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1. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders

Author

Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Julien Thevenon, Hana Safraou, Thomas Besnard, Alice Goldenberg, Benjamin Cogné, Bertrand Isidor, Julian Delanne, Arthur Sorlin, Sébastien Moutton, Mélanie Fradin, Christèle Dubourg, Magali Gorce, Dominique Bonneau, Salima El Chehadeh, François-Guillaume Debray, Martine Doco-Fenzy, Kevin Uguen, Nicolas Chatron, Bernard Aral, Nathalie Marle, Paul Kuentz, Anne Boland, Robert Olaso, Jean-François Deleuze, Damien Sanlaville, Patrick Callier, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, and Antonio Vitobello

Subjects
genome sequencing, RNA-seq, optical genome mapping, long-read sequencing, clinical diagnoses, Biology (General), QH301-705.5
Abstract

Purpose: Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches.Methods: In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%–9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%–6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis.Results: SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization.Conclusion: Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology.

Published
2023
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2. Phenotypes and genotypes in non‐consanguineous and consanguineous primary microcephaly: High incidence of epilepsy

Author

Sarah Duerinckx, Julie Désir, Camille Perazzolo, Cindy Badoer, Valérie Jacquemin, Julie Soblet, Isabelle Maystadt, Yusuf Tunca, Bettina Blaumeiser, Berten Ceulemans, Winnie Courtens, François‐Guillaume Debray, Anne Destree, Koenraad Devriendt, Anna Jansen, Kathelijn Keymolen, Damien Lederer, Bart Loeys, Marije Meuwissen, Stéphanie Moortgat, Geert Mortier, Marie‐Cécile Nassogne, Tayeb Sekhara, Rudy Van Coster, Jenny Van Den Ende, Nathalie Van der Aa, Hilde Van Esch, Olivier Vanakker, Helene Verhelst, Catheline Vilain, Sarah Weckhuysen, Sandrine Passemard, Alain Verloes, Alec Aeby, Nicolas Deconinck, Patrick Van Bogaert, Isabelle Pirson, and Marc Abramowicz

Subjects
brain developmental disorders, consanguinity, epilepsy, Mendeliome, primary microcephaly, rare disease, Genetics, QH426-470
Abstract

Abstract Background Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. Methods We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. Results Pathogenic variants in ASPM and WDR62 were the most frequent causes in non‐consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non‐consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. Conclusion Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.

Published
2021
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3. Kidney and vascular function in adult patients with hereditary fructose intolerance

Author

Nynke Simons, François-Guillaume Debray, Nicolaas C. Schaper, Edith J.M. Feskens, Carla E.M. Hollak, Judith A.P. Bons, Jörgen Bierau, Alfons J.H.M. Houben, Casper G. Schalkwijk, Coen D.A. Stehouwer, David Cassiman, and Martijn C.G.J. Brouwers

Subjects
Case-control study, Hereditary fructose intolerance, Fanconi syndrome, Kidney, Blood, Vessels, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium.Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups.Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.

Published
2020
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4. Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

Author

Julie Harvengt, Catherine Wanty, Boel De Paepe, Christine Sempoux, Nicole Revencu, Joél Smet, Rudy Van Coster, Willy Lissens, Sara Seneca, Laurent Weekers, Etienne Sokal, and François-Guillaume Debray

Subjects
Mitochondrial disease, mtDNA depletion, Gaucher disease, Neurohepatic, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

A 1-year-old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19 months. Subsequent partial splenectomy for persistent cytopenia showed the presence of foamy cells, and Gaucher disease was confirmed by homozygosity for the p.Leu483Pro mutation in the GBA gene. She was treated by enzyme replacement therapy (ERT). Clinical follow-up showed mild developmental delay, strabismus, nystagmus and oculomotor apraxia. Biochemical studies revealed multiple respiratory chain deficiencies and a mosaic pattern of deficient complex IV immunostaining in liver and fibroblast. Molecular analysis identified a mtDNA depletion syndrome due to the homozygous p.Pro98Leu mutation in MPV17. A younger sister unaffected by mtDNA depletion, presented with pancytopenia and hepatosplenomegaly. ERT for Gaucher disease resulted in visceral normalization without any neurological symptom. A third sister, affected by both conditions, had marked developmental delay, strabismus and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs in MPV17-related disease. The combined pathological effect of Gaucher and mitochondrial diseases can negatively impact neurological and liver functions and influence the outcome in consanguineous families. The immunocytochemical staining of OXPHOS protein in tissues and cultured cells is a powerful tool revealing mosaic pattern of deficiency pointing to mtDNA-related mitochondrial disorders.

Published
2014
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5. The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant

Author

Mio Aerden, Anne-Sophie Denommé-Pichon, Dominique Bonneau, Ange-Line Bruel, Julian Delanne, Bénédicte Gérard, Benoît Mazel, Christophe Philippe, Lucile Pinson, Clément Prouteau, Audrey Putoux, Frédéric Tran Mau-Them, Éléonore Viora-Dupont, Antonio Vitobello, Alban Ziegler, Amélie Piton, Bertrand Isidor, Christine Francannet, Pierre-Yves Maillard, Sophie Julia, Anais Philippe, Elise Schaefer, Saskia Koene, Claudia Ruivenkamp, Mariette Hoffer, Eric Legius, Miel Theunis, Boris Keren, Julien Buratti, Perrine Charles, Thomas Courtin, Mala Misra-Isrie, Mieke van Haelst, Quinten Waisfisz, Dagmar Wieczorek, Ariane Schmetz, Theresia Herget, Fanny Kortüm, Jasmin Lisfeld, François-Guillaume Debray, Nuria C. Bramswig, Isis Atallah, Heidi Fodstad, Guillaume Jouret, Berta Almoguera, Saoud Tahsin-Swafiri, Fernando Santos-Simarro, Maria Palomares-Bralo, Vanesa López-González, Maria Kibaek, Pernille M. Tørring, Alessandra Renieri, Lucia Pia Bruno, Katrin Õunap, Monica Wojcik, Tzung-Chien Hsieh, Peter Krawitz, Hilde Van Esch, Human genetics, Amsterdam Reproduction & Development (AR&D), Amsterdam Neuroscience - Complex Trait Genetics, and CCA - Cancer biology and immunology

Subjects
Genetics, Genetics (clinical)
Abstract

Haploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12 gestalt. 38 individuals between 3 and 66 years (F = 20, M = 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12 variants were identified, including frameshift (n = 15) and nonsense (n = 6) variants, as well as missense (n = 5) and splice (n = 3) variants, intragenic deletions (n = 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12 variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance.

