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59 results on '"Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM)"'

1. CRISPR-Cas9 globin editing can induce megabase-scale copy-neutral losses of heterozygosity in hematopoietic cells

Author: Jean-Marc Blouin, F. Prat, J. Rosier, Jean-Philippe Merlio, J. Bouron, Emmanuel Richard, Cécile Ged, Julian Boutin, Isabelle Lamrissi-Garcia, Aurélie Bedel, Sandrine Dabernat, François Moreau-Gaudry, G. Cullot, J. Toutain, Caroline Rooryck, Perrine Pennamen, Véronique Guyonnet-Dupérat, D. Cappellen, Samuel Amintas, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Myopathies, ANR-21-CE18-0002,CRISPR-genotox,Génotoxicité induite par CRISPR-CAS9(2021), Admin, Oskar, and Génotoxicité induite par CRISPR-CAS9 - - CRISPR-genotox2021 - ANR-21-CE18-0002 - AAPG2021 - VALID
Subjects: CRISPR-Cas9 genome editing, Genetic enhancement, Science, General Physics and Astronomy, Gene Expression, Loss of Heterozygosity, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Genome editing, Insulin-Like Growth Factor II, medicine, CRISPR, Humans, Globin, Cells, Cultured, 030304 developmental biology, Sequence Deletion, Genetics, Gene Editing, 0303 health sciences, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Chromosomes, Human, Pair 11, Chromosome, General Chemistry, DNA Methylation, medicine.disease, Hematopoietic Stem Cells, Uniparental disomy, 3. Good health, Telomere, Globins, Targeted gene repair, HEK293 Cells, 030220 oncology & carcinogenesis, RNA, Long Noncoding, CRISPR-Cas Systems, Chromosome Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: CRISPR-Cas9 is a promising technology for gene therapy. However, the ON-target genotoxicity of CRISPR-Cas9 nuclease due to DNA double-strand breaks has received little attention and is probably underestimated. Here we report that genome editing targeting globin genes induces megabase-scale losses of heterozygosity (LOH) from the globin CRISPR-Cas9 cut-site to the telomere (5.2 Mb). In established lines, CRISPR-Cas9 nuclease induces frequent terminal chromosome 11p truncations and rare copy-neutral LOH. In primary hematopoietic progenitor/stem cells, we detect 1.1% of clones (7/648) with acquired megabase LOH induced by CRISPR-Cas9. In-depth analysis by SNP-array reveals the presence of copy-neutral LOH. This leads to 11p15.5 partial uniparental disomy, comprising two Chr11p15.5 imprinting centers (H19/IGF2:IG-DMR/IC1 and KCNQ1OT1:TSS-DMR/IC2) and impacting H19 and IGF2 expression. While this genotoxicity is a safety concern for CRISPR clinical trials, it is also an opportunity to model copy-neutral-LOH for genetic diseases and cancers., CRISPR-Cas9 generates double-strand breaks, which pose a threat to genome integrity. Here the authors show loss of heterozygosity in edited hematopoietic progenitor cells.
Published: 2021
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2. A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

Author: de Boer, Elke, Ockeloen, Charlotte W., Matalonga, Leslie, Horvath, Rita, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Gilissen, Christian, Johari, Mridul, Laurie, Steven, Li, Shuang, Nelson, Isabelle, Peters, Sophia, Paramonov, Ida, Prasanth, Sivakumar, Robinson, Peter, Sablauskas, Karolis, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vitobello, Antonio, Rodenburg, Richard J., Coenen, Marieke J. H., Janssen, Mirian, Henssen, Dylan, Banka, Siddharth, Benetti, Elisa, Casari, Giorgio, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Ellwanger, Kornelia, Faivre, Laurence, Graessner, Holm, Haack, Tobias B., Hammarsjö, Anna, Havlovicova, Marketa, Hoischen, Alexander, Hugon, Anne, Jackson, Adam, Kleefstra, Tjitske, Lindstrand, Anna, López-Martín, Estrella, Macek, Milan, Morleo, Manuela, Nigro, Vicenzo, Nordgren, Ann, Pettersson, Maria, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca Clementina, Renieri, Alessandra, Rooryck, Caroline, Ryba, Lukas, Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Verloes, Alain, Vissers, Lisenka, Votypka, Pavel, Vyshka, Klea, Zurek, Birte, Trimouille, Aurélien, Vissers, Lisenka E. L. M., Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Research Council, Evelyn Trust, Newton Fund, European Project: 825619,AI4EU, Dutch Research Council (Holanda), Medical Research Council (Reino Unido), Lily Foundation, Unión Europea. Comisión Europea. H2020, Ockeloen, Charlotte W [0000-0003-0329-1520], Horvath, Rita [0000-0002-9841-170X], Rodenburg, Richard J [0000-0001-5227-3527], Gilissen, Christian [0000-0003-1693-9699], Steyaert, Wouter [0000-0001-8393-0788], Trimouille, Aurélien [0000-0002-3457-5684], Verloes, Alain [0000-0003-4819-0264], Vissers, Lisenka ELM [0000-0001-6470-5497], Apollo - University of Cambridge Repository, de Boer, E., Ockeloen, C. W., Matalonga, L., Horvath, R., Rodenburg, R. J., Coenen, M. J. H., Janssen, M., Henssen, D., Gilissen, C., Steyaert, W., Paramonov, I., Trimouille, A., Kleefstra, T., Verloes, A., Vissers, L. E. L. M., Nigro, V., Torella, A., and Banfi, S.
Subjects: Male, Proband, Mitochondrial DNA, RNA, Transfer, Leu, Brief Communication, Quadriplegia, Whole Exome Sequencing, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Young Adult, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual Disability, Exome Sequencing, Genetics research, Intellectual disability, Genetics, medicine, Humans, Genetics (clinical), Exome sequencing, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Neurodevelopmental disorders, 030305 genetics & heredity, Correction, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Translational research, medicine.disease, Heteroplasmy, 3. Good health, MT-TL1, Mutation, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Spastic tetraparesis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Neurological disorders, 030217 neurology & neurosurgery
Abstract: Correction: A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis. Eur J Hum Genet. 2021 Sep;29(9):1470-1471. doi: 10.1038/s41431-021-00937-3. The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line. This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to TK and 015.014.066 to LELMV), the European Research Council (ERC to RH), the Well come Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH), and the Evelyn Trust (RH). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257. Sí
Published: 2021
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3. Effects of OP2113 on Myocardial Infarct Size and No Reflow in a Rat Myocardial Ischemia/Reperfusion Model

Author: David Brown, Lifu Zhao, Justin B. Perry, Rodrigue Rossignol, Nivea Dias Amoedo, Wangde Dai, Bruno Le Grand, Juan Carreno, Robert A. Kloner, Aurelie Boucard, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.medical_specialty, Ischemia, Hemodynamics, Infarction, Ischemia/reperfusion injury, Cardio-protection, 030204 cardiovascular system & hematology, Infarct size, 03 medical and health sciences, 0302 clinical medicine, In vivo, Internal medicine, medicine, Myocyte, Pharmacology (medical), Myocardial infarction, Pharmacology, Coronary artery occlusion, business.industry, No-reflow phenomenon, Skeletal muscle, General Medicine, medicine.disease, Mitochondrial ROS generation, ST elevation myocardial infarction, 030104 developmental biology, medicine.anatomical_structure, No reflow phenomenon, Cardiology, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Purpose : The present study was to determine whether OP2113 could limit myocardial infarction size and the no-reflow phenomenon in a rat myocardial ischemia/reperfusion model. Methods : Rat heart–isolated mitochondria (RHM) were used to investigate mitochondrial respiration and mitochondrial reactive oxygen species (mtROS) generation both in normal conditions and in ischemia/reperfusion-mimicking conditions (using high concentrations of succinate). Human skeletal muscle myoblasts (HSMM) in culture were used to investigate the cellular intermittent deprivation in energy substrates and oxygen as reported in ischemia/reperfusion conditions. In vivo, rats were anesthetized and subjected to 30 min of left coronary artery occlusion followed by 3 h of reperfusion. Rats were randomized to receive OP2113 as an intravenous infusion starting either 5 min prior to coronary artery occlusion (preventive), or 5 min prior to reperfusion (curative), or to receive vehicle starting 5 min prior to coronary artery occlusion. Infusions continued until the end of the study (3 h of reperfusion). Results : RHM treated with OP2113 showed a concentration-dependent reduction of succinate-induced mtROS generation. In HSMM cells, OP2113 treatment (5–10 μM) during 48H prevented the reduction in the steady-state level of ATP measured just after reperfusion injuries and decreased the mitochondrial affinity to oxygen. In vivo, myocardial infarct size, expressed as the percentage of the ischemic risk zone, was significantly lower in the OP2113-treated preventive group (44.5 ± 2.9%) versus that in the vehicle group (57.0 ± 3.6%; p
Published: 2021
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4. Effects of capnometry monitoring during recovery in the post-anaesthesia care unit: a randomized controlled trial in adults (CAPNOSSPI)

Author: Stéphanie Roullet, Matthieu Biais, Isabelle Etchebarne, Karine Nouette-Gaulain, Laurent Soubiron, Julien Potvin, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, medicine.medical_specialty, Health Informatics, Anesthesia, General, Critical Care and Intensive Care Medicine, Hypoxemia, law.invention, Pacu, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Laryngeal mask airway, Capnography, 030202 anesthesiology, law, Anesthesiology, medicine, Humans, General anaesthesia, Prospective Studies, Hypoxia, medicine.diagnostic_test, biology, business.industry, Respiration, 030208 emergency & critical care medicine, Perioperative, Carbon Dioxide, biology.organism_classification, Post-anaesthesia care unit, 3. Good health, Anesthesiology and Pain Medicine, Anesthesia, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Purpose: Continuous capnography should be used on patients admitted to post-anaesthesia care units (PACUs) with endotracheal tubes, but this monitoring is not always performed. Optimized ventilation in the PACU could be part of the global standards of practice to maintain the benefits of perioperative ventilation. The main objective was to study the rate of patients with alveolar hypoventilation before tracheal extubation or Laryngeal Mask Airway (LMA) removal upon the measurement of continuous capnography. Methods: In this prospective, parallel-group, randomized controlled study, we enrolled adult patients admitted to the PACU after general anaesthesia with an endotracheal tube or LMA in place. Patients were randomly assigned to two groups: in the Capno + group, nurses managed the patients with access to the capnometer and end-tidal carbon dioxide pressure (PETCO2) measurements; in the Capno- group, nurses monitored the patients without seeing PETCO2 measurements. The primary outcome was the percentage of patients with PETCO2 measurements above 45 mm Hg during the minute before extubation. Secondary endpoints included the delay in recovering spontaneous breathing, rate of hypoxemia, delay before extubation, and length of stay in the PACU. Results: Forty-eight patients were randomized into the two groups. The percentage of patients with PETCO2 > 45 mm Hg the minute before extubation was significantly decreased in the Capno + group (83.3% versus 54,1% in the Capno- and Capno + groups respectively, p = 0.029). There were no significant differences concerning secondary endpoints. Conclusions: The use of PETCO2 monitoring improves patient safety by decreasing the incidence of CO2 retention during recovery from general anaesthesia. This study suggests that this monitoring should be integrated in the PACU. The risk of hypoxemia can also be prevented through the early recognition of apnoea. Clinical Trial registry: clinicaltrial.gov. identifier: NCT03370081
Published: 2021
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5. Clinical and molecular characterization of adult patients with late-onset MTHFR deficiency

Author: Christian Lavigne, Christoph Kessler, Matthias R. Baumgartner, Patricie Burda, François Feillet, Martina Huemer, Viktor Kožich, Mirian C. H. Janssen, Fanny Mochel, Rebecca Schüle, Pavel Ješina, Karolina M. Stepien, Adeline Regnier, Isabelle Redonnet-Vernhet, Jean-François Benoist, Cecilia Marelli, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Delayed Diagnosis, Methylenetetrahydrofolate reductase deficiency, diagnosis [Muscle Spasticity], Gastroenterology, pathology [Epilepsy], Epilepsy, 0302 clinical medicine, late-onset, Medicine, Age of Onset, Cognitive decline, Child, Genetics (clinical), 0303 health sciences, biology, MTHFR deficiency, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Middle Aged, 3. Good health, Neurology, Muscle Spasticity, diagnosis [Psychotic Disorders], Homocystinuria, Female, medicine.symptom, pathology [Homocystinuria], Polyneuropathy, pathology [Muscle Spasticity], Adult, diagnosis [Seizures], medicine.medical_specialty, Adolescent, Late onset, Late-onset, Asymptomatic, pathology [Intellectual Disability], Young Adult, 03 medical and health sciences, Seizures, Intellectual Disability, Internal medicine, Genetics, Humans, pathology [Psychotic Disorders], deficiency [Methylenetetrahydrofolate Reductase (NADPH2)], Inherited metabolic disease, inherited metabolic disease, Methylenetetrahydrofolate Reductase (NADPH2), Retrospective Studies, 030304 developmental biology, pathology [Seizures], business.industry, neurology, diagnosis [Homocystinuria], medicine.disease, diagnosis [Epilepsy], Psychotic Disorders, diagnosis [Intellectual Disability], Methylenetetrahydrofolate reductase, biology.protein, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Item does not contain fulltext 5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.
Published: 2021
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6. Women in Anaesthesia and Intensive Care Medicine in France: Are we making any progress?

Author: Anne-Claire Lukaszewicz, Marie-Laure Cittanova, Hélène Beloeil, Anne Godier, Catherine Paugam-Burtz, Karine Nouette-Gaulain, Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Saint Jean de Dieu, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), and Jonchère, Laurent
Subjects: Critical Care, [SDV]Life Sciences [q-bio], Proportional representation, Population, Specialty, Anaesthesia and Intensive Care Medicine, Critical Care and Intensive Care Medicine, Professional activity, Physicians, Women, 03 medical and health sciences, 0302 clinical medicine, 5. Gender equality, Anesthesiology, Intensive care, Humans, Medicine, Anesthesia, Women, 030212 general & internal medicine, education, Inclusion, Gender equality, education.field_of_study, business.industry, Gender distribution, Gender, 030208 emergency & critical care medicine, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], Parity, Anesthesiology and Pain Medicine, Workforce, Female, France, business
Abstract: International audience; Introduction: Gender imbalance in medicine is a topic of increasing interest. Gender matters, as there is increasing evidence that a gender diverse medical workforce translates into improved patient outcomes. The gender distribution in France among the Anaesthetists-Intensive Care (AIC) physicians has never been considered.Methods: Gender distribution is described during the last two decades in France among the whole population of AIC physicians according to their age, professional activity, leading and academic position.Results: The proportion of female AIC physicians remained stable from 1999 to 2018, between 35 and 38%. Only 40% of residents choosing this specialty in 2018 were female. Female AIC physicians were under-represented in key medico-political and academic positions: in 2018, 0.7% of the 605 presidents of medical commissions from public hospitals and none of the medical university deans were female AIC physicians; 9% of AIC full Professors were female. In the French Society of Anaesthesia and Intensive Care (SFAR), 42% of the members of the Scientific Committee of our Society are women.Conclusions: A gender imbalance is apparent in French AIC Medicine and worsens as physicians progress through their academic or leadership pathways. The French Society of Anaesthesia and Intensive Care campaigns for proportional representation at all levels of leadership, which translates into more gender equality in the committees of the society, including the Scientific Committee. A major policy shift is urgently required to support women, to tend toward gender parity to increase the performance of the French AIC workforce.
Published: 2020
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7. Proteomic Study of Low-Birth-Weight Nephropathy in Rats

