de l’œdème permet au patient de mener une vie la plus normale et le plus longtemps possible en diminuant ainsi les risques des infections graves. En conséquence, le lymphœdème impacterait le développement familial, social et économique d’une personne et celui de son entourage tout au long de sa vie, car il n’existe pas de traitement curatif. Dans tous les cas le lymphœdème a des chances de devenir un handicap important et source d’une altération de la qualité de vie de ces patients. L’objectif principal de notre étude était d’estimer le montant du RAC pour les patients de lymphœdème primaire. Plus du 90% du total des RAC mensuel sont destinés à payer les DM, les transports, les cures thermales et les autres dépenses non médicales occasionnées par le lymphœdème (vêtements et chaussures adaptés, gymnase ou encore des appareils de compression). Le montant restant (<10%), paye les postes mieux remboursés comme les médicaments, examens, consultations médicales et paramédicales ; alors que ces deux derniers occupaient presque 50% des dépenses totales. Un engagement financier est évident de la part des foyers avec existence d’une ou plusieurs complémentaire pour une même famille. Cependant le fait d’avoir changé pour une mutuelle plus chère afin d’être mieux remboursés, ne diminue pas le RAC moyen de ces patients (n=19). Pire, ce groupe a un RAC moyen supérieur de 195€ après AMO et 154€ après AMC sur six mois par rapport à la moyenne de notre population. En plus de cet investissement financier de la part des foyers, presque la moitié des patients ont le statut d’ALD exonérante. Ce statut ouvre droit à la prise en charge à 100% (sans ticket modérateur) par l’AMO pour des soins et traitement liés au lymphœdème sur le tarif de base de la sécurité sociale (consultations médicales et paramédicales, médicaments ou examens). Cet effort de la part du système sanitaire Français semble ne pas être suffisant si on considère le nombre de renoncements aux soins pour des raisons financières (19 cas). En résumé pour une période de 6 mois, le RAC moyen représente, après remboursement AMO et AMC, respectivement 5,9% et 4,35% du salaire moyen net sur 6 mois. Autre enseignement, le coût engagé pour préserver un mode de vie le plus normal et le plus longtemps possible semble avoir un impact économiquement inéquitable. Le groupe des revenus plus élevés, Q5 (Quintile 5) détient un RAC total après le remboursement de l’AMC plus élevé, soit 346€ de plus par rapport au Q1 (Quintile 1) et, 1 048€ de plus du RAC total moyen. Cependant le fardeau financier des soins de leur lymphœdème est nettement plus faible de celui du Q1 (écart de ratios après AMC=0.067). Si on regarde de plus près le RAC moyen mensuel des transports et des DM, cette même iniquité financière des soins est reflétée. Pour les transports l’écart des ratios Q1-Q5 après AMC est de 0.026 en défaveur du Q1 et pour les DM de 0.022. De plus, le RAC par quintiles après le remboursement de l’AMO ne semble pas diminuer avec le remboursement de l’AMC. Différents facteurs peuvent déterminer des RAC élevés. Ils sont composés d’une superposition de participations financières introduites au fil du temps pour « couvrir » 25% des dépenses de santé non couvertes par le système sanitaire. De façon générale toutes les personnes sous le régime de l’AMO ont une participation forfaitaire de 1€ ou 0.50 €, selon le type de soins consommés, ou une franchise médicale pour les médicaments, séances de kiné et transports. Cette participation et franchise sur un plafond maximum de 50 euros à l’année, ne sont pas remboursées par l’AMC et concerne tous les patients sauf les enfants et les bénéficiaires de CMUC (Couverture Maladie Universelle Complémentaire). En outre nous trouvons les tickets modérateurs dont seulement les patients CMUC sont dispensés, ensuite les dépassements d’honoraires, et finalement les soins ou produits non répertoriés dans la liste de produits et prestations remboursables (LPPR) de la sécurité sociale. Dans les recommandations de la HAS en France et dans la bibliographie internationale, la place des DM dans la prise en charge du lymphœdème est très importante pendant la phase d’attaque de réduction du volume ainsi que dans la phase de maintien. Une gamme variée est proposée aux patients selon des facteurs cliniques et caractéristiques techniques des DM. Certains DM ne se trouvent pas dans la LPPR et pour ceux qui sont répertoriés, certains ont un prix limite attribué sur lequel le patient peut être remboursé à la hauteur de 60% ou 100% en cas d’un statut ALD exonérante du prix attribué. Cependant le plus souvent, le prix public d’un produit de la LPPR, qui est libre, sera choisi par le revendeur (pharmacien) et il sera «supérieur » au montant remboursé par l’assurance maladie, ajoutant ainsi le facteur de «dépassement de prix» peut reconnu par certaines mutuelles complémentaires. Par ailleurs, pour limiter les dépenses de santé, l’accès aux remboursements des produits de santé se complexifie en demandant certaines conditions comme les études médico- économiques sur l’efficience du produit pour être candidat aux remboursements. Pour le transport, nous trouvons des déplacements fréquents ou longs pour les séances spécifiques de drainage lymphatique manuel (DLM), pour les cures thermales, pour les consultations médicales, le passage à la pharmacie pour l’achat de médicaments et des DM (commande et récupération) et des déplacements pour les autres types des soins pas toujours répertoriés dans la LPPR mais conseillés par leur médecin, comme le soutien psychologique et le sport. Nos patients utilisent le plus souvent leur propre véhicule personnel pour se déplacer. Ces déplacements avec très peu d’exception ne sont pas du tout couvert par l’AMO. Au total, à ce stade de l’analyse, notre étude met en lumière une problématique importante liée au reste à charge pour les patients souffrant d’un lymphœdème primaire en France. Cette situation est d’autant plus préoccupante que (1) elle concerne des soins faisant l’objet de recommandations de bonne pratique et (2) elle est source d’iniquité financière en pesant plus sur les foyers les plus pauvres. | Humanities and social sciences 3 | |
| 2015 | Michel CASTRA | Lille | Foundation For Rare Diseases | Cystic Fibrosis and Idiopathic Pulmonary Fibrosis (I.P.F.) | Disability and discrimination in the working place and in daily life in the pre-transplant period. A comparative study between two rare pulmonary diseases: cystic fibrosis and Idiopathic Pulmonary Fibrosis (I.P.F.). | Using a multi-disciplinary approach (sociology, philosophy, law, psychology and and comparative approach between two diseases (cystic fibrosis and Idiopathic Pulmonary Fibrosis F.P.I.), the aim of this study is to investigate how patients and their families experience the disease families in the pre-transplant period, i.e. at a time when disability is most keenly felt (physically (weight loss, fatigue), psychologically (anxiety, uncertainty or stigma)), and has the greatest impact on their social participation. The comparison between the two diseases is particularly interesting. Diagnosed at birth, cystic fibrosis leads patients and their families to "build" their lives around the disease and the prospect of a long-term transplant. For patients with F.P.I., diagnosed at around 50/60 years of age, the symptoms of the disease come on suddenly for the patient and his or her family, and the prospect of a transplant may present itself rapidly (6 months) after the disease has been diagnosed. We hypothesize that the experience of the disease at this time varies according to a series of factors: the temporality of the disease (short (2 to 5 years without transplantation for F.P.I.) or longer for cystic fibrosis), the patient's social identity (being a young adult or an aging individual), family identity (being single, in a couple, a parent or grandparent) and professional identity (being at the beginning or end of one's working life), an "anticipated socialization" to the transplant or the existence of a major patient association. With this in mind, we will carry out 60 semi-structured interviews and 30 observations with patients and their close circle. half for each disease. The results of this research are intended to raise medical teams' awareness of the experience of the disease for patients and their families in the pre-transplant period, and to help them consider appropriate support measures to improve the quality of life of patients and their families. to improve disease management during this period. | Premièrement, notre enquête souligne l’ambivalence partagée par l’ensemble des patients d’être porteur d’une maladie pulmonaire rare qui peut être invisibilisée socialement selon les situations. En effet, la mucoviscidose et la FPI sont deux maladies qui peuvent être relativement dissimulées socialement, notamment durant des périodes asymptomatiques, laissant un certain choix de faire connaitre ou non son état de santé. Nous observons que cette situation permet aux patients de mettre à distance le stigmate attaché à la maladie, mais suscite néanmoins des situations vécues comme discriminatoires. La maladie pulmonaire autorise donc une certaine marge de manœuvre dans la manière de se définir socialement. Elle leur permet notamment de choisir de révéler ou de taire la maladie et le besoin de greffe. Ainsi, des patients taisent volontairement leur situation de santé afin de ne pas être étiquetés comme personnes « malades ». Toutefois, l’invisibilité relative de la maladie peut générer des incompréhensions, parfois même des situations conflictuelles, notamment en ce qui concerne l’utilisation des aides mises à la disposition des personnes en situation de handicap dans l’espace public : les caisses réservées aux personnes handicapées dans les supermarchés ou encore les places assises dans les transports en commun. Plusieurs personnes interrogées racontent avoir reçu des critiques, ou bien s’être autocensurés en ne recourant pas à certaines aides mises à leur disposition dans la crainte que des personnes ne leur fassent des reproches en public. Au quotidien, cette représentation dominante du handicap comme quelque chose qui doit se « voir », rend difficile, aux patients porteurs de la mucoviscidose et de la FPI, l’accès aux places réservées aux personnes reconnues comme handicapées dans les parkings par exemple, et ce, même quand les personnes détiennent une carte européenne de stationnement par exemple. Ainsi, nombreux sont les patients qui se censurent et ne font pas valoir leur droit de priorité d’accès aux lieux publics. Soit ils doivent « prouver » leur situation de handicap, en montrant des pièces justificatives à des personnes qui ne sont pas nécessairement supposées les contrôler, et ce, pour légitimer un certain nombre d’actions qu’ils sont autorisés de faire, comme ne pas avoir à faire la file d’attente par exemple ; soit ils doivent gérer des affrontements quotidiens parce qu’ils refusent de devoir se justifier. Ainsi, même si la maladie pulmonaire rare permet aux patients de bénéficier d’une certaine marge de manœuvre dans la manière de se définir socialement, nos résultats montrent que ces marges de manœuvres dépendent grandement de leurs conditions sociales d’existence présentes et antérieures. Nos résultats soulignent également que l’expérience de la discrimination liée à la maladie rare des personnes atteintes de mucoviscidose et de FPI en période pré-greffe est fréquemment cumulative : elle s’ajoute à d’autres traitements inégalitaires. En ce sens, la période de pré greffe est un moment de cristallisation des inégalités, et même de durcissement de celles-ci. Par ailleurs, si la maladie n’est pas toujours vécue comme un handicap de la part des patients, elle donne lieu à des tentatives quotidiennes de normalisation de leurs conduites de plus en plus difficiles à réaliser en période pré- greffe. Pour résumer, la maladie pulmonaire rare donne lieu à des actions répétées, de plus en plus difficiles à réaliser en période pré-greffe, de la part des patients afin de correspondre le plus possible aux normes sociales et déjouer toute forme de stigmatisation qui sont. Les inégalités sociales préexistantes ont tendance à se creuser en période de pré-greffe pour les personnes atteintes de maladie pulmonaire rare. Deuxièmement, nos résultats soulignent combien, au regard des deux maladies, la perception du diagnostic met en jeu un sentiment de reconnaissance sociale ou au contraire d’injustice sociale. Dans ce contexte, le caractère « idiopathique » du diagnostic fait l’effet d’une déconsidération sociale pour les patients qui vivent la FPI comme une maladie professionnelle, sans qu’elle ne droits sociaux particuliers. En effet, montrons que le diagnostic a des effets sur le sentiment de reconnaissance ou bien d’injustice sociale perçu par les patients. En effet, un diagnostic ne sert pas seulement à nommer à un état physiologique, il s’accompagne de la mise en place de tout un dispositif social. Pour une part, notre étude montre que le caractère « idiopathique » de la FPI est vécu, non seulement comme une incompréhension des raisons qui rendent malade, mais aussi comme une forme de préjudice moral et matériel. Une partie des patients vit le diagnostic de la FPI comme une injustice, puisqu’ils associent la maladie à une maladie professionnelle non reconnue comme telle. Ces patients vivent l’absence d’attribution de cause à la maladie comme une non reconnaissance des conséquences de leurs conditions de travail antérieures. Par ailleurs, si l’absence de détermination de la cause de la maladie pulmonaire rare est perçue comme une injustice de la part de patients qui ont connu des conditions de travail précaire dans le domaine du bâtiment ou du nettoyage, et de ce fait ne peuvent accéder à l’ouverture de droits sociaux, nous soulignons que cette absence de détermination de cause est perçue comme un échec de la médecine de la part des soignants. Le caractère idiopathique de la maladie désigne moins l’absence de cause à la malade que l’impossibilité du monde médical à produire un discours explicatif sur la maladie. Cette absence de reconnaissance sociale des causes de la maladie fonde une différence centrale avec la mucoviscidose qui est une maladie génétique développée dès la naissance. Néanmoins, d’autres patients atteints de mucoviscidose mettent en évidence combien le diagnostic a eu des effets sur la manière de se définir socialement. Ainsi nous avons remarqué de manière récurrente que la maladie pulmonaire rare en période de pré-greffe remet en question l’identité de genre des individus, en particulier en ce qui concerne les hommes. Le stéréotype de genre de la virilité, à partir duquel des patients hommes se sont construits socialement, et dans lequel la vulnérabilité a peu de place, les amène à vivre très difficilement la maladie, car cela remet en cause non seulement leur identité de personne dite non-malade, mais aussi celle de figure d’autorité. Nos résultats montrent également que les discriminations vécues par les patients n’ont pas lieu uniquement dans l’espace public et professionnel, mais aussi dans l’espace privé et familial. En période de pré-greffe, la famille n’est pas toujours un espace d’entraide et de soutien. En période de pré-greffe, la famille peut devenir un lieu de violence symbolique et matérielle. Troisièmement, nos résultats soulignent que le parcours médical de pré-greffe n’est pas détaché d’une certaine moralisation des conduites qui agit à bas bruit. Nous rendons compte d’oppositions récurrentes de points de vue des patients et des soignants concernant la compréhension du risque et les actions à privilégier en période de pré-greffe. Selon les situations, la relation thérapeutique peut être porteuse de certains enjeux discriminatoires. Nous montrons que du côté de la prise en charge médicale, les conditions requises pour qu’un patient soit dit « greffable » ne sont ni uniquement biologiques ni uniquement anatomiques, elles sont également sociales. L’attitude à adopter de la part des patients ne consiste pas uniquement à se rendre aux consultations, à observer les traitements prescrits et à réaliser l’ensemble des analyses médicales nécessaires au bilan pré-greffe. Il s’agit plus largement pour les patients d’admettre la greffe comme le dernier recours thérapeutique à leur disposition. En effet, au cours de la période de pré-greffe, l’équipe médicale se positionne non seulement ce qu’il est préférable de faire, à savoir être greffé ou non, mais aussi sur ce que les patients sont jugés capables de faire, comme par exemple suivre un traitement thérapeutique lourd après la greffe. Ce travail médical d’anticipation et de gestion des risques peut véhiculer une certaine idée de ce qui doit être privilégié dans le parcours de vie des patients, et donc une vision normative de la période pré-greffe. Concernant ce qui doit être privilégié en période de pré-greffe, le point de vue des patients et le point de vue des soignants ne coïncide pas nécessairement. Par exemple, ce qui peut être perçu comme un déni de la maladie par l’équipe médicale, quand un patient préfère poursuivre son activité professionnelle plutôt que d’être greffé par exemple, peut aussi être compris comme un attachement des patients à leur trajectoire sociale. Par ailleurs, pour les patients FPI, la perspective de la greffe pulmonaire intervient fréquemment au terme d’une quête longue du diagnostic. Dans leur parcours de soin, les patients ont souvent lutté pour obtenir un diagnostic, qui, pour une part, reste insondable de par le caractère « idiopathique » de la maladie. Face à cette absence de cause de la maladie, le projet de greffe apparaît d’autant plus difficile à admettre. Ainsi l’annonce de la greffe comme dernier recours thérapeutique intervient très souvent peu de temps après l’annonce de la maladie, soit dans les mois qui suivent le diagnostic. Cette annonce rapide fait maintenant partie des pratiques professionnelles recommandées aux pneumologues. Ce rapprochement entre l’annonce de la maladie et la prescription d’une transplantation rend pourtant difficile l’acceptation même de cette transplantation pulmonaire pour les patients. Dans ce contexte, les patients atteints de FPI apparaissent plus largement comme des patients à convaincre du bien-fondé de la greffe pulmonaire, en comparaison avec les patients atteints de mucoviscidose. | Humanities and social sciences 3 | |
| 2015 | Remy POTIER | Paris | Foundation For Rare Diseases | Usher, Wolfram and Stickler syndromes | Psychosocial determinants of deafblindness handicap on autonomy within the life path of people affected with Usher, Wolfram and Stickler syndromes | Multiple disabilities are now a major social concern, as evidenced by the preparation of a specific decree. The aim of this interdisciplinary research project is to provide civil society (from patients to public authorities) with the tools it needs to consider the impact on subjects' autonomy of the deaf-blindness bi-disability associated with the genetic syndromes of Usher, Wolfram and Stickler, using the category of "identity construction" to capture the variety of situations affected by this bi-disability. We'll be working on the interaction between SHS psychology, sociology and anthropology, to contribute to and broaden medical care and the life course. The results of this research will be offered to patients and associations for a participatory exchange, before being published and promoted. The aim is to harness the synergy of SHS to make a direct contribution to quality of life. | Le polyhandicap représente aujourd’hui une préoccupation sociale majeure, comme en témoigne la préparation d’un décret spécifique. En effet, depuis la rédaction de la loi 2005-102 « pour l’égalité des droits et des chances, la participation et la citoyenneté des personnes handicapées », la loi stipule qu’un décret sera promulgué, concernant les personnes polyhandicapées. Parmi celles-ci qu'en est-il de celles présentant un bi-handicap de surdicécité ? La surdicécité est une « une condition combinant une perte variable d'audition à une perte variable de la vision qui interfèrent avec la capacité de communication et d'accès à l'information d'un individu, même si ce dernier possède toujours un certain degré d'audition ou de vision fonctionnelle », (Watters, Owen et Munroe, 2005). Le bi-handicap de surdicécité n'est pas la simple résultante de l'addition de deux handicaps. En effet, la combinaison des deux handicaps accroit l'impact des problèmes relatifs à chacun d'entre eux (Ellis and Hodges, 2013). De fait, les individus atteints de surdicécité sont restreints dans leur capacité à compenser la perte d'un sens par un autre (Watters, Owen et Munroe, 2005). La surdicécité fait partie du tableau clinique de personnes atteintes de certaines maladies génétiques rares. D'après la littérature existante, les sourds-aveugles rencontrent des difficultés dans leur accès à l'information (Ellis et Hodges, 2013), dans la communication (Damen, Krabbe, Kilsby et Mylanus, 2005 ; Gullacksen, Göransson, Rönnblom, Koppen et Jorgensen., 2011 ; Ellis et Hodges, 2013), dans leur mobilité (Schneider, 2006). Ces difficultés ont un impact sur leur insertion sociale et, par conséquent, sur leurs relations interpersonnelles (Bernard, 2013). De part ces difficultés, les sourds-aveugles sont plus à risque de se retrouver dans des situations d'exclusion sociale ou d'isolement social (ou à l'inverse de surprotection), et de présenter des problèmes de santé mentale (Rivajec, 2009, Walhlqvist, Möller, Möller et Danemark, 2013) et/ou des difficultés émotionnelles. Ces difficultés ont également une incidence sur leur sentiment de contrôle de l'environnement ou des évènements de vie, et jouent un rôle dans la capacité des sourds-aveugles à s'autodéterminer et de fait, à construire une image positive d'eux-mêmes. Afin d'apporter une prise en charge médicale et psychothérapeutique adaptée à ces patients, il est primordial d'identifier les stratégies d'adaptation au handicap les plus fréquemment utilisées par ces derniers et ainsi déterminer les obstacles et les facilitateurs (déterminants psychosociaux) à leur autonomie au sein de leur parcours de vie, préalable à une bonne qualité de vie. Il s'agit, également, de comprendre dans quelle mesure le bi-handicap de surdicécité dû à une maladie génétique rare construit l'identité des sujets concernés ; plus précisément, de déterminer l'impact du bi-handicap de surdicécité sur la représentation de soi (estime de soi, confiance en soi, présentation de soi). C'est donc depuis une typologie de ces situations concrètes de perte d'autonomie due au polyhandicap lié à une maladie rare qu'il faut ressaisir la variété des parcours de vie des sourdaveugles, afin de mettre en lumière auprès de la communauté scientifique, des pouvoir publics et de la société civile la spécificité des atteintes de l'autonomie qu'engage la surdicécité. Cette recherche a démontré qu’il était nécessaire d’améliorer les conditions de l’annonce du diagnostic, notamment en apportant une information quand au vocabulaire choisi ( le choix des mots au moment de l’annonce pouvant fortement impacter le parcours de vie des personnes). Cette recherche nous a également permis de comprendre que les personnes interrogées avaient besoin d’avantage d’informations concernant leur syndrome, son évolution et les traitements possibles (et ce qui concerne le syndrome de Usher, plus d’informations concernant la différence entre les types). Les participants rencontrés ont mentionné vouloir obtenir un contre-rendu des examens mais aussi des conférences données dans le cadre hospitalier. Alors que la surdité semble faire partie intégrante de l’identité, la perte de la vue et les transformations y étant associées (passage à la langue des signes tactile, au braille ou encore à la canne blanche) suscitent de vivent résistances et est vécu de manière anxiogène. En effet, il s’avère tout d’abord que les stratégies d’adaptation des patients consistent à surinvestir le registre visuel, ceci à la fois par habitude, par besoin psychologique, en raison de l’aide apportée par les professionnels de la vision et par efficacité de ces stratégies, mais aussi en raison d’une faible connaissance du registre tactile. L’investissement de ce registre, que l’on se réfère à l’usage de la canne, de la LSF tactile, de la communication haptique ou du braille, n’est envisagé qu’en « dernier recours ». De ce fait le passage à la canne par exemple ne peut qu’être perçu que de façon anxiogène car assimilé à un diagnostic de « fin de vue ». La question de l’anticipation positive se joue alors dans tous les registres. Elle consiste à investir différents repères, lieux et activités non pas pour anticiper un ensemble de contraintes (commencer maintenant à agir comme on devra le faire plus tard) mais pour construire des repères, acquérir une expérience, se familiariser avec une diversité de ressources, sur lesquels il sera possible, ensuite, de s’appuyer. Bon nombre de patients ont également émis le besoin de pouvoir s’appuyer sur des référents qui comprennent leurs difficultés et qui sont, de fait, à même de leur apporter des informations précises sur les aides humaines, techniques et financières possibles. Ces informations sont importantes notamment dans le monde du travail, où bon nombre de participants rapportent ne pas avoir suffisamment d’adaptation (que ce soit au niveau des heures de travail, des déplacements, de l’aménagement des locaux). La pratique d’activités de loisir étant fortement associées au bien-être global. De fait, elle devrait être davantage signalée et encouragée. Il est primordial que les personnes puissent avoir accès aux informations y étant reliées, notamment par le biais d’associations spécialisées. Les personnes les plus concernées par les difficultés visuelles sont quant à elles en demande d’information sur les lieux d’activités sportives qui leur sont accessibles (maîtrise des pratiques de communication, utilisation du registre tactile). Toutes les aides pouvant être apportées sont un moyen de soulager les aidants directs (principalement les membres de la famille) pour qui l’accompagnement peut être source de stress, de culpabilité et d’épuisement sur le long terme. De fait un suivi psychologique à l’annonce du diagnostic mais aussi dans le temps apparaît nécessaire (pour accompagner les personnes mais aussi les membres de sa famille au cours des transformations personnelles et sociales engendrées par l’évolution du syndrome), tout comme la sensibilisation de l’entourage (amis, communauté sourde pour les Usher 1, famille), des médecins et des spécialistes au sujet de l’accessibilité à la communication et à l’information médicale, des ophtalmologues non spécialistes au sujet des choix des mots à utiliser et au sujet de l’évolution des difficultés visuelles dans le temps, des assistants sociaux au sujet des conséquences pratiques associées à la surdicécité. Il semble également nécessaire de fournir une formation spécifique aux aides humaines professionnelles (en mettant l’emphase sur l’importance pour les personnes de rester décisionnaires afin de maintenir un sentiment d’autonomie). Il est en outre important de sensibiliser tous les professionnels intervenant auprès de personnes en surdicécité sur l’importance de la canne (même pour les personnes ayant encore une bonne vision) afin de pallier des problèmes d’équilibre, de vision nocturne ou de champ visuel réduit et d’apporter des stratégies positive d’anticipation. Une formation sur l’anticipation positive liée à l’usage de la LSF tactile est également recommandée afin d’offrir aux personnes une pluralité de ressources communicationnelles en fonction des contextes rencontrés. Enfin, des campagnes de sensibilisation dans le milieu scolaire (principalement ordinaire) seraient, également, nécessaires afin de diminuer le risque possible d’incompréhensions des symptômes liés au syndrome de la part des enfants/adolescents et ainsi réduire la présence possible de discrimination. | Humanities and social sciences 3 | |
| 2015 | Sophie ARBORIO | Villers les Nancy | Foundation For Rare Diseases | West syndrome, severe epilepsy | West Syndrome: construction of knowledge and experiences of singularity families | The' present' research' is' based' on' a' multidisciplinary' team' comprising' two' doctors,' two' health' anthropologists' and' four' patient' associations. Through' an' anthropological' problematic,' it' intends' to' better' understand' the' modalities' of' knowledge' construction' relative' to' two' aspects' of' the' life' course' of' families':' the' identification' of' the' disease' and' the' therapeutic' management' of' patients' suffering' from' West' syndrome.' This' severe' form' of' infant' epilepsy' is' a'rare'disease'and'disability'whose'characteristics'call'into'question'the'knowledge'of'the'disease'in'its'more'conventional'forms,'particularly'in'the'context'of'the'doctor-patient'relationship' (deficit'of'diagnostic'knowledge,'discreet'and'unusual'symptomatology,'characterization' of'the'disability'situation..),'but'also'in'the'forms'of'management'that'result'(side'effects'of'medication,'therapeutic'regimen,'lack'of'adapted'structures).' Here,' West'syndrome'is'approached'both'as'a'specific'form'of'epilepsy'and'as'a'disease'emblematic' of'cross-cutting'issues'common'to'various'severe'epilepsies'(notably'tuberous'Bourneville's'sclerosis).''' The' aim' of' the' research' is' to' characterize' and' discern' the' place' of' families' experiential' knowledge' in'identifying'the'disease'and'treatment.'The'knowledge'analyzed'is'derived'from'the'point'of'view'of'families'-'and'patients'where'possible'-'and'will'ultimately'enable'this'lived'experience'to'be'better'taken'into'account'within'the'framework'of'therapeutic'patient'education'(TPE).' The' ethnographic' methodology' is' based' on' interviews' with' families' (60),' observations' (hospitalizations,' day' hospital' and' complementary' examinations' (EEG' and' MRI)' and' TPE' sessions)'and'analysis'of'Facebook'corpus'(pages'"'STB'"'and'"'Children'of'West'"). | - | Humanities and social sciences 3 | |
| 2015 | Sophie QUINTON | Lille | Foundation For Rare Diseases | Systemic sclerosis | Scleroderma and occupational difficulties: identify to better help | BACKGROUND: systemic scleroderma is a rare disease of the immune system responsible for multiple disabilities that differ from one patient to the next. Few studies have looked at the impact of this disease on patients' working lives, so we don't know exactly what difficulties are encountered, nor what solutions or resources are implemented to alleviate them. OBJECTIVES: The primary objective of the study is to estimate the frequency of occupational difficulties in patients with Scl. The secondary objectives are to identify these difficulties, their knowledge of and access to common entitlements and the disabilities involved. METHODS: A questionnaire designed in partnership with scleroderma specialists, a humanities and social sciences researcher and a patient association will be offered to patients with systemic scleroderma as part of their disease follow-up at the Lille University Hospital over a 12-month period, with the aim of obtaining a minimum of 100 responses (from a cohort of around 500 patients). RESULTS: The expected results are a better understanding of the difficulties of reconciling work and disability linked to the disease, of the difficulties of maintaining employment, of functional difficulties and of the extent of the lack of awareness of certain measures to help maintain employment. An interventional phase resulting from this study will aim to set up 1) an early intervention scheme targeting the risk factors of professional disengagement for patients suffering from Scl or another connective tissue disease having a disability in common with Scl, 2) draw up an information document for patients and their carers on the legal provisions and practical professional aids to encourage job retention, and 3) organize meetings and debates to raise awareness of these pathologies among companies. The aim is to promote job retention in line with patients' different disabilities. | Le questionnaire a été proposé à 116 patients du 4/03/2014 au 2/03/2016. 3 patients ont refusé le questionnaire et 2 patients ont été exclus en raison de difficultés de compréhension. Sur les 111 questionnaires restants, 6 ont été exclus a posteriori lors de la revue des dossiers en raison d’un diagnostic incertain. Au total, 104 questionnaires ont été exploités. L’âge moyen des patients inclus était de 54 ±12 ans (± écart type). La cohorte étudiée était composée à 84% (n=87) de femmes. L’âge moyen au premier symptôme (syndrome de Raynaud inclus) était de 39ans ±14 ans et l’âge au diagnostic de 46 ans±13 ans. Parmi les patients inclus, 17% (n=17) présentaient une ScS de type cutanée diffuse, 82% (n=85) présentaient une ScS de type cutanée limitée ou limitée et la donnée était manquante pour 2 patients. Au sein de cette cohorte, 62,5% (65/104) [intervalle de confiance (IC) à 95% : 52,5-71,8] des patients ont déclaré avoir rencontré des difficultés professionnelles en rapport avec la maladie et ses symptômes. Les principaux symptômes responsables de difficultés professionnelles sont le syndrome de Raynaud (55% des patients), les arthromyalgies (56% des arthromyalgiques) et les ulcérations digitales (44% des patients en souffrant). L’asthénie ressentie par les patients est également fortement impliquée dans les difficultés professionnelles des patients sclérodermiques car 63%(41/65) des patients ayant des difficultés professionnelles rapportent que leur asthénie participe à leurs difficultés professionnelles et 17%(11/65) considère que c’est le symptôme principalement responsable de leurs difficultés. Parmi les patients pour lesquels on dispose du type de ScS (n=102), il n’existe pas de différence significative pour les fréquences de ScS cutanées diffuses entre les patients ayant rencontré des difficultés professionnelles (19%, 12/65) et ceux n’ayant pas rencontré de difficulté professionnelle (13%, 5/39) (p=0,464). De la même façon, il n’y a pas de différence significative entre le score moyen de Rodnan chez les patients ayant rencontré des difficultés professionnelles versus chez les patients n’ayant pas rencontré de difficultés professionnelles (p=0,930). Enfin, la comparaison de ces deux groupes en fonction du score de dyspnée NYHA, catégorisé en score=1 versus score >1, ne retrouve pas de différence significative. On retrouve en effet 69%(44/65) des patients ayant rencontré des difficultés professionnelles avec un score NYHA supérieur à 1 versus 54%(21/39) des patients sans difficulté professionnelle avec un score NYHA supérieur à 1 (p=0,158). Il n’y avait pas de différence significative pour l’âge moyen au moment du premier symptôme entre le groupe ayant rencontré des difficultés professionnelles (39 ±14 ans) et le groupe n’ayant pas rencontré de difficulté professionnelle (39ans ±15) (p=0,935). Bien que cette différence ne soit pas significative (p=0,07), on retrouve une tendance à un âge plus jeune au diagnostic chez les patients ayant rencontré des difficultés professionnelles (44±12ans) par rapport aux patients n’ayant pas rencontré de difficultés professionnelles (49 ±14 ans). Les difficultés professionnelles rapportées par les patients sont l’aggravation des symptômes par le travail pour 55% des patients, la diminution de l’efficacité au travail pour 41% des patients, la perte d’emploi pour 19% des patients, le manque de soutien au travail pour 14% des salariés, et la difficulté à articuler soins et travail pour 12% des patients. Face à ces difficultés professionnelles seuls 45% (29/65) des patients ont informé le médecin du travail de leur pathologie et des difficultés associées. Parmi les 36 patients n’ayant pas informé le médecin du travail, dans 44% (16/36) des cas, une méconnaissance de son rôle et de son implication dans le maintien en emploi était en cause. Le recours au médecin du travail n’était pas significativement associé à un type de difficulté professionnelle en particulier. Plusieurs types de démarches ont pu être mises en œuvre par les patients afin de faire face à leurs difficultés professionnelles. Ainsi 40% (26/65) des patients ayant des difficultés professionnelles ont mis en œuvre des démarches avec la Maison Départementale des Personnes handicapées. Ils étaient également 60% (39/65) à mettre en œuvre des actions avec les médecins traitants ou spécialiste. Seuls 35% (23/65) des patients atteints de difficultés professionnelles mettaient en œuvre des démarches actives avec le médecin du travail. Les démarches auprès de la caisse d’assurance maladie concernaient 42% (27/65) des patients. Dans 19% (12/65) des cas, les patients initiaient spontanément et directement une demande auprès de la hiérarchie à type de demande de changement de poste ou de diminution du temps de travail. 