Published
2023
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6. Effect of a high fructose diet on metabolic parameters in carriers for hereditary fructose intolerance

Author

Luc Tappy, Marjorie Fadeur, François-Guillaume Debray, Nicolas Paquot, Kevin Seyssel, and Christel Tran

Subjects
Adult, Blood Glucose, Male, 0301 basic medicine, Heterozygote, medicine.medical_specialty, medicine.medical_treatment, Hereditary fructose intolerance, 030209 endocrinology & metabolism, Fructose, Hyperuricemia, Critical Care and Intensive Care Medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fructose-Bisphosphate Aldolase, Internal medicine, medicine, Humans, Insulin, Meals, Metabolic Syndrome, Cross-Over Studies, 030109 nutrition & dietetics, Nutrition and Dietetics, biology, business.industry, Aldolase B, Fasting, Postprandial Period, medicine.disease, Fructose Intolerance, Uric Acid, Glucose, Postprandial, Endocrinology, Liver, chemistry, biology.protein, Uric acid, Female, Diet, Carbohydrate Loading, Insulin Resistance, Metabolic syndrome, business
Abstract

Hyperuricemia is an independent risk factor for the metabolic syndrome and cardiovascular disease. We hypothesized that asymptomatic carriers for hereditary fructose intolerance (OMIM 22960) would have increased uric acid and altered component of the metabolic syndrome when exposed to fructose overfeeding.Six heterozygotes for HFI (hHFI) and 6 controls (Ctrl) were studied in a randomized, controlled, crossover trial. Participants ingested two identical test meals containing 0.7 g kgHiFruD increased fasting uric acid (p 0.05) and reduced fasting insulin sensitivity estimated by the homeostasis model assessment (HOMA) for insulin resistance (p 0.05), in both groups. Postprandial glucose concentrations were not different between hHFI and Ctrl. However HiFruD increased postprandial plasma uric acid, insulin and hepatic insulin resistance index (HIRI) in hHFI only (all p 0.05).Seven days of HiFruD increased fasting uric acid and slightly reduced fasting HOMA index in both groups. In contrast, HiFruD increased postprandial uric acid, insulin concentration and HIRI in hHFI only, suggesting that heterozygosity for pathogenic Aldolase B variants may confer an increased susceptibility to the effects of dietary fructose on uric acid and hepatic insulin sensitivity. This trial was registered at the U.S. Clinical Trials Registry as NCT03545581.

Published
2021
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7. Diagnosis and monitoring of phenylketonuria by LC-MS-MS in Morocco

Author

Saâd El Kabbaj, Faïza Meiouet, François Boemer, and François-Guillaume Debray

Subjects
Male, Pediatrics, medicine.medical_specialty, Phenylalanine hydroxylase, Phenylalanine, Metabolite, Disease, chemistry.chemical_compound, Tandem Mass Spectrometry, Phenylketonurias, medicine, Humans, Tyrosine, biology, business.industry, Phenylpyruvic acid, General Medicine, Morocco, chemistry, Toxicity, Cohort, biology.protein, Female, business, Chromatography, Liquid
Abstract

Phenylketonuria is an inherited metabolic disease, of autosomal recessive transmission, due to the enzymatic deficit of phenylalanine hydroxylase, which transforms phenylalanine into tyrosine. The deficit leads to an increase in phenylalanine and its metabolite, phenylpyruvic acid which is responsible for the toxicity and symptomatology characterized by serious neurological disorders. Through this work, we wanted to show: 1) the profile of phenylalanine concentrations in a cohort of 52 Moroccan phenylketonuric patients diagnosed in our laboratory by Tandem Mass Spectrometry coupled with HPLC; 2) The value of biological monitoring in the nutritional management of phenylketonuric patients. The results showed that phenylketonuria diagnosed in Morocco is characterized by a predominance of classic and moderate phenylketonuria in both sexes with a median concentration = 1,107 μmol/L, 26 times higher than that observed in the control group (median value = 42 μmol/L - p

Published
2021
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8. Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency

Author

Austin Larson, Carolyn Ellaway, Michel Tchan, Jerry Vockley, Eva Morava, Francjan J. van Spronsen, Francesca Moore, David Gil-Ortega, Saskia B. Wortmann, Matthias Gautschi, Sabine Scholl-Bürgi, Peter Witters, Emmalie A. Jager, François-Guillaume Debray, A. Çiğdem Aktuğlu Zeybek, Johan L.K. Van Hove, Kaustuv Bhattacharya, Kimihiko Oishi, Willemijn J. van Rijt, Derk P. Allersma, Michael T. Geraghty, Andrew A. M. Morris, Terry G J Derks, Manuel Schiff, Center for Liver, Digestive and Metabolic Diseases (CLDM), and İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü

Subjects
medicine.medical_specialty, Abdominal pain, Constipation, D,L-3-hydroxybutyrate treatment, Nausea, 610 Medicine & health, D,l-3-hydroxybutyrate Treatment, Fatty Acid Oxidation, Inborn Error Of Metabolism, Ketone Bodies, Multiple Acyl-coa Dehydrogenase Deficiency, Gastroenterology, Article, Acyl-CoA Dehydrogenase, Interquartile range, multiple acyl-CoA dehydrogenase deficiency, Internal medicine, medicine, inborn error of metabolism, Humans, Multiple Acyl Coenzyme A Dehydrogenase Deficiency, Genetics (clinical), fatty acid oxidation, BETA-HYDROXYBUTYRATE, Retrospective Studies, 3-Hydroxybutyric Acid, business.industry, Infant, GLUCOSE-METABOLISM, Retrospective cohort study, KETONE-BODIES, medicine.disease, ddc, Respiratory failure, Inborn error of metabolism, ketone bodies, Vomiting, L-3-hydroxybutyrate treatment, medicine.symptom, business, Cardiomyopathies
Abstract

Vockley, Jerry/0000-0002-8180-6457; Zeybek, Ayse Cigdem Aktuglu/0000-0001-7256-0750; Vockley, Jerry/0000-0002-8180-6457; Oishi, Kimihiko/0000-0001-9446-8912; Derks, Terry/0000-0002-7259-1095 WOS:000507768800001 PubMed ID: 31904027 Purpose Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking. Methods A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients. Results Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%). Conclusion The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients. Junior Scientific Masterclass from the University of Groningen, University Medical Center Groningen [MD/PhD 15-30, MD/PhD 18-55]; National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-DK78755] The authors thank Katinka A.M. Mulder, legal advisor-research contracts, for her contribution to the realization of the consortium agreement. Pharmaceutical industries did not play any role in this study. The MD/PhD scholarships of W.J.v.R. and E.A.J. are funded by the Junior Scientific Masterclass from the University of Groningen, University Medical Center Groningen (MD/PhD 15-30, MD/PhD 18-55, respectively). J.V. is supported in part by National Institutes of Health (NIH) grant R01-DK78755. The sources of funding had no involvement in the study design; data collection, analysis, and interpretation; reporting of the results; or in the decision to submit the paper for publication.