Author: Nivea Dias Amoedo, Didier Lacombe, Rodrigue Rossignol, Toshiyuki Imasawa, Stéphane Claverol, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Chiba University Hospital, Université de Bordeaux (UB), Cellomet [CHU Pellegrin, Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], and Admin, Oskar
Subjects: Male, Proteome, medicine.medical_treatment, 030232 urology & nephrology, Mitochondrion, Oxidative Phosphorylation, Pathogenesis, Electron Transport Complex III, 0302 clinical medicine, Focal segmental glomerulosclerosis, Pregnancy, Birth Weight, Biology (General), Spectroscopy, 0303 health sciences, Kidney, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Medicine, 3. Good health, Computer Science Applications, mitochondria, Chemistry, Mitochondrial respiratory chain, medicine.anatomical_structure, nephropathy, Female, Kidney Diseases, medicine.drug, medicine.medical_specialty, kidney, NF-E2-Related Factor 2, QH301-705.5, Intraperitoneal injection, Biology, Article, Catalysis, Nephropathy, Inorganic Chemistry, 03 medical and health sciences, proteomics, Internal medicine, medicine, Animals, low birth weight, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, Dexamethasone, 030304 developmental biology, Organic Chemistry, Infant, Low Birth Weight, medicine.disease, Rats, Rapamycin-Insensitive Companion of mTOR Protein, Endocrinology, Animals, Newborn, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The hyperfiltration theory has been used to explain the mechanism of low birth weight (LBW)-related nephropathy. However, the molecular changes in the kidney proteome have not been defined in this disease, and early biomarkers are lacking. We investigated the molecular pathogen-esis of LBW rats obtained by intraperitoneal injection of dexamethasone into pregnant animals. Nor-mal-birth-weight (NBW) rats were used as controls. When the rats were four weeks old, the left kidneys were removed and used for comprehensive label-free proteomic studies. Following uninephrectomy, all rats were fed a high-salt diet until 9 weeks of age. Differences in the molecular composition of the kidney cortex were observed at the early step of LBW nephropathy pathogenesis. Untargeted quantitative proteomics showed that proteins involved in energy metabolism, such as oxidative phosphorylation (OXPHOS), the TCA cycle, and glycolysis, were specifically downregu-lated in the kidneys of LBW rats at four weeks. No pathological changes were detected at this early stage. Pathway analysis identified NEFL2 (NRF2) and RICTOR as potential upstream regulators. The search for biomarkers identified components of the mitochondrial respiratory chain, namely, ubiquinol-cytochrome c reductase complex subunits (UQCR7/11) and ATP5I/L, two components of mitochondrial F1FO-ATP synthase. These findings were further validated by immunohistology. At later stages of the disease process, the right kidneys revealed an increased frequency of focal segmental glomerulosclerosis lesions, interstitial fibrosis and tubular atrophy. Our findings revealed proteome changes in LBW rat kidneys and revealed a strong downregulation of specific mitochon-drial respiratory chain proteins, such as UQCR7.
Published: 2021
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8. Albinism: An Underdiagnosed Condition

Author: Eulalie Lasseaux, Vincent Michaud, Benoit Arveiler, CCSD, Accord Elsevier, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Bordeaux [Bordeaux]
Subjects: Heterozygote, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Prenatal diagnosis, Dermatology, Biochemistry, Diagnosis, Differential, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Oculocutaneous albinism type 1, Prenatal Diagnosis, medicine, Humans, Molecular diagnostic techniques, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Heterozygote advantage, Syndrome, Cell Biology, medicine.disease, [SDV] Life Sciences [q-bio], Ophthalmology, Phenotype, Molecular Diagnostic Techniques, Albinism, Oculocutaneous, Albinism, Female, business
Abstract: International audience; No abstract available
Published: 2020
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9. Changes in dynamic arterial elastance induced by volume expansion and vasopressor in the operating room: a prospective bicentre study

Author: Philippe Boyer, Musa Sesay, Romain Grobost, Matthieu Biais, Romain Lanchon, Karine Nouette-Gaulain, Emmanuel Futier, Hugues de Courson, Service Anesthésie - Réanimation [Bordeaux], CHU Bordeaux [Bordeaux], Service d'Anésthésie Réanimation [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Retinoids, Development and Developmental Diseases (R2D2), Université d'Auvergne - Clermont-Ferrand I (UdA), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), This study was supported from institutional and departmental sources., Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Boullé, Christelle
Subjects: Cardiac output, medicine.medical_specialty, Mean arterial pressure, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030202 anesthesiology, Internal medicine, Heart rate, Article CLINIQUE, medicine, Arterial pressure, business.industry, Research, Doppler, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, Stroke volume, lcsh:RC86-88.9, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pulse pressure, Compliance (physiology), Blood pressure, Cardiology, Arterial line, business
Abstract: Background Dynamic arterial elastance (Eadyn), defined as the ratio between pulse pressure variations and stroke volume variations, has been proposed to assess functional arterial load. We evaluated the evolution of Eadyn during volume expansion and the effects of neosynephrine infusion in hypotensive and preload-responsive patients. Methods In this prospective bicentre study, we included 56 mechanically ventilated patients in the operating room. Each patient had volume expansion and neosynephrine infusion. Stroke volume and stroke volume variations were obtained using esophageal Doppler, and pulse pressure variations were measured through the arterial line. Pressure response to volume expansion was defined as an increase in mean arterial pressure (MAP) ≥ 10%. Results Twenty-one patients were pressure responders to volume expansion. Volume expansion induced a decrease in Eadyn (from 0.69 [0.58–0.85] to 0.59 [0.42–0.77]) related to a decrease in pulse pressure variations more pronounced than the decrease in stroke volume variations. Baseline and changes in Eadyn after volume expansion were related to age, history of arterial hypertension, net arterial compliance and effective arterial elastance. Eadyn value before volume expansion > 0.65 predicted a MAP increase ≥ 10% with a sensitivity of 76% (95% CI 53–92%) and a specificity of 60% (95% CI 42–76%). Neosynephrine infusion induced a decrease in Eadyn (from 0.67 [0.48–0.80] to 0.54 [0.37–0.68]) related to a decrease in pulse pressure variations more pronounced than the decrease in stroke volume variations. Baseline and changes in Eadyn after neosynephrine infusion were only related to heart rate. Conclusion Eadyn is a potential sensitive marker of arterial tone changes following vasopressor infusion.
Published: 2019
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10. Evaluation of least significant changes of pulse contour analysis-derived parameters

Author: Eric Verchère, Matthieu Biais, Gregoire Cane, Hugues de Courson, Karine Nouette-Gaulain, Musa Sesay, Loic Ferrer, Service Anesthésie - Réanimation [Bordeaux], CHU Bordeaux [Bordeaux], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), This study was supported from institutional and departmental sources., Boullé, Christelle, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, Fluid responsiveness, Cardiac index, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030202 anesthesiology, Contour analysis, Internal medicine, Occlusion, Article CLINIQUE, Medicine, Pulse (signal processing), business.industry, Research, Pulse pressure variation, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, Stroke volume, lcsh:RC86-88.9, Precision, Pulse pressure, Lung recruitment, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Stroke volume variation, Cardiology, business, Pulse contour
Abstract: Background Many maneuvers assessing fluid responsiveness (minifluid challenge, lung recruitment maneuver, end-expiratory occlusion test, passive leg raising) are considered as positive when small variations in cardiac index, stroke volume index, stroke volume variation or pulse pressure variation occur. Pulse contour analysis allows continuous and real-time cardiac index, stroke volume, stroke volume variation and pulse pressure variation estimations. To use these maneuvers with pulse contour analysis, the knowledge of the minimal change that needs to be measured by a device to recognize a real change (least significant change) has to be studied. The aim of this study was to evaluate the least significant change of cardiac index, stroke volume index, stroke volume variation and pulse pressure variation obtained using pulse contour analysis (ProAQT®, Pulsion Medical System, Germany). Methods In this observational study, we included 50 mechanically ventilated patients undergoing neurosurgery in the operating room. Cardiac index, stroke volume index, pulse pressure variation and stroke volume variation obtained using ProAQT® (Pulsion Medical System, Germany) were recorded every 12 s during 15-min steady-state periods. Least significant changes were calculated every minute. Results Least significant changes statistically differed over time for cardiac index, stroke volume index, pulse pressure variation and stroke volume variation (p Conclusion To conclude, the present study suggests that pulse contour analysis is able to detect rapid and small changes in cardiac index and stroke volume index, but the interpretation of rapid and small changes of pulse pressure variation and stroke volume variation must be done with caution.
Published: 2019
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11. LC-MS/MS measurements of urinary guanidinoacetic acid and creatine: Method optimization by deleting derivatization step

Author: Rucheton Benoit, Amintas Samuel, Ducint Dominique, Julian Boutin, Redonnet-Vernhet Isabelle, Colombies Brigitte, Mesli Samir, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Urinary system, Clinical Biochemistry, Glycine, Guanidinoacetate methyltransferase deficiency, Urine, Creatine, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Tandem Mass Spectrometry, Lc ms ms, medicine, Humans, Language Development Disorders, Derivatization, Chromatography, High Pressure Liquid, Movement Disorders, Chromatography, Clinical Laboratory Techniques, Chemistry, Ion pairing, Biochemistry (medical), General Medicine, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Guanidinoacetate N-Methyltransferase, Creatine deficiency
Abstract: Cerebral Creatine deficiency syndromes (CCDS) include three hereditary diseases affecting the metabolism of creatine (Cr): arginine glycine amidinotransferase deficiency, guanidinoacetate methyltransferase deficiency and disorders of creatine transporter. These pathologies cause a brain creatine deficiency responsible of non-specific neurological impairments with mental retardation. LC-MS/MS measurements of guanidinoacetic acid (GAA) and creatine in urine and plasma are an important screening test to identify the deficit. Analysis of this polar and basic molecules not hold on standard column requires a derivatization step to butyl-esters. To overcome this long and fastidious derivatization, an ion pairing (IP) method was chosen in this study.IP method was validated using Comité francais d'accréditation (COFRAC) recommendations. Then, urine GAA and creatine of 15 patients with a CDS deficiency suspected were tested y LC-MS/MS using IP technique, and performances were assessed with reference laboratory method (butylation method). Moreover, references values were suggested y the study of 100 urines samples of healthy patients.The method developed provided a good accuracy and precision with intra and inter-day coefficients of variation (CVs)15%. The curve was linear for the biological and pathological concentrations. The comparison with the reference method did not reveal any significant difference for analytical performances but showed a simplification of the preparation of samples.The use of IP technique that we have developed demonstrated a good correlation with the butylation method. Moreover, this new method not only allows a simplification of the technique, but also decreases in run time.
Published: 2019
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12. First description of an IgM monoclonal antibody causing αIIbβ3 integrin activation and acquired Glanzmann thrombasthenia associated with macrothrombocytopenia

Author: Bernard Payrastre, Chloé James, Alexandre Guy, Marie Tuffigo, Xavier Pillois, Jean-François Viallard, Martine Jandrot-Perrus, Émeline Choquet, Jean-Claude Bordet, Mathieu Fiore, Cédric Garcia, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des pathologies plaquettaires (CRPP), CHU Bordeaux [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Boullé, Christelle, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: media_common.quotation_subject, Integrin, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Medicine, Platelet, Ristocetin, Internalization, ComputingMilieux_MISCELLANEOUS, media_common, biology, business.industry, Autoantibody, Hematology, Phenotype, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, chemistry, Article RECHERCHE, Immunology, biology.protein, Phosphorylation, Antibody, business
Abstract: Essentials Acquired Glanzmann thrombasthenia (GT) is generally caused by anti-αIIb β3 autoantibodies. We report the case of a man with an acquired GT phenotype associated with macrothrombocytopenia. Perturbed platelet function were associated with an activating anti-αIIb β3 IgM autoantibody. This novel clinical entity raises interesting questions about the αIIb β3 integrin signaling. SUMMARY: Background Acquired Glanzmann thrombasthenia (GT) is a bleeding disorder generally caused by anti-αII b β3 autoantibodies. Objectives We aimed to characterize the molecular mechanism leading to a progressive GT-like phenotype in a patient with chronic immune thrombocytopenia. Patient, Methods, and Results The patient suffered from repeated episodes of gastrointestinal bleeding; further studies indicated a moderate platelet aggregation defect. A few months later, platelet function showed abolished aggregation using all agonists, but normal agglutination with ristocetin. No platelet-bound antibodies were detected, but the presence of large amounts of an IgM type antibody detected together with αII b β3 in the patient permeabilized platelets suggested that this IgM was an autoantibody causing the internalization of the complex. This was confirmed by the fact that the patient IgM bound to normal platelets but not to platelets from GT type I patients. Moreover, patient's plasma activated αII b β3 on controls' platelets as evidenced by increased PAC-1 binding. We also demonstrated that the patient plasma triggered αII b β3 outside-in signaling, as β3 Tyr773 and FAK were phosphorylated, and increased the rate of actin polymerization in resting platelets reflecting an impairment of cytoskeletal reorganization. Because different signs of dysmegakaryopoiesis were also observed in our patient, we evaluated the ability of its serum to impair proplatelets formation and showed that it significantly decreased the number of proplatelet-bearing megakaryocytes in controls' bone marrow stem cells culture compared with normal serum. Conclusions We present the case of a patient with a progressive and severely perturbed platelet function associated with the presence of an IgM activating autoantibody directed against αII b β3 .
Published: 2019
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13. 10 years of CEMARA database in the AnDDI-Rares network: a unique resource facilitating research and epidemiology in developmental disorders in France

Author: MESSIAEN, Claude, RACINE, Caroline, KHATIM, Ahlem, SOUSSAND, Louis, ODENT, Sylvie, LACOMBE, Didier, MANOUVRIER, Sylvie, EDERY, Patrick, SIGAUDY, Sabine, GENEVIEVE, David, THAUVIN-ROBINET, Christel, PASQUIER, Laurent, PETIT, Florence, ROSSI, Massimiliano, WILLEMS, Marjolaine, ATTIE-BITACH, Tania, ROUX-LEVY, Pierre-Henry, DEMOUGEOT, Laurent, BEN SLAMA, Lilia, LANDAIS, Paul, THE ANDDI-RARES, Network, JANNOT, Anne-Sophie, BINQUET, Christine, SANDRIN, Arnaud, VERLOES, Alain, FAIVRE, Laurence, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Pontchaillou [Rennes], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Lille, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), CHU Marseille, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Montpellier (UM), GHU AP-HP Centre Université de Paris, Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: Adult, 0301 basic medicine, medicine.medical_specialty, Resource (biology), Databases, Factual, Epidemiology, Developmental Disabilities, Population, 030105 genetics & heredity, computer.software_genre, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, Data warehouse, Care organization, Humans, Medicine, Pharmacology (medical), 030212 general & internal medicine, Medical diagnosis, Child, education, Genetics (clinical), Retrospective Studies, education.field_of_study, Database, business.industry, Research, Developmental disorders, General Medicine, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Uncertain diagnosis, Christian ministry, France, business, computer, Rare disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background In France, the Ministry of Health has implemented a comprehensive program for rare diseases (RD) that includes an epidemiological program as well as the establishment of expert centers for the clinical care of patients with RD. Since 2007, most of these centers have entered the data for patients with developmental disorders into the CEMARA population-based registry, a national online data repository for all rare diseases. Through the CEMARA web portal, descriptive demographic data, clinical data, and the chronology of medical follow-up can be obtained for each center. We address the interest and ongoing challenges of this national data collection system 10 years after its implementation. Methods Since 2007, clinicians and researchers have reported the “minimum dataset (MDS)” for each patient presenting to their expert center. We retrospectively analyzed administrative data, demographic data, care organization and diagnoses. Results Over 10 years, 228,243 RD patients (including healthy carriers and family members for whom experts denied any suspicion of RD) have visited an expert center. Among them, 167,361 were patients affected by a RD (median age 11 years, 54% children, 46% adults, with a balanced sex ratio), and 60,882 were unaffected relatives (median age 37 years). The majority of patients (87%) were seen no more than once a year, and 52% of visits were for a diagnostic procedure. Among the 2,869 recorded rare disorders, 1,907 (66.5%) were recorded in less than 10 patients, 802 (28%) in 10 to 100 patients, 149 (5.2%) in 100 to 1,000 patients, and 11 (0.4%) in > 1,000 patients. Overall, 45.6% of individuals had no diagnosis and 6.7% had an uncertain diagnosis. Children were mainly referred by their pediatrician (46%; n = 55,755 among the 121,136 total children referrals) and adults by a medical specialist (34%; n = 14,053 among the 41,564 total adult referrals). Given the geographical coverage of the centers, the median distance from the patient’s home was 25.1 km (IQR = 6.3 km-64.2 km). Conclusions CEMARA provides unprecedented support for epidemiological, clinical and therapeutic studies in the field of RD. Researchers can benefit from the national scope of CEMARA data, but also focus on specific diseases or patient subgroups. While this endeavor has been a major collective effort among French RD experts to gather large-scale data into a single database, it provides tremendous potential to improve patient care.
Published: 2021
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14. Clinical description and mutational profile of a moroccan series of patients with rubinstein taybi syndrome