14% (9/65) des patients mettaient en œuvre une solution personnelle ou informelle avec l’aide de collègues. On retrouve globalement un faible taux de patients ayant effectivement bénéficié des dispositifs d’aide au maintien dans l’emploi avec seulement 23% (24/65) des patients qui bénéficient d’une Reconnaissance en Qualité de Travailleur Handicapé (RQTH). La proportion de patients ayant bénéficié de ce dispositif est significativement plus élevée dans le groupe ayant rencontré des difficultés professionnelles que dans le groupe n’ayant pas rencontré de difficultés professionnelles (p=0,0008). Malgré les démarches effectuées et l’éventuelle aide octroyée, 57% (37/65) des patients présentant des difficultés professionnelles déclaraient ne pas avoir trouvé de solution à leurs problèmes. La moitié de ces patients jugeaient la situation supportable (51% soit 19/37), 41% d’entre eux ont quitté ou perdu leur emploi pour échapper aux difficultés (15/37) et 19% d’entre eux ont connu des difficultés morales qu’ils rapportent directement aux difficultés professionnelles (7/37). On retrouve une diminution de revenu chez 31% (32/104) des patients de la cohorte depuis l’apparition de la maladie. Au sein du groupe sans difficulté professionnelle ils ne sont que 8% (3/39) à avoir eu une baisse de revenu depuis l’apparition de la maladie alors que dans le groupe avec difficultés professionnelles, 45% (29/65) des patients ont connu une baisse de revenu depuis l’apparition de la maladie. Cette différence est significative (p<0,0001). Les raisons de l’absence de solution étaient exploitables chez 36 des 37 questionnaires des patients concernés. L’absence de solution était liée dans 31% (11/36) des cas à une méconnaissance des démarches à réaliser, dans 11% (4/36) des cas à une peur ou un découragement face aux démarches, dans 19% (7/36) des cas à une absence de besoin ressenti par les patients, dans 8% (3/36) des cas au moins une structure sollicitée n’a pas apporté de soutien et dans 36% (13/36) des cas, les solutions apportées ont été insuffisantes pour faire face aux difficultés professionnelles. Lors de la revue des dossiers par le groupe de santé au travail, la cohérence entre les symptômes allégués et le retentissement professionnel rapporté par les patients paraissait logique dans 65% (42/65) des cas (impact « prévisible »). Dans les autres cas (n=23), les praticiens en santé au travail n’auraient pas imaginé spontanément que l’expression clinique de la maladie puisse être à l’origine de difficultés professionnelles (impact « non prévisible »). Pour autant, parmi ces 23 patients, certaines situations avaient tout de même conduit à des pertes d’emploi liées à la maladie. Notre étude a donc mis en évidence que 62,5% des patients interrogés rapportaient des difficultés professionnelles en rapport avec la ScS. Malgré ce taux important, les systèmes d’aide au maintien en emploi ont été peu utilisés puisque moins d’un quart des patients (23%) bénéficiaient d’une Reconnaissance en Qualité de Travailleur Handicapé qui est pourtant un dispositif fondamental dans le maintien dans l’emploi en France. Il s’agit en effet de la pierre angulaire d’accès aux différents dispositifs d’aide au maintien en emploi. Dans cette étude, les principaux symptômes impactant le travail étaient le syndrome de Raynaud, l’asthénie, les arthromyalgies ainsi que les ulcérations digitales. Ainsi, bien que ces symptômes ne correspondent pas aux complications les plus sévères de la ScS (comme le serait l’HTAP ou la fibrose pulmonaire), ils concourent de façon importante à l’altération de la qualité de vie via l’atteinte de la sphère professionnelle. Ce résultat accentue l’importance de la prise en charge de ces quatre symptômes pour lesquels les thérapeutiques sont souvent limitées. Il s’agit donc d’un axe d’améliorations thérapeutiques à poursuivre. De façon surprenante, nous n’avons pas retrouvé de différence significative du score de Rodnan entre le groupe de patients avec difficultés professionnelles et le groupe de patients sans difficulté professionnelle alors que le score retenu était le plus défavorable au cours de l’histoire de la maladie des patients. On peut également souligner que 10% des patients ayant des télangiectasies évoquent des difficultés professionnelles en rapport avec ce symptôme cutané ce qui est important compte tenu du faible impact fonctionnel de ce symptôme. La revue de littérature de Berezné et al en 2013 retrouvent qu’entre un tiers et la moitié des patients atteints de ScS adaptent leur parcours professionnel en raison de la maladie. Notre étude met en évidence plus de difficultés professionnelles (62,5%) ce qui reste cohérent car certains patients ne ressentent pas le besoin de faire des démarches d’adaptation professionnelle malgré leurs difficultés (n=7). Parmi les difficultés les plus importantes, la perte d’emploi concernait 19% (20/104) des patients interrogés. Ce résultat est dans la fourchette basse de ce qui est rapporté dans la littérature par Berezné et al. en 2013 qui retrouve entre 18,2% et 81,2% d’incapacité de travail chez les patients atteints de ScS. L’impact professionnel de la ScS semble plus important comparé à d’autres pathologies chroniques entraînant des symptômes comparables comme la polyarthrite rhumatoïde (PR) selon l’étude comparative de Ouimet et al sur 165 patients. Il retrouve en effet 55,7% de désinsertion du travail au sein des 61 patients atteints de ScS interrogés contre 34,6% au sein des 104 patients atteints de PR. Cependant, contrairement à cette étude, notre travail a retrouvé 19% de perte d’emploi lié à la maladie au sein de la population interrogée ce qui est proche des 19,1% d’incapacité de travailler chez des patients atteints de PR retrouvée par Bertin et al en 2015 dans une étude sur l’impact professionnel de a PR chez 488 patients français. La perte d’emploi n’est pas la seule conséquence professionnelle à redouter. En effet, notre étude retrouve une forte fréquence de symptômes aggravés par le travail, en particulier l’exposition au froid, les efforts physiques et les microtraumatismes des doigts. La diminution d’efficacité au travail est aussi souvent rapportée par les patients (41% des patients de notre cohorte). Face aux difficultés professionnelles, certains patients réduisent leur temps de travail. Nous n’avons malheureusement pas recueilli le travail à temps partiel (même si on peut l’appréhender à travers la réduction des revenus) mais dans d’autres pathologies chroniques comme la sclérose en plaque (SEP) ou la PR, on retrouve de 25 à 40% de patients qui réduisent leur temps de travail en particulier en raison d’une fatigabilité plus importante. Les symptômes les plus rapportés comme étant responsables des difficultés professionnelles sont le syndrome de Raynaud, les arthromyalgies, la fatigue et les ulcérations digitales. Ces données sont cohérentes avec les études disponibles dans d’autres pathologies chroniques. Par exemple, dans la SEP, le travail est principalement impacté par la fatigue et les troubles sensitivo- moteurs et ce dès le début de la maladie. De la même façon, les patients atteints de PR voient leur travail impacté par l’intensité de leurs arthralgies de façon significative. Dans ce contexte de fréquentes difficultés professionnelles, on s’attendrait à davantage de recours au médecin du travail et à la mise en œuvre plus fréquente des dispositifs d’aide au maintien dans l’emploi. Pourtant, seuls 45% des patients en difficulté informaient leur médecin du travail de leur maladie et des difficultés professionnelles associées. La raison principale de l’absence d’information du médecin du travail (45%) était la méconnaissance de son rôle avec notamment une peur de perdre son emploi. Ce résultat conforte l’étude de Barotto en 2015 qui retrouvait que 68,5% des salariés ne connaissaient pas les rôles des services de santé au travail. Cela reste donc un axe d’information et d’éducation thérapeutique majeur à explorer afin de maximiser les chances des patients de rester en emploi. Dans le même ordre d’idées, les patients de notre étude avaient peu mis en jeu et donc peu obtenu les dispositifs d’aide au maintien dans l’emploi. Ils sont en effet seulement 23% à avoir bénéficié du statut de travailleur handicapé. Ce statut est logiquement plus fréquent en cas de difficulté professionnelle (34%, p=0,0008) mais reste très insuffisant. Ce statut est en effet central dans les aides au maintien en emploi. Il rend accessible des aides humaines, financières et matérielles pour aider aux adaptations professionnelles. Il octroie au salarié un statut protégé avec une durée de préavis allongée en cas de licenciement. Peu de patients interrogés bénéficient de la reconnaissance en qualité de travailleur handicapé (RQTH) mais cette constatation est également faite dans d’autres pathologies. Pour la PR, Bertin et al retrouvaient ainsi 34,6% de patients en emploi ayant une RQTH et dans 37,7% des cas, ils avaient pu bénéficier d’adaptation de poste. La RQTH est la pierre angulaire du maintien en emploi et elle doit être anticipée par rapport aux difficultés professionnelles car son obtention peut prendre plusieurs mois. Elle fait partie des axes importants de maintien en emploi, notamment chez les patients algiques comme le sont souvent les patients sclérodermiques en raison des arthromyalgies. Les outils de maintien en emploi sont d’autant plus fondamentaux et sous-utilisés que près de 19% des patients n’ayant pas trouvé de solutions à leurs difficultés professionnelles déclarent avoir souffert de difficultés morales secondaires aux problèmes professionnels en rapport avec la maladie et ils sont 41% à avoir perdu ou quitté leur emploi pour échapper aux difficultés quand aucune solution n’a été trouvée. Or, la littérature rapporte que les personnes sans emploi sont globalement en moins bonne santé physique et morale que celles qui en ont un. Il semble donc urgent d’accompagner les patients vers une plus grande utilisation des aides au maintien en emploi. On relève également que 25% des patients interrogés sont mis en invalidité par l’Assurance maladie et qu’en cas de difficulté professionnelle, 35% sont reconnus invalide (p=0,0016). Cette situation s’accompagne le plus souvent d’un arrêt de l’activité professionnelle alors qu’il est théoriquement possible de poursuivre une activité professionnelle partielle avec une invalidité. Il est cependant souvent nécessaire d’adapter le poste de travail à l’état de santé du patient et les dispositifs d’aide au maintien en emploi sont alors une aide précieuse. Au vu de tous ces éléments professionnels défavorables, il n’est pas surprenant de retrouver une baisse de revenu plus fréquente chez les patients ayant connu des difficultés professionnelles en rapport avec la maladie. Ils sont en effet 45% à voir leurs revenus affectés défavorablement depuis l’apparition de la maladie et cet impact financier se répercute sur de nombreuses sphères de vie. La perte financière semble être un des éléments responsable de l’altération de santé des personnes sans emploi et n’est pas négligeable. Cet élément peut également être un argument à évoquer avec les patients parfois réticents à la RQTH du fait de représentations négatives de ce statut. Enfin notre étude a également mis en évidence que dans près d’un tiers des cas, les difficultés professionnelles n’était pas spontanément envisagées par les praticiens de santé au travail, même en connaissant les symptômes et en les confrontant aux exigences du poste de travail. Ces difficultés pourtant bien réelles entraînent un handicap pour les patients. Ce constat rappelle à quel point le colloque singulier entre le médecin du travail et le salarié est important dans l’accompagnement au maintien en emploi. Il souligne également l’importance de la formation des médecins du travail à l’impact des maladies rares dont la ScS. Tous ces éléments ont permis de faire émerger un besoin d’information des patients et des soignants sur les dispositifs de maintien en emploi et également un intérêt d’informer les médecins du travail sur cette pathologie très particulière. Des actions à type d’échanges et d’information des soignants, professionnels de la santé au travail, patients et entreprises seront mises en place au sein du CHRU de Lille dans ce sens dans les mois à venir en relation avec l’association des sclérodermiques de France. Afin de recueillir des données de qualité, le projet et le questionnaire ont été construits en pluridisciplinarité avec le concours de spécialistes en médecine interne, en santé au travail, en méthodologie et biostatistiques. De plus, la passation sous forme d’hétéroquestionnaire permettait de limiter les questionnaires incomplets et de s’assurer de la compréhension des questions par les patients. Si la qualité de vie et notamment le travail sont des préoccupations de plus en plus présentes dans les prises en charge globales des patients atteints de pathologies chroniques, peu de données sont disponibles sur la ScS dans la littérature. Nous avons choisi d’évaluer les symptômes y compris avant le diagnostic en raison du délai diagnostic parfois long selon la symptomatologie des patients et leur parcours médical. Les résultats obtenus restent à interpréter avec prudence. L’étude était en effet monocentrique et d’effectif modéré (104 patients). Elle n’en est pas moins éclairante sur l’étendue de la méconnaissance des conséquences professionnelles de la ScS sur la vie des patients. On regrette de ne pas disposer de groupe témoin présentant le même type de symptômes pour comparer leur impact sur le travail. Cependant la ScS est une pathologie singulière au polymorphisme important et il semblait complexe de comparer la ScS à d’autres pathologies ne présentant que certains symptômes de la ScS (lupus, polyarthrite rhumatoïde, etc). En outre, le questionnaire n’était pas basé sur des échelles validées (en dehors de certaines évaluations médicales issues de l’observatoire national des patients atteints de sclérodermie). Il n’existait en effet aucun score adapté à une première analyse exploratoire de cette question. Des scores existent pour le suivi longitudinal (score Work Productivity and Activity Impairment par exemple) de l’impact professionnel d’une pathologie mais la durée de l’étude ne permettait pas de mettre en œuvre un tel suivi. De la même façon, le recueil de données rétrospectives induit un potentiel biais de mémorisation. Ce biais est cependant relativement modéré puisqu’on peut s’attendre à ce que les difficultés professionnelles oubliées par les patients soient peu importantes. Enfin, on peut déplorer de ne pouvoir situer les difficultés professionnelles en fonction de l’évolution de la maladie ou de ne pouvoir mieux situer ces difficultés tout au long du parcours professionnel mais le faible nombre de patients ainsi que les biais de mémorisation pour dater ces difficultés de façon rétrospective nous ont incité à ne pas recueillir ces données. En conclusion, notre étude a mis en évidence que près de 2/3 des patients sclérodermiques ont rencontré des difficultés professionnelles rapportées à la maladie. Les symptômes responsables de ces difficultés sont principalement le syndrome de Raynaud (1 patient sur 2), l’asthénie (2 patients sur 3), les arthromyalgies (1 patient sur 2) et les ulcérations digitales. Il est donc important de poursuivre des efforts pour améliorer la prise en charge de ces symptômes. Il semble également important d’améliorer l’information des patients et des soignants sur les dispositifs d’aide au maintien dans l’emploi puisque 1/3 des patients ne fait pas de démarche par méconnaissance des aides et 1 patients sur 2 qui n’informe pas son médecin du travail le fait par méconnaissance de son rôle dans le maintien en emploi. Enfin l’impact social de la maladie est important puisque 1/3 des patients connaissent une baisse de revenu depuis l’apparition de la maladie. | Humanities and social sciences 3 | |
| 2014 | Delphine MEYNARD | Toulouse | Foundation For Rare Diseases | Non-transfusion-dependent thalassemia | Matriptase-2: identification of pharmacological inhibitors to decrease iron overload in non-transfusion-dependent thalassemia | Thalassemias are hereditary diseases of hemoglobin, the substance in red blood cells that carries oxygen throughout the body. To survive, patients must receive red blood cells by transfusion. Among thalassemias, a small group of patients can survive without transfusion. However, because of the reduced number of red blood cells, these patients have a major iron overload in the liver. This iron overload is dangerous, as it leads to fibrosis, cirrhosis and liver cancer. As current treatments are not optimal (side effects, cost), we propose to develop a new therapy for these patients based on matriptase-2. Matriptase-2 is a protein which, when inhibited, blocks the entry of iron into the body. In this project, we will screen for small molecules inhibiting matriptase-2 which, when administered to patients, could correct their iron overload and prevent associated pathologies. What's more, this treatment can be administered to patients in pill form, and will be inexpensive. | - | High-throughput screening 2013 | |
| 2014 | Fabrice LEJEUNE | Lille | Foundation For Rare Diseases | Duchenne Muscular Dystrophy | Correction of nonsense mutations in genetic diseases | 10% of patients suffering from a genetic disease are carriers of a STOP mutation responsible for the pathology. STOP mutations lead to the premature cessation of protein synthesis from the mutant gene. We are looking for chemical molecules that can induce the cellular machinery to ignore the presence of the mutation and thus lead to complete protein synthesis. To identify these molecules, we have built a biological system capable of testing thousands of molecules in order to select those with the property of correcting STOP mutations. The project presented here proposes to use a platform equipped with devices capable of testing tens of thousands of molecules in a matter of days, in order to accelerate the discovery of new molecules and increase the chances of identifying future drugs for patients suffering from a genetic disease. | High-throughput screening 2013 | ||
| 2014 | Fabrice LEJEUNE | Paris | Foundation For Rare Diseases | All nonsense mutation-related diseases | CORRECTION OF NONSENSE MUTATIONS IN GENETIC DISEASES | 10% of patients suffering from a genetic disease are carriers of a STOP mutation responsible for the pathology. STOP mutations lead to the premature cessation of protein synthesis from the mutant gene. We are looking for chemical molecules that can induce the cellular machinery to ignore the presence of the mutation and thus lead to complete protein synthesis. To identify these molecules, we have built a biological system capable of testing thousands of molecules in order to select those with the property of correcting STOP mutations. The project presented here proposes to use a platform equipped with devices capable of testing tens of thousands of molecules in a matter of days, in order to accelerate the discovery of new molecules and increase the chances of identifying future drugs for patients suffering from a genetic disease. | High-throughput screening 2013 | ||
| 2014 | Hanna DEBIEC | Paris | Foundation For Rare Diseases | Membranous nephropathy | Searching for C5b-9 antagonists by high-throughput screening of chemical libraries: Toward new treatment of membranous nephropathy | The aim of our project is to identify new drugs active in extramembranous glomerulopathies, which are kidney diseases caused by antibodies most often directed against the cells of the kidney filters known as glomeruli. When these filters are altered, the result is a massive leakage of albumin into the urine, leading to edema (swelling of the legs) and eventually renal failure. Today, we have immunosuppressive treatments that inhibit antibody production, but their effects are delayed. These antibodies are responsible for activating complement, which attacks cell membranes and induces urinary leakage of albumin. We will use a robotic system to identify new molecules that inhibit complement activation in cell cultures from libraries of potential drugs. In this way, we hope to develop rapidly effective drugs that can be used in other autoimmune diseases such as lupus. | High-throughput screening 2013 | ||
| 2014 | Irene CEBALLOS-PICOT | Paris | Foundation For Rare Diseases | Lesch-Nyhan Disease | Identify molecules able to induce HPRT-like activity in HPRT-deficient fibroblasts and dopaminergic neuronal cells as models for Lesch-Nyhan Disease | Lesch-Nyhan disease (LND) is a rare neurometabolic disorder caused by a deficiency of an enzyme in the purine recycling pathway, hypoxanthine-guanine phosphoribosyltransferase (HPRT). This very severe clinical syndrome combines hyperuricemia, severe dystonia (uncontrollable muscle contractions leading to abnormal, incoordinated movements) and behavioral disorders leading to very severe, compulsive self-mutilation. The HPRT enzyme deficiency is caused by mutations in the HPRT gene, but the pathophysiological mechanisms leading to neurobehavioral disorders remain unclear. In addition to the classic LND form, there is a less severe form of the disease, known as Lesch_Nyhan Variants (LNV). These LNV patients present with hyperuricemia and variable neuromuscular abnormalities, but NO self-mutilation. Mutations in the HPRT gene in LNVs reduce enzymatic activity, and residual HPRT activity (10%) is generally sufficient to prevent major neuromuscular problems. Our aim is therefore to try to restore residual HPRT activity, thereby reducing major neuromuscular and neurobehavioral disorders in LND patients, by screening molecules on a large scale in patients' epidermal cells (fibroblasts). A chemical library (Prestwick) containing 1,200 molecules will be screened using a simple viability test (yes/no). Selected molecules will then be validated for their ability to restore HPRT-like activity on fibroblasts from LND patients. The use of a chemical library made up of molecules already approved for medical use (French marketing authorization) will enable rapid testing of candidate molecules in patients. | High-throughput screening 2013 | ||
| 2014 | Olfa KHALFALLAH | Nice | Foundation For Rare Diseases | Fragile X syndrome | Search for active molecules on a cell model for Fragile X Syndrome by high throughput screening | Fragile X syndrome (FXS) is the most common form of hereditary mental retardation (1/5500), and results from mutation of the FMR1 (Fragile X Mental Retardation 1) gene, and consequent absence of the FMRP protein. In the absence of this protein, communication between neurons is defective. At present, there is still no treatment for FXS. This is because the FMRP protein is important not only for communication between neurons, but also for the formation of these neurons themselves. This latter aspect has been little studied, and constitutes my research project. I have developed a cellular model mimicking the pathology, which has enabled us to better understand how the absence of FMRP alters neuron formation, and that it is possible to pharmacologically correct these alterations. Thus, our model has a twofold interest: - to determine when the absence of FMRP triggers the disease, so as to identify new therapeutic windows - to test pharmacological molecules already available on the market in order to find new, better-adapted therapies and improve the quality of life of FXS children. | High-throughput screening 2013 | ||
| 2014 | Thomas FALGUIÈRES | Paris | Foundation For Rare Diseases | Rare hepatobiliary diseases | Identification of targeting correctors of ABCB4/MDR3 defective mutants by a high throughput screening approach | Bile secretion is an essential function of the liver, playing a detoxifying role and helping to digest dietary fats. One of the compounds in bile, phosphatidylcholine, is secreted through the action of a protein called ABCB4, located on the surface of hepatocytes, the cells of the liver. However, adult and pediatric patients suffering from rare biliary pathologies have mutations in ABCB4, preventing it from reaching the cell surface correctly. Current treatments are not very effective in treating the most severe forms of these diseases, including PFIC3 (progressive familial intrahepatic cholestasis type 3), which affects very young children, with liver transplantation remaining the only alternative for more than half of them. We propose to identify new compounds capable of effectively treating these patients. To achieve this, a high-throughput screening approach will be used: using a robotized system, several thousand compounds will be tested for their ability to restore ABCB4 addressing in a cellular model mimicking the pathological situation. | High-throughput screening 2013 | ||
| 2014 | Damien SANLAVILLE | Lyon | Foundation For Rare Diseases | Intellectual disability / congenital malformations | Study of 9 complex chromosomal rearrangements by massively parallel sequencing: an unifying mechanism? | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Florent SOUBRIER | Paris | Foundation For Rare Diseases | IgA nephropathy (Berger's disease) | Exome sequencing in two large pedigrees with multiple cases of IgA nephropathy | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Giovanni STEVANIN | Paris | Foundation For Rare Diseases | Hereditary spastic paraplegia | Whole genome sequencing in 5 families with hereditary spastic paraplegia | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Jean-Louis MANDEL | Illkirch | Foundation For Rare Diseases | Intellectual disability/autism | Exome sequencing of patients with intellectual disability and no mutation identified in known genes | - | - | High throughput sequencing 2014 - 1 | |
| 2014 | Karine POIRIER | Paris | Foundation For Rare Diseases | Microlissencephaly | Identification of new genes involved in microlissencephaly | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Marion GERARD | Caen | Foundation For Rare Diseases | Sirenomelia / mermaid syndrome | Whole-exome sequencing to identify genetic alterations associated with Sirenomelia (ADEP project) | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Nadia BAHI-BUISSON | Paris | Foundation For Rare Diseases | Aicardi syndrome | Identification of the genetic bases of Aicardi syndrome | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Pascale GUICHENEY | Paris | Foundation For Rare Diseases | Idiopathic ventricular fibrillation with short-coupled variant of torsade de pointes | Identification of a new gene causing idiopathic ventricular fibrillation with short-coupled variant of torsade de pointes | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Patrick CALLIER | Dijon | Foundation For Rare Diseases | Frontonasal dysplasia | Genetic basis of frontonasal dysplasia | - | - | High throughput sequencing 2014 - 1 | |
| 2014 | Patrick REVY | Paris | Foundation For Rare Diseases | Severe bone marrow failure, dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome | Identification of new genes involved in severe bone marrow failure associated with telomere and/or dna repair defects | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Sandrine VUILLAUMIER | Paris | Foundation For Rare Diseases | Glut1 deficiency | Identification of a gene underlying dominant epilepsy in a slc2a1/glut1 negative family (trio analysis) | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Sophie NICOLE | Paris | Foundation For Rare Diseases | Periodic paralysis | Search for a new gene responsible for periodic paralysis by whole exome analysis of one family and sporadic cases | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Valerie CORMIER-DAIRE | Paris | Foundation For Rare Diseases | Ellis-Van Creveld syndrome | Identification of the molecular basis of the Ellis-Van Creveld (EVC) syndrome | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Valerie DELAGUE | Marseille | Foundation For Rare Diseases | Charcot-Marie-Tooth disease | Identification of novel genes in Charcot-Marie-Tooth disease in lebanese consanguineous families, through homozygous by descent analysis of whole genome sequence data | - | High throughput sequencing 2014 - 1 | ||
| 2014 | Veronique PAQUIS-FLUCKINGER | Nice | Foundation For Rare Diseases | Mitochondrial diseases | Early-onset neuromuscular presentations of mitochondrial disorders: identification of new genes by exome sequencing | - | - | High throughput sequencing 2014 - 1 | |
| 2014 | Aude MAGERUS-CHATINET | Paris | Foundation For Rare Diseases | Autoimmune lymphoproliferative syndrome (ALPS) | Search for modifier genes in ALPS-Fas | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Carine LE GOFF | Paris | Foundation For Rare Diseases | Floating Harbor syndrome | Identification of a new gene involved in Floating Harbor syndrome | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Christel DEPIENNE | Paris | Foundation For Rare Diseases | autism-epilepsy | Identification of novel genes responsible for autism-epilepsy phenotypes | - | - | High throughput sequencing 2014 - 2 | |
| 2014 | Eric BIETH | Toulouse | Foundation For Rare Diseases | Congenital bilateral absence of the vas deferens (CBAVD) | Search for new genetic determinants of male infertility due to congenital bilateral absence of the vas deferens | - | - | High throughput sequencing 2014 - 2 | |
| 2014 | Francis COUTURAUD | Brest | Foundation For Rare Diseases | Idiopathic venous thromboembolism | identification of new inherited thrombophilia in selected families | - | - | High throughput sequencing 2014 - 2 | |
| 2014 | Gaël MANES | Montpellier | Foundation For Rare Diseases | Autosomal dominant retinitis pigmentosa | Identification of novel genes in autosomal dominant Retinitis Pigmentosa in 21 fully screened families for known genes | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Gaëlle HARDY | Grenoble | Foundation For Rare Diseases | Hereditary bradykinin-mediated angioedema | News genes involved in bradykinin-mediated angioedema with reduced C1-inhibitor function and no mutation in SERPING1 or F12 genes | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Irene NETCHINE | Paris | Foundation For Rare Diseases | Russell-Silver Syndrome | Identifying new genes responsible for autosomal inheritance of Russell-Silver syndrome | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Jamal GHOUMID | Lille | Foundation For Rare Diseases | Blepharo-cheilo-dontic (BCD) syndrome | Molecular characterization of blepharocheilodontic (BCD) syndrome through exome sequencing in 5 families | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Michel POLAK | Paris | Foundation For Rare Diseases | Congenital hypothyroidism | Identification of new genes involved in brain-lung-thyroid syndrome | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Nadia BAHI-BUISSON | Paris | Foundation For Rare Diseases | Cortical Malformations and 22q11.2 deletion syndrome | Delineation of the molecular basis of cortical malformation in 22q11.2 deletion syndrome | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Reiner VEITIA | Paris | Foundation For Rare Diseases | Primary Ovarian Insufficiency | Genetics and Genomics of primary ovarian insufficiency: an entry point to understand ovarian function | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Rolando MELONI | Paris | Foundation For Rare Diseases | familial form of bipolar disorder | Research of a major gene for familial form of bipolar disorder in an extended pedigree with an ascertained founder effect. | - | High throughput sequencing 2014 - 2 | ||
| 2014 | Sebastien MOUTTON | Bordeaux | Foundation For Rare Diseases | OEIS (omphalocele - exstrophy of bladder - imerforate anus - spinal defects) complex | Identification of the molecular bases of OEIS complex in a multiplex family | - | - | High throughput sequencing 2014 - 2 | |
| 2014 | Marie-Anne COLLE | Nantes | Foundation For Rare Diseases | Pompe Disease (glycogenosis of type II) | Gene therapy for pediatric forms of Pompe disease using AAV gene transfer to the CNS: preclinical feasibility in nonhuman primate | Pompe disease is a progressive genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase, which breaks down glycogen in cells. Glycogen accumulates in the muscles and heart, leading to locomotor, respiratory and cardiac disorders, which in the most severe form are fatal within the first year of life. Current treatment by intravenous delivery of the missing enzyme has corrected the heart and increased patients' life expectancy, but has revealed damage to the central nervous system. Thanks to our gene therapy treatment, which uses a viral vector to deliver the enzyme into the cerebrospinal fluid, we have been able to treat the nervous system of mice suffering from the disease. Before we can consider applying this treatment to humans, we need to evaluate its efficacy and safety in an animal with a brain size and organization more similar to our own: the non-human primate. | Translational Research 2014 | ||
| 2014 | Philippe MOULLIER | Nantes | Foundation For Rare Diseases | Duchenne muscular dystrophy | Systemic injection in the GRMD dog of a recombinant AAV vector encoding for the µdystrophin: efficiency and global safety | The aim of this project is to evaluate a "whole body" gene therapy treatment in dogs with spontaneous Duchenne muscular dystrophy. Not only are we aiming to target the heart and diaphragm, but also the skeletal muscles, in order to deliver a truly global therapeutic benefit. In this respect, the availability and familiarity of the canine model of this disease is a definite advantage in determining the therapeutic dose of our drug. One of the strengths of this project is that we have very encouraging preliminary results for one of our products, which clearly provided a therapeutic benefit in our first 3 dogs injected via a simple intravenous route. The second strength of our project is that all this work is being carried out by a consortium that is unique in the world, in which we have brought together experts in gene vectors, molecular biologists, anatomical pathologists, physiologists, veterinarians, scientists and doctors. This consortium, which has been working together since 2009, is already involved in an exon skipping clinical trial which will shortly be submitted to the French drug agency. | Translational Research 2014 | ||
| 2014 | Pierre-Louis THARAUX | Paris | Foundation For Rare Diseases | Rapidly progressive glomerulonephritis (RPGN) | Treatment of rapidly progressive glomerulonephritis by powerful inhibitors of HB-EGF and miRNA92a pathway in pig | Rapidly progressive glomerulonephritis (RPGN) is an orphan disease linked to an anarchic proliferation of the cells forming the kidney's filtration units. Current treatments are ineffective and very costly, and kidney loss is frequent. The disease is due to overproduction of the growth factor HB-EGF in response to autoantibody deposits in the kidney. Pierre-Louis Tharaux, nephrologist at Georges Pompidou Hospital, has demonstrated that blocking HB-EGF prevents the development of the disease. He has also identified a cellular substance, micro-RNA92a, implicated in the disease. The research project involves reproducing the disease in pigs, and testing as a treatment a therapeutic protein developed at the CEA by Daniel Gillet's team, as well as a micro-RNA92a blocker developed at Inserm U970 at Georges Pompidou Hospital. The experiments will be conducted with the help of INRA at Jouy-en-Josas. | Translational Research 2014 | ||
| 2014 | Sibylle OPSAHL-VITAL | Montrouge | Foundation For Rare Diseases | X-linked hypophosophatemic rickets | Development of a bioengineering treatment for the necrotic pulp of patients with familial rickets: preclinical approach in the mini-pig | Patients with hypophosphatemic rickets are prone to spontaneous dental abscesses. These infections are due to structural abnormalities in the tooth, a consequence of the rickets. The usual treatment is devitalization, which weakens the tooth and deprives it of its nerve sensitivity. Based on the presence of stem cells in the tooth, we aim to offer an alternative to this treatment, by replacing the diseased tissue with artificial pulp, made up of pulp stem cells seeded in a collagen matrix. The regeneration of a new, innervated and vascularized pulp tissue will enable the pulp to maintain its functions of nutrition and sensitivity, guaranteeing the longevity of a functional tooth on the arch. We have already validated this innovative therapy in rats, and before moving on to humans, it is essential to test it in minipigs, which are closer to human physiology. | Translational Research 2014 | ||