Published
2020
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9. Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content

Author

Leanne Hodson, Nicolaas C. Schaper, Judith A P Bons, Casper G. Schalkwijk, Ger H. Koek, Martijn C. G. J. Brouwers, Lucas Lindeboom, Coen D.A. Stehouwer, Carla E. M. Hollak, Edith J. M. Feskens, Nynke Simons, Dirk Lefeber, M. Eline Kooi, François-Guillaume Debray, David Cassiman, Endocrinology, AGEM - Inborn errors of metabolism, Interne Geneeskunde, Promovendi CD, RS: CARIM - R3 - Vascular biology, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, MUMC+: MA Endocrinologie (9), RS: CAPHRI - R2 - Creating Value-Based Health Care, RS: CARIM - R3.02 - Hypertension and target organ damage, Beeldvorming, MUMC+: DA BV Klinisch Fysicus (9), RS: Carim - B06 Imaging, RS: CARIM - R3.11 - Imaging, Nutrition and Movement Sciences, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, MUMC+: MA Maag Darm Lever (9), RS: NUTRIM - R2 - Liver and digestive health, MUMC+: DA CDL Algemeen (9), RS: NUTRIM - R3 - Respiratory & Age-related Health, MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), MUMC+: HVC Pieken Maastricht Studie (9), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, MUMC+: MA Interne Geneeskunde (3), MUMC+: MA Hematologie (9), MUMC+: MA Medische Oncologie (9), MUMC+: MA Nefrologie (9), and MUMC+: MA Reumatologie (9)

Subjects
Blood Glucose, Male, Endocrinology, Diabetes and Metabolism, Hereditary fructose intolerance, Clinical Biochemistry, Biochemistry, Body Mass Index, chemistry.chemical_compound, Endocrinology, Fructose-Bisphosphate Aldolase, Nonalcoholic fatty liver disease, Outpatient clinic, 3-Hydroxybutyric Acid, biology, INSULIN SENSITIVITY, Transferrin, Middle Aged, MAGNETIC-RESONANCE-SPECTROSCOPY, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Fructose Intolerance, Magnetic Resonance Imaging, PREVALENCE, Liver, Body Composition, DIETS, Female, Adult, HEREDITARY FRUCTOSE INTOLERANCE, medicine.medical_specialty, Context (language use), Young Adult, Internal medicine, medicine, Life Science, Humans, HEPATIC STEATOSIS, Triglycerides, VLAG, FATTY LIVER-DISEASE, Global Nutrition, Wereldvoeding, Triglyceride, business.industry, Aldolase B, GLYCOSYLATION, Biochemistry (medical), CONSUMPTION, medicine.disease, ACIDS, Diet, Glucose, chemistry, Inborn error of metabolism, Case-Control Studies, biology.protein, Lean body mass, business, Metabolism, Inborn Errors
Abstract

Context There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B−/−), the enzyme that converts fructose-1-phosphate to triose phosphates. Objective To translate these experimental findings to the human situation. Design Case-control study. Setting Outpatient clinic for inborn errors of metabolism. Patients or Other Participants Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). Main Outcome Measure IHTG content, assessed by proton magnetic resonance spectroscopy. Results IHTG content was higher in aldo B−/− patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B−/− patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B−/− patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B−/− patients than controls (P = 0.009). Conclusions This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.

Published
2019
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10. C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation

Author

Claudia Stollbrink-Peschgens, Patricia Klemm, Lambert P. van den Heuvel, Ingo Kurth, Clara D.M. van Karnebeek, Michael Mull, Eva Lausberg, C. Libioulle, Robert Meyer, Thomas Eggermann, Emile Van Schaftingen, Klaus Tenbrock, Daniela Choukair, Joseph P. Dewulf, François-Guillaume Debray, Joachim Weis, Kim Ohl, Norbert Wagner, Prasad T Oommen, Claudia Haase, Elsa Wiame, Dagmar Wieczorek, Arndt Borkhardt, Matthias Begemann, Sebastian Gießelmann, Anja Holz, Florian Kraft, Harald Surowy, Miriam Elbracht, Clemens Sommer, Ramona Salvarinova, Stephanie Demuth, Till Braunschweig, Martin Häusler, ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, and UCL - (SLuc) Service de biochimie médicale

Subjects
0301 basic medicine, Microcephaly, Respiratory chain, Biology, Mitochondrion, Cell Line, Mitochondrial Proteins, Transcriptome, Mice, Open Reading Frames, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Loss of Function Mutation, Glycogen branching enzyme, medicine, Animals, Humans, Gene, Mice, Knockout, Genetics, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Glycogen Debranching Enzyme System, General Medicine, medicine.disease, Mitochondria, Open reading frame, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Clinical Medicine, Signal transduction, Glycogen
Abstract

BACKGROUND. Deciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell’s function and its pathophysiology. METHODS. Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene. RESULTS. We identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid–Schiff–positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism. CONCLUSIONS. Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways.

Published
2021
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11. A human multisystem disorder with autoinflammation, leukoencephalopathy and hepatopathy is caused by mutations in C2orf69

Author

J. P. Dewulf, Matthias Begemann, E. Van Schaftingen, L. van den Heuvel, C. Van Karnebeek, Thomas Eggermann, Joachim Weis, Prasad T Oommen, Claudia Haase, Daniela Choukair, François-Guillaume Debray, Anja Holz, M. Haeusler, Robert Meyer, S. Giesselmann, Eva Lausberg, Kim Ohl, Harald Surowy, Dagmar Wieczorek, C. Libioulle, Ramona Salvarinova, Stephanie Demuth, Elsa Wiame, Klaus Tenbrock, Florian Kraft, Miriam Elbracht, Till Braunschweig, Clemens Sommer, Michael Mull, Patricia Klemm, Ingo Kurth, and Arndt Borkhardt

Subjects
Signal peptide, Genetics, Transcriptome, Microcephaly, Open reading frame, biology, medicine, Respiratory chain, Glycogen branching enzyme, biology.protein, Signal transduction, medicine.disease, Gene
Abstract

BackgroundDeciphering the function of the many genes previously classified as uncharacterized “open reading frame” (orf) completes our understanding of cell function and its pathophysiology.MethodsWhole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene.ResultsWe identify loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, patients show signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 shows comparable respiratory chain defects. Patient-derived cells reveal alterations in immunological signaling pathways. Deposits of PAS-positive material in tissues from affected individuals together with decreased glycogen branching enzyme 1 (GBE1) activity indicate an additional impact of C2orf69 on glycogen metabolism.ConclusionOur study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways.Graphical Abstract

Published
2021
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12. Phenotypes and genotypes in outbred and inbred Primary microcephaly: high incidence of epilepsy