Author: Benoit Arveiler, Didier Lacombe, Ilham Ratbi, Siham Chafai Elalaoui, Mariam Tajir, Julien Van-Gils, Wiam Smaili, Patricia Fergelot, Abdelaziz Sefiani, Université Mohammed V de Rabat [Agdal], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National d'Hygiène [Maroc], Admin, Oskar, and Université Mohammed V de Rabat [Agdal] (UM5)
Subjects: Male, Microcephaly, Pediatrics, medicine.medical_specialty, Genetic counseling, 030231 tropical medicine, Moroccan, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Short stature, Polymerase Chain Reaction, Rubinstein Taybi syndrome, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, medicine, otorhinolaryngologic diseases, Humans, CREBBP gene, EP300, Child, Sanger sequencing, Rubinstein-Taybi Syndrome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Rubinstein–Taybi syndrome, business.industry, Infant, General Medicine, Articles, medicine.disease, Major gene, 3. Good health, Developmental disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Mutation, symbols, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background: Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is a rare autosomal dominant developmental disorder with an estimated prevalence of one case per 125,000 live births. RSTS is characterized by typical face, broad thumbs and halluces, short stature, and intellectual disability. Facial dysmorphy is characteristic with microcephaly, low frontal hairline, arched eyebrows, long eyelashes, convex profile of nose, narrow palate, and micrognathia. RSTS is mainly due to mutations or microdeletions of the CREBBP gene (about 60%) and more rarely of the EP300 gene (8%). Objective: Clinical description and identification of mutations of patients with Rubinstein Taybi syndrome. Methods: PCR and direct sequencing of CREBBP gene. Results: We report here, the clinical and molecular data of a series of six Moroccan patients with a phenotype of RSTS. The molecular study of the major gene CREBBP (by Sanger Sequencing followed by CGH array, if sequence normal) revealed point mutations in five patients. For the sixth patient, CGH array revealed a microdeletion carrying the CREBBP gene. Through this work, we emphasize the importance of clinical expertise in the diagnosis, management and genetic counseling in Rubinstein Taybi syndrome. Keywords: Rubinstein Taybi syndrome; CREBBP gene; mutation; Moroccan.
Published: 2021
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15. Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder

Author: Didier Lacombe, Frédérique Magdinier, Patricia Fergelot, Julien Van Gils, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Genotype, chromatinopathies, phenotype, Developmental Disabilities, Limb Deformities, Congenital, Context (language use), Review, QH426-470, Biology, CREBBP, Chromatin remodeling, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, EP300, Genetic Association Studies, Rubinstein-Taybi syndrome, Genetics (clinical), acetylation, [SDV.GEN]Life Sciences [q-bio]/Genetics, epigenetics, Rubinstein–Taybi syndrome, Extremities, medicine.disease, Developmental disorder, 030104 developmental biology, Mutation, chromatin, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The Rubinstein-Taybi syndrome (RSTS) is a rare congenital developmental disorder characterized by a typical facial dysmorphism, distal limb abnormalities, intellectual disability, and many additional phenotypical features. It occurs at between 1/100,000 and 1/125,000 births. Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic variants have been reported for the CREBBP gene and 118 for EP300. These two genes encode paralogs acting as lysine acetyltransferase involved in transcriptional regulation and chromatin remodeling with a key role in neuronal plasticity and cognition. Because of the clinical heterogeneity of this syndrome ranging from the typical clinical diagnosis to features overlapping with other Mendelian disorders of the epigenetic machinery, phenotype/genotype correlations remain difficult to establish. In this context, the deciphering of the patho-physiological process underlying these diseases and the definition of a specific episignature will likely improve the diagnostic efficiency but also open novel therapeutic perspectives. This review summarizes the current clinical and molecular knowledge and highlights the epigenetic regulation of RSTS as a model of chromatinopathy.
Published: 2021
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16. CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum

Author: Fowzan S. Alkuraya, Eric J. Mallack, Ingrid M. Wentzensen, John Karl de Dios, Subhadra Ramanathan, Robin D. Clark, Alpa Sidhu, Mais Hashem, Valérie Cormier-Daire, Maya Chopra, Danita Velasco, Shenela Lakhani, Lois J. Starr, Emily Singh, Didier Lacombe, Karin Panzer, Chloe Whitton, Elizabeth E. Palmer, Vincent Michaud, Lance H. Rodan, Christoffer Nellåker, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Pediatrics, medicine.medical_specialty, Developmental delay, Intellectual disability, Nerve Tissue Proteins, 03 medical and health sciences, Epilepsy, Exon, 0302 clinical medicine, Atrophy, Neurodevelopmental disorder, Genetics, Medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Global developmental delay, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, Arthrogryposis, 0303 health sciences, business.industry, Facies, Genomics, Syndrome, medicine.disease, Rare diseases, 3. Good health, Phenotype, Neurodevelopmental Disorders, Child, Preschool, Mutation, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: We describe the clinical features of nine unrelated individuals with rare de novo missense or in-frame deletions/duplications within the « HX motif » of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral-pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication.
Published: 2021
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17. Pain evaluation after day-surgery using a mobile phone application

Author: Nicolas Pages, Jean-Claude Pauchard, Maxim Roy, Florian Robin, Isabelle Quintana, Karine Nouette-Gaulain, Alice Quinart, Jérome Carlier, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Postoperative pain, Critical Care and Intensive Care Medicine, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Postoperative outcome assessment, Medicine, Humans, Adverse effect, Retrospective Studies, Pain, Postoperative, business.industry, Incidence (epidemiology), Retrospective cohort study, General Medicine, mobile application, Missing data, Surgery, Anesthesiology and Pain Medicine, Ambulatory Surgical Procedures, Ambulatory, Observational study, Day surgery, business, 030217 neurology & neurosurgery, Cell Phone, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cohort study
Abstract: Introduction Few studies assess postoperative outcomes after discharge in the ambulatory setting. The aim of this study was to investigate postoperative pain and adverse effects at 24 h and at 7 days after day surgery using an e-health follow-up smartphone-based application named SATELIA®. Materials and methods This retrospective, observational and monocentric cohort study was conducted at the University Hospital of Bordeaux. All eligible patients for SATELIA® follow-up between May 2018 and June 2019 were screened for the analysis. Data were extracted from two databases. Those with a missing primary outcome were excluded from the analysis. The main outcome was the worst pain score on POD 1, self-reported via SATELIA®. The secondary outcomes were the incidence of adverse effects on POD1, as well as the worst pain score and adverse effects on POD7. Quantitative data were reported by the median (IQR) and categorical data were presented as absolute numbers (%). Results A total of 2283 patients were screened for analysis, from which 592 were excluded due to missing data for the main outcome; 1691 patients were thus finally included. The median worst pain score at POD 1 was 3.0 (1.0–5.0); 35.5% (n = 601/1691) and 29.1% (n = 492/1691) of the patients reported moderate-to-severe pain at POD1 and POD7, respectively. Conclusion This retrospective study shows that 35.5% of patients experience moderate-to-severe pain after day surgery. Even if SATELIA® should be further developed and evaluated, it also demonstrates the interest of using phone based software to follow patients after discharge and ensure a better personalised management.
Published: 2021
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18. Management of albinism: French guidelines for diagnosis and care

Author: Benoit Arveiler, Alain Taïeb, E Moreno-Artero, Stéphanie Leclerc-Mercier, Smail Hadj-Rabia, H. Dufresne, I Drumare-Bouvet, B. Jouanne, Dominique Bremond-Gignac, Fanny Morice-Picard, J Kaplan, C Duncombe-Poulet, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.medical_specialty, genetic structures, Albinism, Vision Disorders, Dermatology, Nystagmus, Nystagmus, Pathologic, Melanin, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, medicine, Humans, Hypopigmentation, Melanins, business.industry, Genetic disorder, medicine.disease, Hypoplasia, 3. Good health, 030104 developmental biology, Infectious Diseases, Albinism, Oculocutaneous, Practice Guidelines as Topic, 030221 ophthalmology & optometry, sense organs, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Systematic Reviews as Topic
Abstract: Albinism is a worldwide genetic disorder caused by mutations in at least 20 genes, identified to date, that affect melanin production or transport in the skin, hair and eyes. Patients present with variable degrees of diffuse muco-cutaneous and adnexal hypopigmentation, as well as ocular features including nystagmus, misrouting of optic nerves and foveal hypoplasia. Less often, albinism is associated with blood, immunological, pulmonary, digestive and/or neurological anomalies. Clinical and molecular characterizations are essential in preventing potential complications. Disease-causing mutations remain unknown for about 25% of patients with albinism. These guidelines have been developed for the diagnosis and management of syndromic and non-syndromic forms of albinism, based on a systematic review of the scientific literature. These guidelines comprise clinical and molecular characterization, diagnosis, therapeutic approach and management.
Published: 2021
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19. Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells

Author: Saharnaz Sarlak, Claude Lalou, Rodrigue Rossignol, Andras T. Meszaros, Helmut Klocker, Christian Frezza, Juan Alberto Pérez-Valencia, Ana Carolina B Sant'Anna-Silva, Erich Gnaiger, Laura Tronci, Efterpi Nikitopoulou, Marco Sciacovelli, Innsbruck Medical University [Austria] (IMU), University of Cambridge [UK] (CAM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Perez-Valencia, Juan A. [0000-0002-8282-1763], Tronci, Laura [0000-0002-1217-4046], Klocker, Helmut [0000-0001-7732-9443], Apollo - University of Cambridge Repository, Perez-Valencia, Juan A [0000-0002-8282-1763], Admin, Oskar, and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)
Subjects: 0301 basic medicine, Cancer Research, Cell signaling, cancer metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Oxidative phosphorylation, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, lcsh:RC254-282, Article, 03 medical and health sciences, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biosynthesis, Downregulation and upregulation, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Extracellular, medicine.disease, prostate cancer, succinate, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Citric acid cycle, mitochondria, anaplerosis, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer research
Abstract: Simple Summary Depending on the availability of nutrients and increased metabolic demands, tumor cells rearrange their metabolism to survive and, ultimately, proliferate. Here, the authors investigated the effect of succinate, a metabolite of the mitochondrial citric acid cycle, on malignant and non-malignant prostate cells. They analyzed uptake through membrane transporters and intracellular accumulation, which subsequently fuels metabolism and enhances oncogenic properties of the tumor cells. The findings shed light to the metabolic adaptations that prostate tumor cells undergo, providing a better understanding of metabolic rewiring and strategies for therapeutic intervention. Abstract Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells.
Published: 2021
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20. SOD1-related ALS with anticipation in a large family from Martinique