| 2014 | Alexandre EUSEBIO | Marseille | Foundation For Rare Diseases | Progressive supranuclear palsy | Quality of life and caregiver burden in progressive supranuclear palsy | Contexte : La paralysie supranucléaire progressive (PSP) est une affection neurodégénérative rare faisant partie du groupe des syndromes parkinsoniens atypiques. Elle représente environ 5 à 10% des syndromes parkinsoniens avec un nombre de malades estimé entre 3000 et 10000 en France. La PSP est caractérisée cliniquement par l’association d’un syndrome parkinsonien non-dopasensible à prédominance axiale avec instabilité à la marche et chutes précoces, de troubles oculomoteurs à type de limitation dans la verticalité du regard et de troubles cognitivo-comportementaux se manifestant essentiellement par un ralentissement psychique, une apathie et un syndrome frontal dysexécutif. S’y associent également des troubles de la déglutition qui peuvent entrainer des complications mettant en jeu le pronostic vital (pneumopathies d’inhalation). Actuellement la prise en charge est exclusivement symptomatique faute de traitement curatif disponible. Dans ce contexte thérapeutique limité et compte tenu de ses caractéristiques cliniques, la PSP impacte considérablement la qualité de vie des patients et également de leur entourage naturel impliqué dans leur prise en charge. Pourtant peu d’études documentent précisément ces deux aspects. Mieux connaitre les déterminants de la qualité de vie de ces individus et de leur entourage peut permettre d’optimiser les prises en charge. Objectifs: L’objectif principal de cette étude est d’identifier les déterminants (moteurs, psycho- comportementaux, socioéconomiques, environnementaux...) de la qualité de vie patients PSP Les objectifs secondaires sont: i) d’identifier les déterminants (médicaux, socioéconomiques, comportementaux, environnementaux...) de la qualité de vie et du fardeau des aidants de patients PSP ; ii) réaliser la validation linguistique française de l’échelle de qualité de vie disponible en anglais (PSP-QoL). Méthodes : Une étude transversale multidisciplinaire sera mise en place dans le centre de compétence maladies rares du mouvement et de la cognition de Marseille (Services de Neurologie des Pr Azulay et Ceccaldi, APHM) en collaboration avec Orphandev (Structure affiliée à l’INSERM spécialisée dans l’étude des maladies rares), des structures de recherche dans le champ des sciences humaines et sociales (Equipe Qualité de vie et maladies Chroniques ; Laboratoire de Psychologie sociale de la santé, Aix Marseille Université et l’Unité d’aide Méthodologique à la recherche clinique (APHM). Population d’étude : 2 groupes de sujets seront inclus : i) sujets PSP ; ii) sujets aidant d’un patient PSP (désigné par le patient comme la personne la plus proche de lui), Données recueillies : i) auprès du patient : données sociodémographiques, relatives à l’environnement social et professionnel, cliniques (ancienneté de la maladie, sévérité de la maladie, évaluation neuropsychologique), thérapeutiques, relatives à l’humeur, anxiété, coping, image corporelle, qualité de vie ; ii) auprès de l’aidant : données sociodémographiques, données relatives à l’environnement social et professionnel, lien avec le patient, donnée relatives à son propre état de santé, l’humeur, anxiété, coping, qualité de vie, fardeau. Déroulement : information du patient au cours d’une visite régulière, désignation d’un aidant, recueil de consentements, recueil des données. Analyses statistiques : Pour répondre à l’objectif principal les scores de qualité de vie ‘patient’ seront confrontés aux différentes variables recueillies (test t de Student, coefficient de corrélation). Les résultats seront ajustés aux facteurs de confusion au moyen d’analyses multivariées. Pour répondre à l’objectif secondaire, les scores de qualité de vie et fardeau de l’aidant seront confrontés aux différentes variables recueillies selon le même procédé. La validation transculturelle de l’instrument PSP-QoL sera réalisée selon les standards usuels : méthode forward-backward, test acceptabilité, étude des propriétés métriques. Résultats attendus et impact : Ce travail permettra une meilleure compréhension du handicap social associé à la PSP et pourra aboutir à l’application de nouvelles mesures thérapeutiques dans ce cadre. Pertinence du projet au regard de l’état des connaissances : Il n’existe à l’heure actuelle aucune donnée en France sur la qualité de vie des personnes atteintes de PSP et le fardeau des aidants. En outre, les facteurs impactant particulièrement ces deux aspects sont mal connus. Le handicap moteur réduit naturellement la qualité de vie des patients et augmente le fardeau de l’aidant. En revanche l’impact des troubles cognitivo- comportementaux et notamment la réduction des interactions sociales sur la qualité de vie du patient et la charge de l’aidant a été assez peu étudiée. | - | Humanities and Social Sciences 2 | |
| 2014 | Damien LEGER | Paris | Foundation For Rare Diseases | Rare hypersomnia | Professional career path in patients with rare hypersomnias | Narcolepsy is a rare hypersomnia, or severe wakefulness disorder, characterized essentially by sudden, invincible bouts of sleep that occur several times during the day. It is a rare and under-diagnosed condition, affecting between 0.025% and 0.05% of the population in France, or around 30,000 narcoleptics. This chronic, incapacitating and highly disabling condition persists throughout life, affecting all aspects of the patient's personal, social and family life. At school, narcolepsy represents a loss of opportunity due to the difficulties caused by excessive daytime sleepiness in children. At work, daytime sleepiness and the invincible sleep attacks characteristic of the disease are also a threat to the future, with difficulties in entering or staying in the workplace, leading to frequent job changes or even unemployment. This underlines the importance of early diagnosis, proper treatment and appropriate career guidance. Unfortunately, very little is known about the occupational consequences of narcolepsy, and hypersomnias in general, and very few studies have been carried out on the subject. Using both a clinical and an anthropological approach, including observations and interviews with patients, their families, friends and employers, this project aims to contribute to a better understanding of narcolepsy as experienced by patients: obstacles, restrictions, proscriptions in daily tasks and employment, but also strategies and recourse in personal and professional activities. Thus, the main objective of our study is to better understand and describe the career path of patients with rare hypersomnia in two possible career periods: training and job-seeking, and working, with the aim of better professional integration. Secondary objectives include : describe the type of disability and work restrictions associated with drowsiness, which are often attributed to causes other than the disease; analyze how these patients access and maintain employment; better understand the vulnerability and disruption of social ties in these patients; characterize the activity-sleep rhythm of these patients; provide patients, their families, the Association française des patients narcoleptiques et hypersomniaques (ANC) and occupational physicians with information guides and tools on the difficulties encountered in the workplace, with a view to improving patient orientation, support and information, and guiding them in their career paths. | Narcolepsy has the power to reshape not only professional, family, and personal life, but also to lead to changes and turning points (changes in practices, cessation of activities, reclassification, separation, new choices, etc.). People with narcolepsy will deploy strategies to adapt, compensate, and contain the effects of the disease in order to limit as much as possible the "contagion" effects from one area of activity to another (personal/social/professional). Conversely, in the event of change (job, family organization, home, etc.), their efforts will focus on preventing this from overly affecting the stability and relative effectiveness of their disease management system. Perceptions of the disease evolve over time. Throughout the course of their lives, people with the disease develop different approaches to their condition based on the medical and social recognition they receive regarding the reality and severity of their health status. The weakening of the initial personal identity and the identity process that follows, leading the individual to recognize and accept themselves as "sick" and "disabled," have a strong influence on how social and professional interactions will unfold. Thus, either the individual develops behaviors to mask their symptoms, or they openly express their health condition and allow themselves to develop behaviors to manage the condition "out in the open," which leads to behavioral and cognitive changes in others. In the public sphere, knowledge about the condition is very limited and can lead to distortions in the discourse surrounding this sleep disorder and those who suffer from it: stereotypical images of "lazy," "party-goers," and "addicts" (alcohol or other substances) remain very prevalent and are often associated with value judgments about the person (lack of willpower and character, "weakness"). Awareness-raising efforts are needed among the general public, institutions, and employers to change perceptions of the disease and those who suffer from it. Narcolepsy is a disabling condition that qualifies individuals for disabled worker status. It is a condition that can lead those affected to experience increased social vulnerability and health fragility. Vulnerability is a downward spiral of successive losses of social well-being following successive trials and shocks (medical wandering, diagnosis, treatment issues, difficulties in finding employment and periods of inactivity following layoffs, the end of precarious contracts, the need for retraining, etc., relationship difficulties, etc.) that will lead to various forms and intensities of damage to people's health, their ability to anticipate, resist or adapt to change, and to remain active while retaining their ability to act. | Humanities and Social Sciences 2 | |
| 2014 | Drina CANDILIS HUISMAN | Paris | Foundation For Rare Diseases | Rare diseases with movement disorders | Childbirth and parenthood in women with motor disability related to rare diseases | Contexte La parentalité fait partie intégrante du parcours social et familial des personnes atteintes de maladies rares. Environ 10% des femmes en âge de procréer vivent avec un handicap entravant leur vie quotidienne Elles ont le même désir légitime de devenir mère que les autres femmes, mais se heurtent parfois aux réactions négatives de leur entourage ou des professionnels Les femmes affectées par des maladies rares entrainant un trouble moteur constituent un groupe mal connu, ce qui contribue à leur stigmatisation. Ces maladies sont très diverses, et il n’est pas facile d’en établir la liste exhaustive. Elles partagent certaines caractéristiques : évolutivité au cours de la vie avec parfois un début dans l’enfance, fréquence du polyhandicap (atteinte des 4 membres, complications respiratoires...), fréquence des causes génétiques posant le problème de la transmission à la descendance, méconnaissance des enjeux de la maladie par la majorité des professionnels de santé, même spécialisés. On ne dispose pas de données spécifiques sur la parentalité chez les femmes atteintes de maladies rares entrainant des troubles moteurs aussi bien sur le plan de la littérature nationale qu’internationale. Il est difficile d’établir une liste apriori des maladies rares entrainant un déficit moteur. Citons à titre d’exemple : maladies entrainant des mouvements anormaux, myopathies, malformations congénitales arrivées à l’âge adulte (spinabifida, spina lipome, autres malformations médullaires), autre causes rares de troubles moteurs chez des femmes jeunes (sclérose en plaque avec séquelles majeures, infirmité motrice cérébrales par séquelle de prématurité ou d’anoxie périnatale, tumeurs rares...) Objectif : Appréhender les enjeux spécifiques de la grossesse et la parentalité chez les femmes atteintes de maladies rares avec handicap moteur (groupe d’étude) en comparaison avec les femmes présentant un handicap moteur acquis fréquent (paraplégie post traumatique) et avec la population générale. Méthodes : Nous utiliserons trois approches complémentaires : 1) Epidémiologie : Interrogation des bases de données de l’assurance maladie pour : - estimer la fréquence de trois types de déficit moteur (paraplégie, tétraplégie, hémiplégie) chez les femmes en âge de procréer - déterminer la part des maladies rares à l’origine de ces handicaps par analyse des codages par un groupe d’experts issu des centres de maladies rares - évaluer la consommation de soins de santé en gynécologie obstétrique pour chaque groupe de handicap, stratifié par étiologie, en comparaison avec la population générale. 2) Sociologie: Enquête via internet (réseaux sociaux, association de patients, base de données des centres de maladies rares), portant sur les attentes des femmes en matière de soins de santé en parentalité et leur perception sur la capacité du système de santé à répondre à leurs attentes. 3) Psychologie périnatale: Etude rétrospective du parcours d’accession à la parentalité et étude observationnelle des modalités des interactions et de l’attachement portant sur un sous groupe de femmes ayant accouché depuis moins de 4 ans et identifiées à partir des bases de données des 2 sites de naissances, du service d’accompagnement à la parentalité des personnes en situation de handicap, du site de médecine physique et réadaptation, et des centres de référence participant à l’étude. Résultats attendus Estimation du nombre de femmes en âge de procréer présentant une paraplégie, une tétraplégie, ou une hémiplégie secondaire à une maladie rare. Détermination de leur consommation de soins de santé en matière de contraception, dépistage gynécologique, et maternité en comparaison avec la population générale et avec les femmes vivant avec un déficit moteur non lié à une maladie rare. Détermination de la concordance entre les attentes des femmes et leur perception de l’offre de soin existante. Détermination de la spécificité des modes d’interaction des dyades mères enfant et des modalités de construction de l’attachement de l’enfant chez les femmes vivant avec un déficit moteur lié à une maladie rare, en comparaison avec la population générale et avec les femmes vivant avec un déficit moteur non lié à une maladie rare Impact potentiel - Mieux connaitre les attentes des femmes, l’état actuel de l’offre de soins, et l’impact du handicap sur la relation mère enfant et l’attachement - Proposer des stratégies en matière d’offre de soin en périnatalité, et d’accompagnement social ou psychologique - Pour favoriser l’autonomie dans le choix de devenir mère pour les femmes vivant avec un handicap moteur résultant d’une maladie rare. | - | Humanities and Social Sciences 2 | |
| 2014 | Herve DEVILLIERS | Dijon | Foundation For Rare Diseases | Systemic lupus erythematosus / Systemic sclerosis / Inflammatory myopathy | Impact of autoimmune disease on quality of life: a qualitative study | Contexte Le Lupus Erythémateux Systémique (LES), la sclérodermie systémique (Ssc) et les myopathies inflammatoires (MI) sont des maladies rares, dont la prévalence est estimée respectivement à 43, 15 et 10 cas pour 100 000 habitants en France. Ces pathologies appartiennent au groupe des maladies auto-immunes et nécessitent un suivi spécialisé par un centre expert. Le retentissement du LES, de la Ssc et des MI sur la vie quotidienne des patients est lourd et lié notamment à l’atteinte cutanée, aux diminutions des capacités fonctionnelles et à leur retentissement psychologique. Ces pathologies concernant dans l’immense majorité des situations des individus d’âge moyen, le retentissement socio-professionnel est majeur et trop souvent négligé. Les conséquences de la maladie en termes de qualité de vie pour ces patients sont habituellement approchées par des questionnaires, génériques ou spécifiques. La plupart de ces outils a fait l’objet d’une évaluation psychométrique quantitative. Cependant, aucun questionnaire ne permet d’approcher exhaustivement les problématiques de ces patients. Objectifs Objectifs principaux : - Définir les concepts associés au retentissement du LES, de la Ssc et des MI sur la vie quotidienne des patients. - Analyser l’expérience de la maladie du point de vue du malade - Analyser les conséquences de la maladie sur la vie quotidienne des patients : vie conjugale et familiale, vie professionnelle, vie sociale, relations médecin-patient, etc. - Faire apparaître d’éventuelles différences selon certaines caractéristiques socio-démographiques (sexe, âge, situation familiale, catégorie sociale), économiques et selon le type de maladies. - Faire émerger des problématiques méconnues des soignants ou non explorées par les instruments actuellement utilisés en routine pour évaluer la qualité de vie. Objectif secondaire : - Formuler des items, à partir des données qualitatives, dans la perspective de la constitution ultérieure d'une banque d'items. Méthodes L’étude repose sur une approche sociologique et a recours aux méthodes qui lui sont propres. 1) Après un inventaire exhaustif des instruments d’évaluation de qualité de vie et de santé perceptuelle utilisés au cours du LES, de la Ssc, et des MI, un groupe de travail sera constitué pour chacune des 3 pathologies autour d’un sociologue, de patients et des médecins spécialistes de la pathologie concernée au sein d’un centre de référence labellisé. A partir de l’expérience du groupe de travail et des données de la littérature, une grille d’entretien semi-directif sera élaborée pour chacune des 3 pathologies étudiées. 2) A l’issue de cette phase, un sociologue sera intégré à l’équipe de 3 services de référence (2 services de médecine interne de la Pitié Salpêtrière et service de Médecine Interne du CHU de Lille) et d’un centre de compétence (Service de Médecine Interne du CHU de Dijon) pendant un an. Des entretiens semi- directifs seront réalisés avec des patients jusqu’à saturation des concepts d’intérêt, ce qui nécessite habituellement une trentaine de patients. Chaque entretien sera enregistré et retranscrit par un sociologue expérimenté sous la direction du laboratoire de sociologie de l’université de Dijon pour dégager l’ensemble des dimensions de la vie des patients impactées par les pathologies. 3) Les entretiens feront l’objet d’une analyse de contenu thématique pour déterminer les éléments de la vie des patients qui leur pose problème et qui sont les plus difficiles à supporter. 4) Les différents aspects soulevés par l’analyse thématique seront ensuite formulés sous forme d’items par chacun des 3 groupes de travail, et comparés aux dimensions explorées par les échelles habituellement utilisées. 5) Le contenu de ces items sera ensuite discuté par des focus groupe qui seront constitué pour chacune des trois pathologies Résultats attendus et impacts - Identification des aspects du retentissement de la maladie sur la qualité de vie non pris en compte par les soignants et les instruments actuellement utilisés en routine - Ouverture possible sur la constitution d’une banque d’item exhaustive comprenant les items des échelles existantes complétés par les items formulés à l’issue des problématiques identifiées par cette étude Pertinence au regard de l’état des connaissances : Peu d’études ont porté sur le retentissement spécifique de ces pathologies sur la vie quotidienne des patients à l’aide d’une approche qualitative. Actuellement, l’évaluation du retentissement qualitatif de ces pathologies est peu réalisée en pratique clinique quotidienne par des spécialistes et l’identification de problématiques non habituellement prises en compte par les soignants nous permettraient d’améliorer la prise en charge globale des patients. | The care pathway for patients with systemic lupus erythematosus, systemic scleroderma, and inflammatory myopathies is marked by a lack of continuity of care prior to diagnosis and difficulties in the caregiver-patient relationship. These difficulties are characterized by unclear information prior to diagnosis, insufficient explanations before tests and at the time of diagnosis, the speed of consultations, and the trauma of the words used when the diagnosis is announced. Added to this are cases of clumsiness and negligence encountered by patients both in the referral center and before their arrival there. The multiplicity of people involved in the care process and the lack of listening undermine long-term follow-up. The asymmetrical nature of the relationship with the doctor considerably reduces the patient's room for maneuver and very often puts them in a position of having to endure the therapeutic relationship. In addition to the stress and anxiety caused by the disease, the difficulties encountered in the course of care have psychological repercussions that manifest themselves in some patients as panic attacks, suicidal thoughts, and depression, which are not always treated. Taking the above-mentioned realities and experiences into account is a fundamental step toward better patient care. | Humanities and Social Sciences 2 | |
| 2014 | Laurence FAIVRE-OLIVIER | Dijon | Foundation For Rare Diseases | Developmental anomalies | Preferences and representations of progress linked to the introduction of high-throughput sequencing technologies with regard to practice in medical genetics: from the example of syndromes with developmental abnormalities. | Contexte : Le diagnostic étiologique des maladies rares avec anomalies du développement reste encore trop souvent inconnu, ce qui est source d’errance médicale, de quête diagnostique prolongée et d’incompréhension de la part des familles. De plus, cela représente une potentielle perte de chance pour l’accès à un conseil génétique adapté, à un suivi optimal et à d’éventuelles ressources thérapeutiques. La dynamique des progrès observée ces deux dernières années en termes d’innovations technologiques permet d’entrevoir une véritable révolution dans le diagnostic, la recherche et la thérapeutique pour les patients. Après les découvertes diagnostiques possibles grâce à la généralisation des puces à ADN, le séquençage à haut débit (SHD) est en voie de transformer considérablement le domaine des pathologies du développement, de la recherche fondamentale au soin. Néanmoins, avant le transfert en pratique quotidienne, en particulier pour l’expertise diagnostique par le SHD d'exome, il est nécessaire de pouvoir anticiper l’information à communiquer aux patients et aux parents pour consentir à la réalisation du SHD d’exome. Ces questions dépassent l’usage des techniques, il s’agit d’un véritable enjeu sociétal, imposant d’associer des équipes des sciences humaines et sociales à la réflexion, et en particulier psychologues, sociologues, éthiciens, économistes de la santé, et des associations de patients. L’objectif en termes de santé publique est de permettre aux patients atteints de maladies rares de bénéficier de technologies innovantes dans des conditions d’information et d’accompagnement optimales. Ce projet est à l’initiative de deux centres de références Maladies Rares Anomalies du Développement et Syndromes Malformatifs (interrégions Est et Centre-Est), qui se sont entourés de l’Espace de Réflexion Éthique Bourgogne/Franche-Comté, de l’Équipe d’Économie de la Santé (EES-LEDi UMR 6307 CNRS - université de Bourgogne), de l’équipe de recherche « Éthique et Progrès médical » spécialisée en méthodologie qualitative au sein de l’Inserm CIT 808 du CHRU de Besançon, du Centre Georges Chevrier (UMR CNRS 7366, axe « Soins, vie et vulnérabilité : éthique, rationalités et pratiques des sciences biomédicales»), et d’un collectif d’associations. Ce travail s’appuie sur l’expérience préalable des équipes sur le plan méthodologique et thématique (expérience préalable de l’équipe Lyonnaise qui a mené une étude qualitative du vécu des parents et des médecins après l’introduction de la CGH-array en pratique diagnostique, expérience de l’équipe d’économie de la santé dans les études de révélation des préférences, expérience de l’équipe du CIC-IT éthique dans les études qualitatives). Objectifs : L’objectif de ce projet est 1/ d’évaluer les préférences des familles de patients atteints d’anomalies du développement vis-à-vis de la diffusion des résultats d’interprétation incertaine et fortuits du SHD, en amont des analyses d’exome réalisées en diagnostic, et 2/ de décrire, d’analyser et de comprendre, en aval des analyses d’exome réalisées en diagnostic, les vécus, attentes et réactions des familles et des généticiens vis-à-vis de leur trajectoire diagnostique en général et quant au moment de l’annonce des résultats du SHD en particulier. Il s’agit de mieux appréhender les enjeux de l’usage diagnostic du SHD, notamment quant aux modalités d’information, de consentement et d’annonce des résultats. Ainsi, en étudiant ces situations à l’occasion du passage du SHD en diagnostic dans les deux centres de référence de Dijon et Lyon, le projet se place dans une perspective anticipatrice de la généralisation de ces pratiques cliniques en matière de prescription, d’annonce diagnostique et d’accompagnement des patients/familles. Méthodologie : La méthodologie comprend 2 approches complémentaires : 1/ Étude quantitative permettant de révéler les préférences des familles de patients atteints d’anomalies du développement vis-à-vis de la diffusion des résultats d’interprétation incertaine et fortuits du SHD, en amont des analyses d’exome réalisées en diagnostic. L’étude s’adressera aux parents de patients atteints d’AD venant consulter aux centres de référence de Dijon et de Lyon sur une période de 9 mois, et qui pourraient bénéficier du SHD dès lors qu’il serait proposé à titre diagnostic. Les questionnaires reposent sur la méthode des choix discrets (méthode innovante et reconnue en économie pour révéler les préférences individuelles) et seront élaborés par l’équipe pluridisciplinaire. 2/ Étude qualitative permettant de comprendre les vécus et représentations liées à l’utilisation de cette nouvelle technique de SHD à visée diagnostique à partir d’entretiens menés auprès des familles bénéficiant de cette technologie et des médecins généticiens les accompagnants dans cette démarche. Il s’agira d’analyser, en aval des examens pratiqués, quelles étaient leurs attentes et quelles sont leurs réactions. Les entretiens seront réalisés avec les parents ayant bénéficié d’une analyse d’exome pour leur enfant (10 situations pour lesquelles un diagnostic est posé suite à l’examen ; 10 situations pour lesquelles une anomalie est détectée mais de pathogénicité non certaine ; 10 situations pour lesquelles aucun élément nouveau n’est mis en évidence), selon les principes de la théorie ancrée édictés par Glaser et Strauss et avec une analyse thématique et conceptuelle continue des entretiens audio-enregistrées. Cette étude, en aval des examens d’exome proposés en diagnostic, permettra d’évaluer l’impact des modalités d'information et d’annonce des résultats. Les questionnaires et guides d’entretien seront réalisés par l’équipe pluridisciplinaire, comprenant des représentants d’associations de malades. Le choix s’est porté sur l’association d’une méthodologie quantitative et qualitative, pour allier les avantages et pallier aux limites de chaque méthodologie, permettant ainsi d’étudier les phases en amont et en aval d’une technologie de SHD. En effet, l’étude quantitative permettra d’interroger un nombre important de patients sur la phase en amont de l’indication d’un test de SHD et ainsi de garantir une certaine représentativité de la population, tout en autorisant la mise en évidence de comportements hétérogènes au sein de cette population. L’étude qualitative ne permet d’interroger qu’un nombre limité de patients mais permet de décrire, analyser et comprendre en profondeur des phénomènes complexes en aval des résultats d’un test de SHD. L’exploration de la phase d’amont et d’aval apparait indispensable compte tenu de l’ambition de pouvoir proposer des livrables utilisables sur le plan national. Les équipes proposant ces deux approches complémentaires font partie du même comité de pilotage, ce qui sera une richesse pour la conduite de l’étude. Résultats attendus et impact : Les résultats de ces deux études auront des répercussions opérationnelles en termes d’anticipation de l’annonce, de formation des médecins, de mise en place de supports pédagogiques adaptés pour les familles, de pistes de réflexion pour la rédaction des consentements à un échelon national, de discussion sur la mise en place d’une meilleure organisation des soins. Ce projet contribuera à favoriser la transition de la recherche aux soins pour que les patients atteints de maladies rares et leurs familles puissent bénéficier plus rapidement de technologies innovantes dans des conditions d’information et d’accompagnement optimales. Ce projet pourra servir à tous les autres domaines de la génétique. Sur le plan de la santé publique, il permettra d’anticiper l’accès au SHD du plus grand nombre pour une optimisation amélioration de la prise en charge le plus précocement possible. Livrables : Les résultats de ce projet permettront d’élaborer et de faire valider : 1/ des modèles de contenu des notes d’information et des formulaires de consentement spécifiques à ces situations, 2/ un guide d’aide à l’annonce des résultats, 3/ des supports à visée pédagogique pour les familles. Le projet débouchera aussi sur des publications internationales pour faire connaître l’avancée des connaissances dans le domaine des préférences et représentations vis-à-vis de la nouvelle technologie du SHD et des attentes en termes d’annonce et d’accompagnement. Pertinence du projet au regard de l’état des connaissances : En l’absence de réglementation nationale d’utilisation de cette technologie, il est nécessaire que soient initiées des réflexions sur les informations à communiquer et les modalités d’accompagnement des familles, afin d’anticiper l’arrivée du SHD à titre diagnostique en pratique quotidienne. Les méthodologies proposées (méthode des choix discrets et entretiens individuels qualitatifs) sont à la fois adaptées à la problématique et reconnues comme innovantes dans la littérature. | A la lumière de nos résultats, les familles de patients atteints d’AD et/ou DI expriment une demande pour le SHD à visée diagnostique. Elles valorisent l’accès à des informations génétiques qui peuvent être mises en évidence par ce type de test, même lorsque certaines informations ne sont pas directement reliées à la pathologie de leur enfant. Toutefois, notre recherche souligne que si les répondants souhaitent connaître un maximum d’information génétique (résultats incertains et secondaires), leur objectif premier est bien l’accès à des informations reliées à la pathologie de leur enfant (résultats positifs essentiellement). Dans l’étude des vécus a posteriori, les parents rencontrés nomment les fonctions que représentent pour eux l’accès à un diagnostic. Le diagnostic a une fonction de nomination, voire d’identification, il permet de mettre un nom sur ce qui atteint leur enfant et parfois de mieux en comprendre la genèse. Le diagnostic peut influencer la prise en charge et les projections de la famille vis-à-vis de l’avenir (connaissance de l’évolution de la maladie, grossesse possible, orientation dans le système de santé et d’éducation). En revanche, si pouvoir accéder aux résultats, y compris de type incertain, est un élément majeur dans l’attente des familles comme le montre l’étude des préférences a priori, la valeur accordée aux résultats incertains a posteriori est plus mitigée. Il existe des divergences dans les expériences des patients/parents qui peuvent avoir du mal à identifier, avec un peu de distance (ex-post) la fonction réelle que peuvent représenter pour eux ces informations incertaines. Néanmoins, l’analyse des vécus montre que quelle que soit la valeur accordée aux résultats incertains ou à l’absence de résultat, les familles souhaitent poursuivre l’investigation diagnostique. Un point qui confirme lvaleur a priori accordée par les familles et les médecins à la ré-analyse des examens. D’autre part, la catégorie des résultats dits incertains marque les limites de la technique et de sa puissance. Cette catégorie de résultat «incertain» donne aussi à voir les reconfigurations des classifications nosologiques et permettent de comprendre les doutes et les difficultés des médecins. La recherche d’information en dehors du diagnostic initialement recherché (résultats secondaires) pose la question de l’objectif poursuivi par les familles lorsqu’elles sont demandeuses de telles informations. Les patients/parents souhaitent-ils réellement accéder à ces informations?Cette demande d’information supplémentaire ne serait pas considérée par les familles comme une recherche d’information parallèle à l’objectif principal du test. On peut faire l’hypothèse qu’elle permettrait, du point de vue des patients, de maximiser les chances de recevoir de l’information génétique, quelle qu’elle soit, et donc d’obtenir un diagnostic. En choisissant de pouvoir accéder à un grand nombre d’informations, on élargit, si l’on se place du point de vue des patients, le champ des possibles. Un effet qui peut être expliqué ou renforcé par les faibles connaissances en génétique déclarées par les répondants de l’étude quantitative, et ce même s’ils déclarent avoir bien compris les notions des résultats incertains et secondaires. L’information génétique est difficilement accessible pour les profanes et requiert des connaissances pour être intégrée et comprise. A cela s’ajoute la forte attente diagnostique dans laquelle se trouvent ces familles, un point relaté par les répondants de l’étude des vécus a posteriori mais que l’étude des préférences a priori souligne aussi : les répondants valorisent la ré-analyse des examens, particulièrement lorsque celle-ci est automatique. Là encore, on perçoit la démarche de recherche systématique d’informations dans laquelle semble s’être engagé les familles. De par la problématique posée et donc le design de la recherche, les deux études n’exploitent pas le même échantillon. Chaque échantillon a été construit dans le but de servir un pan particulier de la problématique globale à laquelle chacune des méthodologies développées permet de répondre. L’étude des préférences a priori permet d’estimer des préférences moyennes mais il est probable qu’à l’instar de l’étude qualitative, des groupes de préférence puissent exister et qu’il conviendrait d’approfondir avec d’autres techniques statistiques moins limitées. Concernant, le volet qualitatif, les parents étaient souvent très impliqués dans le parcours médical de leur enfant et très favorables à l’accès aux nouvelles technologies. De plus, ils étaient généralement connus des médecins des services depuis plusieurs années. Les entretiens ont été réalisés juste après la consultation d’annonce et ne permettent donc pas de suivre l’évolution du vécu des parents, de la façon dont ils se sont ou non appropriés les résultats et de la manière dont ils poursuivent ensuite l’investigation diagnostique. Ces points pourraient faire l’objet d’une nouvelle phase de l’étude qualitative qui recueillerait des données longitudinales. Ainsi, cette étude pluridisciplinaire permet d’explorer, via une méthodologie innovante conjuguant la révélation des préférences a priori et analyse des vécus a posteriori, la prise en charge globale des familles autour du SHD, l’environnement informationnel et les besoins d’accompagnement. Les résultats de l’étude posent la question du sens accordé à l’information génétique ex-ante comme ex- post par les parents. Houdayer et al. (2013) a montré dans le cadre de la CGH-Array que l’information diagnostique en ex-post est plus ou moins comprise et retenue par les parents suivant les modalités de l’information : une lettre, un nom alors même qu’il s’agit dans les deux cas d’un diagnostic. Qu’en est-il alors pour un test qui propose potentiellement d’accéder à une information diagnostique certaine, incertaine ou dite secondaire? La fonction ex-post réellement remplie par le test/diagnostic/l’information ne remplit pas nécessairement la fonction ex-ante attendue par les familles. Dans ce contexte, les modalités de diffusion de l’information en amont comme ensuite en aval du SHD constituent un véritable enjeu, auquel pourrait notamment contribuer les conseillers en génomique. Les parents interrogés par l’enquête qualitative ont fait part des questions qu’ils pouvaient avoir en suspend au regard des informations données en consultation par le généticien. Dédier une consultation à l’explication des résultats du SHD, en amont du consentement, permettrait sans doute de lever une partie des barrières à l’accès et à la compréhension de la nature des informations génétiques. Concernant la prise de décision relative à la communication des résultats issus du SHD, l’enquête quantitative révèle que le rôle du médecin généticien est particulièrement important pour les parents. En ce sens, le colloque singulier médecin-patient s’avère pertinent. Un colloque singulier qui n’est toutefois pas envisagé sous une forme paternaliste mais plutôt informative (Emmanuel and Emmanuel, 1992) puisque l’enquête privilégie la révélation a priori des préférences des parents par le généticien à qui reviendra in fine de prendre la décision médicale. Il convient en fait de réunir un maximum de conditions pour que puisse s’exprimer le consentement éclairé des parents. Par ailleurs, cette pertinence du colloque singulier ne limite pas l’intervention d’autres professionnels de santé tout au long de la prise en charge autour du SHD. Les parents interrogés par l’étude qualitative ont souligné l’engagement et le soutien apportés par les équipes de génétique, leur donnant ainsi un sentiment de sécurité. Les deux études ont montré qu’il y avait une place pour les psychologues du point de vue des patients. Ex-ante, les parents interrogés par l’étude quantitative sont indifférents (dans le sens où leur préférence est impactée de la même façon) entre un accompagnement par le généticien ou un(e) psychologue tout au long du processus. Ex-post, les vécus rapportés par les parents interrogés par l’étude qualitative rendent pertinent un accompagnement par une équipe généticien-psychologue : les parents ont notamment souligné la longue attente entre le prélèvement et la consultation d’annonce. Cela montre qu’il est difficile de pouvoir se projeter dans les enjeux d’un examen génétique tant qu’on n’est pas confronté à l’attente et au vécu du résultat. | Humanities and Social Sciences 2 | |