Author

Julie Désir, Catheline Vilain, Sarah Duerinckx, Isabelle Pirson, Olivier Vanakker, Tayeb Sekhara, Bart Loeys, Camille Perazzolo, Marije E.C. Meuwissen, Geert Mortier, Cindy Badoer, Kathelijn Keymolen, Bettina Blaumeiser, Gert Matthijs, Stéphanie Moortgat, Patrick Van Bogaert, Jenneke van den Ende, Yusuf Tunca, Hilde Van Esch, Marc Abramowicz, Julie Soblet, Koen Devriendt, Valérie Jacquemin, Anna Jansen, Sarah Weckhuysen, François-Guillaume Debray, Sandrine Passemard, Damien Lederer, Alain Verloes, Nathalie Van der Aa, Marie-Cécile Nassogne, Helene Verhelst, Alec Aeby, Anne Destree, Winnie Courtens, Isabelle Maystadt, Nicolas Deconinck, Berten Ceulemans, and Rudy Van Coster

Subjects
Oncology, Microcephaly, medicine.medical_specialty, Candidate gene, Genetic heterogeneity, business.industry, Seizure types, medicine.disease, ASPM, Epilepsy, Internal medicine, Cohort, Genotype, medicine, business
Abstract

Primary microcephaly (PM) is defined as a significant reduction in occipito-frontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. We performed detailed phenotypic and genomic analyses in a large cohort (n=169) of patients referred for PM, and could establish a molecular diagnosis in 38 patients. Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in outbred patients (9%). Our series includes 15 previously unreported families and 11 novel pathogenic variants, and we identify novel candidate genes including IGF2BP3, DNAH2, and TSR1. We confirm progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients, with various degrees of severity and seizure types. Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses and improve management of PM patients.

Published
2021
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13. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author

Bertrand Isidor, Ruth Armstrong, Thabo M. Yates, Susan M. White, Ruth Richardson, Solveig Heide, Katherine B. Burke, Tjitske Kleefstra, Marie Vincent, Meena Balasubramanian, Maria Irene Valenzuela Palafoll, Sébastien Küry, Rolph Pfundt, Ruth Newbury-Ecob, Sahar Mansour, Wendy K. Chung, Caroline Nava, Sofia Douzgou, Erika Leenders, Annachiara De Sandre-Giovannoli, Saba Sharif, Andrew E. Fry, Helen Stewart, Nicola K. Ragge, Alexander J. M. Dingemans, Pradeep C. Vasudevan, Alison Foster, Sahar Elouej, Shadi Albaba, François-Guillaume Debray, Boris Keren, Serwet Demirdas, Francis H. Sansbury, Thomas Scheffner, Arie van Haeringen, Alice S. Brooks, Meyke Schouten, Helen Cox, Kate Wilson, Sheffield Children's NHS Foundation Trust, University of Sheffield [Sheffield], Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Birmingham Children’s Hospital, Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], Addenbrooke's Hospital, Cambridge University NHS Trust, University Hospital of Wales, Oxford Brookes University, 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), Hôpital de la Timone [CHU - APHM] (TIMONE), 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), St. George’s Hospital University, Oxford University Hospitals NHS Foundation Trust, Partenaires INRAE, Service de Génétique Cytogénétique et Embryologie [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), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], Leiden University Medical Center (LUMC), Reutlingen University, Centre Hospitalier Universitaire de Liège (CHU-Liège), Murdoch Children's Research Institute (MCRI), University of Melbourne, Vall d'Hebron University Hospital [Barcelona], University Hospitals Bristol, Clinical Genetics, Institut Català de la Salut, [Balasubramanian M] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. Academic Unit of Child Health, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK. [Dingemans AJM] Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands. [Albaba S] Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Richardson R] Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK. [Yates TM] Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK. [Cox H] West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, UK. [Palafoll MIV] Servei de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Medicina Genètica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, University Hospital of Wales (UHW), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), and Universiteit Leiden

Subjects
Male, Pediatrics, Genetic testing, Developmental Disabilities, Craniofacial Abnormalities, Intellectual disability, Missense mutation, Child, Genetics (clinical), trastornos mentales::trastornos del desarrollo neurológico::discapacidades del desarrollo [PSIQUIATRÍA Y PSICOLOGÍA], 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 030305 genetics & heredity, Cognition, Syndrome, Autism spectrum disorders, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Hypotonia, 3. Good health, Fenotip, Sin3 Histone Deacetylase and Corepressor Complex, Phenotype, Autism spectrum disorder, Child, Preschool, Cohort, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Trastorns del desenvolupament - Aspectes genètics, Infants, medicine.medical_specialty, Adolescent, personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], Article, 03 medical and health sciences, Mental Disorders::Neurodevelopmental Disorders::Developmental Disabilities [PSYCHIATRY AND PSYCHOLOGY], Intellectual Disability, Genetics, medicine, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, Attention deficit hyperactivity disorder, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Infant, Persons::Age Groups::Child [NAMED GROUPS], medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Genetic Phenomena::Phenotype [PHENOMENA AND PROCESSES], Autism, business, fenómenos genéticos::fenotipo [FENÓMENOS Y PROCESOS]
Abstract

Trastornos del espectro autista; Prueba genética Trastorns de l'espectre autista; Prova genètica Autism spectrum disorders; Genetic testing Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12. Funding for the project was provided by the Wellcome Trust and by grants from the Netherlands Organization for Health Research and Development (ZonMw grant 91718310 and the Dutch Scientific Organization (NWO, grant NWA 1160.18.320). WKC is supported by grants from SFARI and the JPB Foundation

Published
2021
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14. Kidney and vascular function in adult patients with hereditary fructose intolerance

Author

Carla E. M. Hollak, Edith J. M. Feskens, Casper G. Schalkwijk, David Cassiman, François-Guillaume Debray, Jörgen Bierau, Nynke Simons, Alfons J.H.M. Houben, Judith A P Bons, Coen D.A. Stehouwer, Martijn C. G. J. Brouwers, Nicolaas C. Schaper, Interne Geneeskunde, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, RS: Carim - V02 Hypertension and target organ damage, RS: CAPHRI - R2 - Creating Value-Based Health Care, MUMC+: MA Endocrinologie (9), MUMC+: DA CDL Algemeen (9), RS: NUTRIM - R3 - Respiratory & Age-related Health, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: Centrum voor Chronische Zieken (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), Endocrinology, and AGEM - Inborn errors of metabolism