Author: Rémi Bellance, Cyril Goizet, Thomas Barnetche, Séverine Jeannin, Cécile Cazeneuve, Pascale Olive, Fabienne Clot, Sophie Duclos, Juliette Smith-Ravin, Anna-Gaelle Giguet-Valard, Oriane Allard-Saint-Albin, Pittion-Vouyovitch Sophie, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche, Région Hauts-de-France, ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), and ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010)
Subjects: SOD1, Next Generation Sequencing, Neurological disorder, Degeneration (medical), Anticipation, 03 medical and health sciences, Superoxide Dismutase-1, 0302 clinical medicine, CoDE-Seq method, medicine, Humans, Martinique, Amyotrophic lateral sclerosis, Genetic Amyotrophic Lateral Sclerosis, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, 3. Good health, DNA-Binding Proteins, nervous system, Neurology, Mutation, Anticipation (genetics), Neurology (clinical), business, Neuroscience, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Amyotrophic Lateral Sclerosis (ALS) is a rare neurological disorder that causes degeneration of upper and lower motor neurons and their axons. ALS is mostly sporadic, but there are familial forms. In more than half of the familial forms, a pathogenic variant is found in one of the following genes: C9ORF72, SOD1, TDP-43, FUS, and VCP. SOD1 is the 2nd most common gene involved in genetic forms of ALS. Genotype-phenotype relationships are occasionally established in genetic forms of ALS associated with SOD1 mutations pathogenic variants. The c.281G > T (p.[G93V]) variant in SOD1 is associated with a rarely described and unexplained anticipation phenomenon. We report a large family from Martinique in whom ALS is associated with a c.281G > T (p.[G93V]) pathogenic variant in SOD1 and a statistically suggested anticipation. A whole-exome study and detection of CNVs (CoDESeq) from 3 affected members of this family revealed the presence of variants of uncertain signification (VUS) in other ALS genes. VUS in DCTN1 and NEFH were present in patients of the 2nd generation, and CNVs involving UBQLN2 and C21orf2 were found in the youngest case of the family.
Published: 2021
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21. Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Author: Petter Strømme, Ferda Ozkinay, Heike Philippi, Pontus Wasling, Sebastien Moutton, Dagmar Timmann, Maria Vázquez-López, Pedro S Pinto, Annette Bley, A. Blaschek, Gabriel Á. Martos-Moreno, A. Micheil Innes, Alan Hill, Argirios Dinopoulos, Fiona Haslam McKenzie, Janice M. Fletcher, Barbara Plecko, Hanna Mierzewska, Matthis Synofzik, Cathy A. Stevens, Raphael Schiffmann, Janina Gburek-Augustat, Miriam Nickel, Constantin Polychronakos, Kether Guerrero, Susan M. Kirwin, Icíar Cimas, Inga Harting, Bwee Tien Poll-The, Vera Popovic, Coriene E. Catsman-Berrevoets, Simona Orcesi, Nicole I. Wolf, Laura Roos, Grace M. Hobson, Norberto Rodriguez Espinosa, Gert Wiegand, Bernard Brais, Julia Rankin, Marjo S. van der Knaap, Cyril Goizet, Michelle Demos, Sandra Pekic, Ingrid Tejera-Martin, Adeline Vanderver, Stefanie Perrier, Brent L. Fogel, Eriskay Liston, Meriel McEntagart, Ferdy K. Cayami, Bart P.C. van de Warrenburg, Anne Ronan, Paolo Gasparini, Bernard Corenblum, Joost Rotteveel, Mercedes Pineda Marfa, Roberta La Piana, Richard Webster, Eugen Boltshauser, Amytice Mirchi, Dietz Rating, Klara Brozova, Ingeborg Krägeloh-Mann, Marcelo Andrés Kauffman, Nesrin Senbil, Gerhard Kluger, Brenda Banwell, Flavio Faletra, Michel Sylvain, Urania Kotzaeridou, Tahir Atik, Raymond Fernandez, Stephan Saikali, William S. Benko, Fernando I Monton, Dorota Gieruszczak-Białek, Dolores Gonzalez Moron, Charles Marques Lourenço, Amy Pizzino, Ana Potic, Elsa Rossignol, Ton J. de Grauw, William T. Gibson, Luan T. Tran, Davide Tonduti, Rosalina M. L. van Spaendonk, Rocío Sánchez-Carpintero, Raymond P J Murphy, Guillaume Sébire, Daniela Pohl, Joshua L. Bonkowsky, Christopher Clough, Sandya Tirupathi, Maria Eugenia Garcia Garcia, Christoph Hertzberg, Serge Melançon, Anjum Misbahuddin, Félixe Pelletier, Evangeline Wassmer, Gail Dolan, Marie-France Rioux, Geneviève Bernard, Sunita Venkateswaran, Steffi Patzer, Aline Hamati, Helio Pedro, Hüseyin Onay, Drago Bratkovic, Petra Kolditz, Daniel Tibussek, Sakkubai Naidu, Nicole Ulrick, Emmanouil Rampakakis, William McClintock, Anna Schossig, Mohnish Suri, Grace Yoon, László Sztriha, John R. Østergaard, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Canadian Institutes of Health Research, Fonds de recherche du Québec, Fonds de Recherche du Québec - Santé, Neurology, Functional Genomics, Pelletier, F., Perrier, S., Cayami, F. K., Mirchi, A., Saikali, S., Tran, L. T., Ulrick, N., Guerrero, K., Rampakakis, E., van Spaendonk, R. M. L., Naidu, S., Pohl, D., Gibson, W. T., Demos, M., Goizet, C., Tejera-Martin, I., Potic, A., Fogel, B. L., Brais, B., Sylvain, M., Sebire, G., Lourenco, C. M., Bonkowsky, J. L., Catsman-Berrevoets, C., Pinto, P. S., Tirupathi, S., Stromme, P., de Grauw, T., Gieruszczak-Bialek, D., Krageloh-Mann, I., Mierzewska, H., Philippi, H., Rankin, J., Atik, T., Banwell, B., Benko, W. S., Blaschek, A., Bley, A., Boltshauser, E., Bratkovic, D., Brozova, K., Cimas, I., Clough, C., Corenblum, B., Dinopoulos, A., Dolan, G., Faletra, F., Fernandez, R., Fletcher, J., Garcia Garcia, M. E., Gasparini, P., Gburek-Augustat, J., Gonzalez Moron, D., Hamati, A., Harting, I., Hertzberg, C., Hill, A., Hobson, G. M., Innes, A. M., Kauffman, M., Kirwin, S. M., Kluger, G., Kolditz, P., Kotzaeridou, U., La Piana, R., Liston, E., Mcclintock, W., Mcentagart, M., Mckenzie, F., Melancon, S., Misbahuddin, A., Suri, M., Monton, F. I., Moutton, S., Murphy, R. P. J., Nickel, M., Onay, H., Orcesi, S., Ozkinay, F., Patzer, S., Pedro, H., Pekic, S., Pineda Marfa, M., Pizzino, A., Plecko, B., Poll-The, B. T., Popovic, V., Rating, D., Rioux, M. -F., Rodriguez Espinosa, N., Ronan, A., Ostergaard, J. R., Rossignol, E., Sanchez-Carpintero, R., Schossig, A., Senbil, N., Sonderberg Roos, L. K., Stevens, C. A., Synofzik, M., Sztriha, L., Tibussek, D., Timmann, D., Tonduti, D., van de Warrenburg, B. P., Vazquez-Lopez, M., Venkateswaran, S., Wasling, P., Wassmer, E., Webster, R. I., Wiegand, G., Yoon, G., Rotteveel, J., Schiffmann, R., van der Knaap, M. S., Vanderver, A., Martos-Moreno, G. A., Polychronakos, C., Wolf, N. I., Bernard, G., Human genetics, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), and Amsterdam Neuroscience - Cellular & Molecular Mechanisms
Subjects: Male, Recessive Mutations, Mitochondrial Diseases, genetics [Mitochondrial Diseases], hypomyelination, etiology [Endocrine System Diseases], Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Medizin, POLR3A protein, human, genetics [Endocrine System Diseases], Biochemistry, Cohort Studies, 0302 clinical medicine, Endocrinology, etiology [Growth Disorders], Diagnosis, epidemiology [Growth Disorders], 4H leukodystrophy, Online Only articles, Child, Prospective cohort study, Growth Disorders, genetics [Growth Disorders], POLR3-related leukodystrophy, 0303 health sciences, DNA-Directed RNA Polymerases, Pattern-Recognition, Diffuse Hypomyelination, Classification, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, epidemiology [Hereditary Central Nervous System Demyelinating Diseases], Hormone Deficiency, POLR1C protein, human, Child, Preschool, Female, medicine.symptom, AcademicSubjects/MED00250, Adult, Delayed puberty, Subunit, medicine.medical_specialty, Adolescent, Context (language use), Endocrine System Diseases, Short stature, genetics [Hereditary Central Nervous System Demyelinating Diseases], Genetic Heterogeneity, Young Adult, 03 medical and health sciences, SDG 3 - Good Health and Well-being, hypogonadotropic hypogonadism, Hypogonadotropic hypogonadism, etiology [Hypogonadism], Internal medicine, medicine, genetics [RNA Polymerase III], Humans, Endocrine system, ddc:610, POLR3B protein, human, genetics [DNA-Directed RNA Polymerases], Clinical Research Articles, Retrospective Studies, 030304 developmental biology, complications [Hereditary Central Nervous System Demyelinating Diseases], business.industry, Hypogonadism, Biochemistry (medical), Leukodystrophy, Infant, Newborn, Infant, RNA Polymerase III, medicine.disease, complications [Mitochondrial Diseases], epidemiology [Mitochondrial Diseases], epidemiology [Endocrine System Diseases], Hereditary Central Nervous System Demyelinating Diseases, Cross-Sectional Studies, Biological Variation, Population, Mutation, epidemiology [Hypogonadism], business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Hormone
Abstract: Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder., Canadian Institutes of Health Research [201610PJT-377869, MOP-G2-341146-159133-BRIDG]; Fondation Les Amis d'Elliot; Leuco-Action; Fondation Lueur d'Espoir pour Ayden; Fondation le Tout pour Loo; Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante; Compute Canada; Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship; Fondation du Grand defi Pierre Lavoie Doctoral Scholarship; McGill Faculty of Medicine F. S.B. Miller Fellowship; Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research; Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia; CIHR [201603PJT-148695]; BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP); National Institute for Neurological Disorders and Stroke [R01NS082094]; Jakob Kamens Chair in Translational Neurotherapeutics; Fonds de Recherche du Quebec-Sante (FRQS); Canadian Institutes of Health Research; European Reference Network for Rare Neurological Disorders (ERN-RND) [739510], This study was supported by grants from the Canadian Institutes of Health Research (201610PJT-377869, MOP-G2-341146-159133-BRIDG), Fondation Les Amis d'Elliot, Leuco-Action, Fondation Lueur d'Espoir pour Ayden, Fondation le Tout pour Loo, and Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante to G. Bernard. This research was enabled in part by support provided by Compute Canada (www.computecanada.ca).S.Perrier is supported by the Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship, the Fondation du Grand defi Pierre Lavoie Doctoral Scholarship, the McGill Faculty of Medicine F. S.B. Miller Fellowship, and the Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research. F. K.C. is a recipient of the Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia. W.T. G. received funding from the CIHR (201603PJT-148695) and is supported by the BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP). B.L. F. was supported by the National Institute for Neurological Disorders and Stroke (R01NS082094). A.V. receives funding from the Jakob Kamens Chair in Translational Neurotherapeutics. G. Bernard has received a Research Scholar Junior 1 award from the Fonds de Recherche du Quebec-Sante (FRQS) (2012-2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017-2022). I.K.M., M. Synofzik, D. Tonduti, B.P.v.d.W., M.S. V.d.K., and N.I.W. are members of the European Reference Network for Rare Neurological Disorders (ERN-RND), project ID 739510.
Published: 2021
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22. Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas

Author: Isabelle Redonnet-Vernhet, Nadège Bellance, Floriant Bellvert, Matthieu Thumerel, Nathalie Dugot-Senan, Mariana Figueiredo Rodrigues, Hamid Reza Rezvani, Hugues Begueret, Elodie Dumon, Fatima Mechta-Grigoriou, Rodrigue Rossignol, Didier Lacombe, Pauline Esteves, Giuseppe Punzi, Yann Kieffer, Julien Izotte, Nivea Dias Amoedo, Ciro Leonardo Pierri, Tony Lionel Palama, Saharnaz Sarlak, Benoit Rousseau, Jean-Marc Baste, Lara Gales, Stéphane Claverol, Emilie Obre, Alexis Dupis, Laetitia Dard, Véronique Guyonnet-Duperat, Walid Mafhouf, Cellomet [CHU Pellegrin, Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU de Bordeaux, Università degli studi di Bari Aldo Moro (UNIBA), Inserm U1035, Biotherapies des Maladies Genetiques et Cancers, Univ Bordeaux, CHU de Bordeaux, Pole de Biologie et Pathologie, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Flow Cytometry Facility / TransBioMed Core [Bordeaux] (INSERM US005 - CNRS UMS 3427 - UB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Proteomics Core Facility (Protim), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®, Institut National de la Sante et de la Recherche Medicale (Inserm), National Council for Scientific and Technological Development (CNPq), Fondation ARC, French National Institute against cancer (Inca), Ligue nationale contre le cancer, ITN Marie Curie TRANSMIT (H2020-MSCA-ITN-2016) 722605, SIRIC-Brio2 (Project PRIME/IMS/COMMUCAN), CAPES, Canceropole GSO (Club Metabo-Cancer), Plan Cancer, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), TBM-Core [Bordeaux] (UMS3427 - INSERM US005), Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®, Astruc, Suzette, Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005)
Subjects: 0301 basic medicine, Lung Neoplasms, Bioenergetics, Trimetazidine, Oxidative phosphorylation, Mitochondrial trifunctional protein, 03 medical and health sciences, 0302 clinical medicine, Drug Delivery Systems, In vivo, Cell Line, Tumor, medicine, Humans, Beta oxidation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Electron Transport Complex I, biology, Chemistry, Cancer, General Medicine, medicine.disease, 3. Good health, Neoplasm Proteins, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Adenocarcinoma, Mitochondrial Trifunctional Protein, alpha Subunit, Oxidation-Reduction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, Research Article
Abstract: International audience; Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [F-18]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [F-18]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.
Published: 2021
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23. Novel variants in the BLOC1S3 gene in patients presenting a mild form of Hermansky-Pudlak syndrome

Author: Fabienne Giuliano, Carolina Marçon, Eulalie Lasseaux, Claudio Plaisant, Saba Azarnoush, Benoit Arveiler, Didier Lacombe, Catherine Vincent-Delorme, Angèle Tingaud-Sequeira, Yline Capri, Fanny Morice-Picard, Perrine Pennamen, Vincent Michaud, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, Adolescent, Albinism, Lymphocyte, HPS-8, Dermatology, General Biochemistry, Genetics and Molecular Biology, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Pulmonary fibrosis, medicine, Humans, Child, Gene, Immunodeficiency, Platelet dense granule deficiency, integumentary system, business.industry, Hermansky-Pudlak syndrome, respiratory system, medicine.disease, eye diseases, 3. Good health, Pedigree, Bleeding diathesis, 030104 developmental biology, medicine.anatomical_structure, Phenotype, Oncology, Hermanski-Pudlak Syndrome, 030220 oncology & carcinogenesis, Immunology, Mutation, Female, Hermansky–Pudlak syndrome, business, Carrier Proteins, BLOC1S3, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Hermansky-Pudlak syndrome (HPS) associates oculocutaneous albinism and systemic affections including platelet dense granules anomalies leading to bleeding diathesis and, depending on the form, pulmonary fibrosis, immunodeficiency, and/or granulomatous colitis. So far, 11 forms of autosomal recessive HPS caused by pathogenic variants in 11 different genes have been reported. We describe three HPS-8 consanguineous families with different homozygous pathogenic variants in BLOC1S3 (NM_212550.3), one of which is novel. These comprise two deletions leading to a reading frameshift (c.385_403del, c.338_341del) and one in frame deletion (c.444_467del). All patients have moderate oculocutaneous albinism and bleeding diathesis, but other HPS symptoms are not described. One patient diagnosed with HPS-8 suffered from lymphocyte-predominant Hodgkin lymphoma. The mild severity of HPS-8 is consistent with other HPS forms caused by variants in BLOC-1 complex coding genes (HPS-7, DTNBP1; HPS-9, BLOC1S6, HPS-11, BLOC1S5).
Published: 2021
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24. Dopachrome tautomerase variants in patients with oculocutaneous albinism

Author: Vincent Michaud, Ian J. Jackson, Angèle Tingaud-Sequeira, Margaret A. Keighren, Didier Lacombe, Souad Gherbi Halem, Josseline Kaplan, Perrine Pennamen, Sandrine Marlin, Lisa McKie, Benoit Arveiler, Sophie Javerzat, Eulalie Lasseaux, Cédric Delevoye, Iveta Gazova, Claudio Plaisant, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], University of Edinburgh, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Admin, Oskar, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Mouse, Albinism, 030105 genetics & heredity, Biology, Compound heterozygosity, Frameshift mutation, Mice, 03 medical and health sciences, Exon, 0302 clinical medicine, medicine, Animals, Humans, Missense mutation, Genetics (clinical), Zebrafish, 030304 developmental biology, Hypopigmentation, Genetics, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Pigmentation, DCT, medicine.disease, Oculocutaneous albinism, 3. Good health, Intramolecular Oxidoreductases, Mice, Inbred C57BL, 030104 developmental biology, Albinism, Oculocutaneous, 030220 oncology & carcinogenesis, Mutation, medicine.symptom, Dopachrome tautomerase, INDEL Mutation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: PurposeAlbinism is a clinically and genetically heterogeneous condition. Despite analysis of the nineteen known genes, ∼30% patients remain unsolved. We aimed to identify new genes involved in albinism.MethodsWe sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients.ResultsWe identified variants in theDopachrome tautomerase(DCT) gene in two patients. One was compound heterozygous for a 14 bp deletion in exon 9 and c.118T>A p.(Cys40Ser). The second was homozygous for c.183C>G p.(Cys61Trp). Both patients had mild hair and skin hypopigmentation, and classical ocular features. CRISPR/Cas9 was used in C57BL/6J mice to create mutations identical to the missense mutations carried by the patients, along with one loss-of-function indel mutation. When bred to homozygosity the three mutations revealed hypopigmentation of the coat, milder for Cys40Ser compared to Cys61Trp or the frameshift mutation. Histological analysis identified significant hypopigmentation of the retinal pigmented epithelium (RPE) indicating that defective RPE melanogenesis could be associated with eye and vision defects.DCTloss of function in zebrafish embryos elicited hypopigmentation both in melanocytes and RPE cells.ConclusionsDCTis the gene for a new type of oculocutaneous albinism that we propose to name OCA8.
Published: 2021
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25. A new case with Hermansky-Pudlak syndrome type 9, a rare cause of syndromic albinism with severe defect of platelets dense bodies

Author: Yoann Huguenin, Mathieu Fiore, Fanny Morice-Picard, Claudio Plaisant, Vincent Michaud, Jean-Claude Bordet, Benoit Arveiler, V. Coste, Eulalie Lasseaux, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Blood Platelets, Pathology, medicine.medical_specialty, Albinism, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Humans, Platelet, Hermansky-Pudlak Syndrome, integumentary system, business.industry, Infant, Hematology, General Medicine, respiratory system, medicine.disease, Oculocutaneous albinism, eye diseases, 3. Good health, 030104 developmental biology, Hermanski-Pudlak Syndrome, Female, Hermansky–Pudlak syndrome, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Hermansky-Pudlak syndrome (HPS) is a rare form of syndromic oculocutaneous albinism caused by disorders in lysosome-related organelles. Ten genes are associated with different forms of HPS. HPS type 9 (HPS-9) is caused by biallelic variants of BLOC1S6. To date, only three patients with HPS-9 have been reported. We described one patient presenting with ocular features of albinism. Genetic analysis revealed two compound heterozygous variants in the BLOC1S6 gene. Extended hematological studies confirmed the platelet storage pool disease with absence of dense granules and abnormal platelet aggregation. By reviewing the previous published cases we confirm the phenotype of HPS-9 patients. This patient is the only one described with dextrocardia and abnormal psychomotor development.
Published: 2021
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26. Human γδ T cell sensing of AMPK-dependent metabolic tumor reprogramming through TCR recognition of EphA2