| 2014 | Pascal ANTOINE | Villeneuve d'Ascq | Foundation For Rare Diseases | Holt-Oram syndrome (HOS) - Nail Patella syndrome (NPS) - Rendu Osler disease (ROD) | Impact of three rare genetic diseases: comparative and exploratory psychosocial research | Contexte : Les connaissances sur le vécu et l’expérience des maladies rares sont limitées, car ces affections sont nombreuses, différentes dans leur expression, évolutivité et mode de transmission. Il est probable que ces aspects impactent le vécu et la qualité de vie de manière différente. Pour ce projet, nos deux équipes peuvent s’appuyer sur leurs expertises respectives sur les interactions sociales et familiales dans le domaine de la santé physique et mentale, et la génétique et le suivi des anomalies du développement, notamment des membres, et de la maladie de Rendu-Osler, ainsi que sur leur expérience de travail en commun. Objectifs : Nous proposons un projet original étudiant trois maladies héréditaires rares avec les objectifs suivants: 1. Analyser le vécu des patients et évaluer leur qualité de vie afin d’améliorer les connaissances sur ces affections et, en les comparant, dégager les éléments impactant le plus le vécu. 2. Evaluer pour chacune, les représentations qu’ont les patients de leur maladie, de son histoire naturelle et des modalités de surveillance (suivi du parcours de soin). Méthode: Nous étudierons 3 maladies héréditaires rares (syndrome de Holt-Oram, HOS, syndrome Nail Patella, NPS, et maladie de Rendu Osler, RO) transmises sur le même mode autosomique dominant avec variabilité d’expression, mais différentes dans leurs modes de révélation, leurs symptomatologies et leurs évolutions en nous appuyant sur nos files actives de patients et, pour la maladie de RO, avec l’aide de l’association AMRO. La littérature actuelle en SHS étant limitée pour ces trois affections, cette recherche est basée sur les connaissances actuelles concernant les maladies chroniques en général, les caractéristiques des maladies rares et des maladies génétiques en particulier pour étudier : 1) L’expérience et le vécu des patients (retentissement fonctionnel, social et professionnel, détresse émotionnelle et difficultés d’ajustement) 2) La situation psychosociale, conditions d’accès au diagnostic, à l’information, aux soins et aides institutionnelles. 3) Les représentations associées à la maladie et leur influence sur le parcours de soin et la surveillance médicale puisque les 3 affections ont un risque de complications potentiellement graves, justifiant une surveillance adaptée dès le diagnostic. En effet, cette surveillance semble diversement mise en place et suivie dans le temps. 4) L’aide apportée par les associations de patients car seule le RO en possède une (AMRO- France). Pour cette étude observationnelle et comparative transversale d’une durée de 24 mois, nous proposons une méthodologie mixte associant : Une approche quantitative, qui permettra des comparaisons entre les groupes de patients touchés par les différents syndromes étudiés (analyses statistiques inférentielles) afin de 1) décrire les caractéristiques de chaque groupe, avant de les comparer entre eux, 2) mettre en relation les phénomènes étudiés (anxiété, dépression, adhésion thérapeutique) avec les représentations de la maladie, 3) identifier les caractéristiques cliniques qui prédisent le mieux la qualité de vie. Une approche qualitative par Analyse Phénoménologique. Ce type d’approche, issue des évolutions récentes en psychologie qualitative, met l’accent sur la compréhension de l’expérience vécue par la personne. Elle implique une démarche « idiographique », chaque cas étant étudié en détail avant de tendre vers des conclusions plus générales présentées sous forme narrative. Cette analyse est particulièrement utile quand le domaine d’étude est dynamique, subjectif, récent ou relativement méconnu et lorsque des thèmes comme la détresse psychologique, la qualité de vie, l’identité ou la recherche de sens mobilisent les personnes concernées. Critères d’inclusion et de non inclusion: seront inclus les patients atteints par HOS, NPS ou RO, âgés de plus de 18 ans et en mesure de signer un consentement libre et éclairé. Ne pourra pas être inclus tout patient présentant une comorbidité hors spectre des pathologies étudiées. Résultats attendus et impact : Ce projet, original dans sa conception, a l’ambition non seulement de faire progresser les connaissances sur les conséquences individuelles et sociales, dans trois maladies héréditaires rares transmises sur le même mode autosomique dominant, mais aussi de dégager, grâce à la comparaison entre celles-ci, les éléments qui impactent le plus le vécu des patients et de leurs familles. Nos résultats permettront de proposer des recommandations pour l’amélioration de la prise en charge et l'accompagnement des personnes atteintes et de leurs proches, de sensibiliser les équipes soignantes et les pouvoirs publics aux particularités de ces pathologies. Il permettra aussi de développer des outils (actuellement inexistants) permettant de mesurer les dimensions de l’altération de la qualité de vie subjective dans le cadre des maladies rares et de déboucher sur un projet de recherche interventionnelle portant sur l’accompagnement psychosocial, si nécessaire. Pertinence du projet au regard de l’état des connaissances : ce projet s’attaque à un sujet quasiment vierge, les connaissances sur les impacts respectifs du HOS, du NPS et du RO sur le vécu des patients et de leurs familles étant inexistantes ou très limitées. Il constitue donc une expérience pilote et les données recueillies des éléments de référence. Ce protocole pourra ultérieurement être étendu à d’autres syndromes rares. | Les résultats sont présentés pour chaque maladie rare. ‘Maladie de Rendu-Osler’ : Une étude qualitative réalisée par entretiens semi-structurés auprès de 13 patients atteints de la maladie de Rendu-Osler (MRO) a été réalisée. L’objectif de cette recherche était de comprendre en profondeur le contexte du diagnostic de la maladie ainsi que les conséquences que cette maladie génétique pouvait générer dans la vie quotidienne des patients. Jusqu’à présent, les quelques études menées sur la RO présentes dans la littérature avaient permis de constater que le diagnostic avait tendance à être établi tardivement sans pour autant en connaitre la cause. Notre étude a non seulement appuyé ces précédents résultats, mais elle a surtout permis de découvrir un facteur influençant de manière non-négligeable le délai précédant la réalisation du diagnostic : la banalisation des épistaxis. En effet, les familles non diagnostiquées dont les membres présentent couramment des saignements de nez sont habituées à ces symptômes et ne s’en inquiètent pas car ces symptômes ne sont pas mis en lien avec une maladie quelconque. Dès lors, les personnes souffrant d’épistaxis depuis leur enfance se sont adaptées à ces saignements et les considèrent comme une caractéristique familiale. Ce n’est que lorsqu’un membre de la famille est diagnostiqué pour la maladie, généralement lors d’examens médicaux concernant d’autres symptômes, que l’information se répand au sein de la famille et les pousse à effectuer rapidement le diagnostic. Seules les personnes confrontées à une apparition tardive des épistaxis (aux alentours des 40 ans) s’en inquiètent, dès qu’elles constatent la survenue fréquente de ces saignements, et consultent rapidement un spécialiste. Le diagnostic génétique est rapporté comme une étape difficile dans la vie des patients, affectant leur quotidien sur le long terme. En effet, un choc émotionnel suite à l’annonce des résultats génétiques est fréquemment ressenti, se traduisant, pour certains, par un état de sidération. A ce choc émotionnel s’ajoute la peur pour leurs enfants ainsi que le dilemme concernant l’éventuelle demande de diagnostic génétique chez eux : est-il préférable d’effectuer ce diagnostic quitte à être face à la réalité ? ou de retarder le diagnostic jusqu’à ce que la maladie l’impose, à l’apparition des premiers symptômes ? Certains parents n’ont pas la force de faire subir ce qu’ils perçoivent comme une série d’examens médicaux à leurs enfants en bas âge. Ils estiment que leurs enfants, trop jeunes, ne comprendraient pas la raison de ces examens, et s’en inquièteraient. Ces parents ont alors préféré reporter le diagnostic avec l’idée que la maladie ne gâche pas l’enfance de leur enfant. A l’inverse, d’autres parents ont quant à eux fait le choix de réaliser rapidement le diagnostic de leurs enfants afin que leur état de santé soit pris en charge le plus précocement et le mieux possible. Cependant, le fait que leurs enfants suivent le protocole de surveillance médicale préconisé par les médecins ne permet pas de rassurer les parents qui ressentent, depuis l’annonce des résultats, une anxiété constante au sujet de l’évolution de la maladie chez leurs enfants et ne peuvent s’empêcher d’envisager le pire. Au niveau des activités quotidiennes, la maladie génère une fatigue importante suite aux épistaxis. Cette fatigue ainsi que l’apparition imprévisible des épistaxis limitent fortement les patients dans le quotidien. En effet, nombreux sont ceux ayant été obligés de réduire, voire arrêter, leurs activités ménagères, de loisirs (notamment sportives) ainsi que professionnelles (impliquant des difficultés financières). De plus, l’abondance et l’imprévisibilité des épistaxis obligent fréquemment les patients à devoir arrêter momentanément leur activité en cours afin de tenter de stopper leur hémorragie. Ces écoulements de sang pouvant se produire à des moments jugés inopportuns sont difficiles à vivre pour les patients qui doivent alors faire face aux regards et inquiétudes des personnes présentes autour d’elles. Les épistaxis ne semblent laisser aucun répit aux patients car, même lorsque ces derniers ne saignent pas, ils les anticipent, laissant ainsi la maladie être constamment présente dans leurs pensées. Cette présence constante de la maladie est renforcée par l’incertitude de l’évolution de la maladie à laquelle sont soumis les patients. En effet, étant donné que la maladie peut évoluer de nombreuses manières et à n’importe quel moment, les patients sont constamment dans l’angoisse. Enfin, le manque, voire même l’absence ressentie de connaissance sur la maladie de la part de certains professionnels de santé est difficile à gérer pour les patients. Il est fréquent que les patients rencontrent des médecins à qui ils doivent expliquer eux-mêmes la maladie. Les patients ont alors le sentiment que leur prise en charge ne peut pas être optimale dans de telles conditions, par exemple dans le cadre des hospitalisations d’urgence suite à l’apparition d’un épisode intense d’épistaxis. Ils expliquent que, suite à de mauvaises expériences, ils ressentent de la peur à l’idée de devoir se rendre à l’hôpital en urgence. ‘Syndrome Nail Patella’ : Une étude qualitative a été réalisée auprès de 9 personnes atteintes du syndrome Nail Patella (NPS). L’objectif est similaire à celui de l’étude précédente. Les résultats s’organisent ici différemment de ceux des participants avec une MRO, le syndrome apparaissant très précocement, affectant une trajectoire de vie plus large. Les participants rapportent d’importantes difficultés d’acceptation de leurs corps durant l’enfance puis l’adolescence. Ils expliquent avoir été complexés et gênés par leurs malformations physiques, qu’ils avaient tendance à cacher par peur du regard des personnes de leur âge. La majorité rapportent des moqueries de leurs camarades d’école et un sentiment de stigmatisation. A l’adolescence, ce sont plus des sentiments de différence et de solitude qui sont évoqués. Ces sentiments ont été exacerbés par le fait que de nombreuses activités ordinaires, notamment sportives, leur étaient inaccessibles en raison de leurs spécificités physiques : l’incapacité d’effectuer certains efforts physiques les a empêché de participer aux mêmes activités que les jeunes de leur âge, renforçant ainsi la difficulté de créer et d’entretenir des relations sociales. Cette dynamique marquée par des ressentis de gêne, une stigmatisation et une limitation des activités physiques et sociales évolue à l’âge adulte. Les participants accordent moins d’importance au regard des autres et ont progressivement et partiellement appris à composer leur existence en fonction de leurs malformations. Certains continuent à éviter de dévoiler leurs spécificités physiques mais déclarent ne pas en souffrir. Bien que des activités leur soient toujours inaccessibles, ils éprouvent moins de difficultés à accepter ces limites. Ils ont tendance à relativiser leurs difficultés en se référant à d’autres situations de handicaps qu’ils évaluent plus graves et dont ils estiment qu’ils auraient pu être atteints. Ils s’orientent vers la recherche de solutions leur permettant d’effectuer certaines activités du quotidien tout en évitant de faire souffrir leur corps. Tout comme ils ont adapté leur mode de vie quotidienne à leurs capacités physiques, les participants ont eu tendance à se diriger vers des métiers exigeant peu d’efforts physiques. Ainsi le bilan qu’ils réalisent au niveau professionnel est plutôt positif. On relève un décalage entre d’une part ce bilan de vie adulte plutôt positif et mobilisant des ressources adaptatives contournant le handicap et d’autre part une peur quant à l’évolution de la maladie : l’incertitude est centrale dans les discours. Les participants ont tendance à anticiper une aggravation de leurs symptômes, cette peur étant exacerbée lorsqu’un membre de leur famille également concerné par le syndrome est lui-même confronté à des complications somatiques. Un second sujet d’inquiétude, plus important encore, concerne l’état de santé de leurs enfants. La plupart des participants qui sont parents se sentent coupables d’avoir transmis la maladie à leur enfant, même s’ils n’étaient pas au courant du caractère génétique de leur affection lors de la conception. Les personnes n’ayant pas encore d’enfant s’interrogent quant à elles sur ce risque. Enfin, les participants rapportent leur expérience que la maladie est très peu connue par les médecins. Ils doivent régulièrement informer eux-mêmes les praticiens des symptômes de la maladie afin d’être pris en charge de manière adéquate. Ce manque de connaissance du syndrome Nail Patella entraine un sentiment de frustration et d’inquiétude chez les patients qui ont peur de ne pas recevoir un suivi médical satisfaisant. Dans la même idée, ils témoignent d’un manque d’informations reçues de la part du corps médical au sujet de la maladie et restent avec des questions sans réponse. ‘Syndrome Holt Oram’ : Les résultats acquis auprès de 10 participants permettent de faire émerger différents éléments dans la façon dont les participants vivent la maladie. La dimension qui ressort en premier correspond à un sentiment d’envahissement. En effet, les symptômes très hétérogènes de la maladie atteignent très précocement différentes sphères de la vie des patients. Les altérations physiques au niveau des membres sont synonymes de renoncement parfois difficiles à accepter. En effet, les patients expriment que certaines activités sont rendues impossibles malgré leurs efforts d’adaptation. Dès lors, le sentiment de « vivre sur les freins » vient altérer la qualité de vie des personnes qui souffrent du syndrome Holt Oram. Face à ces difficultés, les patients utilisent majoritairement la réévaluation positive comme stratégie d’adaptation. C’est-à-dire qu’ils viennent évaluer les conséquences de la maladie en termes de défi et d’expériences positives. Ainsi, ils expriment que n’ayant pas eu d’autre choix que de rebondir, la maladie leur a permis de se « forger le caractère » et d’avoir une autre vision de la vie. Ils ont bien conscience qu’il n’y aura pas de guérison donc ils préfèrent réévaluer la situation plutôt que d’être fatalistes. C’est notamment la raison pour laquelle la majorité d’entre eux ne souhaiteraient pas s’investir dans une association de patients afin de ne pas « tomber dans la plainte ». Le second élément du vécu des participants concerne la question de l’hérédité de la maladie et de la transmission génétique qui émerge lorsque ces derniers souhaitent avoir un enfant. Face au risque de transmission, tous n’ont pas la même réaction. Certains ne souhaitent pas prendre le risque et décident donc qu’ils n’auront pas d’enfants. D’autres font le choix d’avoir un enfant mais se retrouvent confrontés à une forte détresse psychologique lorsque la grossesse se passe mal. Quelle que soit leur décision face à ce risque, tous déclarent que c’est là l’aspect le plus difficile à vivre de la maladie génétique. Enfin, les analyses mettent en exerce un aspect du vécu des participants marqué par la rareté de leur maladie. Ils ont le sentiment d’être isolés et impuissants face au manque de connaissance et d’intérêt qui leur est porté. Ils expérimentent une « inversion des rôles » avec le corps médical ce qui provoque beaucoup de colère chez certains des patients. En effet, ils expriment avoir besoin de se référer à des professionnels pour être plus armés face à l’incertitude de l’évolution de leur maladie dans l’avenir. Les résultats mettent notamment en avant un manque d’éducation thérapeutique pour les patients qui souffrent du syndrome Holt Oram. La majorité d’entre eux n’ont pas toujours été au courant du suivi qu’il était nécessaire de réaliser afin d’éviter toute complication. Néanmoins, face à cette difficulté, les personnes qui souffrent du syndrome mettent en place des stratégies d’adaptation actives, basées sur la recherche d’informations. Ainsi, elles retrouvent un certain contrôle sur leur quotidien en se sentant mieux préparés aux conséquences de leur maladie. | Humanities and Social Sciences 2 | |
| 2014 | Philippe CHARRON | Paris | Foundation For Rare Diseases | Hereditary cardiac diseases | Predictive genetic testing in hereditary cardiac diseases: Evaluation of psycho-social impact and multidisciplinary management | Background: Hereditary heart disease is a rare genetic disorder, but a major cause of sudden death and heart failure in young people under 40. Cardiac expression is often delayed into adulthood, and so-called "predictive" genetic testing is proposed for asymptomatic relatives, to identify those who are not at risk of developing the disease, and to identify those who should benefit from targeted medical management and early initiation of therapy. However, the psycho-social impact of predictive genetic testing is poorly understood, and the precise modalities of support during the genetic consultation vary widely from team to team. Objective: The 1st objective is to assess the psychological and socio-professional impact of revealing genetic status on people at risk of developing hereditary heart disease who have undergone predictive genetic testing. The 2nd objective is to take stock of the organization of predictive test consultations in France (pre-genetic test and post-test consultation, presence or absence of cardiologist, presence or absence of psychologist, reflection period or not before blood sampling) and to assess the influence of this medical organization on the psychological and socio-professional impact of consultants. Methods: The project concerns adult relatives who are undergoing, or have undergone, predictive genetic testing for hereditary heart disease. It comprises three separate studies. 1/ Prospective multicenter study. The study will be carried out in a few selected centers, using self-questionnaires (quantitative and qualitative scales) filled in by consultants (100 to 150 subjects) at three different times (before consultation, before results are returned, after results are returned). The impact of the genetic result will be analyzed by weighting according to various parameters. A more in-depth semi-structured interview consultation with a clinical psychologist will also be offered to a sub-group of consultants. 2/ National retrospective study. The study will be carried out using self-questionnaires (quantitative and qualitative scales) sent by all volunteer French centers to the homes of consultants seen in the past in genetic consultation for predictive testing (400 subjects). The self-questionnaires are given out only once, and at a distance from the genetic results. 3/ National survey of genetic services in France. A survey of the organization of genetic consultations will be carried out by sending questionnaires to the various practitioners involved in genetic consultations in France. The information will then be used to weight the interpretation of the questionnaires completed by the consultants. Impact: The results will provide innovative and decisive information on the practice of predictive genetic testing in France and its psychosocial impact. The lessons learned will be used to revise the methods used to support and carry out predictive genetic consultations in hereditary heart disease, with the definition of new optimal methods to be proposed to French centers in order to harmonize practices and the care pathway in France. Our project is based on strong interactions between teams with complementary expertise (reference center for these pathologies, university clinical psychology team, biostatistics team), who have already collaborated in the past and recently reported preliminary work on the impact of predictive testing in hereditary heart disease (oral communication at congress). | - | Humanities and Social Sciences 2 | |
| 2014 | Arnaud MONTEIL | Montpellier | Foundation For Rare Diseases | Infantile neuroaxonal dystrophy (INAD) | Modeling infantile neuroaxonal dystrophy, a nalcn channel-related disorder, in zebrafish | Our ability to identify the genetic origin of certain neurological diseases continues to expand. Such is the case with Infantile Neuroaxonal Dystrophy (INAD), which has just been linked to a "loss-of-function" mutation in a NALCN ion channel. Our aim is to understand the link between this mutation and the mechanisms responsible for the pathology, which requires the development of an animal model. The mouse is not always the model of choice in which this mutation could be lethal. We have therefore chosen, on the basis of our preliminary studies, to study the mutation responsible for INAD using the zebrafish. We will introduce this mutation into the zebrafish genome and perform a series of molecular, biochemical and functional tests on the mutated zebrafish during its development from larva to adult. The zebrafish is a vertebrate with great similarities to humans, enabling us to study the mechanisms of pathologies. The advantage of this model is also that it enables research into drugs that can treat symptoms: drugs that may one day be able to cure INAD patients. | Small animal models 2014 | ||
| 2014 | Dimitrios SKOUFIAS | Grenoble | Foundation For Rare Diseases | Microcephaly-Lymphedema-Chorioretinal Dysplasia human rare syndrome | Generation of a zebrafish model to study KIF11 motor protein mutations associated with the human MLDRC rare syndrome | Small animal models are used to understand the pathogenic nature of genetic mutations identified in humans that are associated with rare diseases. They can also be used to screen orphan drugs for rare diseases. Recently, mutations in the mitotic motor protein Eg5, encoded by the KIF11 gene, have been linked to autosomal dominant transmission of the rare human syndrome Microcephaly-Lymphoedema-Chorioretinal Dysplasia. However, to date, there is no evidence that the mutations identified in the KIF11 gene are pathogenic. Therefore, we propose the development of a zebrafish model to study the cause and effect of the identified Eg5 mutations in order to elucidate the pathogenic nature of the identified mutations and understand the roles of Eg5 in the development of nervous tissues (e.g. brain, retina) and the lymphatic system affected by the syndrome. | Small animal models 2014 | ||
| 2014 | Frederic PERROS | Le Plessis Robinson | Foundation For Rare Diseases | Pulmonary arterial hypertension | Role of KCNK3 in the pathogenesis of pulmonary arterial hypertension | Pulmonary arterial hypertension (PAH), a rare and incurable disease, is characterized by obstruction of the pulmonary arteries, leading to right heart failure and death. Recently, mutations in the KCNK3 gene have been implicated in the development of PAH. Unlike the mouse, the rat is an excellent model of cardiovascular disease, and of PAH in particular. However, until recently, the absence of reliable tools for transgenesis in this species has prevented the creation of genetically modified rat models. The 'Small animal models and rare diseases' call for projects will enable us to generate rats invalidated (KO) for KCNK3, thanks to the TRIP-Nantes platform. We believe that KCNK3 KO rats will spontaneously develop PAH, providing a relevant model for the human disease. Many molecules successfully tested in current iatrogenic models of PAH have proved disappointing in humans. We believe that this model, which has a similar etiology to human PAH, will be a better screen for the identification of new PAH therapies. | Small animal models 2014 | ||
| 2014 | Gregoire MICHAUX | Rennes | Foundation For Rare Diseases | Microvillus inclusion disease | Towards a model for rare intestinal absorption diseases in c. elegans | Several rare diseases, such as microvillous inclusion disease or epithelial dysplasia of the intestine, affect intestinal absorption by preventing intestinal cells from absorbing food; these pathologies most often occur from birth and have a major impact on children's development. Patients receive total parenteral nutrition, i.e. their entire diet is supplied intravenously. To better understand how these pathologies arise, we propose to use the small roundworm C elegans. The main advantage of this well-characterized model organism is an intestine which, although very simple, has an absorption surface on a cellular scale identical to that found in humans, and is directly accessible by conventional microscopy methods. This makes it possible to characterize absorption defects in vivo, and then seek to compensate for them in order to identify new therapeutic avenues. | - | Small animal models 2014 | |
| 2014 | Herve TRICOIRE | Paris | Foundation For Rare Diseases | Friedreich ataxia | Generation of new endogenous drosophila models of trinucleotide repeat expansion diseases | Triplet expansion diseases are rare and incurable. The creation of new animal models is essential to better understand the mechanisms involved in these diseases. To this end, we aim to develop new Drosophila fly models of 3 of these diseases: Huntington's disease, spinocerebellar ataxia type 2 and Friedreich's ataxia. In recent years, the Drosophila has established itself as an excellent model for genetic studies, as well as for testing compounds for therapeutic purposes. The new Drosophila models we intend to develop will be based on the integration of a pathogenic triplet repeat in the Drosophila gene corresponding to the human gene involved in the disease. These models, developed in collaboration with TEFOR infrastructure platforms, will more closely resemble what happens in humans and mimic pathologies better than existing models. They will then be studied by our research team, enabling us to develop new therapeutic approaches. | Small animal models 2014 | ||
| 2014 | Isabelle RICHARD | Evry | Foundation For Rare Diseases | Limb-girdle muscular dystrophy type 2A | Rat model for calpainopathies | Sarcoglycanopathies belong to the limb-girdle muscular dystrophies, myopathies grouped on the basis of common clinical features: predominant involvement of the proximal limb muscles. They are progressively disabling, leading to loss of the ability to walk. No curative treatment is currently available. They are caused by mutations in one of the 4 genes coding for sarcoglycans. We have developed a therapeutic strategy based on the use of molecules that modify the quality control of proteins within the cell, enabling even mutated sarcoglycans to take their place in the membrane of muscle fibers. Our promising results must now be validated in a suitable animal model, which our mouse model reproducing a human mutation does not allow us to do. Indeed, protein quality control must be different in mice and humans. We would therefore like to build a rat model for sarcoglycanopathies, in order to test our therapeutic approaches in a model more closely resembling humans. | Small animal models 2014 | ||
| 2014 | Jamile HAZAN | Paris | Foundation For Rare Diseases | Hereditary Spastic Paraplegia (HSP) | Dangerous liaisons: the link between spastin, atlastin and BMP signaling in the pathogenesis of hereditary spastic paraplegia | Our team is seeking to understand how motor neuron axons in the medulla are guided to specific muscle targets in vertebrates. We approach this problem by exploring the consequences of a malfunction in these motor circuits, via the study of genes responsible for hereditary spastic paraplegia (HSP) during zebrafish embryonic development. HSP encompasses a heterogeneous group of rare neurodegenerative diseases characterized by progressive stiffness of the legs, leading to severe walking difficulties. Among the genes responsible for PSH, the genes encoding atlastin and spastin are frequently incriminated in this group of diseases. We have shown that both atlastin and the two isoforms of spastin control, in their own way, the axonal growth of spinal motor neurons and hence the mobility of larvae. Our project now consists in exploring the cellular and molecular defects resulting from the loss of function of these proteins, through the phenotypic analysis of zebrafish mutants of each of these proteins. | Small animal models 2014 | ||
| 2014 | Jocelyn LAPORTE | Illkirch | Foundation For Rare Diseases | Congenital myopathies and dystrophies, limb girdle muscular dystrophies | Validation and pathophysiological characterization of novel genes for myopathies (MYO-fish) | Genetic myopathies lead to severe chronic disability, representing a major burden for patients, their families and our health service. A third of patients have no genetic diagnosis, and there are no specific therapies. Our objectives are to identify and validate the genes responsible for myopathies and to better understand the pathological mechanisms in order to provide patients with an accurate diagnosis and potential treatments. Thanks to a major sequencing project funded in part by the Fondation Maladies Rares, we have identified new genes involved in several myopathies. We now propose to validate in zebrafish the importance of these genes for muscle function, and to generate animal models to study pathological mechanisms and enable the testing of chemical compounds that improve these diseases. | - | Small animal models 2014 | |
| 2014 | Kathrin GIESELER | Villeurbanne | Foundation For Rare Diseases | Muscular dystrophies | Development of C. elegans models for human muscular dystrophies | Muscular dystrophies are rare diseases characterized by progressive loss of muscle, particularly skeletal muscle, but also cardiac and respiratory muscle. To date, over 72 forms of muscular dystrophy and 46 different associated genes are known. Taken together, these diseases affect a significant number of patients, but today there are no effective treatments for them. Our team uses a small nematode worm to study human muscular dystrophies. In this project, we propose to create various new nematode models of these diseases and include them in a large-scale study aimed at better understanding the mechanisms of muscle degeneration and proposing new avenues for the development of treatments for muscular dystrophies. | Small animal models 2014 | ||
| 2014 | Nicolas CHARLET-BERGUERAND | Illkirch | Foundation For Rare Diseases | Amyotrophic lateral sclerosis & frontotemporal dementia | A rat model of amyotrophic lateral sclerosis & frontotemporal dementia | Amyotrophic lateral sclerosis (ALS), also known as Charcot's disease, is a devastating neurodegenerative disorder. It is characterized by the death of motor neurons in the spinal cord, leading to progressive and fatal paralysis. Recently, it has been shown that the most common cause of ALS mutation is a GGGGCC nucleotide repeat expansion in the C9ORF72 gene. However, despite the importance of the C9ORF72 gene, its function is still unknown. Our preliminary data show that the function of C9ORF72 is to participate in the elimination of protein aggregates toxic to neurons (autophagy). These data are important because they suggest that loss of C9ORF72 function may be involved in neurodegeneration in ALS patients. We would therefore like to obtain funding from the Foundation for Rare Diseases to establish an animal model (KO rat) of this disease. In conclusion, this project will lead to a better understanding of the causes of ALS, an essential step towards establishing therapeutic strategies. | - | Small animal models 2014 | |
| 2014 | Olivier LOREAL | Rennes | Foundation For Rare Diseases | Hereditary aceruloplasminemia | Hereditary aceruloplasminemia: mechanisms involved in the expression of the disease and development of new therapeutic approaches. | Hereditary aceruloplasminemia, linked to a mutation in the ceruloplasmin gene, is a rare genetic disease that manifests itself in adulthood. It is characterized by the development of atypical iron overload, particularly affecting the liver and brain. It is responsible for major neurological syndromes that severely impair quality of life and shorten life expectancy. Treatment does not satisfactorily remove excess iron from the brain, and the prognosis remains severe. The development of an animal model of aceruloplasminemia in rats will enable us to characterize the disease, gain a better understanding of the mechanisms at both systemic and cerebral levels, and develop innovative therapeutic approaches. A better understanding of this rare disease will also lead to a better understanding of the alterations in cerebral iron metabolism frequently encountered in neurodegenerative diseases. | Small animal models 2014 | ||