Subjects
glutamic acid, (Glu), Hereditary fructose intolerance, leucine, (Leu), BLOOD-PRESSURE, CKD-EPI equation based on serum creatinine, (eGFRcr), MICROVASCULAR DYSFUNCTION, tyrosine, (Tyr), Kidney, UP-REGULATION, chemistry.chemical_compound, soluble E-selectin, (sE-selectin), Endocrinology, perfusion units, (PU), isoleucine, (Ile), methionine, (Met), cysteine, (Cys), threonine, (Thr), von willebrand factor, (vWF), phenylalanine, (Phe), Pulse wave velocity, lcsh:QH301-705.5, lcsh:R5-920, CKD-EPI equation based on cystatin c, (eGFRcys), biology, difference, (Δ), citrulline, (Cit), GLOMERULAR HYPERFILTRATION, asparagine, (Asn), Case-control study, estimated glomerular filtration rate, (eGFR), 95% confidence interval, (95% CI), aldolase B, (ALDOB), glutamine, (Gln), Pulse pressure, lysine, (Lys), Blood, hereditary fructose intolerance, (HFI), histidine, (His), CKD-EPI equation based on creatinine and cystatin c combined, (eGFRcr-cys), lcsh:Medicine (General), alanine, (Ala), glycine, (Gly), ARTERIAL STIFFNESS, reactive hyperemia index, (RHI), Research Paper, medicine.medical_specialty, valine, (Val), ALDOLASE-B, ratio of tubular maximum reabsorption of phosphate to GFR, (TmP/GFR), BODY-FLUIDS, Urology, Renal function, DIAGNOSIS, ornithine, (Orn), Genetics, medicine, arginine, (Arg), tubular reabsorption of phosphate, (TRP), serine, (Ser), intrahepatic triglyceride, (IHTG), Molecular Biology, reactive hyperemia peripheral arterial tonometry, (RH-PAT), VLAG, chronic kidney disease epidemiology collaboration, (CKD-EPI), Global Nutrition, Creatinine, Wereldvoeding, proline, (Pro), business.industry, DIETARY-SODIUM, laser doppler flowmetry, (LDF), medicine.disease, glucokinase regulatory protein, (GKRP), taurine, (Tau), Fanconi syndrome, SERUM CYSTATIN C, Blood pressure, chemistry, Cystatin C, lcsh:Biology (General), Arterial stiffness, biology.protein, tryptophan, (Try), Vessels, carotid-femoral pulse wave velocity, (cf-PWV), business, statistical package of social sciences, (SPSS)
Abstract

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study. ispartof: MOLECULAR GENETICS AND METABOLISM REPORTS vol:23 ispartof: location:United States status: published

Published
2020

15. Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network

Author

Heard, Jean-Michel, Vrinten, Charlotte, Schlander, Michael, Bellettato, Cinzia Maria, van Lingen, Corine, Scarpa, Maurizio, Gert, Matthijs, Marie-Cécile, Nassogne, François-Guillaume, Debray, Dominique, Roland, Teodora, Chamova, Viktor, Kozich, Jesina, Pavel, Martin, Zenker, Christina, Lampe, Anihb Martin Das, Julia, Hennermann, Stefan, Kölker, Natalie, Weinhold, Klaus, Mohnike, Sarah, Gruenert, Allan Meldgaard Lund, Montserrat, Morales-Conejo, Mireia Del Toro-Riera, Luis, Aldámiz-Echevarría, Maria-Teresa, Garcia-Silva, Manuel, Schiff, Laurent, Gouya, Pascale de Lonlay, Nadia, Belmatoug, Dominique, P Germain, Aline, Cano, Dries, Dobbelaere, Simon, Jones, Charlotte, Dawson, Patrick, Deegan, Saikat, Santra, Suresh, Vijay, Danijela Petkovic Ramadza, Ivo, Barić, Tamara, Žigman, György, Pflieger, Katalin, Szakszon, Rita, Kaposta, Serena, Gasperini, Alberto, Burlina, Giancarlo, Parenti, Pietro, Strisciuglio, Giovanni, Ceccarini, Antonio, Federico, Simonati, Alessandro, Birute, Tumiene, Hidde, Huidekoper, Francian van Spronsen, Annet, Bosch, Maria-Estela, Rubio-Gozalbo, Gepke, Visser, Trine, Tangeraas, Aasne, Aarsand, Beata, Kieć-Wilk, Ana-Maria Simões Mendes Gaspar, Dulce, Quelhas, Elisa, Leao-Teles, Olga, Azevedo, Esmeralda-Maria Ferreira Rodriges Silva, Luísa-Maria de Abreu Freire Diogo Matos, Esmeralda, Martins, Svetlana, Lajic, Niklas, Darin, Urh, Groselj, Mojca-Zerjav, Tansek, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie pédiatrique, Pediatrics, RS: GROW - R4 - Reproductive and Perinatal Medicine, Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), Paediatric Metabolic Diseases, and AGEM - Inborn errors of metabolism

Subjects
Orphan Drug Production, lcsh:Medicine, Disease, Research & Experimental Medicine, Hereditary Metabolic Diseases, European Reference Network, Surveys and Questionnaires, Health care, Agency (sociology), Access to treatment, Inborn errors of metabolism, Orphan medicinal product, Medicine, Genetics(clinical), Pharmacology (medical), Drug Approval, Genetics (clinical), media_common, Genetics & Heredity, General Medicine, Product (business), Medicine, Research & Experimental, Life Sciences & Biomedicine, medicine.medical_specialty, media_common.quotation_subject, Marketing authorization, Unmet needs, access to treatment, hereditary metabolic diseases, inborn errors of metabolism, orphan medicinal product, Rare Diseases, Metabolic Diseases, Excellence, DRUGS, Humans, Medical prescription, MetabERN collaboration group, Science & Technology, business.industry, Research, lcsh:R, Family medicine, business, Metabolism, Inborn Errors, 1199 Other Medical and Health Sciences
Abstract

Background The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. Results Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients’ clinical status, characteristic, and personal choice. Conclusions Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.

Published
2020
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16. Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function

Author

Yanick J. Crow, Dorit Lev, Evangeline Wassmer, Adeline Vanderver, Diedre A Kelly, Annette Bley, Jonas Denecke, Sameer M. Zuberi, Despina Eleftheriou, Callum Wilson, Julie Harvengt, François-Guillaume Debray, Laura Adang, Veronica Saletti, Diane Doummar, Simona Orcesi, Bernt Popp, Fanny Mochel, Ayelet Zerem, Margherita Estienne, Arnaud Wiedemann, Itxaso Marti, Cia Sharpe, Tracy A Briggs, Sehoon Park, Stefan Berg, Lien Van Eyck, Alexandre Belot, Thierry Billette de Villemeur, John H. Livingston, Elisa Fazzi, Marie-Christine Nougues, Lubov Blumkin, Miguel Tomas Vila, Christiane Zweier, Francesco Gavazzi, Odile Boespflug-Tanguy, Gunilla Drake Af Hagelsrum, François Feillet, Niklas Darin, Luis Seabra, Davide Tonduti, Bénédicte Héron, Elise Brimble, Roberta Battini, Keith Van Haren, Christophe Barrea, Mathieu P Rodero, Belén Pérez-Dueñas, Gayatri Vadlamani, Ilena Oppermann, Diana Rodriguez, Julie Vogt, Virginie Levrat, Russell C. Dale, Delphine Héron, Gillian I. Rice, Jessica Galli, Sun Hur, Nicholas L. Hartog, Cyril Mignot, Valentina De Giorgis, Loveline A Ayuk, European Commission, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Developmental Neuroscience, IRCCS Stella Maris Institute, Autophagie infection et immunité - Autophagy Infection Immunity (APY), Centre International de Recherche en Infectiologie - UMR (CIRI), 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 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), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
Male, Models, Molecular, Interferon-Induced Helicase, IFIH1, Aicardi–Goutières syndrome, Protein Conformation, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Aicardi-Goutières syndrome, medicine.disease_cause, Variable Expression, Aicardi-Goutieres syndrome, Interferon, Genotype, Type I interferonopathy, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, IFIH1, Genetics, 0303 health sciences, Mutation, 030305 genetics & heredity, function mutation, High-Throughput Nucleotide Sequencing, type I interferonopathy, Phenotype, 3. Good health, Gain of Function Mutation, Female, medicine.drug, Singleton Merten syndrome, MDA5, In silico, Biology, Nervous System Malformations, Article, 03 medical and health sciences, Structure-Activity Relationship, Autoimmune Diseases of the Nervous System, medicine, Humans, Alleles, Genetic Association Studies, 030304 developmental biology, disease, medicine.disease
Abstract