Author: Emilie Obre, Jean-François Moreau, Rodrigue Rossignol, Christelle Harly, Benoit Viollet, Angela Pappalardo, Vincent Pitard, Isabelle Soubeyran, Charlotte Domblides, Fiyaz Mohammed, Stéphane Claverol, Omar Hawchar, Sonia Netzer, Carla Cano, Layal Massara, Julie Déchanet-Merville, Carrie R. Willcox, Lydia Lartigue, Charlotte Mannat, S.P. Joyce, Benjamin Faustin, Isabelle Mahouche, Thomas Bachelet, Benjamin E. Willcox, Lionel Couzi, Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), University of Birmingham [Birmingham], TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Cellomet [CHU Pellegrin, Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Université de Bordeaux (UB), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, ImCheck Therapeutics [Marseille], Laboratoire d'immunologie et d'immunogénétique [CHU Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5), Janssen Research & Development, Bernardo, Elizabeth, Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Flow Cytometry Facility / TransBioMed Core [Bordeaux] (INSERM US005 - CNRS UMS 3427 - UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: 0301 basic medicine, T cell, CD3, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, AMP-Activated Protein Kinases, Cell Line, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, medicine, Ephrin, Animals, Humans, Antigens, Intraepithelial Lymphocytes, Tissue homeostasis, Mice, Knockout, Receptor, EphA2, T-cell receptor, AMPK, Antibodies, Monoclonal, Receptors, Antigen, T-Cell, gamma-delta, General Medicine, EPH receptor A2, Cell biology, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer cell, biology.protein
Abstract: International audience; Human γδ T cells contribute to tissue homeostasis and participate in epithelial stress surveillance through mechanisms that are not well understood. Here, we identified ephrin type-A receptor 2 (EphA2) as a stress antigen recognized by a human Vγ9Vδ1 TCR. EphA2 is recognized coordinately by ephrin A to enable γδ TCR activation. We identified a putative TCR binding site on the ligand-binding domain of EphA2 that was distinct from the ephrin A binding site. Expression of EphA2 was up-regulated upon AMP-activated protein kinase (AMPK)-dependent metabolic reprogramming of cancer cells, and coexpression of EphA2 and active AMPK in tumors was associated with higher CD3 T cell infiltration in human colorectal cancer tissue. These results highlight the potential of the human γδ TCR to cooperate with a co-receptor to recognize non-MHC-encoded proteins as signals of cellular dysregulation, potentially allowing γδ T cells to sense metabolic energy changes associated with either viral infection or cancer.
Published: 2021
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27. Re-focusing on Agnathia-Otocephaly complex

Author: Consolato Sergi, Didier Lacombe, Jelena Martinovic, Tania Attié-Bitach, M.J. Perez, Julie Plaisancié, Christelle Cabrol, C.P. Chen, J. Aziza, Christel Thauvin-Robinet, Nicolas Chassaing, Estelle Colin, M. Aubert-Mucca, Patrick Calvas, C. Dubucs, Stéphanie Arpin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Otocephaly, Agnathia, Biology, Bioinformatics, medicine.disease_cause, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Treacher-Collins syndrome, medicine, General Dentistry, Genetic testing, Sanger sequencing, Mutation, Aglossia, medicine.diagnostic_test, Point mutation, 030206 dentistry, medicine.disease, Phenotype, 3. Good health, Agnathia-otocephaly complex, CNBP, 030220 oncology & carcinogenesis, symbols, PRRX1, Craniofacial development, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, OTX2
Abstract: Objectives: Agnathia-otocephaly complex is a rare condition characterized by mandibular hypoplasia or agnathia, ear anomalies (melotia/synotia) and microstomia with aglossia. This severe anomaly of the first branchial arch is most often lethal. The estimated incidence is less than 1 in 70.000 births, with etiologies linked to both genetic and teratogenic factors. Most of the cases are sporadic. To date, two genes have been described in humans to be involved in this condition: OTX2 and PRRX1. Nevertheless, the overall proportion of mutated cases is unknown and a significant number of patients remain without molecular diagnosis. Thus, the involvement of other genes than OTX2 and PRRX1 in the agnathia-otocephaly complex is not unlikely. Heterozygous mutations in Cnbp in mice are responsible for mandibular and eye defects mimicking the agnathia-otocephaly complex in humans and appear as a good candidate. Therefore, in this study, we aimed (i) to collect patients presenting with agnathia-otocephaly complex for screening CNBP, in parallel with OTX2 and PRRX1, to check its possible implication in the human phenotype and (ii) to compare our results with the literature data to estimate the proportion of mutated cases after genetic testing. Materials and methods: In this work, we describe 10 patients suffering from the agnathia-otocephaly complex. All of them benefited from array-CGH and Sanger sequencing of OTX2, PRRX1 and CNBP. A complete review of the literature was made using the Pubmed database to collect all the patients described with a phenotype of agnathia-otocephaly complex during the 20 last years (1998-2019) in order (i) to study etiology (genetic causes, iatrogenic causes...) and (ii), when genetic testing was performed, to study which genes were tested and by which type of technologies. Results: In our 10 patients’ cohort, no point mutation in the three tested genes was detected by Sanger sequencing, while array-CGH has allowed identifying a 107-kb deletion encompassing OTX2 responsible for the agnathia-otocephaly complex phenotype in 1 of them. In 4 of the 70 cases described in the literature, a toxic cause was identified and 22 out the 66 remaining cases benefited from genetic testing. Among those 22 patients, 6 were carrying mutation or deletion in the OTX2 gene and 4 in the PRRX1 gene. Thus, when compiling results from our cohort and the literature, a total of 32 patients benefited from genetic testing, with only 34% (11/32) of patients having a mutation in one of the two known genes, OTX2 or PRRX1. Conclusions: From our work and the literature review, only mutations in OTX2 and PRRX1 have been found to date in patients, explaining around one third of the etiologies after genetic testing. Thus, agnathia-otocephaly complex remains unexplained in the majority of the patients, which indicates that other factors might be involved. Although involved in first branchial arch defects, no mutation in the CNBP gene was found in this study. This suggests that mutations in CNBP might not be involved in such phenotype in humans or that, unlike in mice, a compensatory effect might exist in humans. Nevertheless, given that agnathia-otocephaly complex is a rare phenotype, more patients have to be screened for CNBP mutations before we definitively conclude about its potential implication. Therefore, this work presents the current state of knowledge on agnathia-otocephaly complex and underlines the need to expand further the understanding of the genetic bases of this disorder, which remains largely unknown. Clinical relevance: We made here an update and focus on the clinical and genetic aspects of agnathia-otocephaly complex as well as a more general review of craniofacial development.
Published: 2021
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28. Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56

Author: Xavier Jeunemaitre, Christophe Orssaud, Mathilde Renaud, Clarisse Billon, Lucia Ziccardi, Claire Pujol, Nicolas Villain, Christophe Duranton, Cyril Mignot, Ana Berta Sousa, Carlo Casali, Claire Ewenczyk, Nicolas Pietrancosta, Jean-Luc Boucher, Cecilia Marelli, Alexandra Durr, Juliette Albuisson, Marguerite Hureaux, Isabelle Rubera, Anne Legrand, Cyril Goizet, Stéphane Zuily, Giovanni Stevanin, Aurélie Mesnil, Christelle M Durand, Salma Adham, Centre national de référence des maladies vasculaires rares, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Compétences Régional des Maladies Vasculaires Rares, Centro Académico de Medicina de Lisboa, Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Unité Fonctionnelle d’Ophtalmologie [AP-HP HEGP, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Centre de référence des Maladies Rares en Ophtalmologie [CHU HEGP] (OPHTARA), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Sapienza University Rome, Department of SBMC, Fondazione GB Bietti per l'Oftalmologia, IRCCS, Via Livenza 3, 00198, Roma, Département de Génétique, Hôpital de la Pitié-Salpêtrière, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Département de Biologie et pathologie des tumeurs [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Systèmes glutamatergiques normaux et pathologiques = Normal and Pathologic Glutamatergic Neurons (NPS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Analyse, Interactions Moléculaires et Cellulaires (LBM-E2), Laboratoire des biomolécules (LBM UMR 7203), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Lemesle, Marie
Subjects: 0301 basic medicine, Proband, Pathology, medicine.medical_specialty, Hereditary spastic paraplegia, Mutation, Missense, ABCC6, 030204 cardiovascular system & hematology, Eye, 03 medical and health sciences, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Internal Medicine, medicine, Humans, Missense mutation, Pseudoxanthoma Elasticum, Cytochrome P450 Family 2, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Skin, biology, Spastic Paraplegia, Hereditary, business.industry, Calcinosis, Pseudoxanthoma elasticum, medicine.disease, 3. Good health, Angioid streaks, HEK293 Cells, Phenotype, 030104 developmental biology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Multidrug Resistance-Associated Proteins, CYP2U1, business
Abstract: Purpose Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. Methods First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. Results 6.4% of ABCC6-negative PXE patients (n=3) harbored biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. Conclusion CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.
Published: 2021
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29. Prise en charge du patient adulte atteint de syndrome d’apnées obstructives du sommeil en chirurgie ambulatoire

Author: Julien Potvin, Karine Nouette-Gaulain, Thibaud Cavaillez, Service d'Anesthésie-Réanimation, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and CCSD, Accord Elsevier
Subjects: [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Anesthesiology and Pain Medicine, 030202 anesthesiology, [SDV]Life Sciences [q-bio], Emergency Medicine, Emergency Nursing, 030217 neurology & neurosurgery, 3. Good health
Abstract: Resume La gestion des patients atteints de syndrome d’apnees obstructives du sommeil (SAOS) a fait l’objet de plusieurs recommandations et d’etudes recentes. Cependant, la prise en charge de ces patients en ambulatoire est moins bien codifiee. Les complications de ce syndrome dans le contexte perioperatoire sont nombreuses et peuvent etre graves. Le maintien de la ventilation non invasive preoperatoire, sa reprise rapide en post-extubation, l’utilisation de l’anesthesie loco-regionale quand elle est possible et l’epargne des morphiniques font partie des bonnes pratiques a envisager dans la prise en charge de ces patients. Un depistage des patients a risque a l’aide du score STOP-BANG a la consultation pre-anesthesie est egalement necessaire. Enfin, une surveillance renforcee des patients avant leur sortie de la salle de surveillance post-interventionnelle permettra de minimiser le risque de complications respiratoires apres le retour a domicile.
Published: 2020
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30. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author: Thomas Roux, Mathieu Barbier, Mélanie Papin, Claire-Sophie Davoine, Sabrina Sayah, Giulia Coarelli, Perrine Charles, Cecilia Marelli, Livia Parodi, Christine Tranchant, Cyril Goizet, Stephan Klebe, Ebba Lohmann, Lionel Van Maldergem, Christine van Broeckhoven, Marie Coutelier, Christelle Tesson, Giovanni Stevanin, Charles Duyckaerts, Alexis Brice, Alexandra Durr, Frédéric Darios, Sylvie Forlani, Pitié-Salpêtrière Site, Guillaume Banneau, Cécile Cazeneuve, Bertrand Fontaine, Jean-Philippe Azulay, Odile Boesfplug-Tanguy, Didier Hannequin, Jamilé Hazan, Andrea Burgo, Christophe Verny, Michel Koenig, Pierre Labauge, Karine N’guyen, Diana Rodriguez, Soraya Belarbi, Abdelmadjid Hamri, Meriem Tazir, Sylvia Boesch, Massimo Pandolfo, Jardim Laura, Velina Guergueltcheva, Ivalo Tournev, Olga Lucia Pedraza Linarès, Jørgen E. Nielsen, Kirsten Svenstrup, Maha Zaki, Peter Bauer, Lüdger Schöls, Rebecca Schüle, Alexander Lossos, Maria-Teresa Bassi, Manuela Basso, Enrico Bertini, Alfredo Brusco, Carlo Casali, Giorgio Casari, Chiara Criscuolo, Alessandro Filla, Laura Orsi, Filippo M. Santorelli, Enza Maria Valente, Marinela Vavla, Giovanni Vazza, André Megarbane, Ali Benomar, Berry Kremer, Willeke Van Roon-Mom, Richard Roxburgh, Anne Kjersti Erichsen, Chantal Tallaksen, Isabel Alonso, Paula Coutinho, José Léal Loureiro, Jorge Sequeiros, Mustapha Salih, Vladimir S. Kostic, Idoia Rouco Axpe, Liena Elsayed, Martin Arce Paucar, Samir Roumani, Soong Bing-Wen, Evan Reid, Nethisinghe Suran, Thomas Warner, Nicholas Wood, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), CHU Strasbourg, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), University of Tübingen, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University of Antwerp (UA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), SPATAX Network, Roux, T., Barbier, M., Papin, M., Davoine, C. -S., Sayah, S., Coarelli, G., Charles, P., Marelli, C., Parodi, L., Tranchant, C., Goizet, C., Klebe, S., Lohmann, E., Van Maldergen, L., van Broeckhoven, C., Coutelier, M., Tesson, C., Stevanin, G., Duyckaerts, C., Brice, A., Durr, A., Darios, F., Forlani, S., Site, P. -S., Banneau, G., Cazeneuve, C., Fontaine, B., Azulay, J. -P., Boesfplug-Tanguy, O., Hannequin, D., Hazan, J., Burgo, A., Verny, C., Koenig, M., Labauge, P., N'Guyen, K., Rodriguez, D., Belarbi, S., Hamri, A., Tazir, M., Boesch, S., Pandolfo, M., Laura, J., Guergueltcheva, V., Tournev, I., Pedraza Linares, O. L., Nielsen, J. E., Svenstrup, K., Zaki, M., Bauer, P., Schols, L., Schule, R., Lossos, A., Bassi, M. -T., Basso, M., Bertini, E., Brusco, A., Casali, C., Casari, G., Criscuolo, C., Filla, A., Orsi, L., Santorelli, F. M., Valente, E. M., Vavla, M., Vazza, G., Megarbane, A., Benomar, A., Kremer, B., Van Roon-Mom, W., Roxburgh, R., Erichsen, A. K., Tallaksen, C., Alonso, I., Coutinho, P., Loureiro, J. L., Sequeiros, J., Salih, M., Kostic, V. S., Rouco Axpe, I., Elsayed, L., Paucar, M. A., Roumani, S., Bing-Wen, S., Reid, E., Suran, N., Warner, T., and Wood, N.
Subjects: Male, Pathology, MESH: Ataxia, Purkinje cell, Medizin, MESH: Cognitive Dysfunction, 0302 clinical medicine, spinocerebellar ataxia, ATP-Dependent Proteases, SCA48, Medicine, Genetics (clinical), 0303 health sciences, Penetrance, 3. Good health, MESH: Cerebellar Ataxia, MESH: ATPases Associated with Diverse Cellular Activities, medicine.anatomical_structure, Spinocerebellar ataxia, Female, medicine.symptom, Frontotemporal dementia, medicine.medical_specialty, Ataxia, Cerebellar Ataxia, MESH: Spinocerebellar Ataxias, Ubiquitin-Protein Ligases, Neuropathology, 03 medical and health sciences, MESH: ATP-Dependent Proteases, Atrophy, Humans, Spinocerebellar Ataxias, Cognitive Dysfunction, 030304 developmental biology, cognitive impairment, SCAR16, STUB1, MESH: Humans, Cerebellar ataxia, business.industry, medicine.disease, MESH: Ubiquitin-Protein Ligases, MESH: Male, ATPases Associated with Diverse Cellular Activities, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Human medicine, business, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48).Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance.Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease-like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) "second hits" in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects.Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.
Published: 2020
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31. CHN1 and duane retraction syndrome: Expanding the phenotype to cranial nerves development disease