| 2014 | Sophie NICOLE | Paris | Foundation For Rare Diseases | Muscle channelopathies, congenital myasthenic syndromes | Neuromuscular excitability disorders in zebrafish: progressive muscle weakness in periodic paralysis and congenital myasthenia. | Despite important advances, a major remaining clinical concern in diseases with abnormal neuromuscular excitability is the progressive permanent disability that develops over time. Vacuolar myopathy can occur in hypokalemic periodic paralysis resulting from dominant missense mutations in voltage-sensitive calcium and sodium channels, and muscle atrophy in a recessive form of congenital myasthenia with agrin mutations. Determining the origin of these events and identifying an appropriate treatment requires the use of animal models. We propose to model these two pathologies in zebrafish through constitutional modification of its genome. We will study the phenotype, motor behavior, morphology and neuromuscular physiology of the mutants obtained. We will determine the effect of currently available treatments on the evolution of the disease in adult fish. We then hope to use these animals to identify new compounds against the development of these progressive phenotypes, thus opening up new therapeutic avenues for these orphan diseases which are disabling for everyday life. | Small animal models 2014 | ||
| 2014 | Thomas PIETRI | Paris | Foundation For Rare Diseases | Rett syndrome | Characterization of a zebrafish model of Rett syndrome | Rett syndrome is a rare neurodevelopmental disorder caused by mutations in the MECP2 gene. The syndrome is characterized by a rapid regression of cognitive and motor functions, after apparently normal development. In order to understand the role of MECP2, several mouse models carrying different mutations in this gene were created. These models have revealed numerous alterations in the functioning of the central nervous system, but have not yet enabled us to understand all the functions of MECP2. We therefore intend to create a new model of Rett syndrome, in another vertebrate model, the zebrafish, to gain a better understanding of the functions of this gene. In addition, the zebrafish is a model of choice for high-throughput drug screening, due to its small size and high progeny number. In the future, we hope to be able to use this model for drug screening. | Small animal models 2014 | ||
| 2014 | Veronique MOREL | Lyon | Foundation For Rare Diseases | Emery Dreifuss Muscular Dystrophy Autosomal recessive Cerebellar ataxia Beauce type (ARCA1) | Direct access to Nesprin1 variants contribution to Emery Dreifuss Muscular Dystrophy and Autosomal Recessive Cerebellar Ataxia ARCA1 | Emery Dreifuss Muscular Dystrophy (EDMD) and Autosomal Recessive Cerebellar Ataxia of Beauce (ARCA1) are both associated with mutations in the Nesprin1 gene. Several different proteins, or variants, are produced from Nesprin1. It has been proposed that muscles or neurons do not express the same Nesprin1 variants. This hypothesis helps to explain how the same gene is associated with muscular or neuronal pathologies: a mutation in the Nesprin1 gene, depending on whether it affects a neuronal or muscular variant, would thus result in a different pathology. We propose to test this hypothesis using the Drosophila fly as a model animal. We have shown that when the Drosophila Nesprin1 gene is mutated in muscles or neurons, the fly displays motor deficits reminiscent of the symptoms associated with Emery Dreifuss muscular dystrophy or ARCA1 Autosomal Recessive Cerebellar Ataxia. | Small animal models 2014 | ||
| 2014 | Vincent BERINGUE | Jouy-en-Josas | Foundation For Rare Diseases | Prion diseases | Zebrafish model of prion disease | Prion diseases are a group of rare neurodegenerative disorders affecting humans and animals. The conversion of a host protein, the cellular prion protein PrPC, into an abnormally folded and aggregated form, PrPSc, is a key element in the pathogenesis of these diseases. In humans, prion diseases can be sporadic, genetic or infectious in nature. In all cases, the conformational change of PrPC is involved. A major public health challenge is to gain a better understanding of the neurodegenerative mechanisms involved in the pathogenesis of these diseases, leading to the irreversible death of affected individuals. To this end, we aim to develop a zebrafish model transgenic for mammalian prion proteins that develops prion-like neurodegeneration, either spontaneously or after experimental infection with mammalian prions. The zebrafish has the unique advantage of being able to visualize in situ, and potentially in real time, the phenomena that take place at cellular and molecular level. | Small animal models 2014 | ||
| 2014 | Yann HERAULT | Illkirch | Foundation For Rare Diseases | 16p11.2 microdeletion syndrome | A rat model for the 16p11.2 microdeletion syndrome to better understand and treat the cognitive and metabolic disorders induced in human | Deletion of a region of around 600 kb on the short arm of human chromosome 16 is associated with intellectual deficit and obesity. In addition, some patients show autism-like disorders. This deletion is observed with an estimated prevalence of 1-5 in 10,000 in the general population. Mouse models have been designed and show cognitive deficits. They are now being used to test therapeutic approaches to restore normal function. Here, we aim to develop a rat model of the proximal 16p11 deletion. We will use a combination of technologies combining CrispR/Cas9 and Cre to create the deletion of the homologous region in the rat, well conserved in terms of gene content and orientation. Next, we will use the rat model to characterize phenotypes using standardized functional analyses, in order to compare changes between human patients, mice and rats. Our aim is to analyze the pathophysiology of 16p11 deletion and validate a treatment in these two preclinical model species. | Small animal models 2014 | ||
| 2014 | Yvon TROTTIER | Illkirch | Foundation For Rare Diseases | SpinoCerebellar Ataxia 7 (SCA7) | A zebrafish model of SCA7 for physiopathological analyses and drug evaluation | Spinocerebellar ataxia 7 (SCA7) is a rare disease causing impaired vision and ataxia. The disease is caused by a mutation that confers neurotoxic properties on a protein called ataxin-7. We have recently discovered that this toxicity affects the function of the cilium, a multifunctional cellular organelle, and that affected neurons progressively lose their characteristic features, leading to death. However, the exact mechanisms of toxicity remain to be elucidated. Our project aims to study these mechanisms in a zebrafish model, to complement and assist our studies already undertaken in mice. On the other hand, we aim to use this model to make an initial assessment of drugs that could have beneficial effects on the disease, before undertaking more costly and time-consuming studies in mice. | Small animal models 2014 | ||
| 2014 | Sonia ABDELHAK | Tunis | Foundation For Rare Diseases | Consanguinity and hereditary rare disease | Consanguinity and hereditary rare diseases : challenges and perspectives in post genomics | - | TWAS | ||
| 2013 | Agnes ROTIG | Paris | Foundation For Rare Diseases | Hepatic failure of mitochondrial origin | Targeted region sequencing in hepatic failure of mitochondrial origin | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Alain TAIEB | Bordeaux | Foundation For Rare Diseases | Trichothiodystrophy | TFIIH sequencing of a new TTD (trichothiodystrophy) phenotype | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Benoit ARVEILER | Bordeaux | Foundation For Rare Diseases | Oculocutaneous albinism | Exome sequencing to find new gene(s) involved in oculocutaneous albinism | - | - | High throughput sequencing 2013 - 1 | |
| 2013 | Bertrand ISIDOR | Nantes | Foundation For Rare Diseases | Camurati-Engelmann disease | Identification of the disease causing gene in sporadic and familial forms of Camurati- Engelmann syndrome not linked to TGFB1 | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Cecile JULIER | Paris | Foundation For Rare Diseases | Juvenile onset insulin-independent diabetes | Identification of genes responsible for monogenic forms of juvenile onset insulindependent diabetes | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Fabienne ESCANDE | Lille | Foundation For Rare Diseases | Holt-Oram syndrome | Identification of new genes involved in Holt Oram Syndrome by Exome Sequencing | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Helene DOLLFUS | Strasbourg | Foundation For Rare Diseases | Bardet-Biedl syndrome | Novel genes identification in Bardet-Biedl Syndrome (BBS) | - | - | High throughput sequencing 2013 - 1 | |
| 2013 | Mathilde VARRET | Paris | Foundation For Rare Diseases | Familial hypercholesterolemia | Identification of new genes involved in rare forms of autosomal dominant hypercholesterolemia | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Pascale DELONLAY | Paris | Foundation For Rare Diseases | Rhabdomyolysis | Identification of the gene(s) responsible for recessive rhabdomyolysis in 10 patients from 5 families presenting the same phenotype | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Pascale RICHARD | Paris | Foundation For Rare Diseases | Inherited cardiomyopathy | Identification of new genes associated with inherited cardiomyopathies. | Erythropoietic porphyrias (EP) are genetic disorders linked to a defect in hemoglobin synthesis in the erythroid cells of the bone marrow, leading to the accumulation of toxic compounds (porphyrins) in red blood cells and causing skin photosensitivity and anemia in affected patients. Allogeneic bone marrow transplantation remains the only curative treatment, but requires an immunologically compatible donor. We have shown that pharmacological agents can correct the pathological phenotype in a PE mouse model, but their secondary toxicity makes their clinical evaluation difficult. The objective of this project is to identify new therapeutic molecules in a large-scale screening test using PE patient cells as a model. The candidate molecules identified that reduce the toxic accumulation of intracellular porphyrins will then be optimized for clinical use (therapeutic efficacy in a PE mouse model, toxicity and bioavailability tests). | High throughput sequencing 2013 - 1 | ||
| 2013 | Patrice BOUVAGNET | Lyon | Foundation For Rare Diseases | Tetralogy of Fallot | Tetralogy of Fallot | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Richard REDON | Nantes | Foundation For Rare Diseases | Arrhythmia syndromes: Early repolarisation syndrome | A genetic survey on Early Repolarisation Syndrome | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Rima NABBOUT | Paris | Foundation For Rare Diseases | Febrile Induced Refractory Epilepsy in School | Exome sequencing to identify genes associated with FIRES (Febrile Induced Refractory Epilepsy in School) | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Sophie SAUNIER | Paris | Foundation For Rare Diseases | Nephronophthisis | Identification of new genes involved in nephronophthisis | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Stephane BEZIEAU | Nantes | Foundation For Rare Diseases | Acrodermatitis enteropathica, zinc deficiency type | Whole-exome sequencing of a cohort of patients with inherited forms of zinc deficiency acrodermatitis enteropathica-like | - | High throughput sequencing 2013 - 1 | ||
| 2013 | Alexandra HENRION-CAUDE | Paris | Foundation For Rare Diseases | Biliary atresia | Biliary atresia in consanguineous and familial cases | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Annick TOUTAIN | Towers | Foundation For Rare Diseases | X-linked intellectual disability | Identification of the causal gene in a family with non-specific X-linked disability | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Claude FEREC | Brest | Foundation For Rare Diseases | Autosomal dominant polycystic kidney disease | Search for a new locus involved in dominant cystic kidney disease | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Claude JARDEL | Paris | Foundation For Rare Diseases | Mitochondrial diseases | Towards the identification of novel genes involved in mitochondrial functions in genetically and biochemically informative patients | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Corinne ANTIGNAC | Paris | Foundation For Rare Diseases | Idiopathic steroid-sensitive nephrotic syndrome | Identification of genes involved in autosomal recessive steroid-sensitive nephrotic syndrome (SSNS) | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Cyril MIGNOT | Paris | Foundation For Rare Diseases | Septo-optic dysplasia | Identification of a gene involved in septo optic dysplasia with schizencephaly | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Emmanuel FLAMAND-ROZE | Paris | Foundation For Rare Diseases | Paroxysmal kinesigenic dyskinesia | Identification of new genes involved in paroxysmal kinesigenic dyskinesias | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Eric PASMANT | Paris | Foundation For Rare Diseases | Carcinoid tumor and carcinoid syndrome | Exome sequencing for identification of the gene responsible for a rare familial midgut carcinoid tumor syndrome | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Federico DI ROCCO | Paris | Foundation For Rare Diseases | Familial scaphocephaly syndrome | Exome sequencing of familiar isolated scaphocephalies | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Florent SOUBRIER | Paris | Foundation For Rare Diseases | Hereditary hemorrhagic telangiectasia | Genetics of hereditary hemorrhagic telangiectasia | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Gaetan LESCA | Lyon | Foundation For Rare Diseases | West syndrome | Identification of novel genes involved in West syndrome in ten patients with extensive pre-screening. | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Jean-Baptiste RIVIERE | Dijon | Foundation For Rare Diseases | Spondylocostal dysostosis | Unraveling the genetic basis of spondylocostal dysostosis | - | - | High throughput sequencing 2013 - 2 | |
| 2013 | Jean-Jacques SCHOTT | Nantes | Foundation For Rare Diseases | Familial mitral valve prolapse | Genetic analysis of inherited mitral valve prolapse | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Laurent VILLARD | Marseille | Foundation For Rare Diseases | Early infantile epileptic encephalopathy | Identifying genetic causes of early infantile epileptic encephalopaties | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Mathieu BARBIER | Paris | Foundation For Rare Diseases | Familial thoracic aortic aneurysm and aortic dissection | Identification of new gene involved in familial thoracic aortic aneurysm and dissection (FTAAD) | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Patricia FERGELOT | Bordeaux | Foundation For Rare Diseases | Rubinstein-Taybi syndrome | Exome study in Rubinstein-Taybi syndrome patients with no alteration in the CREBBP and EP300 genes | - | - | High throughput sequencing 2013 - 2 | |
| 2013 | Rosa VARGAS POUSSOU | Paris | Foundation For Rare Diseases | Distal renal tubular acidosis | Identification of new gene(s) responsible for recessive distal Renal Tubular Acidosis | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Sandrine VUILLAUMIER-BARROT | Paris | Foundation For Rare Diseases | Type I congenital disorder of glycosylation | Exome sequencing of 8 patients with a neurologic form of type I congenital disorder of glycosylation | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Severine DRUNAT | Paris | Foundation For Rare Diseases | Baraitser-Winter syndrome | Baraitser-Winter syndrome - searching causal genes in patients without ACTB/G1 mutations | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Stephane VIVILLE | Illkirch | Foundation For Rare Diseases | Partial chromosome Y deletion | Genetics of male infertility: genes implicated in non-obstructive azoospermia | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Sylvain LATOUR | Paris | Foundation For Rare Diseases | Inherited lymphoproliferation syndromes | Molecular identification of novel forms of inherited lymphoproliferation syndromes associated with a susceptibility to EBV infection | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Valerie CORMIER-DAIRE | Paris | Foundation For Rare Diseases | Spondylodysplastic dysplasia | Further identification of the molecular basis of the spondylodysplastic dysplasias group through the study of 6 families | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Veronique PINGAULT | Creteil | Foundation For Rare Diseases | Waardenburg syndrome | Identifying new genes of Waardenburg syndrome | - | High throughput sequencing 2013 - 2 | ||
| 2013 | Christel THAUVIN-ROBINET | Dijon | Foundation For Rare Diseases | Rare head and neck malformations | Creation of a mouse model of Cohen's syndrome | - | Outside AAP | ||
| 2013 | Claude BESMOND | Paris | Foundation For Rare Diseases | Other rare diseases | NiNi | - | Outside AAP | ||
| 2013 | Jean-Luc GALZI | Strasbourg | Foundation For Rare Diseases | Immune deficiency disorders | Identification of CXCL12 neutraligands and CXCR4 antagonists to block WHIM-related gain of signaling function | - | Outside AAP | ||
| 2013 | Laurence LEGEAI-MALLET | Paris | Foundation For Rare Diseases | Rare head and neck malformations | Craniofacial anomalies and FGFR3 | - | Outside AAP | ||
| 2013 | Laurent GOUYA | Paris | Foundation For Rare Diseases | Hereditary metabolic diseases | Treatment of Acute Hepatic and Erythropoietic Porphyria: Search for inhibitors of the regulatory enzymes ALAS1 and ALAS2 | - | Outside AAP | ||
| 2013 | Alain HOVNANIAN | Paris | Foundation For Rare Diseases | Netherton syndrome | Development of a murine model overexpressing human Kallikrein 14 in the context of Netherton syndrome | - | Mouse models 2013 | ||
| 2013 | Alain LILIENBAUM | Paris | Foundation For Rare Diseases | Desminopathy | A mouse model for desmin-related myopathies | - | Mouse models 2013 | ||
| 2013 | Antoine MARTINEZ | Clermont | Foundation For Rare Diseases | Carney complex | Pathogenic potential of R1α truncated mutants found in severe forms of Carney complex | - | Mouse models 2013 | ||
| 2013 | Claire FRANCASTEL | Paris | Foundation For Rare Diseases | Immunodeficiency, centromeric region instability, facial anomalies syndrome | Creation and epigenetic/phenotypic characterization of a mouse model for the ICF type II syndrome | - | Mouse models 2013 | ||
| 2013 | Delphine DELACOUR | Paris | Foundation For Rare Diseases | Congenital tufting enteropathy | Functional characterization of Spint2 in intestinal morphogenesis - Physiopathological repercussions in the pathogenesis of CTE | - | Mouse models 2013 | ||
| 2013 | Fiona FRANCIS | Paris | Foundation For Rare Diseases | Heterotopia | Molecular and cellular causes, and physiopathology of heterotopia | - | Mouse models 2013 | ||
| 2013 | Frederic SAUDOU | Orsay | Foundation For Rare Diseases | Huntington disease | Huntington's disease: modelling huntingtin proteolysis in mouse (proteo-htt) | - | Mouse models 2013 | ||
| 2013 | Hamid-Reza REZVANI | Bordeaux | Foundation For Rare Diseases | Xeroderma pigmentosum complementation group C | Role of NADPH oxidase 1 in Xeroderma pigmentosum C | - | Mouse models 2013 | ||
| 2013 | Jean-Jacques MERCADIER | Chatenay-Malabry | Foundation For Rare Diseases | Catecholaminergic polymorphic ventricular tachycardia | Advances in the understanding and treatment of Catecholamine Polymorphic Ventricular Tachycardia (CPVT) | - | Mouse models 2013 | ||
| 2013 | Jeanne AMIEL | Paris | Foundation For Rare Diseases | Epiphyseal, vertebral, and ear dysplasia | Proposal to create a mouse model of EVE dysplasia by generating Hspa9 knockout mice | - | Mouse models 2013 | ||
| 2013 | Laurent GOUYA | Paris | Foundation For Rare Diseases | Erythropoietic protoporphyria | Antisense oligonucleotide therapeutic strategy in EPP: Development of a humanized mouse model. | - | Mouse models 2013 | ||
| 2013 | Luc DUPUIS | Strasbourg | Foundation For Rare Diseases | Amyotrophic lateral sclerosis | Generation of an inducible model of amyotrophic lateral sclerosis through conditional truncation of fus/als | - | - | Mouse models 2013 | |
| 2013 | Marie-Christine CHABOISSIER | Nice | Foundation For Rare Diseases | Disorders of sex development | Analysis of R-spondin1 functions in transdifferentiation and maintenance of the ovary | - | Sexual development disorders (SDDs) are rare heterogeneous diseases. Despite intensive research over the past 30 years, only about 50% of SDDs can be explained at the molecular level to date. This highlights our ignorance of the mechanisms that control sex determination. DSD causes a variety of conditions ranging from intersexuality with dysfunctional genitalia to infertility and hormonal imbalance, all of which cause severe psychological and social distress for the affected individual. In addition, patients often have a high risk of developing gonadal cancers. Understanding normal and defective gonadal development has therefore become a key research question, as it may have a significant impact on future diagnoses for sex assignment and surgery. This knowledge is valuable for medical counseling to families in their decision for or against gonadectomy for their children with these conditions. Frasier syndrome is an ADS that leads to malformations of the urogenital system, renal pathologies, and gonadal dysgenesis with the appearance of nephro- and gonado-blastomas. Our study identified the causes of these developmental abnormalities through single-cell RNA sequencing. We discovered that this pathology is due to the abnormally high expression of a variant of the Wilms tumor suppressor, Wt1. This variant is the main regulator of ovarian differentiation, and our work has identified for the first time the molecular mechanism that initiates ovarian differentiation. Furthermore, this gives us a starting point for identifying the factors responsible for developmental pathologies in this organ. These new factors will help clarify the etiology of sexual development abnormalities and provide new tools for better diagnosis and anticipation of the consequences on an individual's development. | Mouse models 2013 | |
| 2013 | Michael MITCHELL | Marseille | Foundation For Rare Diseases | Partial chromosome Y deletion | Role of the homologue of a human oligozoospermia factor gene, during mouse spermatogenesis | - | Mouse models 2013 | ||
| 2013 | Michaël SEBBAGH | Marseille | Foundation For Rare Diseases | Peutz-Jeghers syndrome | STRAD beta involvement in Peutz-Jeghers syndrome | - | Mouse models 2013 | ||
| 2013 | Rima NABBOUT | Paris | Foundation For Rare Diseases | Rare epilepsies | KI Mouse model for Migrating partial seizures in infancy | - | Mouse models 2013 | ||
| 2013 | Sabine BAILLY | Grenoble | Foundation For Rare Diseases | Hereditary hemorrhagic telangiectasia | BMP10 in HHT disease | - | Mouse models 2013 | ||
| 2013 | Thierry LEVEILLARD | Paris | Foundation For Rare Diseases | Retinitis pigmentosa | Inactivation of the thioredoxin-like protein RdCVFL encoded by the Nucleoredoxin-like71 gene: RdCVFL7-7 mouse | - | Mouse models 2013 | ||
| 2013 | Xavier JEUNEMAITRE | Paris | Foundation For Rare Diseases | Arterial hypertension | Generation of CUL3 delta-ex9 mouse model reproducing a mendelian form of arterial hypertension | - | Mouse models 2013 | ||
| 2013 | Chantal HARDY | Nantes | Foundation For Rare Diseases | Steinert myotonic dystrophy | Sociological approach to lifestyle habits of adults with myotonic dystrophy type 1 | Le changement des habitudes de vie des personnes atteintes d’une maladie chronique invalidante est mal connu et pourtant essentiel à prendre en compte pour soigner efficacement dans la durée. La dystrophie myotonique de type1 (DM1 ou maladie de Steinert) est une maladie chronique exemplaire (ou typique) : elle est rare, génétique, évolutive, altère plusieurs fonctions, son traitement est, actuellement, exclusivement symptomatique. La problématique médicale intègre relativement facilement cette diversité clinique dans une prise en charge interdisciplinaire, mais les soins sont caractérisés par un contexte relationnel conflictuel entre soignants et soignés. En effet, ces patients sont souvent décrits comme revendicatifs tout en manifestant un « manque de motivation » dans la gestion de leur maladie. Le contexte français du développement de l’éducation thérapeutique et les besoins de préventions des complications de la DM1 identifiés par les soignants, font apparaître des besoins pédagogiques qu’il convient d’interroger au regard des représentations sociales, des manières de vivre et des habitudes de vie des personnes atteintes de cette maladie. Se situant à la croisée des champs médical et social, cette étude vise à comprendre le changement des habitudes de vie au cours des stratégies d’adaptation des hommes et des femmes adultes atteints d’une maladie neuro-dégénérative, la DM1. La méthode se caractérise d’abord par une approche pluridisciplinaire (sociologique, infirmière et médicale) autour d’un projet commun : mieux comprendre pour mieux soigner. Dans un contexte de reconfigurations régionales, le projet s’appuie sur une approche réellement transdisciplinaire en intégrant une coopération étroite entre une équipe SHS (UMR6297, Droit et changement social) et le Centre de Référence de Maladies Neuromusculaires Rares (CRMNMR) Nantes-Angers. Il s’inscrit en outre dans la démarche de réflexivité soin-recherche engagée au sein du DHU 2020 centré sur la médecine personnalisée des maladies chroniques. Ce projet a pour ambition de poser les bases d’une réflexion sur une vision davantage compréhensive que normative de la maladie permettant à l’ensemble des acteurs de s’approprier les résultats susceptibles d’enrichir et de modifier les pratiques. Pour y parvenir, un groupe de pilotage, composé des deux équipes de recherche, complété de représentants des usagers et de la recherche fondamentale, sera sollicité aux étapes cruciales du projet. La méthodologie de cette étude s’appuie sur le modèle conceptuel de développement humain et de processus de production du handicap (MDH-PPH) développé au Québec, complété de l’étude des dispositions incorporées par les individus au cours de leur vie les conduisant à un hexis particulier. Les données seront collectées à l’aide d’outils relevant de la sociologie et de l’anthropologie (analyse de dossiers de patients, observations de séances d’hôpital de jour, entretiens et observations de patients à domicile, entretiens avec des soignants). Elles seront analysées selon la méthodologie de la théorie ancrée afin de modéliser les interactions entre la personnalité, l’environnement et les habitudes de vie de notre population. L’échantillon d’au moins 20 personnes atteintes de DM1 dont les manifestations cliniques sont apparues après l’âge de 20 ans est issu en priorité de la file active du CRMNR Nantes-Angers. Une première étude de cette population montre des caractéristiques médicales, cognitives, sociales et culturelles compatibles avec les objectifs de l’étude. L’approche originale de cette étude devrait produire une description précise des caractéristiques de la population, des déterminants qui influencent l’adaptation à la vie quotidienne, une compréhension approfondie des interactions entre les différents acteurs et une modélisation du changement des habitudes de vie. Ces connaissances scientifiques seront largement communiquées et publiées pour permettre aux professionnels du soin et aidants à domicile de préciser, voire de modifier leurs pratiques de soins et de prévention, d’adopter la posture la plus respectueuse et efficace pour accompagner, dans la durée, cette population à définir ses propres normes et l’accompagner dans l’accomplissement de son projet de vie. Les formateurs, les concepteurs d’actions de prévention et d’éducation thérapeutique pourront s’appuyer sur ces nouvelles données pour enrichir leurs programmes. En rompant avec une approche souvent normative des déterminants sociaux de santé, habituellement utilisés dans les travaux sur les inégalités sociales de santé, cette étude propose ainsi une approche inductive prenant en compte les interactions entre soignants et soignés et la diversité des habitudes de vie. | The lifestyle habits of people with chronic debilitating diseases are poorly understood, yet taking them into account is essential for effective long-term care. Myotonic dystrophy type 1 (MD1 or Steinert) is a rare and chronic disease with specific characteristics: it is genetic, progressive, impairs several functions, and its treatment is currently exclusively symptomatic. Given this complexity, the medical approach can relatively easily integrate this clinical diversity into interdisciplinary care, but it is more complicated from a relational point of view. The objective of this qualitative study was to understand the changes in lifestyle and the social determinants of coping strategies in men and women over the age of 20 whose symptoms of MD1 appeared in adulthood. This is a social science and nursing science study based on a healthcare issue and an ethnosociological approach. The study revealed different types of patient behavior based on a combination of factors: age, social and professional status, family situation, values and beliefs, living environment, etc. It revealed the gap between the medical representation of the disease and the daily, socialized experience of patients. The different stages that patients go through provide insight into their coping strategies and prompt reflection on ways to improve their care. | Humanities and Social Sciences 1 | |
| 2013 | Federico DI ROCCO | Paris | Foundation For Rare Diseases | Craniosynostosis | Craniosynostosis: how to improve the announcement of the diagnosis and support patients and their families? | Context: this project is part of a collaborative effort involving social science researchers, a medical team and neuropsychologists from a reference center for patients with craniostenosis, and a dedicated patient association. Craniostenosis is a primitive growth abnormality of the cranial skeleton associated with premature closure of one or more cranial sutures. These malformations - some forms of which are genetic in origin - have morphological as well as functional implications: cranial and facial dysmorphia with psychological consequences in terms of relationships with others, and a potentially degraded self-image; but also a growth conflict between cranium and brain, which can lead to cerebral compression, mental retardation, learning difficulties and visual disturbances. Treatment is surgical. It aims to correct the deformation of the cranial skeleton, while normalizing intracranial pressure and helping to prevent complications. The moment of the announcement in the Reference Center is crucial because of the impact it has on the child himself, on the parents' view of their child and on the view of others (siblings, educational team, carers, etc.), as well as on the place of the dysmorphic child within the family scheme. Aims: to improve diagnosis and management: 1. better understand the experience of the announcement for patients and their families 2. improve understanding of the announcement and its appropriation according to the patient's age 3. identify intra-family issues surrounding the announcement of a genetic mutation 4. reconstruct the patient's care pathway by analyzing the consequences of the announcement time. Methods : In order to achieve the objectives of this research project, it was deemed appropriate to use a combination of quantitative and qualitative methods, combining a desire for an exhaustive approach with the consideration of subjective elements during the announcement. This research will favour a longitudinal perspective. The methodological tools to be developed are interview guides, questionnaires and observation reports. For the qualitative part, complementary analyses of two types will be carried out: a thematic content analysis of the verbatims, and an interpretative analysis aimed at reconstructing the subjects' journeys, avoiding the division caused by the thematic analysis. For the quantitative part, cross-tabulation will be used. Expected results: A typology of the forms of announcement will highlight the issues linked to the specificities of the disease, such as the announcement of the genetic mutation, and will enable improvements to be made in this area, as well as in the management and support of parents. Oral presentations will be given at the study day organized by the Centre de Référence des dysostoses cranio-faciales, at the annual Patients' Association day, at the Craniofacial Surgery congress and at social science symposia. The presentations will focus on research findings and present the specificities of the care pathway for these patients, particularly with regard to the announcement phase. Dissemination within the scientific community is envisaged through two publications in international peer-reviewed scientific journals. Impact of the project: This research will help to identify the specific features of the announcement phase and of patient support by taking into account the diversity of patient pathways, by analyzing patient pathways. The originality of this research lies in the interdisciplinarity of the teams involved, and the cross-fertilization of perspectives from the different professional fields involved. The aim of this research is to provide medical teams and patients with a better understanding of the announcement process and the support provided to patients and their families, with a view to improving the announcement protocol. It will also provide an inventory of the current situation, a prerequisite for drawing up part of a national plan for the diagnosis and care of craniostenosis. | Craniostenosis is a primitive abnormality in the growth of the cranial skeleton associated with the premature closure of one or more cranial sutures. It is a rare condition. These malformations—some of which are genetic in origin—have morphological and functional implications: craniofacial dysmorphia leading to psychological and social consequences in terms of interpersonal relationships and a degraded self-image; but also a growth conflict between the skull and the brain, which can cause cerebral compression, mental retardation, or visual disturbances. Treatment is surgical. It aims to correct the deformation of the skull while normalizing intracranial pressure and helping to prevent complications. The overall objective of this retrospective, quantitative, and qualitative research was to understand the impact of a diagnosis of craniosynostosis with a view to improving the delivery of the news. The results of our research show that this malformation has repercussions not only for the dysmorphic child, particularly in terms of school and social life, but also for their siblings in terms of empowerment, feelings of injustice, and relationship problems with parents. Significant differences appear in terms of the form of craniostenosis, but also in terms of the child's gender. These elements confirm the impact of craniostenosis on all areas of life (identity, school, social, professional, and family) and the importance of appropriate support from the Reference Center as soon as the diagnosis is announced. | Humanities and Social Sciences 1 | |