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutieres syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate. Yanick J. Crow acknowledges The University of Maryland Brain and Tissue Bank of the NIH NeuroBioBank. Yanick J. Crow acknowledges the European Research Council (786142-E-T1IFNs), a state subsidy managed by the National Research Agency (France) under the "Investments for the Future" program bearing the reference ANR-10-IAHU-01 and the MSDAvenir fund (DEVO-DECODE Project). Tracy A. Briggs acknowledges the National Institute for Health Research (NIHR; NIHR Transitional Research Fellowship, TRF-2016-09-002; with the views expressed were those of the author and not necessarily those of the NHS, the NIHR or the Department of Health). Adeline L. Vanderver is supported by the Kamens endowed chair for Translational Neurotherapeutics and the Myelin Disorders Bioregistry Project. Adeline L. Vanderver and Laura A. Adang acknowledge the CURE Pennsylvania Frontiers in Leukodystrophy grant and U01HD082806. Laura A. Adang also acknowledges the National Center for Advancing Translational Sciences of the National Institutes of Health under award number KL2TR001879. Lien Van Eyck received funding from Research Foundation Flanders (FWO).

Published
2020
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17. Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations

Author

Alonso, Cárdenas-de-la-Parra, Sandra, Martin-Brevet, Clara, Moreau, Borja, Rodriguez-Herreros, Vladimir, S Fonov, Anne, M Maillard, Nicole, R Zürcher, 2 European Consortium, 16p11., Nouchine Hadjikhani 48, Jacques, S Beckmann 49, Alexandre Reymond 50, Bogdan Draganski 51, Sébastien Jacquemont 52, D Louis Collins 1, Marie-Claude Addor, 7, Joris Andrieux, 8, Benoît Arveiler, 9, Geneviève Baujatm 10, Frédérique Sloan-Bénan 11, Marco, Belfiore, Dominique Bonneau 12, Sonia Bouquillon 13, Odile Boute 14, Brusco, Alfredo, Tiffany Busa 16, Jean-Hubert Caberg 17, Dominique Campion 18, Vanessa Colombert 19, Marie-Pierre Cordier 20, Albert David 21, François-Guillaume Debray 22, Marie-Ange Delrue 23, Martine Doco-Fenzy 24, Ulrike Dunkhase-Heinl 25, Patrick Edery 20, Christina Fagerberg 26, Laurence Faivre 27, Francesca, Forzano, David Genevieve 29, Marion Gérard 30, Giachino, Daniela Francesca, Agnès Guichet 32, Olivier Guillin 33, Delphine Héron 34, Bertrand Isidor 21, Aurélia Jacquette 34, Sylvie Jaillard 35, Hubert Journel 19, Boris Keren 36, Didier Lacombe, 9, Sébastien Lebon 37, Cédric Le Caignec 38, Marie-Pierre Lemaître 39, James Lespinasse 40, Michèle Mathieu-Dramart 41, Sandra Mercier 21, Cyril Mignot 34, Chantal Missirian 16, Florence Petit 42, Kristina Pilekær Sørensen 26, Lucile Pinson 29, Ghislaine Plessis 30, Fabienne Prieur 43, Caroline Rooryck-Thambo 44, Rossi, Massimiliano, Damien Sanlaville 45, Britta Schlott Kristiansen 26, Caroline Schluth-Bolard 45, Marianne Till 20, Mieke Van Haelst 46, Lionel Van Maldergem, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), McConnell Brain Imaging Centre (MNI), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Human Genetics, Université de Lausanne (UNIL), Service de génétique médicale, Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, EHESP-Irset (EHESP-Irset), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], National Institute of Child Health and Human Development, National Institute on Drug Abuse, 3388, MIRI Brain Canada, 201803PJT 400528 BSB, IVADO fund: a Canadian Institute of Health Research, Fonds de Recherche Nature et technologies du Québec, Roger De Spoelberch, Partridge Foundations, National Institute of Mental Health, N01-MH9-0002, National Institute of Neurological Disorders and Stroke, 33CS30-148401, National Science Foundation, MOP-111169, Canadian Institutes of Health Research, 31003A_160203, Schweizerischer Nationalfonds zur F&#x00F6, rderung der Wissenschaftlichen Forschung, Horizon 2020, Fondation Leenaards, and McGill University-McGill University

Subjects
Adult, Adolescent, DNA Copy Number Variations, Cognitive Neuroscience, Biology, computer.software_genre, 050105 experimental psychology, Imaging, White matter, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Voxel, Chromosome Duplication, Gene duplication, medicine, Genetics, Humans, 0501 psychology and cognitive sciences, Copy-number variation, Child, ComputingMilieux_MISCELLANEOUS, 16p11.2 Copy number variants, Brain development, Neurodevelopmental disorders, Normative growth trajectories, [SCCO.NEUR]Cognitive science/Neuroscience, 05 social sciences, Brain, medicine.anatomical_structure, Neurology, Evolutionary biology, Child, Preschool, Endophenotype, Human genome, Chromosome Deletion, Insula, computer, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract

Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4–5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age. In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry. Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23. Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace.