Author: Benoit Arveiler, Eulalie Lasseaux, Nobuyasu Ichinose, Didier Lacombe, Caroline Espil-Taris, Chloé Angelini, Aurélien Trimouille, Thomas Tourdias, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), and INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France
Subjects: Male, Neurodevelopment, Mutation, Missense, Duane Retraction Syndrome, 03 medical and health sciences, 0302 clinical medicine, Duane syndrome, Genetics, medicine, Humans, Child, Abducens nerve, Genetics (clinical), Exome sequencing, 030304 developmental biology, Chimerin 1, 0303 health sciences, business.industry, Cranial nerves, digestive, oral, and skin physiology, Cranial Nerves, General Medicine, Anatomy, Aplasia, Middle Aged, medicine.disease, Deglutition, Pedigree, Palpebral fissure, Phenotype, MAFB, 030221 ophthalmology & optometry, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Duane retraction syndrome is a congenital eye movement disorder characterized by a failure of abducens nerve to develop normally, resulting in restriction or absence of abduction, adduction, or both, and narrowing of the palpebral fissure and retraction of the globe on attempted adduction. There is a genetic heterogeneity in Duane retraction syndrome (DURS). DURS maps to chromosome 8q13 in some patients, and pathogenic variants in CHN1 and MAFB genes are known to lead to DURS. We report here a child and his father with Duane retraction syndrome, associated to swallowing difficulties and unilateral trapeze aplasia. A whole exome sequencing revealed a heterozygous missense variant in CHN1 gene. This gene encodes GTPase-activating protein and is involved in the assembly of neuronal locomotor circuits. A patient with a 8q deletion has previously been described with a Duane retraction syndrome associated to trapeze aplasia. We provide an additional description to support the role in cranial nerves development of the CHN1 gene.
Published: 2020
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32. Early-onset epileptic encephalopathy related to germline PIGA mutations: A series of 5 cases

Author: Le Roux, Marie, van Gils, Julien, Gueden, Sophie, de Cepoy, Patrick Desbordes, Aeby, Alec, Vilain, Catheline, Hirsch, Edouard, Martin, Anne de Saint, Des Portes, Vincent, Lesca, Gaetan, Riquet, Audrey, Chaton, Laurence, Villeneuve, Nathalie, Villard, Laurent, Cances, Claude, Valton, Luc, Renaldo, Florence, Vermersch, Anne-Isabelle, Altuzarra, Cecilia, Nguyen-Morel, Marie-Ange, Angelini, Chloé, Biraben, Arnaud, Arnaud, Lionel, Riant, Florence, van Bogaert, Patrick, Hôpital des Enfants - Groupe hospitalier Pellegrin - CHU de Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Hôpital Necker, Centre Hospitalier de la Côte Basque (CHCB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Nouvel Hôpital Civil de Strasbourg, Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique] (HUDERF), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Bordeaux [Bordeaux], CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [AP-HP], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Angevin de Recherche en Ingénierie des Systèmes (LARIS), Université d'Angers (UA), Gall, Valérie, Le CHCB, Centre Hospitalier de la Côte Basque, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Jonchère, Laurent
Subjects: Male, medicine.medical_specialty, Neurology, [SDV]Life Sciences [q-bio], Mutation, Missense, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bioinformatics, Germline, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Germline mutation, 030225 pediatrics, medicine, Humans, Missense mutation, STXBP1, PIGA- Glycosylphosphatidylinositol-encephalopathy –early-onset epilepsy- whole-exome sequencing-next-generation sequencing 1, Child, Germ-Line Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, High-Throughput Nucleotide Sequencing, Infant, Membrane Proteins, Electroencephalography, General Medicine, medicine.disease, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], Epileptic spasms, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Pediatrics, Perinatology and Child Health, Neurology (clinical), business, Spasms, Infantile, 030217 neurology & neurosurgery
Abstract: International audience; The molecular diagnosis of early-onset epileptic encephalopathy (EOEE), an expanding field in child neurology, is becoming increasingly possible thanks to the widespread availability of next-generation sequencing and whole-exome sequencing. In the past 15 years, mutations in STXBP1, KCNQ2, SCN2A, SCN8A and numerous other genes have been reported, giving a more accurate insight for these rare diseases. Among these genes, germline mutations in Phosphatidyl Inositol Glycan A (PIGA) gene were first reported in 2012. Located on Xp22.2, PIGA is involved in the synthesis of GPI (glycosylphosphatidylinositol) which acts as a membrane anchor for different proteins: enzymes, adhesion molecules, regulation of the complement way, and co-receptor in transduction signal. Children suffering from this condition exhibit developmental delay with early-onset epilepsy, severe dysmorphic signs, multi-visceral anomalies and early death in the most severe forms. Here, we report five cases of germline PIGA mutations, with two missense mutations that have not been reported to date. We provide a new insight into the electroclinical phenotype. At the onset, epileptic spasms and focal-onset seizures with upper limbs and ocular involvements were present. Epilepsy proved pharmacoresistant in 4 out of 5 cases. Interictal EEG may be normal at the onset of epilepsy, but abnormalities in electroencephalographic studies were eventually present in all cases. Different types of seizures may be present simultaneously, and epileptic phenotypes evolve with aging.
Published: 2020
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33. A comparative study of cognitive and socio-emotional development in children with Rubinstein-Taybi syndrome and children with Autism Spectrum Disorder associated with a severe intellectual disability, and in young typically developing children with matched developmental ages

Author: Marie-Anna Paulais, Grégory Michel, Yves Contejean, Annika Dean, Kelley Kaye, Jean-Louis Adrien, Catherine Barthélémy, Maria Pilar Gattegno, Emmanuelle Taupiac, Julien Van-Gils, Romuald Blanc, Didier Lacombe, Éric Thiébaut, Laboratoire de Psychopathologie et Processus de Santé (LPPS (URP_4057)), Université de Paris (UP), CHU Bordeaux [Bordeaux], Laboratoire lorrain de psychologie et neurosciences de la dynamique des comportements (2LPN), Université de Lorraine (UL), Cabinet de Psychologie ESPAS, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Sciences Criminelles et de la Justice (ISCJ), Université de Bordeaux (UB), Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Object permanence, Cognitive, Joint attention, Autism Spectrum Disorder, media_common.quotation_subject, Emotions, [SHS.PSY]Humanities and Social Sciences/Psychology, Developmental psychology, 03 medical and health sciences, 0302 clinical medicine, Cognition, Intellectual Disability, Intellectual disability, Developmental and Educational Psychology, medicine, Developmental heterogeneity, Humans, 0501 psychology and cognitive sciences, Emotional expression, Child, ComputingMilieux_MISCELLANEOUS, media_common, Rubinstein-Taybi Syndrome, Psycho-educational interventions, Rubinstein–Taybi syndrome, 05 social sciences, Infant, Typically developing, medicine.disease, Clinical Psychology, Autism spectrum disorder, Child, Preschool, Psychology, Imitation, Socio-emotional development, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract: Background Cognitive and socio-emotional profiles of children with CREBBP-related Rubinstein-Taybi syndrome (RSTS 1), children with Autism Spectrum Disorder (ASD) with severe intellectual disability and developmental ages (DA) under 24 months, and typically developing (TD) children with similar DA were compared. Participants Thirty-one children with RSTS 1 (mean chronological age, CA = 59,8 months; 33−87) and thirty children with ASD, matched on CA and DA and developmental quotients (DQ), were compared to thirty TD children (CA ranged from 12 to 24 months). Methods Cognitive and socio-emotional developmental levels, DA and DQ were assessed with appropriated tests. Results More socio-emotional developmental similarities were observed between TD and RSTS 1 than between TD and ASD children. Clinical groups displayed similar developmental delays in cognitive (self-image, symbolic play, means-ends, and object permanence) and socio-emotional domains (language and imitation). Children with RSTS 1 exhibited higher developmental levels in behavior regulation, joint attention, affective relations, emotional expression domains, and a lower developmental level in spatial relations domain. Conclusions Common interventions centered on symbolic play, self-image, language, and imitation for both clinical groups, and differentiated interventions centered on spatial abilities for RSTS 1 children and on social abilities for ASD could be used by caregivers were suggested.
Published: 2020
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34. Lipogenesis and innate immunity in hepatocellular carcinoma cells reprogrammed by an isoenzyme switch of hexokinases

Author: Marc-Thorsten Hütt, Keedrian I. Olmstead, Pierre-Olivier Vidalain, Rautureau Gjp, Rodrigue Rossignol, Fabian V. Filipp, Piotr Nyczka, Olivier Diaz, Lotteau, Baptiste Panthu, Laure Perrin-Cocon, Anne Aublin-Gex, Clémence Jacquemin, Patrice Andre, Nivea Dias Amoedo, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Helmholtz Zentrum München Institute of Computational Biology Neuherberg, Germany, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de RMN à très hauts champs de Lyon (CRMN), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Jacobs University [Bremen], Cellomet [CHU Pellegrin, Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)
Subjects: 0303 health sciences, Innate immune system, Glycogen, Glucokinase, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Isozyme, digestive system diseases, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Cell culture, 030220 oncology & carcinogenesis, Lipogenesis, Cancer research, Glycolysis, Secretion, 030304 developmental biology
Abstract: Hexokinases catalyze the first step of glycolysis by phosphorylating glucose. In the liver, normal hepatocytes express the low-affinity hexokinase 4, also known as glucokinase (GCK), which is adapting hepatocyte function to glycaemia. Conversely, hepatocellular carcinoma (HCC) cells express the high-affinity hexokinase 2 (HK2) to sustain tumor proliferation even at low glucose concentrations. A switch from GCK to HK2 isoenzymes is occurring during the transition from primary hepatocytes to HCC. HK2 induction is a recurrent event in the carcinogenic process and relates to the highly glycolytic phenotype of HCC but the consequence of GCK loss is unknown. To explore functional consequences of the GCK-to-HK2 isoenzyme switch, HK2 was knocked-out in the HCC cell line Huh7 and replaced by GCK, to generate the Huh7-GCK+/HK2- cell line. We then compared the transcriptomic, metabolomic and immunological profiles of both cell lines. The analysis of transcriptomic data from human HCC tumors shows that GCK and HK2 expression levels are inversely correlated and associated with patient survival. The replacement of HK2 by GCK rewired central carbon metabolism and restored some essential metabolic functions of normal hepatocytes such as lipogenesis, VLDL secretion and glycogen storage. It also reactivated innate immune responses and sensitivity to NK lysis. Our results suggest that the GCK-to-HK2 isoenzyme switch is playing a key role in dedifferentiation and immune escape of HCC cells.
Published: 2020
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35. Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

Author: Cyril Goizet, Fanny Morice-Picard, Annachiara De Sandre-Giovannoli, Sébastien Cabasson, Nathalie Aladjidi, Chloé Angelini, Cindy Colson, Caroline Espil-Taris, Jean-Michel Pedespan, Marie Thibaud, Pierre Bessou, Marie Husson, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE), Service de Génétique Clinique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, genetic structures, education, Wrinkled skin, cutis laxa, 030105 genetics & heredity, 03 medical and health sciences, Consanguinity, 0302 clinical medicine, medicine, Humans, Neurological findings, vascular tortuosity, ALDH18A1, Heterogeneous group, business.industry, Infant, General Medicine, Aldehyde Dehydrogenase, medicine.disease, eye diseases, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Severe phenotype, Pediatrics, Perinatology and Child Health, Neurology (clinical), sense organs, business, human activities, neurological findings, 030217 neurology & neurosurgery, Cutis laxa
Abstract: Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in ALDH18A1. Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.
Published: 2020
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36. Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene

Author: Jean-François Korobelnik, Xavier Zanlonghi, Dominique Bonneau, Benoit Arveiler, Caroline Rooryck-Thambo, Perrine Pennamen, Yaurama Perdomo, Vincent Michaud, Sabine Defoort-Dhellemmes, C. Paya, Hélène Dollfus, Fanny Morice-Picard, Christian P. Hamel, Claudio Plaisant, Solene Monfermé, Catherine Duncombe-Poulet, Eulalie Lasseaux, Isabelle Drumare, CHU Bordeaux [Bordeaux], Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Visual acuity, Photophobia, albinism, Compound heterozygosity, 0302 clinical medicine, Child, A/p.Arg402Gln), Aged, 80 and over, Monophenol Monooxygenase, Middle Aged, Oculocutaneous albinism, Sensory Systems, Hypoplasia, Pedigree, Phenotype, Albinism, Oculocutaneous, Child, Preschool, Brown hair, visual_art, Albinism, foveal hypoplasia, Female, medicine.symptom, hypopigmentation, nystagmus, Adult, medicine.medical_specialty, Adolescent, R402Q (c.1205G&gt, genotype-phenotype correlation, TYR gene, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, visual_art.color, Ophthalmology, medicine, Humans, Aged, Retrospective Studies, Hypopigmentation, business.industry, Infant, Newborn, Infant, medicine.disease, 030104 developmental biology, Mutation, 030221 ophthalmology & optometry, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: AimOculocutaneous albinism type 1 (OCA1) is due to TYR mutations. c.1205G>A/p.Arg402Gln (R402Q) is a thermosensitive variant of the TYR gene that has been reported to be responsible for mild forms of OCA1. The aim of our study was to define the phenotype associated with this variant.MethodsIn our retrospective series, among 268 patients diagnosed with OCA1, 122 (45.5%) harboured one pathogenic variant of TYR, and the R402Q variant ensured to be in trans by segregation analysis in 69 patients (25.7%), constituting the ‘R402Q-OCA1’ group. 146 patients harboured two pathogenic variants of the TYR gene other than R402Q. Clinical records were available for 119 of them, constituting the ‘Classical-OCA1’ group.ResultsMost R402Q-OCA1 patients presented with white or yellow-white hair at birth (71.43%), blond hair later (46.97%), a light phototype but with residual pigmentation (69.64%), and blue eyes (76.56%). Their pigmentation was significantly higher than in the classical-OCA1 group. All patients from the R402Q-OCA1 group presented with ocular features of albinism. However the prevalence of photophobia (78.13%) and iris transillumination (83.87%) and the severity scores of iris transillumination, retinal hypopigmentation and foveal hypoplasia were lower in the R402Q-OCA1 group. Visual acuity was higher in the R402Q-OCA1 group (0.38±0.21 logarithm of the minimum angle of resolution vs 0.76±0.24). Investigations concerning a possible additive effect of the c.575C>A/p.Ser192 (S192Y) variant of TYR in cis with R402Q, suggested by others, showed no significant impact on the phenotype.ConclusionThe R402Q variant leads to variable but generally mild forms of albinism whose less typical presentation may lead to underdiagnosis.
Published: 2018
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37. Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

Author: Rodrigue Rossignol, Emilie Obre, G. Le Masson, Marc Bonneu, Didier Lacombe, C. Léger, Marion Szelechowski, L. Allard, Stéphane Claverol, S. Oliet, Nivea Dias Amoedo, S. Chevallier, Oliet, Stephane, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellomet [CHU Pellegrin, Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), and Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2]
Subjects: 0301 basic medicine, Proteome, Bioenergetics, Cell Survival, lcsh:Medicine, Oxidative phosphorylation, Biology, Article, Oxidative Phosphorylation, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, medicine, Animals, Humans, TRNA aminoacylation, Uncoupling Protein 2, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Viability assay, Amyotrophic lateral sclerosis, Cell adhesion, lcsh:Science, Beta oxidation, Skin, Motor Neurons, Multidisciplinary, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Fatty Acids, lcsh:R, Fibroblasts, medicine.disease, Cell biology, Disease Models, Animal, 030104 developmental biology, Spinal Cord, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Q, Oxidation-Reduction, 030217 neurology & neurosurgery
Abstract: Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients’ skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients’ skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.
Published: 2018
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38. Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5