| 2013 | Herve CHAMBOST | Marseille | Foundation For Rare Diseases | Haemorrhagic diseases | Input of a multidisciplinary management approach in announcing the diagnosis for young children with serious constitutional haemorrhagic diseases and their families | Severe hemophilia and associated severe forms of constitutional hemorrhagic disease (CHD) expose patients to recurrent joint and muscle bleeding, which is a major factor in the functional prognosis of these conditions. Although modern therapies have radically transformed these patients' life expectancy and orthopedic status, the occurrence of complications such as cerebral hemorrhage or the development of an inhibitory antibody can significantly alter the prognosis. The announcement of the diagnosis of these rare pathologies, which usually occurs in an infant, represents a definite trauma. Changes in the psychological functioning of children with hemophilia and their parents have been described. The evidence of psychomotor development disorders in these children points to the impact of hyperprotective behavior on the part of the parents, which can be identified as soon as the diagnosis is announced. The development of preventive therapeutic approaches using long-term prophylactic substitution (LDP) aims to improve orthopedic functional prognosis by reducing spontaneous joint bleeding. However, the success of such prophylaxis can be hampered by a number of factors, of which poor compliance is an important one. At the hemophilia treatment center, we have developed a multi-disciplinary support system to accompany the announcement of the diagnosis, focusing on a psychological approach and reassurance, with the aim of facilitating psychomotor development, improving quality of life and encouraging acceptance of early prophylaxis. This program, which includes a variety of actions (individual psychological interviews, discussion groups, "Chemin faisant" workshop, therapeutic education program), is set up very early on after the announcement and is carried out in conjunction with the Association Française des Hémophiles (French Hemophilia Association), which offers complementary actions, notably within the framework of its family commission. In this context, we propose to set up a monocentric, descriptive, cross-sectional pilot study for around 30 children aged 2 to 10, suffering from hemophilia or associated HCM and cared for at the Marseille CRTH as soon as they are diagnosed. For these children, who have therefore been able to benefit from all or part of the diagnostic announcement support system over the past 10 years, the aims of our study are as follows: 1/ Primary objective: to study adherence to prophylaxis recommendations and quantify compliance with treatment, in relation to participation in the scheme offered by the CTH. 2/ Secondary objectives: 2a/ to compare adherence results for the Marseille CTH patient population with those analyzed in other centers (data from a PHRC currently underway); 2b/ to describe the psycho-affective state of the patient and his or her entourage (parents), as well as their appropriation of the disease, in our model of care which favors the intervention of a psychologist; 2c/ to describe the quality of life of this population. The tools used for this research will include - Analysis of PLD compliance data (N days of prophylaxis and treatment regimen) - Clinical assessment, based on the number of joint bleeds over a period of time and an orthopedic score - Psychological and psychopathological assessment through detailed tests - A detailed study of quality of life, using questionnaires adapted to the evaluation of children's QOL by themselves and/or by their parents according to age, but also studying the parents' QOL. This type of single-center study will be a prerequisite for larger-scale studies, to determine the real impact of making this type of organization available in pediatric HTCs. This study, and any others that may follow, will provide a basis for discussion of the possibility of allocating budgets specifically for this type of care in other centers, as described and implemented in our center. | Severe hemophilia and associated severe forms of constitutional bleeding disorders (CBD) constitute a group of rare diseases for which modern therapies have radically improved patients' life expectancy and health status. The natural progression of these diseases, marked by repeated joint bleeding, leads to degenerative damage that causes disability. The orthopedic status of patients can be preserved through preventive treatments. The diagnosis of such a condition at a very young age causes psychological trauma for parents, whether or not they are already aware of cases in the family. Among other consequences, the implementation of overprotective measures following this diagnosis could hinder the psychomotor development of these children. Based on this clinical observation, we have developed, in collaboration with the patient association, a multidisciplinary support system for the diagnosis announcement that focuses on a psychological approach and reassurance. The pilot study carried out as part of this call for projects aimed to evaluate this system in the population of children who have benefited from it since the diagnosis announcement in our center. This study, which included 21 children, or 95% of the eligible population, shows an improvement in the emotional state, psychomotor development, and quality of life of patients participating in the program. The quality of life of parents also appears to have improved as a result of participating in the program. These results support the extension of such a program to other centers in France. | Humanities and Social Sciences 1 | |
| 2013 | Maria TEIXEIRA | Paris | Foundation For Rare Diseases | Sickle cell disease - Cystic fibrosis | Transition and insertion in the adult world of young people with sickle cells disease or cystic fibrosis | Contexte : La drépanocytose est une maladie autosomique récessive. Cette pathologie se caractérise par une modification de la forme des globules rouges qui entraîne une anémie dite anémie falciforme et des douleurs chroniques aiguës, de graves infections bactériennes et des nécroses. Cette maladie atteint surtout les populations d’Afrique, de certaines régions méditerranéennes, du Moyen-Orient et d’Asie. Chaque année, en France métropolitaine et dans les Dom Tom environ 400 nouveau-nés viennent au monde avec un syndrome drépanocytaires clinique majeur dont 250 à 270 en Ile-de-France. Cette pathologie nécessite une prise en charge médicale qui s’étend de l’enfance à l’âge adulte. Celle-ci implique que les jeunes passent d’une prise en charge pédiatrique à une prise en charge adulte par un processus de transition or celui-ci pose des problèmes ayant des conséquences sur leur qualité de vie médicale et sociale. Objectifs : Notre perspective de recherche est constituée de deux axes. D’une part, nous évaluerons rétrospectivement la transition de la médecine pédiatrique vers la médecine adulte et d’autre part nous analyserons l’impact de cette transition sur la socialisation des jeunes atteints de drépanocytose. Nous évaluerons les réussites et les échecs du dispositif mis en place à l’hôpital Robert Debré par les Dr Benkerrou et Lionnet pour accompagner la transition de la médecine pédiatrique vers la médecine adulte. En effet, certains jeunes parviennent à s’insérer au monde médical et social adulte, mais d’autres n’y parviennent pas, sont perdus de vue et d’un point de vue sanitaire mettent leur santé et parfois leur vie en danger. Aussi nous nous interrogerons sur l’impact de la réussite ou de l’échec de cette transition sur l’insertion sociale de ces jeunes. Nous nous attacherons à l’analyse des dimensions somatiques et des expressions sociales des émotions. Nous étudierons les représentations sociales de la douleur et de la maladie, les représentations du corps individuel et du corps familial et la place de ces jeunes malades au sein de leur famille. Nous analyserons l’impact de ces représentations et de cette place sur le vécu des maux et l’insertion sociale, qu’elle soit scolaire, professionnelle, affective ou médicale. Une problématique en termes d’origine géographique devra également être conduite puisque la drépanocytose associe le stigmate de la maladie à celui des origines et de la migration. Méthodes : Notre approche méthodologique est pluridisciplinaire. Nous associons ici à la fois des thérapeutes et des professionnels des dimensions sociales de la maladie. Seront réalisés : • 24 entretiens individuels avec des jeunes de 18 à 25 ans dont la transition en médecine adulte est effective. Parmi ces 24 jeunes, 12 auront réussi leur transition et 12 seront en rupture de suivi. Les entretiens se dérouleront au domicile des patients. • 24 entretiens individuels ou en groupe avec les membres de la famille présents au domicile le jour de l’entretien avec le jeune. • Des entretiens avec les professionnels de santé qui ont suivi les jeunes jusqu’à leur transition et qui connaissent l’histoire clinique des patients. Au sein des entretiens, nous identifierons les thématiques qui émergent et les récurrences. Chaque entretien fera l’objet d’un portrait résumé récapitulatif et problématisé qui rend compte de manière synthétique de l’expérience singulière de chaque interviewé. Nous observerons les conditions de vie des patients et de leur famille. Nous consignerons sur un carnet de terrain les discours informels. Les matériaux recueillis (entretiens) et élaborés (portraits résumé, notes de terrain) seront organisés dans le logiciel Nvivo10. Résultats attendus et impact : Cette étude nous permettra de recueillir des données : (1) sur les représentations de la douleur, de la maladie et le vécu de la transition du point de vue des jeunes et de leur famille, (2) afin d’évaluer rétrospectivement l’efficacité de l’accompagnement entre médecine pédiatrique et médecine adulte. (3) Ainsi nous améliorerons la qualité de cette transition pour qu’elle ait un impact positif sur les stratégies développées par les patients pour s’insérer au niveau scolaire, professionnel, affectif ou médical. (4) Ceci nous permettra de mettre en place une meilleure prise en charge des difficultés psychologiques spécifiques rencontrées par les jeunes atteints de drépanocytose. (5) Par cette recherche nous contribuerons à l’identification des différents mécanismes sociaux qui favorisent les discriminations. Ainsi nous pourrons les déconstruire et les révéler. Pertinence du projet au regard de l’état des connaissances : Peu de recherches sur les dimensions sociales et culturelles du vécu de la drépanocytose existent en France et une seule recherche sur la transition de la médecine pédiatrique vers la médecine adulte dans cette pathologie est en cours. Aucune évaluation de cette transition n’a pu encore être effectuée ni l’impact d’une réussite ou d’un échec de cette transition sur l’insertion sociale des jeunes. | Humanities and Social Sciences 1 | ||
| 2013 | Melanie JACQUOT | Strasbourg | Foundation For Rare Diseases | Neuromuscular disease | Clinical and psychopathological approach of neuromuscular disease on gender identity | The onset of a rare neuromuscular disease leads to limitations in bodily performance. Yet sexual identity, as the feeling of recognizing oneself and being recognized as belonging to a gender, directly involves the body, in its performative and relational dimension. While the question of sexuality in disabled people is currently the subject of a great deal of research, we propose an original approach that shifts sexual identity away from genital sexuality and inscribes it in an intersubjective dimension. Current psychological research on sexual identity reveals that it remains dependent on the gaze of others, and particularly subject to the events that punctuate the subject's life, such as the onset of illness. Using a qualitative methodology (semi-structured interview, projective tests) and a quantitative one (questionnaires on quality of life, depression, anxiety and family functioning), this research aims to assess the effects of the onset of a neuromuscular disease on sexual identity as it is understood in its relational dimensions: love, family and work. In addition, we wish to explore the impact of family economy, professional maintenance and the relationship with caregivers in the reorganization and rearrangement of sexual identity specific to rare neuromuscular diseases. The aim of this descriptive research is to identify concrete actions to be developed in the context of the psychological care of patients, and in particular : - identify possible risks of psychopathological decompensation (particularly the presence of depressive elements) - identify family dynamics and the support provided by parents and siblings - train and support those involved in the patient's professional integration - assess the need for psychological support. The proposed descriptions of the psychological impact of rare neuromuscular diseases, and the avenues for action identified in relation to career paths and the organization of care, could be used to benefit descriptions of other rare diseases. | Les hypothèses directement centrées sur la problématique de l’identité sexuelle ont été en partie réfutée par les éléments cliniques, lesquels révèlent la centralité de la mise à l’épreuve de l’identité. La question de l’identité sexuelle apparaît secondaire au vu de l’analyse partielle des résultats.L’analyse des entretiens de recherche révèle que, pour les personnes rencontrées, la particularité des maladies neuromusculaires réside dans une symptomatologie qui, souvent dans les premiers temps de la maladie, ne se repère pas comme spécifique d’une atteinte somatique, ce dont témoigne tout particulièrement l’errance diagnostique très souvent traversée par les personnes rencontrées. La fatigue inexpliquée, ces douleurs diffuses, ces sensations perturbées brouillent les repères d’un corps qui leur échappe et provoque chez chacun une sensation d’étrangeté à soi-même, souvent renforcée par l’incapacité des médecins à poser, rapidement, un diagnostic sur leur trouble. (hypothèse 2) Or, cette étrangeté se trouve redoublée par une autre spécificité de ce type d’atteinte « invisible »: la maladie ne se porte pas d’emblée au regard de l’autre. Ce travail de recherche nous a amené à proposer une conception originale de la notion d’identité. Si cette dernière peut en effet paraître centrale en psychologie, sa conceptualisation est beaucoup plus complexe. L’identité est couramment rapprochée d’une modélisation « statique » issue de la sociologie, dont la dimension de stabilité se rapproche du sentiment continu d’exister décrit par D.W. Winnicott (le self). Or, la place centrale faite au regard de l’autre dans la déstabilisation de l’identité des sujets rencontrés, consécutive aux symptômes des MNM rares, souligne la nécessité de s’appuyer sur un modèle qui place comme centrale la place de l’autre dans le fonctionnement psychique. C’est à partir de là que nous proposons l’idée d’un récolement de l’identité dans le sens d’un mouvement permanent de vérification, dans la relation à l’autre, de ce qui est tenu par le sujet comme véritable constituant de son identité. A la lumière de cette proposition théorique, l’analyse de l’expérience rapportée par les personnes rencontrées dans le cadre de cette recherche révèle toute la singularité de l’expérience des MNM rares sur les réaménagements de l’identité. Les sujets rencontrés témoignent de ce que la symptomatologie des MNM rares vient troubler leurs éprouvés corporels du sujet sans qu’ils ne puissent d’emblée leur donner sens, ce qui provoque chez eux un sentiment d’étrangeté à soi-même. Toujours identique et pourtant si différent. Ce sentiment d’étrangeté engendre une destabilisation profonde de l’identité du sujet. La sécurité interne constituée sur l’expérience du sentiment continu d’être soit (dimension statique de l’identité) est ébranlée. Face aux bouleversements de leurs repères internes, les sujets rencontrés vont chercher, d’abord dans le regard de leurs proches et tout particulièrement de leur conjoint si ils vivent en couple, à valider les changements qu’ils perçoivent de leur propre corps (dimension récolative de l’identité) (hypothèse 3). Si ce sentiment d’étrangeté est souvent accentué par une non-reconnaissance par les proches, des changements vécus par le malade, cette attitude du sujet révèle l’exigence de mise en sens face à laquelle le place la survenue de la maladie. Dans cette perspective, nous avons pu relever chez certaines des personnes rencontrées, que des évènements de vie propres aux sujets atteints d’une NMN rares pouvaient opérer comme des réorganisateurs de sens, véritables aides à la nécessite du travail psychique. Ainsi, ce constat nous a amené à nous décaler d’une approche seulement traumatique de l’annonce du diagnostic. Ce dernier peut en effet opérer comme véritable déclencheur de ces réaménagements psychique au travers, par exemple, de la façon dont le sujet va s’en emparer pour (re)donner sens à une symptomatologie diffuse. De même, les effets des évolutions « visibles » de la maladie et l’introduction, par exemple, d’aides techniques peuvent alors être envisagées comme participants pleinement à ce travail d’élaboration psychique. Bien que la nature, l’évolution et les symptômes de la NMN rare affectant les personnes rencontrées dans le cadre de cette recherche ont pu être très variables, toutes décrivent une perte d’autonomie certaine consécutive à l’évolution de la maladie qui les conduit à envisager une dépendance nouvelle à leur entourage. Cette situation les confronte à l’absence de maîtrise et ainsi à la dimension de la passivation, ce qui est finalement assez classique dans le cas des maladies somatiques évolutives. Or, il apparaît que, pour les personnes encore en activité professionnelle, la problématique de l’autonomie, dans ses rapports avec l’autre, peut se trouver redéployée à nouveau frais dans l’expérience subjective du travail (hypothèse 5). Ainsi les réaménagements de la vie professionnelle (adaptation du poste de travail, changement de poste, de profession,...) sont autant d’occasion de mise au travail psychique permettant de réenvisager, par exemple, la question de l’autonomie dans le travail voire même de l’histoire de son parcours professionnel, comme autant de possibilités de poursuivre l’exercice de la créativité singulière. | Humanities and Social Sciences 1 | |
| 2013 | Pascal JOLY | Rouen | Foundation For Rare Diseases | Pemphigus | Identification of vulnerability factors in the course of pemphigus patients | Context: The etiological diagnosis of rare diseases with developmental anomalies is still too often unknown, leading to medical wandering, prolonged diagnostic searches and incomprehension on the part of families. Moreover, this represents a potential loss of opportunity for access to appropriate genetic counseling, optimal follow-up and possible therapeutic resources. The dynamic progress observed over the last two years in terms of technological innovation points to a veritable revolution in diagnosis, research and treatment for patients. Following on from the diagnostic discoveries made possible by the widespread use of DNA chips, high throughput sequencing (HTS) is set to transform the field of developmental pathologies considerably, from basic research to care. However, before transferring this technology into daily practice, particularly for exome HDS diagnostic expertise, we need to be able to anticipate the information that needs to be communicated to patients and parents in order to consent to exome HDS, and the questions raised in terms of diagnostic announcement (uncertain results, incidental results of chance discovery). These questions go beyond the use of technology, and represent a real societal challenge, requiring the involvement of teams from the human and social sciences, in particular psychologists, sociologists and ethicists, to ensure that patients suffering from rare diseases can benefit from innovative technologies under optimum conditions of information and support. This project is the initiative of 2 Maladies Rares Anomalies du Développement et Syndromes Malformatifs reference centers, which have joined forces with teams from the Human and Social Sciences at the University of Burgundy, the "Ethics and Medical Progress" research team led by the Espace de Réflexion Ethique Bourgogne/Franche-Comté within Inserm CIT 808 at the Besançon CHRU, and patient associations. Objectives: The aim of this project is to develop the modalities and content of the information to be provided to parents and prescribing physicians in order to consent to the performance of an HHS. The aim is to anticipate clinical practices in terms of prescribing, diagnosis and support for patients/families. Methodology: The project will be carried out in three phases: 1/ Qualitative study among parents, prescribing physicians and geneticists who will announce the results, concerning their expectations, representations and issues linked to the arrival of high-speed sequencing. Individual interviews will be conducted using human and social science methods, by a researcher trained in clinical and qualitative research. 2/ Collection, from the 8 French FeCLAD centers and European reference centers, of information and consent documents and procedures currently in use. 3/ Design by a multidisciplinary group of the methods and content of the information to be given to doctors and parents, based on the results of the qualitative study, the documents collected and the synthesis of the relevant literature. Definition by this group of a protocol for evaluating the implementation of the selected information actions. Expected results and impact: This will have repercussions in terms of anticipating the announcement, training doctors, setting up appropriate support for families, providing a basis for reflection on the drafting of consents at national level, and discussing how to improve the organization of care, particularly in delicate situations. Relevance of the project to the current state of knowledge: In the absence of national regulations governing the use of this technology, it is necessary for groups to initiate discussions on the information to be communicated, in order to anticipate the arrival of HDS as a diagnostic tool in daily practice. The teams involved in this call for projects have already begun to think about this issue, and have operational teams in their laboratories who can rapidly implement these techniques, and therefore feel the need to be able to answer the questions posed. | Une trajectoire diagnostique différenciée socialement ? L'expérience des trajectoires diagnostiques apparaît socialement située. Les épargnés se retrouvent davantage chez les catégories les plus populaires, alors que les catégories moyennes et supérieures se retrouvent davantage parmi les vulnérabilisés et les écorchés. Considérer que ces catégories plus privilégiées pourraient rencontrer davantage de difficultés à obtenir un diagnostic s'opposerait à la fois aux constats récurrents dans les pays du Nord et à la littérature scientifique largement établie depuis les années 1970. En outre, les classes populaires n'accèdent pas plus rapidement au bon diagnostic. Par conséquent, tout laisse à penser que les catégories sociales les plus privilégiées en tiennent davantage rigueur aux médecins et développent davantage de méfiance suite à ces expériences douloureuses. Les catégories populaires développent plutôt des formes de résilience. Elles semblent moins armées pour dénoncer ces expériences difficiles. Des trajectoires de PVP sont marquées par la progressive mise en cause du pouvoir médical avec ses limites, parfois sa violence. Trois postures médicales sont particulièrement dénoncées : - la négligence (le sentiment de ne pas être pris au sérieux est particulièrement perceptible parmi les femmes qui semblent davantage en faire l'expérience et l’exprimer), - le défaut d'engagement des médecins, - l'immodestie professionnelle (et notamment le fait de ne pas reconnaitre ses difficultés face aux symptômes). De manière assez remarquable, c'est moins l'incompétence que la manière dont les PVP peuvent être prises en charge et faiblement écoutées qui est le plus souvent dénoncée. Au centre des difficultés morales et psychologiques de ces PVP se trouve donc le manque de reconnaissance en tant que malade, et plus largement en tant que personne. A l'issue de cette épreuve diagnostique, et malgré la dénonciation - pour nombre d'entre eux - de comportements professionnels déplacés, rares sont ceux qui cherchent réparation (au sens judiciaire), et même aucun à notre connaisance, comme s'il s'agissait d'une suite d'évènements à oublier. Pour la majorité, la critique est localisée, isolée, et ne peut être généralisée au monde médical, en particulier si les médecins qui les suivent aujourd'hui leur donnent satisfaction. En ce sens, cette série d'expériences ne semble affecter qu'à la marge les relations médecins-patients une fois le diagnostic posé. On relève toutefois des dispositions plus critiques chez les PVP à l’égard des médecins et du système public de prise en charge du pemphigus. A la suite de cette expérience, les associations de malades ont un rôle essentiel. Elles permettent, en effet, de redéfinir comme injuste et immorale une situation précédemment perçue comme le résultat de l'infortune d’une trajectoire singulière. Dans cet environnement, l'expérience du mépris médical peut être partagée, et donc retraduite comme une forme d'injustice partagée. Le passage de l'expérience du mépris à la dénonciation de cette expérience est facilité par le constat d'une épreuve collective. Les dimensions de genre dans l’expérience de la maladie Dans notre enquête, les hommes sont moins enclins à faire part de leurs états d'âme autour d'eux, ce qui est ailleurs relevé dans la littérature (Seale et al., 2006). Ils se focalisent davantage sur les aspects techniques de leur maladie, sur les informations qu'ils peuvent glaner. Une première piste d’analyse, classique, sous l’ange des masculinités et féminités hégémoniques , se dessine. Les hommes vivant avec un pemphigus semblent ici plus à même de mettre à distance l’expression de leurs difficultés. Ils ne demandent pas explicitement de l’aide, mais la reçoivent fréquemment, notamment de leur conjointe. Les femmes au contraire sont davantage portées à valoriser l’expression du soutien émotionnel, et à rapporter parallèlement davantage d’attentes déçues. En rapport à leurs attentes, les femmes semblent également disposer d'un moindre espace d'attention : les aidants hommes apparaissent ainsi moins attentifs aux signes de la maladie de leur compagne. Les hommes malades apparaissent ici à la fois protégés (par les mécanismes classiques du care), mais également moins à même, pour certains au moins, d’évoquer leurs difficultés (par leur adhésion à une masculinité rejetant la plainte). Ces rapports au care doivent donc être associés tout à la fois à des attentes, elles-mêmes liées à des manières d’incarner les féminités et les masculinités, et aux manières de faire de l’entourage. Surtout, ces effets sont cumulatifs : les attentes, partiellement construites par les dimensions de genre, rencontrent des attitudes elles-mêmes partiellement déterminées par les dynamiques de genre. L’expression traditionnelle du genre offre donc une première toile d’explication, mais sans doute partielle. Prendre en compte la perspective du proche offre de la richesse à l’analyse car, bien souvent, celui-ci s’engage, à sa manière. Ces proches expérimentent d’ailleurs le sentiment de se trouver sans soutien (helplessness), et composent avec les perturbations émotionnelles (Miller, Timson, 2004). Difficile pour eux de savoir comment se comporter. La plupart des compagnons se renseignent sur la maladie, montrant ainsi qu’ils ne s’en désintéressent pas, mais qu’ils l’expriment dans des cadres qui ne correspondent pas toujours aux attentes de leur compagne. Et c'est là, en creux, l'une des clés de ce processus d'isolement : les attentes ne sont pas toujours exprimées ou comprises, et peuvent même être refoulées par une distribution minimaliste de l'information, alors même que le manque d'attention est source de frustrations. Cette altération des relations conjugales et de la compréhension mutuelle, dont les femmes malades sont les principales victimes, est exacerbée quand elle ne se révèle pas dans le cadre de la maladie. La vie avec un pemphigus exige de construire un nouveau mode de communication, toujours à négocier avec le partenaire. Dans le cadre de cette enquête, au niveau des relations aux proches, l’expérience la plus difficilement vécue est donc le manque de soutien émotionnel. La répartition et la redistribution des tâches domestiques font très peu l’objet de plaintes, quand bien même elles apparaissent largement inégalitaires au regard extérieur. Un nombre conséquent de femmes aménagent par exemple leur temps disponible - rognant sur leur temps de travail ou de loisirs -, afin de poursuivre l’activité domestique, et cela malgré la fatigue. L'énergie disponible est redéployée pour la pérennisation du foyer (Wilson, 2007), mais aussi pour la normalisation du quotidien, pour la personne malade comme pour les autres, et notamment les enfants. Globalement, les difficultés à l’égard du care, quand elles sont relevées, sont donc liées aux fondements de la relation conjugale et au défaut de soutien émotionnel du conjoint. Cette frustration n’est toutefois pas unanimement relevée chez les femmes vivant avec un pemphigus : la moitié de notre population n’en fait ainsi pas mention, et s’estiment même soutenues par leur entourage, et leur compagnon en particulier. Et certaines femmes malades - minoritaires il est vrai - considèrent que cette épreuve a même renforcé leur couple. Les configurations sont multiples, et évolutives dans le temps, et différencient radicalement les expériences de la maladie. Nous constatons aussi que cet investissement largement féminin dans les activités du care est également associé à l'acquisition de dispositions et de connaissances en lien avec la prise en charge antérieure de proches malades. Tout se passe comme si l’investissement passé dans cet accompagnement était prédictif d’une action de soutien ensuite. L’expérience de la maladie d’un proche et son accompagnement, parfois jusqu’à la mort, semblent agir comme un « évènement sentinelle » (Thébaud-Mony, 2008, 243). S’être occupé directement d’une personne malade active en quelque sorte des compétences mobilisées lorsque la maladie frappe de nouveau et s’installe au long cours dans une famille. Ces mécanismes entretiennent une division du travail genrée qui, d’une certaine manière, s’auto-justifie : les tâches dont se sont investis certains membres de la famille créent des attentes. Il devient légitime de les reproduire. Ainsi, qu’elles le vivent ou non comme une charge, les éléments qui pèsent sur les femmes aidantes sont multiples. Et ce rôle d’aidant, parfois gratifiant, n'en est pas moins enfermant, dès lors qu'il se présente comme un devoir moral, comme ici lorsqu’il touche la santé d'un proche. Fréquemment associé à un travail de compassion, les logiques le sous-tendant peuvent être davantage coercitives, mêlant sentiment de responsabilité, de dette ou même sens du devoir (Cresson, 2006). Surtout, le rôle de soutien s'accompagne d'une charge mentale importante (Røthing et al., 2015). Entre la légitimité à s'immiscer dans les problèmes de santé d'un proche, la volonté et le devoir moral de le faire, les frontières sont troubles. Elles sont négociables, parfois, mais de manière implicite le plus souvent. La délégation des tâches ménagères : un support négligé dans l’expérience de la maladie Les réticences à déléguer certaines tâches domestiques, en particulier en lien avec les enfants, sont à lire au croisement de deux faisceaux d'interprétation : le maintien de l'identité et de la vie d'avant, mais relève aussi de l'ordre de la contrainte et de la négociation à l'intérieur du foyer. Le renversement des rôles n'est ainsi pas, loin s'en faut, acquis lorsque la femme tombe malade. Elles sont au contraire nombreuses à tenter de garder certaines responsabilités à la maison, même si elles doivent pour cela être aidées, ou aménager leur emploi du temps ou leurs manières de faire. Il faut répondre selon les jours au besoin, plus que de tout faire continuellement (Richardson et al., 2007). Et cela est particulièrement visible dans les ménages où la répartition des tâches était traditionnelle avant la maladie. Réaménager ses temps de loisirs et de travail permet de conserver son identité, et en particulier son identité de mère et de femme du foyer pour nombre de ces PVP. Comme le suggère Wilson (2007), les individus touchés par la maladie sont amenés à recentrer leurs activités sur ce qui fait sens, notamment quand d'autres types d'identité (au travail en particulier) sont en péril ou n'existent plus. Pour les hommes atteints de cette maladie rare, la normalisation semble pour beaucoup s’effectuer davantage par le travail (salarié). Le processus de normalisation par le travail vaut également pour quelques femmes, mais dans une moindre mesure. Cette normalisation par le travail est facilitée par le filet de sécurité dont bénéficie une partie de ces hommes. Les conjointes prennent, en effet, fréquemment en charge des tâches qui rendent possible la continuité de cette vie « comme avant ». Xavier en est un bon exemple, lui qui a limité au maximum les jours de congé pour poursuivre son activité professionnelle. La corticothérapie l'astreignant à un régime à très faible dose de sel et de sucre, c'est sa femme qui « lui fai[sai]t [ses] gamelles » et change même pour cela sa propre alimentation. Quand il se révèle trop faible physiquement, c’est elle encore qui le conduit et le soutient dans ses actions quotidiennes, lui permettant ainsi de poursuivre sa vie professionnelle, particulièrement intense, en adaptant à la marge son quotidien. Dans ce cadre, on peut d’ailleurs supposer que la mise en place d’un double plat pour le repas est un risque, à terme, pour la perpétuation du régime alimentaire pour la PVP. Outre la tentation, c’est davantage la difficulté pratique et l’exclusion du « faire-famille » qui se joue. Et si nous avons peu de personnes mettant clairement en évidence cette causalité, elle nous semble toutefois une potentialité non négligeable. C’est le cas de Géraldine, qui a abandonné son régime : « faire à manger pour les autres et puis vous, à côté, manger autre chose, vous ne pouvez pas faire ça. » Les changements biographiques pluriels des vies avec pemphigus Les trajectoires des PVP prennent des formes très différentes, à la fois dans leurs réalités objectives, mais aussi subjectives. A atteintes similaires, le vécu de cette maladie peut différer drastiquement. Les éléments participant à la continuité biographique sont d’ordre différent, nous l’avons vu. Il croise, encore une fois, les solidarités familiales et amicales, parfois augmentée par l’épreuve de la maladie rare. En focalisant sur la rupture ou au contraire sur la continuité biographique, nous avons pu saisir les variations des situations, et surtout les différentes manières de les vivre. L’absorption du choc des premiers symptômes et du diagnostic est plus ou moins aisée. Vivre avec une maladie rare auto-immune conduit ponctuellement ou plus durablement à des incapacités avec lesquelles il s’agit de s’accommoder. Ces nouveaux engagements, quand ils sont pris, cristallisent ce que des auteurs ont proposé d’appeler des « alternations » (Beauchez, 2014). La personne participe à trans¬former sa réalité subjective en opérant sur les principales blessures de son parcours. En prenant soin de ce corps malmené par l’atteinte de la maladie rare et de ses traitements, la personne panse/pense ses blessures, et restaure une capacité d’action à la fois d’un point de vue moteur (de nouveaux mouvements sont expérimentés, appris, intégrés…), à la fois d’un point de vue axiologique en adoptant de nouvelles valeurs (douceur, assurance, détente). Si nous essayons de mettre en lien ce sentiment de rupture biographique avec d’autres caractéristiques des enquêtés, la situation apparait complexe et parfois ambivalente. Le plus souvent les PVP de ce sous-groupe vivent avec un pemphigus depuis quelques années seulement et se situent dans la moyenne de temps de vie depuis le diagnostic de notre corpus. Tout se passe comme si l’avènement du pemphigus, plutôt récent, focalisait leur attention au point de le considérer comme un point de véritable bascule dans leur vie. Le choc de l’annonce semble perdurer que cette dernière soit « bien » ou « mal » menée et reçue par la PVP (Giraudet, 2006). Soit quelque chose comme une « vision » d’un choc à court et moyen termes. Deux exceptions sont notées dans ce sous-groupe avec des personnes qui, elles, vivent depuis beaucoup plus longtemps avec la maladie (presque deux décennies). Après presque deux décennies de vie avec le pemphigus, cette maladie n’intervient sans doute plus autant comme une mort annoncée. Le pemphigus a, en ce sens, perturbé leur quotidien, comme un évènement malvenu qui a bouleversé la suite de leur vie, et continue de le faire (en raison des rechutes, des traitements supplémentaires et des conséquences iatrogènes des traitements qui se révèlent à plus long terme comme l’ostéoporose). Notons en outre que réfléchir en termes de ruptures versus continuité ne permet pas d’appréhender toute la complexité de ces trajectoires. Pour certaines PVP, rares finalement, leur trajectoire biographique s’apparente davantage à une bifurcation suite à la maladie, comme une évolution différente, bien davantage qu’une rupture radicale. L’arrivée de la maladie peut alors engager à une remise en question de son rapport à la vie, sous ses différentes formes. Ce peut être le cas dans le monde du travail, lorsque des changements d’emploi sont envisagés, révélant par exemple des aspirations profondes. La bifurcation apparait aussi aux détours des changements induits par le traitement ; certaines PVP ont accepté ce changement de vie imposé par le traitement initial, par exemple en adoptant un régime alimentaire spécifique, qui, au final, leur convient plutôt et qu’ils maintiennent une fois le traitement terminé. Des inégalités sociales dans l’accès aux loisirs De manière intéressante, nous avons pu noter une cristallisation des inégalités dans l’accès aux loisirs après la maladie, alors que ces inégalités, dans notre enquête, se révèlent avec moins d’acuité ailleurs. Rappelons que les activités physiques et sportives, et plus largement les loisirs, sont investis différemment selon les groupes sociaux, mais aussi selon l’âge, le genre, etc. Ensuite, les pratiques physiques sont fortement plébiscitées pour améliorer la santé des populations, en tous les cas sous une forme modérée ces dernières années . Au final, la question de l’engagement dans les loisirs met à jour les contraintes et les ressources que les PVP mobilisent pour vivre mieux. Or, loin d’être futile, les loisirs participent largement au sentiment de rupture mais aussi au sentiment d’inscription dans le monde environnant. Notons pour conclure, deux autres grands types de difficultés que nous ne pourrons développer ici : les difficultés administratives, liées aux particularités des maladies rares, et du pemphigus en particulier ; les informations contradictoires quant à l’après maladie, et à l’éventualité d’une guérison, qui contribue largement à laisser la personne malade dans le doute, voire dans l’angoisse d’une rechute. | Humanities and Social Sciences 1 | |