Published
2019
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20. Quantifying the effects of 16p11.2 copy number variants on brain structure: A multisite genetic-first study

Author

Sandra Martin-Brevet, Borja Rodríguez-Herreros, Jared A. Nielsen, Clara Moreau, Claudia Modenato, Anne M. Maillard, Aurélie Pain, Sonia Richetin, Aia E. Jønch, Abid Y. Qureshi, Nicole R. Zürcher, Philippe Conus, Wendy K. Chung, Elliott H. Sherr, John E. Spiro, Ferath Kherif, Jacques S. Beckmann, Nouchine Hadjikhani, Alexandre Reymond, Randy L. Buckner, Bogdan Draganski, Sébastien Jacquemont, Marie-Claude Addor, Joris Andrieux, Benoît Arveiler, Geneviève Baujat, Frédérique Sloan-Béna, Marco Belfiore, Dominique Bonneau, Sonia Bouquillon, Odile Boute, Alfredo Brusco, Tiffany Busa, Jean-Hubert Caberg, Dominique Campion, Vanessa Colombert, Marie-Pierre Cordier, Albert David, François-Guillaume Debray, Marie-Ange Delrue, Martine Doco-Fenzy, Ulrike Dunkhase-Heinl, Patrick Edery, Christina Fagerberg, Laurence Faivre, Francesca Forzano, David Genevieve, Marion Gérard, Daniela Giachino, Agnès Guichet, Olivier Guillin, Delphine Héron, Bertrand Isidor, Aurélia Jacquette, Sylvie Jaillard, Hubert Journel, Boris Keren, Didier Lacombe, Sébastien Lebon, Cédric Le Caignec, Marie-Pierre Lemaître, James Lespinasse, Michèle Mathieu-Dramart, Sandra Mercier, Cyril Mignot, Chantal Missirian, Florence Petit, Kristina Pilekær Sørensen, Lucile Pinson, Ghislaine Plessis, Fabienne Prieur, Caroline Rooryck-Thambo, Massimiliano Rossi, Damien Sanlaville, Britta Schlott Kristiansen, Caroline Schluth-Bolard, Marianne Till, Mieke Van Haelst, Lionel Van Maldergem, Hanalore Alupay, Benjamin Aaronson, Sean Ackerman, Katy Ankenman, Ayesha Anwar, Constance Atwell, Alexandra Bowe, Arthur L. Beaudet, Marta Benedetti, Jessica Berg, Jeffrey Berman, Leandra N. Berry, Audrey L. Bibb, Lisa Blaskey, Jonathan Brennan, Christie M. Brewton, Randy Buckner, Polina Bukshpun, Jordan Burko, Phil Cali, Bettina Cerban, Yishin Chang, Maxwell Cheong, Vivian Chow, Zili Chu, Darina Chudnovskaya, Lauren Cornew, Corby Dale, John Dell, Allison G. Dempsey, Trent Deschamps, Rachel Earl, James Edgar, Jenna Elgin, Jennifer Endre Olson, Yolanda L. Evans, Anne Findlay, Gerald D. Fischbach, Charlie Fisk, Brieana Fregeau, Bill Gaetz, Leah Gaetz, Silvia Garza, Jennifer Gerdts, Orit Glenn, Sarah E. Gobuty, Rachel Golembski, Marion Greenup, Kory Heiken, Katherine Hines, Leighton Hinkley, Frank I. Jackson, Julian Jenkins, Rita J. Jeremy, Kelly Johnson, Stephen M. Kanne, Sudha Kessler, Sarah Y. Khan, Matthew Ku, Emily Kuschner, Anna L. Laakman, Peter Lam, Morgan W. Lasala, Hana Lee, Kevin LaGuerre, Susan Levy, Alyss Lian Cavanagh, Ashlie V. Llorens, Katherine Loftus Campe, Tracy L. Luks, Elysa J. Marco, Stephen Martin, Alastair J. Martin, Gabriela Marzano, Christina Masson, Kathleen E. McGovern, Rebecca McNally Keehn, David T. Miller, Fiona K. Miller, Timothy J. Moss, Rebecca Murray, Srikantan S. Nagarajan, Kerri P. Nowell, Julia Owen, Andrea M. Paal, Alan Packer, Patricia Z. Page, Brianna M. Paul, Alana Peters, Danica Peterson, Annapurna Poduri, Nicholas J. Pojman, Ken Porche, Monica B. Proud, Saba Qasmieh, Melissa B. Ramocki, Beau Reilly, Timothy P.L. Roberts, Dennis Shaw, Tuhin Sinha, Bethanny Smith-Packard, Anne Snow Gallagher, Vivek Swarnakar, Tony Thieu, Christina Triantafallou, Roger Vaughan, Mari Wakahiro, Arianne Wallace, Tracey Ward, Julia Wenegrat, Anne Wolken, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, CSIR-Institute of Microbial Technology [Chandigarh] (IMTech), Council of Scientific and Industrial Research [India] (CSIR), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Human Genetics, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), The Wellcome Trust Sanger Institute [Cambridge], Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Guglielmo Marconi University [Roma], Laboratoire de biomécanique (LBM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Systèmes de Référence Temps Espace (SYRTE), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medical Sciences, Università degli studi di Torino (UNITO), 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), 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), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Liège (CHU-Liège), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Department of Clinical Genetics, Vejle Hospital, Institute of Child Health, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique [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), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, CHU Bordeaux [Bordeaux], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Genomics of Common Disease, Imperial College London, Regional Hospital, Department of Psychiatry and Behavioral Sciences! (UW psychiatry), University of Washington [Seattle], University of California, San Francisco (UCSF), UCSF, Unité de Recherches Zootechniques (URZ), Institut National de la Recherche Agronomique (INRA), University of California [San Francisco] (UCSF), University of California, UCL Institute of Neurology, Biomagnetic Imaging Laboratory - University of California, SFARI219193, Simons Foundation, 31003A160203, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Roger De Spoelberch, Partridge Foundations, Jeanne et Jean Louis Levesque Foundation, 604102, Seventh Framework Programme, Canada Research Chairs, CRSII33-133044, SNSF Sinergia, 32003B_159780, SNSF National Centre of Competence in Research Synapsy, Foundation Parkinson Switzerland, Foundation Synapsis, Université de Lausanne = University of Lausanne (UNIL), CHU Sainte Justine [Montréal], Harvard University [Cambridge], Odense University Hospital (OUH), Department of radiology (Massachusetts General Hospital), Department of Psychiatry Massachusetts General Hospital (MGH), Columbia University [New York], Simons Foundation, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Gothenburg (GU), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vejle Hospital [Danemark], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), 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), Harvard University, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), University of Lausanne (UNIL), Centre de recherche du CHU Sainte-Justine [Montreal], 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), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Human genetics, Institute of Microbial Technology (IMTECH), Intitute of Microbial Technology, Gillberg Neuropsychiatry Centre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], PSL Research University (PSL)-PSL Research University (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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 [APHP], Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [APHP], Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Addor, M.C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Béna, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J.H., Campion, D., Colombert, V., Cordier, M.P., David, A., Debray, F.G., Delrue, M.A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gérard, M., Giachino, D., Guichet, A., Guillin, O., Héron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaître, M.P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekær Sørensen, K., Pinson, L., Plessis, G., Prieur, F., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A.L., Benedetti, M., Berg, J., Berman, J., Berry, L.N., Bibb, A.L., Blaskey, L., Brennan, J., Brewton, C.M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A.G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J.E., Evans, Y.L., Findlay, A., Fischbach, G.D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S.E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F.I., Jenkins, J., Jeremy, R.J., Johnson, K., Kanne, S.M., Kessler, S., Khan, S.Y., Ku, M., Kuschner, E., Laakman, A.L., Lam, P., Lasala, M.W., Lee, H., LaGuerre, K., Levy, S., Cavanagh, A.L., Llorens, A.V., Campe, K.L., Luks, T.L., Marco, E.J., Martin, S., Martin, A.J., Marzano, G., Masson, C., McGovern, K.E., McNally Keehn, R., Miller, D.T., Miller, F.K., Moss, T.J., Murray, R., Nagarajan, S.S., Nowell, K.P., Owen, J., Paal, A.M., Packer, A., Page, P.Z., Paul, B.M., Peters, A., Peterson, D., Poduri, A., Pojman, N.J., Porche, K., Proud, M.B., Qasmieh, S., Ramocki, M.B., Reilly, B., Roberts, TPL, Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A.S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., and Wolken, A.