Author: Cecilia Marelli, Alexandra Durr, Patrick J. Babin, David Hajage, Elodie Petit, Elisabeth Ollagnon, Isabelle Coupry, Giovanni Castelnovo, Claire Ewenczyk, Christel Thauvin-Robinet, Urielle Ullmann, Gaetan Lesca, Foudil Lamari, Marie-Lorraine Monin, Sylvie Odent, Claude Wolf, Pierre Labauge, Dominique Rainteau, Cyril Goizet, Julie Pilliod, Alexandre Lafourcade, Julie Lavie, Fanny Mochel, Guillaume Banneau, Imen Benyounes, Claire Guissart, Rabab Debs, Lydie Humbert, Giovanni Stevanin, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Pharmacoépidémiologie de l'AP-HP (Cephepi), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité de neurophysiologie [CHU Saint-Antoine], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service des Maladies du Système Nerveux [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Nimes] (Pôle NIRR), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire [Rennes], Service de pharmacologie - Dosage de médicaments [CHU Saint-Antoine], École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Male, 0301 basic medicine, spastic paraplegia type 5, Atorvastatin, Gastroenterology, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Chenodeoxycholic acid, Spastic, Medicine, Child, Neurologic Examination, Anticholesteremic Agents, Deoxycholic acid, atorvastatin, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Cholesterol, oxysterols, Female, chenodeoxycholic acid, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Deoxycholic Acid, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Oxysterol, CYP7B1, Cytochrome P450 Family 7, Bile Acids and Salts, Young Adult, 03 medical and health sciences, Internal medicine, Humans, Spastic Paraplegia, Hereditary, business.industry, Infant, biomarkers, Crossover study, Hydroxycholesterols, 030104 developmental biology, ROC Curve, chemistry, Resveratrol, Mutation, Steroid Hydroxylases, sense organs, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: IF 10.292; International audience; The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7α-hydroxylase implicated in cholesterol and bile acids metabolism. We developed a method based on ultra-performance liquid chromatography electrospray tandem mass spectrometry to validate two plasma 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) as diagnostic biomarkers in a cohort of 21 patients with SPG5. For 14 patients, SPG5 was initially suspected on the basis of genetic analysis, and then confirmed by increased plasma 25-OHC, 27-OHC and their ratio to total cholesterol. For seven patients, the diagnosis was initially based on elevated plasma oxysterol levels and confirmed by the identification of two causal CYP7B1 mutations. The receiver operating characteristic curves analysis showed that 25-OHC, 27-OHC and their ratio to total cholesterol discriminated between SPG5 patients and healthy controls with 100% sensitivity and specificity. Taking advantage of the robustness of these plasma oxysterols, we then conducted a phase II therapeutic trial in 12 patients and tested whether candidate molecules (atorvastatin, chenodeoxycholic acid and resveratrol) can lower plasma oxysterols and improve bile acids profile. The trial consisted of a three-period, three-treatment crossover study and the six different sequences of three treatments were randomized. Using a linear mixed effect regression model with a random intercept, we observed that atorvastatin decreased moderately plasma 27-OHC (∼30%, P < 0.001) but did not change 27-OHC to total cholesterol ratio or 25-OHC levels. We also found an abnormal bile acids profile in SPG5 patients, with significantly decreased total serum bile acids associated with a relative decrease of ursodeoxycholic and lithocholic acids compared to deoxycholic acid. Treatment with chenodeoxycholic acid restored bile acids profile in SPG5 patients. Therefore, the combination of atorvastatin and chenodeoxycholic acid may be worth considering for the treatment of SPG5 patients but the neurological benefit of these metabolic interventions remains to be evaluated in phase III therapeutic trials using clinical, imaging and/or electrophysiological outcome measures with sufficient effect sizes. Overall, our study indicates that plasma 25-OHC and 27-OHC are robust diagnostic biomarkers of SPG5 and shall be used as first-line investigations in any patient with unexplained spastic paraplegia.
Published: 2017
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39. Metabolic reprogramming by tobacco-specific nitrosamines (TSNAs) in cancer

Author: Saharnaz Sarlak, Claude Lalou, Rodrigue Rossignol, Nivea Dias Amoedo, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, Early cancer, Nitrosamines, Bioenergetics, [SDV]Life Sciences [q-bio], Metabolic reprogramming, Biology, Tobacco smoke, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Tobacco, medicine, Humans, Tobacco-specific nitrosamines, Carcinogen, Cancer, Cell Biology, medicine.disease, Cellular Reprogramming, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cancer research, Skin cancer, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Metabolic reprogramming is a hallmark of cancer and the link between oncogenes activation, tumor supressors inactivation and bioenergetics modulation is well established. However, numerous carcinogenic environmental factors are responsible for early cancer initiation and their impact on metabolic reprogramming just starts to be deciphered. For instance, it was recently shown that UVB irradiation triggers metabolic reprogramming at the pre-cancer stage with implication for skin cancer detection and therapy. These observations foster the need to study the early changes in tissue metabolism following exposure to other carcinogenic events. According to the International Agency for Research on Cancer (IARC), tobacco smoke is a major class I-carcinogenic environmental factor that contains different carcinogens, but little is known on the impact of tobacco smoke on tissue metabolism and its participation to cancer initiation. In particular, tobacco-specific nitrosamines (TSNAs) play a central role in tobacco-smoke mediated cancer initiation. Here we describe the recent advances that have led to a new hypothesis regarding the link between nitrosamines signaling and metabolic reprogramming in cancer.
Published: 2020
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40. Mitochondrial functions and rare diseases

Author: W. Blanchard, L. Dard, Didier Lacombe, Christophe Hubert, Rodrigue Rossignol, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, Programmed cell death, Bioenergetics, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Inflammation, Biology, Mitochondrion, Biochemistry, Mitochondrial Proteins, 03 medical and health sciences, Rare Diseases, 0302 clinical medicine, medicine, Animals, Humans, Genetic Predisposition to Disease, Epigenetics, Molecular Biology, Genetics, General Medicine, Mitochondria, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Gene Expression Regulation, 030220 oncology & carcinogenesis, Mutation, Disease Progression, Molecular Medicine, Human genome, medicine.symptom, Oxidation-Reduction, Function (biology), Hormone
Abstract: Mitochondria are dynamic cellular organelles responsible for a large variety of biochemical processes as energy transduction, REDOX signaling, the biosynthesis of hormones and vitamins, inflammation or cell death execution. Cell biology studies established that 1158 human genes encode proteins localized to mitochondria, as registered in MITOCARTA. Clinical studies showed that a large number of these mitochondrial proteins can be altered in expression and function through genetic, epigenetic or biochemical mechanisms including the interaction with environmental toxics or iatrogenic medicine. As a result, pathogenic mitochondrial genetic and functional defects participate to the onset and the progression of a growing number of rare diseases. In this review we provide an exhaustive survey of the biochemical, genetic and clinical studies that demonstrated the implication of mitochondrial dysfunction in human rare diseases. We discuss the striking diversity of the symptoms caused by mitochondrial dysfunction and the strategies proposed for mitochondrial therapy, including a survey of ongoing clinical trials.
Published: 2020
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41. EQSAR: A national survey of sleep duration among French Anaesthesiologists and Intensivists

Author: Florian Robin, Joffrey Lemeux, Karine Nouette-Gaulain, Hugues de Courson, Pierre Philip, Maxim Roy, Stéphanie Bioulac, Groupe hospitalier Pellegrin, CHU Bordeaux [Bordeaux], Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Sommeil, Addiction et Neuropsychiatrie [Bordeaux] (SANPSY), Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, and Sommeil, Attention et Neuropsychiatrie [Bordeaux] (SANPSY)
Subjects: Adult, Sleep Wake Disorders, medicine.medical_specialty, Multivariate analysis, [SDV]Life Sciences [q-bio], Critical Care and Intensive Care Medicine, Bedtime, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, medicine, Humans, survey, 030212 general & internal medicine, Univariate analysis, sleep time, business.industry, 030208 emergency & critical care medicine, sleep quality, General Medicine, Sleep time, Anesthesiologists, [SDV] Life Sciences [q-bio], Anesthesiology and Pain Medicine, Emergency medicine, Quality of Life, anaesthesiologists, sleep disorders, Observational study, Sleep (system call), business, Sleep, Sleep duration
Abstract: International audience; Introduction: The US National Sleep Foundation recommends more than 7 hours of sleep per night for adults. Anaesthesiologists and intensivists (AI) are at high risk of short sleep time. The aim of this present survey was to assess the sleep duration of French AI and to identify independent factors related to a sleep time less than the recommended 7 hours.Methods: This prospective observational study was conducted between April and June 2018 and included 6,210 French AI with night-work obligations. The primary outcome variable was sleep duration strictly inferior to 7 hours per night. The covariables included in the multivariable model were selected after the univariate analysis, with those with a p < 0.05 included in the final model.Results: Of the 6,210 AI, 3,699 responded to the survey, and 2,483 were included in the analysis. Of the 2,483 responders, 1,533 (61.7%) reported sleep duration strictly less than 7 hours per night. After the multivariate analysis, the following risk factors were independently associated with sleep duration strictly under 7 hours: age (OR: 1.28 ; IC [1.19 - 1.37]), more than 5 on-call shifts per month, (OR: 1.41 ; IC [1.30 - 1.50]), active smoking (OR: 1.37 ; IC [1.07 - 1.75]), and screen consultation at bedtime (OR: 1.85 ; IC [1.31 - 2.62]).Conclusion: This study gives a recent overview of sleep time and quality of French AI. It could be a useful tool for monitoring sleep disorders among the practitioners and their impact on quality of life.
Published: 2020
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42. Br J Anaesth

Author: Matthieu Biais, Eric Verchère, Karine Nouette-Gaulain, Lisa Le Gall, Philippe Boyer, Hugues de Courson, Julie Chauvet, Delphine Georges, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and CCSD, Accord Elsevier
Subjects: Male, Cardiac output, Operating Rooms, Supine position, Cardiac index, Hemodynamics, Blood volume, Neurosurgical Procedures, haemodynamic, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Predictive Value of Tests, fluid responsiveness, medicine, Supine Position, Humans, Prospective Studies, Aged, Blood Volume, Receiver operating characteristic, business.industry, cardiac output, Stroke Volume, Stroke volume, end-tidal carbon dioxide, Carbon Dioxide, Middle Aged, medicine.disease, Respiration, Artificial, Anesthesiology and Pain Medicine, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Heart failure, Anesthesia, Fluid Therapy, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Background From a physiological viewpoint, changes in end-tidal carbon dioxide (EtCO2) could be a simple, noninvasive, and inexpensive way to monitor changes in cardiac index. This study aimed to assess the utility of changes in EtCO2 as a marker of fluid responsiveness after volume expansion in the operating room. Methods A prospective observational study was conducted in a tertiary university teaching hospital, from August 2018 to February 2019. A total of 109 non-consecutive, mechanically ventilated adults undergoing neurosurgery in the supine position with cardiac output monitors were included. Patients with major respiratory disease, arrhythmia, or heart failure were excluded. Volume expansion with 250 ml of saline 0.9% was performed over 10 min to maximise cardiac output during surgery, according to current guidelines. A positive fluid challenge was defined as an increase in stroke volume index of more than 10% from baseline. Changes in stroke volume index (monitored using pulse contour analysis) and EtCO2 were recorded before and after infusion. Results A total of 242 fluid challenges in 114 patients were performed, of which 26.9% were positive. Changes in EtCO2 > 1.1% induced by infusions had utility for identifying fluid responsiveness, with a sensitivity of 62.9% (95% confidence interval [CI], 62.5–63.3%) and a specificity of 77.8% (95% CI, 77.6–78.1%). The area under the receiver operating characteristic curve for changes in EtCO2 after volume expansion was 0.683 (95% CI, 0.680–0.686). Conclusions Changes in EtCO2 induced by rapid infusion of 250 ml saline 0.9% lacked accuracy for identifying fluid responsiveness in mechanically ventilated patients in the operating room. Clinical trial registration NCT03635307.
Published: 2020
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43. The A2B trial, antibiotic prophylaxis for excision-graft surgery in burn patients: a multicenter randomized double-blind study

Author: Francis Remerand, Kada Klouche, Simon Sztajnic, François Dépret, Boris Farny, Eric Vicaut, Mathieu Jeanne, Antoine Roquilly, Matthieu Legrand, Olivier Pantet, Anne-Françoise Rousseau, Thomas Leclerc, Karine Nouette-Gaulain, Sandrine Wiramus, Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Centre hospitalier Saint Joseph - Saint Luc [Lyon], Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Université de Paris (UP), Centre d'Investigation Clinique - Innovation Technologique de Lille - CIC 1403 - CIC 9301 (CIC Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Hôpital d'Instruction des Armées du Val de Grâce, Service Anesthésie - Réanimation [Bordeaux], CHU Bordeaux [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'anesthésie et réanimation chirurgicale [Nantes], Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapeutiques cliniques et expérimentales des infections (EA 3826) (EA 3826), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Universitaire de Liège (CHU-Liège), Département d'Anesthésie-Réanimation [Toulouse], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service d'anesthésie et de réanimation [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of California [San Francisco] (UCSF), University of California, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Herrada, Anthony, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Université Paris Cité (UPCité), Pôle Anesthésie Réanimation [CHU de Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of California [San Francisco] (UC San Francisco), and University of California (UC)
Subjects: Excision-graft, Burn injury, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Antibiotics, Medicine (miscellaneous), Cardiorespiratory Medicine and Haematology, Study Protocol, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Multicenter Studies as Topic, Pharmacology (medical), 030212 general & internal medicine, Prospective Studies, Antibiotic prophylaxis, Randomized Controlled Trials as Topic, Hematology, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 6.1 Pharmaceuticals, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Patient Safety, Burns, Infection, 6.4 Surgery, Adult, medicine.medical_specialty, Physical Injury - Accidents and Adverse Effects, medicine.drug_class, Clinical Trials and Supportive Activities, Clinical Sciences, Burn, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, A2B trial investigators, Sepsis, 03 medical and health sciences, Double-Blind Method, Clinical Research, General & Internal Medicine, medicine, Humans, Surgical Wound Infection, Adverse effect, business.industry, Prevention, Evaluation of treatments and therapeutic interventions, 030208 emergency & critical care medicine, Perioperative, medicine.disease, Surgery, Cardiovascular System & Hematology, Bacteremia, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Antimicrobial Resistance, business, Total body surface area
Abstract: Background The indication for antibiotic prophylaxis in burn patients remains highly controversial, with no consensus having been reached. The objective of antibiotic prophylaxis is to reduce the risk of postoperative local and systemic infections. Burn surgery is associated with a high incidence of bacteremia, postoperative infections, and sepsis. However, antibiotic prophylaxis exposes patients to the risk of selecting drug-resistant pathogens as well as to the adverse effects of antibiotics (i.e., Clostridium difficile colitis). The lack of data precludes any strong international recommendations regarding perioperative prophylaxis using systemic antibiotics in this setting. The goal of this project is therefore to determine whether perioperative systemic antibiotic prophylaxis can reduce the incidence of postoperative infections in burn patients. Methods The A2B trial is a multicenter (10 centers), prospective, randomized, double-blinded, placebo-controlled study. The trial will involve the recruitment of 506 adult burn patients with a total body surface area (TBSA) burn of between 5 and 40% and requiring at least one excision-graft surgery for deep burn injury. Participants will be randomized to receive antibiotic prophylaxis (antibiotic prophylaxis group) or a placebo (control group) 30 min before the incision of the first two surgeries. The primary outcome will be the occurrence of postoperative infections defined as postoperative sepsis and/or surgical site infection and/or graft lysis requiring a new graft within 7 days after surgery. Secondary outcomes will include mortality at day 90 postrandomization, skin graft lysis requiring a new graft procedure, postoperative bacteremia (within 48 h of surgery), postoperative sepsis, postoperative surgical site infection, number of hospitalizations until complete healing (> 95% TBSA), number of hospitalization days living without antibiotic therapy at day 28 and day 90, and multiresistant bacterial colonization or infection at day 28 and day 90. Discussion The trial aims to provide evidence on the efficacy and safety of antibiotic prophylaxis for excision-graft surgery in burn patients. Trial registration ClinicalTrials.gov NCT04292054. Registered on 2 March 2020
Published: 2020
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44. Reducing the greenhouse gas emissions from halogenated agents in daily clinical practice: An audit at the University Hospital of Bordeaux