| 2013 | Philippe ALLAIN | Angers | Foundation For Rare Diseases | Huntington disease | Behavioural disorders in Huntington's disease: Analysis and valorisation of the expertise of the patients and their caregivers | Contexte. La maladie de Huntington (MH) est une maladie neurodégénérative rare se manifestant par des symptômes moteurs, cognitifs, psychiatriques et/ou comportementaux. Il s’agit d’une maladie génétique, autosomique dominante à pénétrance complète; cela signifie que le risque de transmission pour un sujet atteint est de 50% et qu’un sujet porteur d’un allèle muté développera inéluctablement la maladie. La MH débute le plus souvent entre 30 et 45 ans, sans prédominance de sexe ni d’ethnie. L’ordre d’apparition des symptômes varie d’un patient à l’autre, mais ceux-ci conduisent inéluctablement à une démence par dégénérescence des circuits neuronaux striato-frontaux. Les personnes atteintes de MH et leurs proches rencontrent des restrictions importantes dans leur participation à la vie en société. Ces restrictions sont souvent secondaires aux troubles cognitifs, psychiatriques et aux modifications comportementales accompagnant la maladie. La situation des personnes atteintes de MH peut être analysée dans le cadre d’un modèle social du handicap, en analysant les déterminants de l’environnement, et notamment les comportements des proches, comme des facilitateurs ou des obstacles à leur participation sociale. Objectifs et rationnel L’objectif du travail vise à recueillir, décrire et analyser le corpus de connaissances des proches sur les troubles du comportement accompagnant la MH et de le transcrire dans deux registres : un registre théorique et un registre pratique. Le registre théorique visera à élaborer une typologie des interactions conduisant au processus de production du handicap. Le registre pratique se voudra plus pragmatique et formatif. Nous pensons en effet que le traitement des troubles du comportement dans la maladie de Huntington relève pour partie d’une adaptation de l’environnement relationnel du patient. A partir des données recueillies dans cet environnement relationnel et de leur formalisation théorique, nous pensons pouvoir développer un module de formation, destiné aux familles et aux professionnels, notamment du secteur médico-social, qui permettront la transmission de cette expertise d’usage. Méthodes. Il s’agira d’une étude transversale descriptive monocentrique. Une double approche quantitative et qualitative sera utilisée. La méthodologie employée consistera en un recueil de données quantitatives et une analyse qualitative fondée sur des entretiens semi-directifs de malades et de proches. La population étudiée comprendra 80 patients avec MH avérée (stades 1 et 2) et leurs proches, vivant à domicile. Le recrutement s’appuiera sur les usagers du Centre National de Référence pour les Maladies Neurogénétiques et de l'Adulte d’Angers (Coordonateurs : Pr D. Bonneau, généticien, Pr C. Verny, neurologue). Les évaluations quantitatives reposeront sur les outils utilisés dans le Centre (l'Unified Huntington's Disease Rating Scale qui évalue les facultés dans les domaines moteur, cognitif, comportemental et fonctionnel, une échelle évaluant les signes et symptômes de la dépression et de l’affaiblissement émotionnel, un auto-questionnaire des signes suggérant la dépression, une échelle du risque suicidaire, une échelle de qualité de vie, une échelle mesurant l’impact socio-économique de la MH et des problèmes de santé liés à la MH, une échelle permettant de rendre compte de l’influence d’un sujet porteur de la mutation de la MH / ou personne à risque sur la cellule familiale et l’environnement social). Nous y ajouterons des épreuves neuropsychologiques permettant d’évaluer les aptitudes à la base des conduites sociales (empathie, perception des émotions, théorie de l’esprit affective et cognitive) ainsi qu’un questionnaire ciblant les troubles comportementaux liés au syndrome dysexécutif. Les variables qualitatives recueillies seront basées sur 40 entretiens semi-directifs de « couples » patient MH-proche. Une analyse de contenu thématique sera réalisée, a posteriori. Elle portera sur le retentissement des troubles dans la vie quotidienne, la fréquence des troubles, leur évolutivité, la limitation éventuelle de la participation sociale, les attitudes aggravant ou diminuant les troubles, les adaptations mises en place par les proches. Cette analyse de contenu s’appuiera sur la méthode par catégorisation de mots et de thèmes récurrents émergeant dans les discours des sujets. Résultats attendus, impact et pertinence du projet. Les résultats quantitatifs attendus sont l’évaluation de l’importance et de la fréquence des troubles du comportement accompagnant la MH, des variables neuropsychologiques susceptibles d’en rendre compte et de leur retentissement sur la participation sociale. Les résultats qualitatifs attendus sont la description des interactions personne/environnement et de la typologie des situations aggravant ou palliant les troubles comportementaux, la description des connaissances et représentations des proches. Cette étude aura un impact sur les personnes inclues et fera l’objet d’une large diffusion par communications et publications scientifiques et par la création d’un module de formation. | - | Humanities and Social Sciences 1 | |
| 2013 | Philippe METELLUS / David TAIEB | Marseille | Foundation For Rare Diseases | Von Hippel-Lindau disease | Psychosocial consequences of screening for Von Hippel-Lindau disease in patients operated for an hemangioblastoma of the central nervous system | BACKGROUND: Von Hippel Lindau syndrome (VHL) is a serious, under-diagnosed, autosomal dominant inherited disorder predisposing to numerous tumors, some of which are malignant, such as clear-cell carcinoma, which is a major prognostic factor in this condition. CNS hemangioblastoma (HB) is one of the conditions currently recommended for VHL screening. Screening of affected subjects would enable us to diagnose around 20% of VHL subjects, and thus to detect other conditions at an early stage, since this is chronologically the 2nd condition to occur during the course of VHL. This approach poses a number of problems. Indeed, the announcement of a potentially serious disease is delicate, and there is inevitably a psychosocial impact linked to the family dimension of the disease. OBJECTIVES: The primary objective of this study is to assess the impact in terms of anxiety of genetic screening for VHL gene mutations in patients with CNS hemangioblastoma operated on in the neurosurgery department of La Timone from 1999 onwards, by comparing patients who are ultimately considered to be non-mutated with those in whom the mutation has been identified. Secondary objectives are to assess the impact of screening on various other pyschosocial parameters for these two groups, and the prevalence of other VHL-related conditions in mutated patients. This study will be carried out in conjunction with the PREDIR reference center and the VHL France association. METHOD: The primary endpoint is anxiety. Anxiety will be assessed by means of the Anxiety Trait Inventory (STAI). Secondary evaluation criteria: Depressive symptoms will be assessed using the Beck scale. Quality of life will be measured using a generic questionnaire: the SF36. Psychological consequences of screening will be assessed using the Psychological Consequences Questionnaire. These parameters will be assessed before the genetic screening is carried out and after the results are returned, Close follow-up by a psychologist will be offered to all patients. EXPECTED RESULTS AND IMPACT: 42 distinct patients were identified from the neurosurgery registry of the Timone department, based on data from the anatomopathology department. After consulting the molecular biology software of Pr Barlier at CHU Conception, 6 patients have already been identified (including 2 mutated patients). There are therefore 36 potential patients to be included, to whom we can add 5 potential new patients during the course of the study (number extrapolated from the number of HB cases operated on per year in the neurosurgery department), giving a total of 41 patients. We hope to obtain an 80% response to our letter, i.e. 33 patients. The expected proportion of mutated patients is 30%, i.e. 10 mutated and 23 non-mutated patients. This number of subjects, 10 cases for 23 controls, will enable us to highlight a 12-point difference in anxiety levels, with a standard deviation of 10, a power of 80% and an alpha risk of 5%. PROJECT RELEVANCE: Our approach is also prospective, with the introduction of systematic screening for new cases of hemangioblastoma. In view of the ongoing discovery of new cancer-causing genes, this model study will enable us to better assess the psychosocial impact of genetic screening, and thus better manage it in everyday medical practice. | 1. Caractéristiques initiales de la population étudiée La liste initiale de patients extraite à partir de la base de données du service de neurochirurgie regroupait 55 patients opérés d’un Hémangioblastome (HB) du SNC entre 1999 et 2013. Parmi eux, 11 patients avaient en fait déjà été dépistés et 3 patients étaient décédés. Le courrier proposant la consultation avec le neurochirurgien (VISITE 1) a donc été envoyé à 41 patients. Une patiente opérée en 2015 a été incluse en cours d’étude. Sur l’ensemble de ces 42 patients, 24 se sont présentés à la VISITE 1, visite d’inclusion avec le neurochirurgien. Après interrogatoire et examen clinique, aucun des patients n’avait d’autre pathologie évocatrice du syndrome de VHL excepté son antécédent d’HB. La découverte de cet HB du SNC s’est faite sur des symptômes neurologiques chez la grande majorité des patients (22 patients c’est à dire 92%) et de manière fortuite pour 2 patients seulement. Sur ces 24 patients, 21 patients se sont présentés à la VISITE 2 afin de voir en consultation l’oncogénéticienne et de se faire prélever le cas échéant un échantillon sanguin pour dépistage génétique. 3 patients inclus dans l’étude ne se sont donc pas présentés en consultation d’oncogénétique. Un des patients a invoqué son souhait de consacrer plutôt son temps à sa rééducation neurologique et les deux autres ont été perdus de vue. Une des patientes s’étant présentée à la VISITE 2 a refusé le prélèvement génétique en expliquant au médecin du service d’oncogénétique qu’elle ne voulait pas connaître le résultat étant donné son grand âge et en exprimant ses craintes vis à vis de sa famille qu’elle craignait de perturber. L’analyse d’un prélèvement était toujours en cours au moment de l’analyse statistique, les résultats génétiques étaient donc disponibles pour 19 patients au moment de cette analyse. Au moment de l’analyse statistique, 12 patients s’étaient présentés à la VISITE 4 pour recevoir le résultat de ce dépistage. Les patients s’étant présenté à la consultation d’oncogénétique (VISITE 2) étaient plutôt des patients âgés (médiane d’âge 58,3 ans). Le sex ratio était équilibré avec 11 hommes pour 10 femmes. Les patients étaient plutôt en couple avec seulement 19% de célibataires, et le niveau scolaire était plutôt élevé avec 61,9% de patients ayant un niveau baccalauréat ou supérieur. Il s’agissait pour la plupart de patients ayant des enfants avec un nombre d’enfants médian à 2. La plupart des patients avaient été opérés plusieurs années auparavant avec un délai moyen entre la chirurgie et la VISITE 4 de 81,7 mois soit environ 6,8 ans. Les scores établis lors de la VISITE 1 en vue d’évaluer l’état de base des patients ont révélé que les patients étaient globalement peu anxieux d’une manière générale, (moyenne ASTA en général= 42,4 +/- 10,1) et qu’ils semblaient de plus peu perturbés d’une part par la consultation avec le neurochirurgien et d’autre part de se retrouver dans ce contexte hospitalier devant un score d’ASTA en ce moment bien inférieur à la moyenne (moyenne ASTA en ce moment= 39,7 +/- 15,3). Par ailleurs, le score de BECK montrait une très faible prévalence des symptômes dépressifs (moyenne Score de BECK =3,9+/-3,4) et aucun patient ne présentant de syndrome dépressif de forte intensité. Par ailleurs le score PCQ ne rapportait qu’une faible inquiétude de la part des patients (moyenne Score PCQ=4,8 +/- 1,8). Cependant, les faibles moyennes obtenues aux scores composites physiques et psychiques de qualité de vie (moyenne PCS=47,2 +/- 9,7 ; moyenne MCS=41,2 +/- 11) rendent compte d’une qualité de vie probablement altérée du fait des séquelles physiques liées aux HB et à leur chirurgie. Lors de la VISITE 1, la médiane des scores d’anxiété étaient significativement plus élevés chez les patients célibataires (ASTA en ce moment 18,3, p=0,009* ; ASTA en général 17,4 ; p=0,022*). Les données qualitatives recueillies par la psychologue du service d’oncogénétique à l’occasion de la VISITE 2 sont disponibles pour 11 des 21 patients s’étant présentés à cette visite. Il apparaît que la plupart des patients n’avaient pas d’inquiétude particulière vis à vis de ce dépistage et semblaient au contraire plutôt sereins. Quand des difficultés étaient évoquées par le patient, on retrouvait fréquemment une souffrance morale en rapport avec une altération des capacités physiques, elle- même en lien avec l’HB du SNC et la chirurgie correspondante. L’angoisse liée au dépistage semblait, elle, plutôt s’inscrire dans le cadre d’une angoisse générale retrouvée chez des patients présentant des séquelles de leur pathologie initiale. Du point de vue de la plupart des patients, le dépistage apparaissait plutôt comme une chance, puisqu’il pouvait le cas échéant offrir la possibilité de savoir pourquoi cette HB était apparu et de donner des informations d’une importance majeure pour la santé de leurs proches. 2. Résultats concernant les conséquences psychologiques liées à l’attente du résultat Le délai moyen entre le prélèvement génétique lors de la VISITE 2 et l’annonce du résultat lors de la VISITE 4 a été en moyenne de 7,3 +/- 2,9 mois, (médiane 7 mois ; min 2 mois, max ; 11 mois). Au moment de l’analyse statistique, 12 patients s’étaient présentés à la VISITE 4. Seule une mutation a été retrouvée. Si le séquençage n’avait pas mis en évidence d’anomalie, l’analyse MLPA a retrouvé une grande délétion hétérozygote touchant le gène VHL (exons 1, 2 et 3 et la région promotrice du gène) ainsi que d’autres gènes FANCD2 et C3ORF10 situés à proximité. Les conséquences psychosociales liées à l’attente du résultat du dépistage génétique ont donc pu être évaluées pour 12 des patients de notre cohorte. Huit de ces patients ont par ailleurs définitivement terminé l’étude psychosociale en remplissant les questionnaires à domicile. | Humanities and Social Sciences 1 | |
| 2013 | Severine COLINET - Laurence HEIDET | Gennevilliers | Foundation For Rare Diseases | Renal fetal pathology | Announcement of a severe renal fetal pathology detected during pregnancy | Background: Severe kidney disease diagnosed before birth can result in severe renal failure early in life. The prognosis is often uncertain. Faced with this situation, parents are faced with the dramatic choice of whether or not to carry out a medical termination of pregnancy (Engelmann, 2002). While this choice is guided by psychological, ethical, cultural and religious considerations specific to each individual, it is obviously also largely determined by what the doctor tells them, and in particular by the way in which they are presented with their child's kidney disease. The doctor finds himself in an individually difficult position, confronted as he is with his own questions, anxieties and representations. The announcement is by its very nature singular, and therefore differs from one practitioner to another. It is essential to reflect on the determinants of the announcement, the content of the discourse, and how it is perceived by future parents. The aim of this study is to provide a basis for this reflection by analyzing doctor-parent interviews and the way they are perceived by each party. To this end, the project will involve social science researchers and medical teams from three renal disease reference centers (Paris-Necker, Lyon, Grand Ouest) that regularly perform antenatal diagnosis, in conjunction with the Centres Pluridisciplinaires de Diagnostic Pré Natal (CPDPN). The project will be led by social science researchers, with a university professor and a senior lecturer. They will coordinate the work of a post-doctoral social scientist. At each of the three sites, from the very first month, the teams will be made up of members of the reference centers and CPDPNs: pediatric nephrologists, obstetricians, geneticists, radiologists, psychologists and/or child psychiatrists. A referent will be proposed for each center. Objectives: Stimulate collective reflection on practices for announcing and presenting information on renal disease before birth, in order to improve the announcement to couples and their management as part of their care pathway. Over a 14-month period, we propose to: 1) draw up an inventory and analysis of announcement practices. 2) analyze the way in which patients perceive, hear and integrate the announcement, and the impact of this announcement on the parents' decision concerning the unborn child, whether to terminate or continue the pregnancy. In this case, the aim is to analyze the impact on the representation of the unborn baby, the parent(s)-child bond, the child-fraternity bond and the future of the family structure (couples, siblings). Methods The methodological tools to be developed are semi-structured interview guides, questionnaires and observation reports. Quantitative and qualitative surveys will be carried out in each of the three centers. Retrospective quantitative survey 300 questionnaires will be distributed and sent out to all couples who have visited the three renal disease reference centers (Paris, Lyon, Grand Ouest) over the past three years. Variables will be analyzed using multiple correspondence sorting. Prospective qualitative survey Patients and their spouses (when present): 15. These subjects will be interviewed twice, at different times: 6 months and 1 year after the announcement. A total of 30 interviews will be conducted. At the same time, 10 interviews will be conducted with doctors, and observations will be made during consultations with the nephrologist and obstetrician, as well as with the psychologist or child psychiatrist. As for the qualitative part, two types of complementary analysis will be carried out: a thematic content analysis of the verbatims, and an interpretative analysis designed to avoid the division caused by the thematic analysis. | In order to improve care for couples, this research aims to develop a reflection on practices for announcing a diagnosis of fetal kidney abnormality. The announcement requires medical support to enable the couple to embark on a course of treatment or even a decision-making process (for severe situations that could lead to a potential medical termination of pregnancy). This work falls within the fields of education sciences and the sociology of birth. We hypothesize that the heterogeneity of disclosure practices leads to a lack of transparency in the forms of patient support. This research is based on two surveys using semi-structured interviews (62) conducted with doctors (30) and patients (32). The originality of this study lies in the comparison of the perspectives of these two actors on the same disclosure situation. Three types of analysis (thematic, discourse, and interpretive) are used to identify the constraints in the disclosure process for patients and to identify the disclosure approaches used by physicians. Three types of communication approaches were identified: "support," "objectivity" in conveying the message, and "formulation for the couple." The practice of communication by physicians is complex and relies on informal learning. Two major elements of medical discourse relating to the medical uncertainty of fetal renal abnormalities and the timing of disclosure emerge from patients' discourse. These fundamental factors of medical discourse determine the communication skills (cognitive, social, and emotional) expected by couples. Our research thus contributes to opening up the debate on training doctors in disclosure. | Humanities and Social Sciences 1 | |
| 2013 | Virginie POSTAL | Bordeaux | Foundation For Rare Diseases | Prader-Willi syndrome | Assessment of the impact of cognitive, executive and emotional abilities on the difficulties of adaptation and socialization of patients with PWS | Prader-Willi syndrome (PWS) is a rare genetic disorder (incidence 1/15,000 to 1/25,000, Whittington et al., 2007) described in 1956 (Prader, Labhart&Willi, 1956). It is a neurodevelopmental disorder of genetic origin linked to the absence of gene expression in the 15q11-q13 region of chromosome 15 of paternal origin (parental genomic imprinting). This is an extremely complex disease, due to the diversity and severity of the disorders involved. There are major difficulties in managing the disease, partly due to behavioral disorders that are often linked to difficulties in understanding and adapting to the individual's environment, present from childhood onwards (sociable but unsocializable individuals -Dr. Thuilleaux). At birth, there is major hypotonia (enabling early diagnosis) associated with sucking and eating disorders, followed by the rapid and early onset of obesity with hyperphagia and satiety deficit, leading in the absence of prevention and treatment to the development of extremely severe morbid obesity (Goldstone et al. 2008). There are also endocrine disorders, with multiple hypothalamic-pituitary hormone deficiencies (Diene et al. 2010). Various behavioral disorders are associated with the syndrome: obsessive-compulsive disorders, temper tantrums, stubbornness, a tendency to steal and lie, plus learning and communication difficulties. Patients have a lower IQ than the general population, with a normal distribution around an average of 60 and variations according to genetic origin (Copet et al., 2010). While behavioral descriptions and recommendations in terms of diagnosis and medical management are currently relatively well supported (cf. Protocole national de diagnostic et de soinspour les maladies rares, HAS, 2012), the identification of specific cognitive and emotional disorders and their impact on individuals' day-to-day adaptation are very poorly understood. Socialization difficulties become very prevalent in adulthood, with over 50% of adults remaining in their families without occupation. The presence of an intellectual deficit and executive dysfunction specific to the syndrome means that life plans need to be adapted to this population, which is rarely the case at present. The aim of this project is to describe abilities (cognitive, executive, emotional and social adjustment) at different ages of life, in order to propose adjustments to life projects from childhood to adulthood, both in medical and social care, and in everyday life via families. The knowledge acquired will enable us to develop an information tool for care providers. Firstly, various neuropsychological tests will be administered to assess general cognitive and executive functioning in relation to emotional components (also in relation to food) in PWS patients followed up at the Toulouse and Hendaye reference centers (60 children and adolescents and 60 adults). In a second phase, we will compare the results of the research with the experience and observations of families "in real-life situations" (lay experts) and a group of experts from the reference center. This work will make it possible to implement the theoretical side of the best practice guide currently being drafted, and to produce an information medium for training meetings at the competence centers, with a longer-term evaluation. The project will involve the sites of the PWS Reference Center, the Prader-Willi France association, the 22 competence centers and the University of Bordeaux. | The PRASOC (PRAder-willi SOCialisation) project aims to enrich knowledge about the abilities of people with Prader-Willi syndrome (PWS) with a view to improving their care and support. This unique project brings together a psychology research laboratory (University of Bordeaux), two reference centers (Marin Hospital in Hendaye and Toulouse University Hospital), and the Prader Willi France association. The aim is to identify the cognitive and executive abilities (memory, reasoning, planning) that are deficient or, at least, whose efficiency differs from that of the normal population and which could explain some of the difficulties in adaptation and socialization experienced by people with PWS. A vast program of cognitive process assessment (four 1.5-hour experimental sessions, 13 neuropsychological tests or trials administered, electrodermal response measurements) in which the valence of information (positive, negative, neutral) and the relationship to food were manipulated was conducted in children and young adults (nearly 200 participants, including 71 people with SPW). This transdisciplinary project in the humanities and health sciences made it possible to specify the deficit in executive functions linked to the syndrome by distinguishing it from deficits linked to intellectual level. Indeed, several results indicate that the level of intellectual efficiency explains some of the patients' difficulties and therefore their difficulties in adapting to everyday life. Other results also highlight difficulties specific to the syndrome (independent of intellectual level) and the influence of the emotional context on information processing. | Humanities and Social Sciences 1 | |
| 2012 | Andreas HARTMANN | Paris | Foundation For Rare Diseases | Tourette syndrome | Identification of variants and genes involved in Gilles de la Tourette syndrome | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Cecile JULIER | Paris | Foundation For Rare Diseases | Neonatal diabetes mellitus | Identification of a gene responsible for syndromic neonatal diabetes | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Cecile SAINT-MARTIN | Paris | Foundation For Rare Diseases | Autosomal dominant hyperinsulinism | Identification of the gene(s) responsible for dominant congenital diazoxide-responsive hyperinsulinism in a large family | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Celine BOUCHET-SERAPHIN | Paris | Foundation For Rare Diseases | Cobblestone lissencephaly | Identification of a novel gene responsible for lissencephaly type II in a consanguineous multiplex family | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Christel THAUVIN-ROBINET | Dijon | Foundation For Rare Diseases | Orofaciodigital syndrome | Identification in the gene(s) implicated in OFD syndrome with median defects | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Cyril GOIZET | Bordeaux | Foundation For Rare Diseases | Lipodystrophy and leukodystrophy syndrome | Identification of a gene involved in a new syndrome associating lipodystrophy and leukodystrophy (LLD syndrome) | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Jeanne AMIEL | Paris | Foundation For Rare Diseases | Neurocristopathy | Identification of the molecular bases of a rare neurocristopathy leading to congenital malformation and tumour predisposition | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Jerôme BERTHERAT | Paris | Foundation For Rare Diseases | Macronodular adrenal hyperplasia | Genetic of macronodular adrenocortical hyperplasia (GENEHYPER) | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Karine POIRIER | Paris | Foundation For Rare Diseases | Subcortical band heterotopia | Identification of new genes involved in subcortical band heterotopia | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Marc BARTOLI | Marseille | Foundation For Rare Diseases | Inclusion Body Myositis, Paget disease and Fronto-temporal Dementia/Amyotrophic Lateral Sclerosis | Identification of a disease-causing gene for IBMPFD / ALS (Inclusion Body Myositis, Paget disease and Fronto-temporal Dementia/Amyotrophic Lateral Sclerosis) | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Nicolas CHASSAING | Toulouse | Foundation For Rare Diseases | Anophthalmia - microphthalmia | Identification of new anophthalmic/microphthalmic genes by exome sequencing | - | - | High throughput sequencing 2012 - 1 | |
| 2012 | Pascale GUICHENEY | Paris | Foundation For Rare Diseases | Idiopathic ventricular fibrillation- Brugada syndrome | Identification of a new gene responsible for idiopathic ventricular fibrillation associated with short-coupled variant of torsade de pointes | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Patrice BOUVAGNET | Lyon | Foundation For Rare Diseases | Hypoplastic left heart syndrome | Hypoplastic Left Heart Syndrome (HLHS) | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Rima NABBOUT | Paris | Foundation For Rare Diseases | Epilepsy with myoclonic-astatic seizures | Exome sequencing to identify genes associated with myoclonic astatic epilepsy | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Sandrine VUILAUMIER-BARROT | Paris | Foundation For Rare Diseases | Type I congenital disorder of glycosylation | Exome sequencing of one CDG Ix patient (congenital disorder of glycosylation type I) in a family with one healthy sibling | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Sandrine VUILLAUMIER-BARROT | Paris | Foundation For Rare Diseases | Type I congenital disorder of glycosylation | Exome sequencing of one CDG Ix patient (congenital disorder of glycosylation type I) presenting with a novel biochemical phenotype | - | High throughput sequencing 2012 - 1 | ||
| 2012 | Agnes BLOCH-ZUPAN | Illkirch | Foundation For Rare Diseases | Enamel knot and dental cusps anomaly | Morphodent: Identification of a gene involved in the enamel knot signaling center and dental cusps morphogenesis and anomalies | - | - | High throughput sequencing 2012 - 2 | |
| 2012 | Annick TOUTAIN | Towers | Foundation For Rare Diseases | Spastic paraplegia - glaucoma - intellectual deficit | Identification of the causal gene of a rare syndrome comprising intellectual disability, glaucoma and spastic paraplegia | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Bernard GRANDCHAMP | Paris | Foundation For Rare Diseases | Microcytic anemia | Identification of causative gene(s) in rare inherited microcytic anemias | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Catherine BADENS | Marseille | Foundation For Rare Diseases | Metabolic disease | Application of high throughput sequencing to the study of patients suffering from metabolic syndrome with an abnormal nuclear cell profile | - | - | High throughput sequencing 2012 - 2 | |
| 2012 | Delphine HERON | Paris | Foundation For Rare Diseases | Intellectual deficiency syndrome | Identification of the gene involved in a new form of syndromic recessive intellectual deficiency | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Franck RUMMELE | Paris | Foundation For Rare Diseases | Bowel disease | Genetic causes of very-early onset inflammatory bowel diseases | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Frederic RIEUX-LAUCAT | Paris | Foundation For Rare Diseases | Systemic lupus erythematosus | Identification of genetic factors involved in the pathophysiology of early-onset Systemic Lupus Erythematosus | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Gaël MANES | Montpellier | Foundation For Rare Diseases | Retinitis pigmentosa | Identification of novel genes in autosomal dominant retinitis pigmentosa in three extensively pre-screened large families | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Guy LENAERS | Montpellier | Foundation For Rare Diseases | Autosomal dominant optic atrophy | New genes for Autosomal Dominant Optic Atrophy | - | - | High throughput sequencing 2012 - 2 | |
| 2012 | Gwenaelle COLLOD-BEROUD | Marseille | Foundation For Rare Diseases | Focal dystonia | In search of new genes responsible for dystonia | - | - | High throughput sequencing 2012 - 2 | |
| 2012 | Jocelyn LAPORTE | Illkirch | Foundation For Rare Diseases | Myopathies | Identification of novel genes implicated in different myopathies by exome sequencing | - | - | High throughput sequencing 2012 - 2 | |
| 2012 | Lydie BURGLEN | Paris | Foundation For Rare Diseases | Congenital cerebellar ataxia | Identification of congenital ataxias genes by exome sequencing | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Marie-Christine ALESSI | Marseille | Foundation For Rare Diseases | Macrothrombocytopenia | Identify new causes of hereditary Macrothrombocytopenia | - | - | High throughput sequencing 2012 - 2 | |
| 2012 | Patrick CALLIER | Dijon | Foundation For Rare Diseases | Pai syndrome | Identification of the gene for Pai syndrome through complete exome sequencing | - | - | High throughput sequencing 2012 - 2 | |
| 2012 | Philippe CHEVALIER | Lyon | Foundation For Rare Diseases | Familial atrial fibrillation | Identification of novel gene responsible of familial atrial fibrillation | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Pierre RAY | Grenoble | Foundation For Rare Diseases | Oocyte maturation failure | Investigation of the genetic aetiology of oocyte maturation failure (OMF) by exome sequencing. | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Pierre VABRES | Dijon | Foundation For Rare Diseases | SACRAL/PELVIS syndrome | Identification of postzygotic mutations in SACRAL/PELVIS syndrome | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Sophie NICOLE | Paris | Foundation For Rare Diseases | Hereditary thermosensitive neuropathy | Search for the gene responsible for the hereditary neuropathy with thermosensitivity (complementary whole exome) | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Stephane DECRAMER | Toulouse | Foundation For Rare Diseases | Congenital hyperechogenic kidney | Identification of new genes involved in congenital hyperechogenic kidneys | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Sylvie ODENT | Rennes | Foundation For Rare Diseases | Amelo-cerebro-hypohidrotic syndrome (Kohlschütter-Tönz syndrome) | Whole exome sequencing in Köhlschutter-Tonz syndrome with probable autosomal dominant transmission | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Thierry BIENVENU | Paris | Foundation For Rare Diseases | Neonatal epileptic encephalopathies | Identification of new genes involved in neonatal epileptic encephalopathies associated with Rett-like features | - | High throughput sequencing 2012 - 2 | ||
| 2012 | Thierry BRUE Serge AMSELEM | Paris | Foundation For Rare Diseases | Pituitary hormone deficiency | Exome Project In Combined Pituitary Hormone deficiency (EPIC) Study | - | - | High throughput sequencing 2012 - 2 | |
| 2012 | Veronique PAQUIS-FLUCKINGER | Nice | Foundation For Rare Diseases | Mitochondrial diseases | Mitochondrial diseases with multiple respiratory chain deficiency : Identification of new genes by exome sequencing | - | - | High throughput sequencing 2012 - 2 |
Register of Models of rare diseases funded by the Foundation
The table below lists the rare disease models developed with funding from the Rare Diseases Foundation as part of the “Models” call for proposals and in collaboration specialized partner platforms.
These cellular and animal models provide a better understanding of the molecular and cellular basis of rare diseases and enable the testing of new therapeutic compounds.
Scroll through the columns on the right using the orange scroll bar ⟶
| Model type | Model name | Genetic background | Gene Symbol | Gene name | Standard transfer | Mutation / Construct | Disease | Publication (PubMed link) | Contact |
|---|---|---|---|---|---|---|---|---|---|
| Caenorhabditis elegans | MCP725 | N2 | Act 1 | Act 1 | Deletion | Full gene deletion | actinopathies | Anne-Cécile REYMANN | |
| Caenorhabditis elegans | MCP828 | MCP725 | Act 1 | Act 1 | SNP | R197H | actinopathies | Anne-Cécile REYMANN | |
| Caenorhabditis elegans | MCP849, MCP850, MCP851 | MCP725 | Act 1 | Act 1 | SNP | R197C | actinopathies | Anne-Cécile REYMANN | |
| Caenorhabditis elegans | MCP917, MCP918 | N2 | Act 2 | Act 2 | Deletion | Full gene deletion | actinopathies | Anne-Cécile REYMANN | |
| Caenorhabditis elegans | MCP57, MCP58, MCP59 | N2 | erm-1 | erm-1 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/31110027/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP64 | N2 | erm-1 | erm-1 | Insertion | wrmScarlet insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/31110027/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP167 | N2 | erm-1 | erm-1 | Insertion | mTagBFP2-degron insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/34704594/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP221, MCP222 | N2 | erm-1 | erm-1 | Insertion | mTagBFP2 insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP91 | N2 | unc-64 | unc-64 | Insertion | wrmScarlet insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/31110027/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP105 | N2 | slcf-1 | slcf-1 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP93, MCP94, MCP95 | N2 | slcf-1 | slcf-1 | Insertion | wrmScarlet insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP129 | N2 | syx-3 | syx-3 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP117, MCP119, MCP121 | N2 | syx-3 | syx-3 | Insertion | wrmScarlet insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP110, MCP111 | N2 | pgp-1 | pgp-1 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/31110027/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP113, MCP114, MCP115 | N2 | pgp-1 | pgp-1 | Insertion | wrmScarlet insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP153, MCP154 | N2 | ifb-2 | ifb-2 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/34704594/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP142, MCP143 | N2 | ifb-2 | ifb-2 | Insertion | wrmScarlet insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/34704594/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP288 | N2 | ifb-2 | ifb-2 | Insertion | mKate2 insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP140, MCP141 | N2 | eps-8 | eps-8 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/34704594/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP137, MCP138, MCP139 | N2 | eps-8 | eps-8 | Insertion | wrmScarlet insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP162, MCP163 | N2 | eps-8 | eps-8 | Insertion | mTagBFP2-degron insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/34704594/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP337, MCP336 | N2 | eps-8 | eps-8 | Insertion | mKate2 insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP151 | N2 | par 4 | par 4 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP286, MCP287 | N2 | par 4 | par 4 | Insertion | mKate2-degron insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP282 | N2 | by-1 | by-1 | Insertion | mKate2-degron insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP354 | N2 | elt-2 | elt-2 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP331 | N2 | plst-1 | plst-1 | Insertion | mTagBFP2 insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP251, MCP270 | N2 | let-413c | let-413 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP189 | N2 | Hmm-5 | Hmm-5 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/34704594/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP329 | N2 | fln-2 | fln-2 | Insertion | mKate2 insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP332, MCP333 | N2 | skn-1 | skn-1 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP224 | N2 | cdc-25.1 | cdc-25.1 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP429 | N2 | cdc-25.1 | cdc-25.1 | Insertion | mTagBFP2-degron insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP352, MCP353 | N2 | cdc-25.2 | cdc-25.2 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP392, MCP293 | N2 | cki-1 | cki-1 | Insertion | mTagBFP2-degron insertion at the locus | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP572 | N2 | end-1 | end-1 | Insertion | end-1p::mKate2::PH::end-1 3'UTR | MVID - FHL5 | Grégoire MICHAUX | |
| Caenorhabditis elegans | MCP184 | N2 | Hmm-2 | Hmm-2 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/34704594/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP223 | N2 | exl-1 | exl-1 | Insertion | mNeonGreen insertion at the locus | MVID - FHL5 | https://pubmed.ncbi.nlm.nih.gov/34704594/ | Grégoire MICHAUX |
| Caenorhabditis elegans | MCP13, MCP14 | N2 | sgcb-1 | sgcb-1 | Deletion | Full gene deletion | autosomal recessive limb-girdle muscular dystrophy type 2E and muscular dystrophy | https://pubmed.ncbi.nlm.nih.gov/38858388/ | Kathrin GIESELER |
| Caenorhabditis elegans | MCP15 | N2 | ferl-1 | ferl-1 | Deletion | Full gene deletion | recessive limb-girdle muscular dystrophy type 2 (LGMDR2) | Kathrin GIESELER | |
| Caenorhabditis elegans | MCP16 | N2 | frg-1 | frg-1 | Deletion | Full gene deletion | Facio-scapulo-humeral Muscular Dystrophy (FSHD) | Kathrin GIESELER | |
| Caenorhabditis elegans | MCP17, MCP18 | N2 | sgn-1 | sgn-1 | Deletion | Full gene deletion | Autosomal recessive limb-girdle muscular dystrophy type 2C | https://pubmed.ncbi.nlm.nih.gov/38858388/ | Kathrin GIESELER |
| Caenorhabditis elegans | MCP19, MCP20 | N2 | cav-1 | cav-1 | Deletion | Full gene deletion | Caveolinopathies | Kathrin GIESELER | |
| Caenorhabditis elegans | MCP21, MCP22 | N2 | W02B3.4 | W02B3.4 | Deletion | Full gene deletion | Fukuyama congenital muscular dystrophy | Kathrin GIESELER | |
| Caenorhabditis elegans | MCP229, MCP230, MCP231, MCP232 | N2 | sel-2 | sel-2 | SNP | E1542K | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP240, MCP241, MCP244 | N2 | sel-2 | sel-2 | SNP | G2257R | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP246, MCP247, MCP248 | N2 | sel-2 | sel-2 | SNP | D2349K | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP252, MCP253, MCP254, MCP255, MCP256 | N2 | sel-2 | sel-2 | SNP | H1023Y | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP271, MCP272 | N2 | sel-2 | sel-2 | SNP | P2194C | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP273, MCP274, MCP275, MCP276, MCP277 | N2 | sel-2 | sel-2 | SNP | P1063S | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP278, MCP279 | N2 | sel-2 | sel-2 | SNP | V555A | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP283, MCP284, MCP285 | N2 | sel-2 | sel-2 | SNP | P2194S | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP289, MCP290, MCP291 | N2 | sel-2 | sel-2 | SNP | R1527H | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP292, MCP293, MCP294 | N2 | sel-2 | sel-2 | SNP | F2240P | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP297, MCP298, MCP299, MCP300 | N2 | sel-2 | sel-2 | SNP | N2428S | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP301, MCP302, MCP303 | N2 | sel-2 | sel-2 | SNP | G2425R | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP304, MCP305 | N2 | sel-2 | sel-2 | SNP | T2271I | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP306, MCP307 | N2 | sel-2 | sel-2 | SNP | V2287M | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Caenorhabditis elegans | MCP308, MCP309 | N2 | sel-2 | sel-2 | SNP | A1548T | NEDEGE (OMIM 619157) | Thomas BOULIN | |
| Human iPSC | AGS1530 | ATAD3A | ATPase family AAA domain-containing 3A | Type I interferonopathy | Alice LEPELLEY | ||||
| Human iPSC | MOTars | ATAD3A | ATPase family AAA domain-containing 3A | Type I interferonopathy | Alice LEPELLEY | ||||
| Human iPSC | VANdie | ATAD3A | ATPase family AAA domain-containing 3A | Type I interferonopathy | Alice LEPELLEY | ||||
| Human iPSC | REFcri | PAX6 | paired box 6 | Aniridia pigmentary | https://doi.org/10.1093/stmcls/sxad067 | Daniel ABERDAM | |||
| Human iPSC | BIGcha | PAX6 | paired box 6 | Aniridia pigmentary | https://doi.org/10.1093/stmcls/sxad067 | Daniel ABERDAM | |||
| Human iPSC | BERste | PAX6 | paired box 6 | Aniridia pigmentary | https://doi.org/10.1093/stmcls/sxad067 | Daniel ABERDAM | |||
| Human iPSC | 4-200 | YIF1B | YIF1B | KABAMAS, ciliopathy | Justine MASSON | ||||
| Human iPSC | CLT420 | YIF1B | YIF1B | KABAMAS, ciliopathy | Justine MASSON | ||||
| Human iPSC | FPb | YIF1B | YIF1B | KABAMAS, ciliopathy | Justine MASSON | ||||
| Human iPSC | VPc | YIF1B | YIF1B | KABAMAS, ciliopathy | Justine MASSON | ||||
| Human iPSC | AROme | YIF1B | YIF1B | KABAMAS, ciliopathy | Justine MASSON | ||||
| Human iPSC | 715 | RHO | Rhodopsin | Retinal degeneration | Olivier GOUREAU | ||||
| Human iPSC | 1068 | RHO | Rhodopsin | Retinal degeneration | Olivier GOUREAU | ||||
| Human iPSC | 2634 | RHO | Rhodopsin | Retinal degeneration | Olivier GOUREAU | ||||
| Human iPSC | 5079 | RHO | Rhodopsin | Retinal degeneration | Olivier GOUREAU | ||||
| Human iPSC | 7850 | RHO | Rhodopsin | Retinal degeneration | Olivier GOUREAU | ||||
| Human iPSC | 7849 | RHO | Rhodopsin | Retinal degeneration | Olivier GOUREAU | ||||
| Human iPSC | MPS III B 11565 | NAGLU | α-N-acetylglucosaminidase | Sanfilippo syndrome (mucopolysaccharidosis type III) | Stéphanie TRUDEL | ||||
| Human iPSC | MPS III B 11736 | NAGLU | α-N-acetylglucosaminidase | Sanfilippo syndrome (mucopolysaccharidosis type III) | Stéphanie TRUDEL | ||||
| Mouse | Involucrin-Kallikrein 14 | C57BL/6N | Involucrin-Kallikrein 14 | transgenic (random insertion) | transgenic | Netherton syndrome | https://pubmed.ncbi.nlm.nih.gov/32169475/ | Alain HOVNANIAN | |
| Mouse | Col7a1 | C57BL/6N | Col7a1 | COL7A1 | BAC-hCOL7A1-c.425A>G (exon 3) Tg | BAC-hCOL7A1-c.425A>G (exon 3) Tg | Recessive Dystrophic Epidermolysis Bullosa | Alain HOVNANIAN | |
| Mouse | conditional overexpression of PRKAR1A delta ex6 in Rosa | C57BL/6N | PRKAR1A | protein kinase, cAMP-dependent regulatory, type I, alpha | KI in Pink | conditional overexpression of delEx6 PRKAR1A | Carney complex | Antoine MARTINEZ | |
| Mouse | R105Q PM in Orc1 by CRISPR | C57BL/6N | Orc1 | origin recognition complex, subunit 1 | R105Q PM in Orc1 | R105Q PM in Orc1 | Meier-Gorlin Syndrome | Benoit MIOTTO / Anne LETESSIER | |
| Mouse | I499V conditional point mutation in Smad4 | C57BL/6N | Smad4 | SMAD family member 4 | conditional I499V PM/WT first | conditional I499V PM/WT first | Myhre syndrome | Carine LE GOFF | |
| Mouse | Impg1 | C57BL/6J | Impg1 | interphotoreceptor matrix proteoglycan 1 | cKO | cKO | Macular Dystrophy | Christian HAMEL | |
| Mouse | Zbtb24 | C57BL/6N | Zbtb24 | zinc finger and BTB domain-containing protein 24 | A missense mutation that results in a premature stop codon | PM | Type II ICF syndrome | https://pubmed.ncbi.nlm.nih.gov/39562305/ | Claire FRANCASTEL |
| Mouse | Tmprss6 | C57BL/6N | Tmprss6 | transmembrane serine protease 6 | cKO | cKO | beta-thalassemia | Delphine MEYNARD | |
| Mouse | R418W mutation in Adcy5 caused by CRISPR-Cas9 | C57BL/6N | Adcy5 | adenylate cyclase 5 | R418W PM in Adcy5 | R418W PM in Adcy5 | dyskinesia | Denis HERVE | |
| Mouse | Eml1 | C57BL/6N | Eml1 | Echinoderm microtubule-associated protein-like 1 | cKO | cKO | subcortical heterotopia | https://pubmed.ncbi.nlm.nih.gov/39316454/ | Fiona FRANCIS |
| Mouse | C57bl6/J | Kcnk9 | potassium two-pore domain channel subfamily K member 9 | knock-in | Kcnk9_G236R_PM | Birk-Barel Syndrome | Florian LESAGE | ||
| Mouse | C57bl6/J | Kcnk9 | potassium two-pore domain channel subfamily K member 9 | knock-in | Kcnk9_M159I_PM | Birk-Barel Syndrome | Florian LESAGE | ||
| Mouse | Lrba | C57BL/6N | Lrba | LPS-responsive beige-like anchor | cKO | cKO | Primary immunodeficiency with autoimmunity | Frédéric RIEUX-LAUCAT | |
| Mouse | D563ENLYFQS in Htt | C57BL/6N | Htt | huntingtin | PMs | PMs | Huntington's disease | Frédéric SAUDOU | |
| Mouse | Chmp2b | C57BL/6N | Chmp2b | charged multivesicular body protein 2B | truncated Chmp2b and tagged IRES eYFP chrmp2b with WT potential | AI | Amyotrophic Lateral Sclerosis | Frédérique RENE | |
| Mouse | NOX1 | C57BL/6N | NOX1 | NADPH oxidase 1 | KO and cKO | KO and cKO | Xeroderma pigmentosum Type C | Hamid Reza Rezvani | |
| Mouse | P1003Q PM in Vps15 | C57BL/6N | Vps15 | phosphoinositide-3-kinase regulatory subunit 4 | PM | P1003Q PM (corresponds to R998Q in humans) | ciliopathy | Hélène DOLLFUS | |
| Mouse | C57BL/6N | Delta-sarcoglycan | knock-in | E262K | Limb-girdle muscular dystrophy | Isabelle RICHARD | |||
| Mouse | M509T Polymorphism in LhCGR Detected by CRISPR | C57BL/6N | LHCP | luteinizing hormone/chorionic gonadotropin receptor | M509T PM in LhCGR | M509T PM in LhCGR | hyperandrogenism | Jacques YOUNG | |
| Mouse | Neddl4 R897Q conditional PM by FLeX2 | C57BL/6N | Neddl4 | neural precursor cell-expressed, developmentally downregulated gene 4-like | conditional R897Q PM/WT first | focal cortical dysplasia | Jamel CHELLY | ||
| Mouse | pCAG_lox_STOP_lox_Isthmin-1 knockout in Rosa | C57BL/6N | Isthmin-1 | Ism1 | conditional overexpression of Ism1 | KI in Pink | idiopathic nephrotic syndrome | Jean-Jacques BOFFA | |
| Mouse | aMHC-FKBP12.6 Tg | C57BL/6N | FKBP12.6 | Fkbp1b | FK506-binding protein 1b | aMHC-FKBP12.6 Tg | Inherited cardiac arrhythmias | https://pubmed.ncbi.nlm.nih.gov/38224852/ | Jean-Jacques MERCADIER |
| Mouse | G424R mutation in Pak3 caused by CRISPR | C57BL/6N | Pak3 | p21 (RAC1)-activated kinase 3 | G424R PM in Pak3 | G424R | Severe intellectual disability and agenesis of the corpus callosum | Jean-Vianney BARNIER | |
| Mouse | Fat1 double knockout (Dre and LoxP) | C57BL/6N | Fat1 | FAT atypical cadherin 1 | double KO | Ex27a roxed and Ex27c floxed | FACIO-SCAPULO-HUMERAL DYSTROPHY (FSHD) | Julie DUMONCEAUX | |
| Mouse | V128M PM in Adat3 by CRISPR | C57BL/6N | Adat3 | Adat3 | V128M PM in Adat3 | V128M PM in Adat3 | defect in cortical development | Juliette GODIN | |
| Mouse | 3x nls-mScarlett KI in Chrnd | C57BL/6N | Chrnd | cholinergic receptor, nicotinic, delta polypeptide | 3x nls-mScarlett KI in Chrnd | 3x nls-mScarlett KI in Chrnd | neuromuscular system | Laurent SCHAEFFER | |
| Mouse | fus/als | C57BL/6N | fus/als | fused in sarcoma | delta nls conditional / WT first | delta nls conditional / WT first | amyotrophic lateral sclerosis | currently being submitted | Luc DUPUIS |
| Mouse | Rspo1 | C57BL/6N | Rspo1 | R-spondin1 | KO and cKO | KO and cKO | disorders of sexual development | Marie-Christine CHABOISSIER | |
| Mouse | Scn2a conditional L1314P PM | C57BL/6N | scn2a | voltage-gated sodium channel, type II, alpha | Conditional PM | L1314P conditional PM/WT first | autism | pending | Massimo MANTEGAZZA |
| Mouse | Lrpprc PM via CRISPR/Cas9 | C57BL/6N | Lrpprc | containing a leucine-rich PPR motif | A353V PM in Lrpprc | Leigh syndrome (French-Canadian variant) | Metodi METODIEV | ||
| Mouse | Stradb | C57BL/6N | Stradb | STE20-related kinase adaptor beta | KO and cKO | KO and cKO | Peutz-Jeghers Syndrome | Michaël SEBBAGH | |
| Mouse | Claudin 16 | Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC) | Pascal HOUILLIER | ||||||
| Mouse | C57BL/6N | Gan | A49E mutation | Giant Axonal Neuropathy | Pascale BOMONT | ||||
| Mouse | Childhood Cerebellar Atrophy | Philippe LORY | |||||||
| Mouse | KCNT1 | Migrating partial seizures | Rima NABBOUT | ||||||
| Mouse | Bmp10 | C57BL/6N | Bmp10 | bone morphogenetic protein 10 | KO and cKO | KO and cKO | Huntington's disease | https://pubmed.ncbi.nlm.nih.gov/30165893/ | Sabine BAILLY |
| Mouse | FVIII-specific human T-cell receptor (TCR) transgenic | C57BL/6N | F8 | FVIII-specific human T-cell receptor (TCR) transgenic | transgenic (random insertion) | FVIII-specific human T-cell receptor (TCR) transgenic | Sébastien LACROIX-DESMAZES | ||
| Mouse | Stéphane NEDELEC | ||||||||
| Mouse | C395Y point mutation in Cckar induced by CRISPR | C57BL/6N | Cckar | cholecystokinin A receptor | PM | C395Y PM in Cckar | anorexia nervosa | Thierry BIENVENU | |
| Mouse | Nxnl1 PM (premature stop codon) | C57BL/6N | Nxnl1 | nucleoredoxin-like 1 | Nxnl1 PM (premature stop codon) | PM | Retinitis pigmentosa | Thierry LEVEILLARD | |
| Mouse | synonym: PM in Shh (AGC>AGT; S293S) | C57BL/6N | Shh | Sonic the Hedgehog | PM | AGC>AGT (S293S) in Shh | holoprosencephaly | Valérie DUPE | |
| Mouse | CHCHD10 | CHCHD10-related diseases | Véronique PAQUIS | ||||||
| Psammomys obesus | ABCA4 | ATP-Binding Cassette, Subfamily A, Member 4 | Stargardt's Disease | David HICKS | |||||
| Rat | Atp13a2 knockout | Sprague-Dawley | Atp13a2 | Cation-transporting ATPase 13A2 | KO | Kufor-Rakeb Syndrome | Phenotypic characterization of an Atp13a2 knockout rat model of Parkinson’s disease. Kinet et al. Submitted 2025 | Benjamin DEHAY | |
| Rat | Anks3 (p.P269L) | Sprague-Dawley | Anks3 | ankyrin repeat and sterile alpha motif domain-containing 3 | AI | Anks3 (p.P269L) mutation | Nephronophthisis | in progress | Brigitte LELONGT |
| Rat | Cftr-F508del | Sprague-Dawley | See | cystic fibrosis transmembrane conductance regulator | AI | F508del mutation | cystic fibrosis | https://pubmed.ncbi.nlm.nih.gov/31942562/ | Charles-Henry COTTART |
| Rat | Hcrt-YFP | Long Evans | Hcrt | hypocretin neuropeptide precursor | KO/KI | YFP | Type 1 narcolepsy | in progress | Christelle PEYRON |
| Rat | Igλ LC | Sprague-Dawley | Igk | kappa immunoglobulin | AI | hAmyl-Igλ | AL amyloidosis | https://pubmed.ncbi.nlm.nih.gov/33480298/ | Christophe SIRAC |
| Rat | loxP-Orai1 | Sprague-Dawley | Orai1 | ORAI calcium release-activated calcium modulator 1 | AI | loxP-Orai1 | pulmonary arterial hypertension | Additive Effects of the Orai1 Inhibitor (CM5480) on Pulmonary Arterial Hypertension and Right Ventricular Dysfunction in Combination with Specific Therapy. Saint-Martin Willer A et al. Submitted 2025 | Fabrice ANTIGNY |
| Rat | Kcnk3 knockout | Sprague–Dawley | Kcnk3 | potassium two-pore domain channel subfamily K member 3 | KO | pulmonary arterial hypertension | https://pubmed.ncbi.nlm.nih.gov/31347976/ | Frédéric PERROS | |
| Rat | R-DMDdup10-17 | Sprague-Dawley | DMD | Dystrophin | Duplication | DMDdel10-17 | Duchenne Muscular Dystrophy | https://pubmed.ncbi.nlm.nih.gov/40490752/ | Frédéric RELAIX |
| Rat | R-DMDdel48 | Sprague-Dawley | DMD | Dystrophin | Deletion | DMDdel48 | Becker Muscular Dystrophy | Frédéric RELAIX | |
| Rat | Calpain 3 KO | Sprague–Dawley | Capn3 | Calpain 3 | KO | Limb-girdle muscular dystrophy type 2A, calpainopathies | in progress | Isabelle RICHARD | |
| Rat | p.Tyr867*-NF-κB2 | Sprague-Dawley | Nfkb2 | Nuclear Factor Kappa B Subunit 2 | AI | p.Tyr867*-NF-κB2 mutation. | Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome | Matthieu GIRAUD | |
| Rat | C9orf72 KO | Sprague–Dawley | C9orf72 | Chromosome 9, open reading frame 72 | KO | amyotrophic lateral sclerosis & frontotemporal dementia | in progress | Nicolas CHARLET-BERGUERAND | |
| Rat | ceruloplasmin knockout | Sprague-Dawley | Cp | ceruloplasmin | KO | Hereditary aceruloplasminemia | https://pubmed.ncbi.nlm.nih.gov/31560858/ | Olivier LOREAL | |
| Rat | 16p11.2 | Sprague–Dawley and Long Evans | Sult1a1 | sulfotransferase family 1A member 1 | KO | autism spectrum disorders | https://pubmed.ncbi.nlm.nih.gov/37465586/ | Yann HERAULT | |
| Xenope | IGHMBP2 | immunoglobulin-binding protein 2 | Spinal Muscular Atrophy with respiratory distress, type 1 distress | Bruno DELLA GASPERA | |||||
| Xenope | XPC | Xeroderma pigmentosum complementation group C | Xeroderma Pigmentosum Type C | Hamid-Reza REZVANI | |||||
| Xenope | tp63 | Tumor protein p63 | junctional epidermolysis bullosa | Yann AUDIC | |||||
| Xenope | itga6 | Integrin Subunit Alpha 6 | junctional epidermolysis bullosa | Yann AUDIC | |||||
| Zebrafish | PRKAG2 | Dilated Cardiomyopathy and Endocardial Fibroelastosis | Gilles MILLAT | ||||||
| Zebrafish | RNU4ATAC | Taybi-Linder syndrome | Sylvie MAZOYER |
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