Author: Jean-Claude Pauchard, Gauthier Gress, Karine Nouette-Gaulain, Hélène Beloeil, Matthieu Biais, Service Anesthésie - Réanimation [Bordeaux], CHU Bordeaux [Bordeaux], Polyclinique d’Aguilera [Biarritz], Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Jonchère, Laurent
Subjects: Anaesthetics, [SDV]Life Sciences [q-bio], Audit, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Medicine, Humans, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Waste management, business.industry, General Medicine, Carbon Dioxide, University hospital, Hospitals, 3. Good health, Fresh gas flow, [SDV] Life Sciences [q-bio], Clinical Practice, Anesthesiology and Pain Medicine, Greenhouse gases, 13. Climate action, Greenhouse gas, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business
Abstract: Letter to the Editor; International audience
Published: 2020
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45. Cornea verticillata and acroparesthesia efficiently discriminate clusters of severity in Fabry disease

Author: Marie Matignon, Olivier Benveniste, Agathe Masseau, Kim-Heang Ly, Didier Lacombe, Gérard Besson, François Maillot, Christian Lavigne, D. Amelin, Esther Noel, Foudil Lamari, Catherine Caillaud, Wladimir Mauhin, Hélène Maillard, Olivier Lidove, C. Montagner, Thierry Zenone, Marjolaine Willems, Vanessa Leguy-Seguin, Pauline D’Halluin, Bertrand Dussol, Fabien Labombarda, Claire Douillard, Groupe Hospitalier Diaconesses Croix Saint-Simon, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de biochimie métabolique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Aix Marseille Université (AMU), Centre d'Investigation Clinique [Hôpital de la Conception - APHM] (CIC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Assistance Publique - Hôpitaux de Marseille (APHM), Service de médecine interne et immunologie clinique (SOC 1) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Le CHCB, Centre Hospitalier de la Côte Basque, CHU Strasbourg, Centre hospitalier de Valence, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Bordeaux [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Claude Huriez [Lille], CHU Lille, Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Myologie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre Hospitalier de la Côte Basque (CHCB)
Subjects: Hydrolases, 030232 urology & nephrology, Otology, 030204 cardiovascular system & hematology, Deafness, Pathology and Laboratory Medicine, Vascular Medicine, Biochemistry, Cornea, Cohort Studies, 0302 clinical medicine, Lysosomal storage disease, Medicine and Health Sciences, Renal Transplantation, Cornea verticillata, Prospective Studies, Registries, Hearing Disorders, Multidisciplinary, Proteinuria, Hypertrophic cardiomyopathy, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Phenotype, 3. Good health, Enzymes, Stroke, Neurology, Medicine, Female, France, medicine.symptom, Anatomy, Cardiomyopathies, Research Article, Adult, medicine.medical_specialty, Glycoside Hydrolases, Science, Ocular Anatomy, Cerebrovascular Diseases, Cardiology, Surgical and Invasive Medical Procedures, Urinary System Procedures, 03 medical and health sciences, Young Adult, Signs and Symptoms, Ocular System, Diagnostic Medicine, Internal medicine, medicine, Genetics, Humans, Paresthesia, Acroparesthesia, Transplantation, business.industry, Biology and Life Sciences, Proteins, Human Genetics, Organ Transplantation, medicine.disease, Fabry disease, Human genetics, Otorhinolaryngology, Enzymology, Fabry Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: International audience; Backgroud: Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity.Methods: Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients.Results: We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p
Published: 2020
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46. MRI of neurodegeneration with brain iron accumulation

Author: Stéphane Lehéricy, Cyril Goizet, F. Mochel, Emmanuel Roze, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Gestionnaire, Hal Sorbonne Université, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: 0301 basic medicine, Neurodegeneration with brain iron accumulation, Iron, [SDV]Life Sciences [q-bio], Neuroimaging, Substantia nigra, Corpus callosum, 03 medical and health sciences, 0302 clinical medicine, Basal ganglia, medicine, Humans, Gray Matter, Brain Chemistry, medicine.diagnostic_test, business.industry, Brain, Magnetic resonance imaging, Magnetic Resonance Imaging, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Dentate nucleus, Globus pallidus, Neurology, nervous system, Neurology (clinical), business, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Purpose of review: The diagnosis of neurodegeneration with brain iron accumulation (NBIA) typically associates various extrapyramidal and pyramidal features, cognitive and psychiatric symptoms with bilateral hypointensities in the globus pallidus on iron-sensitive magnetic resonance images, reflecting the alteration of iron homeostasis in this area. This article details the contribution of MRI in the diagnosis by summarizing and comparing MRI patterns of the various NBIA subtypes.Recent findings: MRI almost always shows characteristic changes combining iron accumulation and additional neuroimaging abnormalities. Iron-sensitive MRI shows iron deposition in the basal ganglia, particularly in bilateral globus pallidus and substantia nigra. Other regions may be affected depending on the NBIA subtypes including the cerebellum and dentate nucleus, the midbrain, the striatum, the thalamus, and the cortex. Atrophy of the cerebellum, brainstem, corpus callosum and cortex, and white matter changes may be associated and worsen with disease duration. Iron deposition can be quantified using R2 or quantitative susceptibility mapping.Summary: Recent MRI advances allow depicting differences between the various subtypes of NBIA, providing a useful analytical framework for clinicians. Standardization of protocols for image acquisition and analysis may help improving the detection of imaging changes associated with NBIA and the quantification of iron deposition.
Published: 2020
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47. Do changes in perfusion index reflect changes in stroke volume during preload-modifying manoeuvres?

Author: Karine Nouette-Gaulain, Frederic Michard, Camille Chavignier, Hugues de Courson, Matthieu Biais, Eric Verchère, Université de Bordeaux (UB), MiCo [Denens, Switzerland], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Boullé, Christelle
Subjects: Cardiac output, medicine.medical_specialty, medicine.medical_treatment, Fluid responsiveness, Health Informatics, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030202 anesthesiology, Internal medicine, Article CLINIQUE, medicine, Perfusion index, Humans, Pulse oximeter, Saline, Tidal volume, Monitoring, Physiologic, Mechanical ventilation, business.industry, Pulse (signal processing), Hemodynamics, Stroke Volume, 030208 emergency & critical care medicine, Stroke volume, Respiration, Artificial, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Preload, Anesthesiology and Pain Medicine, Lung recruitment manoeuvre, Cardiology, Fluid Therapy, business, Airway
Abstract: International audience; Changes in stroke volume (deltaSV) induced by a lung recruitment manoeuvre (LRM) have been shown to accurately predict fluid responsiveness during protective mechanical ventilation. Cardiac output monitors are used in a limited number of surgical patients. In contrast, all patients are monitored with a pulse oximeter, that may enable the continuous monitoring of a peripheral perfusion index (PI). We postulated that changes in PI (deltaPI) may reflect deltaSV during brief modifications of cardiac preload. We studied 47 patients undergoing neurosurgery and ventilated with a tidal volume of 6-8 ml/kg. All patients were monitored with a pulse contour system enabling the continuous monitoring of SV and with a pulse oximeter enabling the continuous monitoring of PI. LRMs were performed by increasing airway pressure up to 30 cmH20 for 30 s. Fluid loads (250 ml of saline 0.9% in 10 min) were performed only in patients who experienced a deltaSV > 30% during LRMs (potential fluid responders). LRMs induced a 26% decrease in SV (p 30% with a sensitivity of 83% and a specificity of 78% (AUC = 0.84, 95%CI 0.71-0.93). 24 patients experienced a deltaSV > 30% and subsequently received fluid. Fluid loads induced a 16% increase in SV and a 17% increase in PI, but fluid-induced deltaPI and deltaSV were weakly correlated (r2 = 0.19). In neurosurgical patients, we conclude that deltaPI may be used as a surrogate for deltaSV during LRMs but not during fluid loading.
Published: 2019
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48. Confirmation of Atypical Presentation With Nonprogressive Leukodystrophy in eIF2B-Related Disorders

Author: Jean-François Chateil, Clémence Scappaticci, Odile Boespflug-Tanguy, Simon Samaan, Didier Lacombe, Pierre Bessou, Julien Van-Gils, Jean-Luc Saves, Cyril Goizet, Jean-Michel Pedespan, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, Pediatrics, medicine.medical_specialty, business.industry, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Leukodystrophy, medicine.disease, 03 medical and health sciences, Presentation, 0302 clinical medicine, Developmental Neuroscience, Neurology, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Published: 2019
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49. The value of electrocardiography and echocardiography in distinguishing Fabry disease from sarcomeric hypertrophic cardiomyopathy

Author: Philippe Charron, Olivier Lairez, Nicolas Junqua, P. Reant, Fabien Labombarda, Hélène Maillard, Cyril Goizet, Damien Legallois, Sophie Segard, Paul Milliez, Service de cardiologie et de pathologie vasculaire [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Signalisation, électrophysiologie et imagerie des lésions d’ischémie-reperfusion myocardique (SEILIRM), Normandie Université (NU)-Normandie Université (NU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital de Rangueil, CHU Toulouse [Toulouse], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Claude Huriez [Lille], CHU Lille, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CCSD, Accord Elsevier
Subjects: Male, Cardiomyopathie hypertrophique, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Left ventricular hypertrophy, Ventricular Function, Left, Electrocardiography, 0302 clinical medicine, Heart Rate, 030212 general & internal medicine, Observer Variation, medicine.diagnostic_test, Ventricular Remodeling, Hypertrophic cardiomyopathy, General Medicine, Right bundle branch block, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Echocardiography, Cardiology, Female, Cardiology and Cardiovascular Medicine, Wall thickness, Électrocardiogramme, Adult, medicine.medical_specialty, Diagnosis, Differential, 03 medical and health sciences, QRS complex, Predictive Value of Tests, Internal medicine, Maladie de Fabry, medicine, Humans, In patient, cardiovascular diseases, Aged, Retrospective Studies, business.industry, Reproducibility of Results, Stroke Volume, Cardiomyopathy, Hypertrophic, medicine.disease, Fabry disease, Electrocardiogram, Ventricular Function, Right, Fabry Disease, business
Abstract: International audience; Background: Screening for Fabry disease is sub-optimal in non-specialised centres.Aim: To assess the diagnostic value of electrocardiographic scores of left ventricular hypertrophy and a combined electrocardiographic and echocardiographic model in Fabry disease.Methods: We retrospectively reviewed the electrocardiograms and echocardiograms of 61 patients (mean age 55.6±11.5 years; 57% men) with Fabry disease and left ventricular hypertrophy, and compared them with those from 59 patients (mean age 44.8±18.3 years; 66% men) with sarcomeric hypertrophic cardiomyopathy. Six electrocardiography criteria for left ventricular hypertrophy were specifically analysed: Sokolow-Lyon voltage index; Cornell voltage index; Gubner index; Romhilt-Estes score; Sokolow-Lyon product (voltage index×QRS duration); and Cornell product (voltage index×QRS duration).Results: Right bundle branch block was more frequent in patients with Fabry disease (54% vs. 22%; P=0.001). QRS duration, Gubner score and Sokolow-Lyon product were significantly higher in patients with Fabry disease. Maximal wall thickness was higher in patients with sarcomeric hypertrophic cardiomyopathy (21.9±5.1 vs. 15.5±2.9mm; P
Published: 2019
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50. De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Callosum, Axon, Cardiac, Ocular, and Genital Defects

Author: Andrea Accogli, Sara Calabretta, Judith St-Onge, Nassima Boudrahem-Addour, Alexandre Dionne-Laporte, Pascal Joset, Silvia Azzarello-Burri, Anita Rauch, Joel Krier, Elizabeth Fieg, Juan C. Pallais, Allyn McConkie-Rosell, Marie McDonald, Sharon F. Freedman, Jean-Baptiste Rivière, Joël Lafond-Lapalme, Brittany N. Simpson, Robert J. Hopkin, Aurélien Trimouille, Julien Van-Gils, Amber Begtrup, Kirsty McWalter, Heron Delphine, Boris Keren, David Genevieve, Emanuela Argilli, Elliott H. Sherr, Mariasavina Severino, Guy A. Rouleau, Patricia T. Yam, Frédéric Charron, Myriam Srour, Maria T. Acosta, David R. Adams, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Stephan Zuchner, McGill University Health Center [Montreal] (MUHC), Istituto di ricovero e cura a carattere scientifico Azienda Ospedaliera Universitaria 'San Martino' (IRCCS AOU San Martino), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], University hospital of Zurich [Zurich], Universität Zürich [Zürich] = University of Zurich (UZH), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Duke University [Durham], Duke University Medical Center, Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), University of Cincinnati (UC), Cincinnati Children's Hospital Medical Center, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), GeneDx [Gaithersburg, MD, USA], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of California [San Francisco] (UCSF), University of California, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institute of Physics, Saink School Post, Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Genomics Program and Division of Genetics, Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Représentations musicales (Repmus), Sciences et Technologies de la Musique et du Son (STMS), Institut de Recherche et Coordination Acoustique/Musique (IRCAM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche et Coordination Acoustique/Musique (IRCAM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Drapper, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Queen Mary University of London (QMUL), Institute of Child Health, Department of Molecular and Human Genetics (Baylor College of Medicine), Baylor College of Medecine, Division of Biomedical Statistics and Informatics, Mayo Clinic, Facultat de Fisica, Departament Universitari d'Optica, Universitat de València (UV), Department of Pathology, University of Alabama at Birmingham [ Birmingham] (UAB), Center for Neuroscience Research (CNMC), Center for Neuroscience Research, Oregon Health and Science University [Portland] (OHSU), Baylor College of Medicine (BCM), Baylor University, Stanford University School of Medicine [CA, USA], Department of Molecular Cellular and Developmental Biology, University of California [Los Angeles] (UCLA), University of California-University of California-Howard Hughes Medical Institute (HHMI), Human Genetics, Department of Mathematics [Sussex], University of Sussex, Genomics Program and Division of Genetics [Boston, USA], Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Biological Sciences Division, Pacific Northwest National Laboratory (PNNL), Departament de Fisica i Enginyeria Nuclear (DEPARTAMENT DI FISICA), Universitat Politècnica de Catalunya [Barcelona] (UPC), Institute of Human Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, National University of Singapore (NUS), Institute of Neuroscience [Eugene, OR, États-Unis], University of Oregon [Eugene], Boston Children's Hospital, Department of Molecular and Human Genetics [Houston, USA], Metacohorts Consortium, Department of Biological Sciences [Nashville], Vanderbilt University [Nashville], Columbia University Medical Center (CUMC), Columbia University [New York], School of Irish, Celtic Studies, Irish Folklore and Linguistics, University College Dublin [Dublin] (UCD), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genomics, University of Miami [Coral Gables], ZFIN, Graduate School of Information Systems, University of Electro-Communications [Tokyo] (UEC), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Heart Defects, Congenital, Heterozygote, [SDV]Life Sciences [q-bio], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, CDH2, Eye, Frameshift mutation, genital defects, corpus callosum, 03 medical and health sciences, 0302 clinical medicine, Report, Genetics, medicine, Missense mutation, Humans, Genitalia, Axon, Frameshift Mutation, Genetics (clinical), N-cadherin, Corpus Callosum Agenesis, Cadherin, eye defects, Cadherins, Molecular biology, Axons, cardiac defects, 030104 developmental biology, medicine.anatomical_structure, ACOG, Neurodevelopmental Disorders, cell-cell adhesion, intellectual disability, Axon guidance, Neural development, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).
Published: 2019
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