Subjects
Adult, Male, 0301 basic medicine, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Autism Spectrum Disorder/diagnostic imaging, Autism Spectrum Disorder/genetics, Brain/pathology, Child, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 16/genetics, Cognitive Dysfunction/diagnostic imaging, Cognitive Dysfunction/genetics, Female, Humans, Intellectual Disability/diagnostic imaging, Intellectual Disability/genetics, Language, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders/diagnostic imaging, Neurodevelopmental Disorders/genetics, Schizophrenia/diagnostic imaging, Schizophrenia/genetics, Young Adult, 16p11.2, Autism spectrum disorder, Copy number variant, Genetics, Imaging, Neurodevelopmental disorders, Biology, Biological Psychiatry, 03 medical and health sciences, 0302 clinical medicine, Transverse temporal gyrus, Neuroimaging, Intellectual Disability, medicine, Cognitive Dysfunction, Copy-number variation, ComputingMilieux_MISCELLANEOUS, Brain morphometry, Brain, medicine.disease, 16p112, 030104 developmental biology, Schizophrenia, Williams syndrome, Neuroscience, Insula, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.METHODS: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion < control; Cohen's d < -1), and the caudate and hippocampus (control > duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.

Published
2018
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21. Diagnostic pitfall in antenatal manifestations of CPT II deficiency

Author

C. Dugauquier, G. Senterre, Stephanie Gaillez, François-Guillaume Debray, Sacha Ferdinandusse, Katty Delbecque, Jean-Hubert Caberg, Anne-Christine François, Roland Schoos, P. Maton, Nathalie Demonceau, François Boemer, Michelle Deberg, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Laboratory Genetic Metabolic Diseases

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Amniotic fluid, Physiology, Prenatal diagnosis, 03 medical and health sciences, Dysgenesis, Fatal Outcome, Pregnancy, Internal medicine, Genetics, medicine, Humans, Carnitine palmitoyltransferase II, Carnitine O-palmitoyltransferase, Genetics (clinical), Fetus, Carnitine O-Palmitoyltransferase, business.industry, Infant, Newborn, medicine.disease, 030104 developmental biology, Endocrinology, Inborn error of metabolism, Female, business, Metabolism, Inborn Errors
Abstract

Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of energetic failure affecting muscle and liver, a small subset of patients presents antenatal malformations including brain dysgenesis and neuronal migration defects. Here, we report recurrence of severe cerebral dysgenesis with Dandy-Walker malformation in three successive pregnancies and review previously reported antenatal cases. Interestingly, we also report that acylcarnitines profile, tested retrospectively on the amniotic fluid of last pregnancy, was not sensitive enough to allow reliable prenatal diagnosis of CPT2 deficiency. Finally, because fetuses affected by severe cerebral malformations are frequently aborted, CPT2 deficiency may be underestimated and fatty acid oxidation disorders should be considered when faced with a fetus with Dandy-Walker anomaly or another brain dysgenesis.

Published
2016
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22. Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy

Author

Vinciane Dideberg, François-Guillaume Debray, Jean-Hubert Caberg, Rudy Van Coster, Joél Smet, Arnaud Vanlander, François Boemer, Vincent Bours, René Stevens, Sara Seneca, Claire Josse, Claudia Stümpfig, Roland Lill, Reproduction and Genetics, and Clinical sciences

Subjects
Iron-Sulfur Proteins, Male, Iron-sulfur cluster assembly, Heterozygote, Mitochondrial Diseases, Respiratory chain, Biology, Fatal Outcome, Leukoencephalopathies, Mutant protein, Genetics, medicine, Humans, Genetics (clinical), Exome sequencing, Electron Transport Complex I, Homozygote, Leukodystrophy, Respiratory chain complex, Infant, medicine.disease, Disease gene identification, Magnetic Resonance Imaging, Molecular biology, Mitochondria, Phenotype, Mutation, Carrier Proteins, Protein lipoylation
Abstract

Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive leukoencephalopathy. Homozygosity mapping, whole exome sequencing, and functional studies were used to define the underlying molecular defect. Respiratory chain studies in skeletal muscle isolated from the proband revealed a combined deficiency of complexes I and II. In addition, western blotting indicated lack of protein lipoylation. The combination of these findings was suggestive for a defect in the iron-sulfur (Fe/S) protein assembly pathway. SNP array identified loss of heterozygosity in large chromosomal regions, covering the NFU1 and BOLA3, and the IBA57 and ABCB10 candidate genes, in 2p15-p11.2 and 1q31.1-q42.13, respectively. A homozygous c.436C > T (p.Arg146Trp) variant was detected in IBA57 using whole exome sequencing. Complementation studies in a HeLa cell line depleted for IBA57 showed that the mutant protein with the semi-conservative amino acid exchange was unable to restore the biochemical phenotype indicating a loss-of-function mutation of IBA57. In conclusion, defects in the Fe/S protein assembly gene IBA57 can cause autosomal recessive neurodegeneration associated with progressive leukodystrophy and fatal outcome at young age. In the affected patient, the biochemical phenotype was characterized by a defect in the respiratory chain complexes I and II and a decrease in mitochondrial protein lipoylation, both resulting from impaired assembly of Fe/S clusters.

Published
2015
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23. Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

Author

Diana Rodriguez, Vincent Bondet, Alexandre Belot, Luis Seabra, Claude Cances, Isabelle Desguerre, Virginie Levrat, Diane Doummar, Elodie Henry, Marie Hully, Mathieu P Rodero, Isabelle Melki, Magalie Barth, Alba Llibre, Agathe Roubertie, François-Guillaume Debray, Jean-Marc Tréluyer, Michaela Semeraro, Valérie Jolaine, Nathalie Boddaert, Pierre Meyer, Christine Barnerias, Carolina Uggenti, Jinmi Baek, Gillian I. Rice, Flore Rozenberg, Darragh Duffy, Stéphane Blanche, Marie-Louise Frémond, Florence Renaldo, Naïm Bouazza, Hendy Abdoul, Leo A. H. Zeef, Mame N Sambe, Candice Meyzer, Yanick J. Crow, Marie-Christine Nougues, Alice Lepelley, Naoki Kitabayashi, University of Manchester [Manchester], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Institut Pasteur [Paris] (IP), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université de Lyon, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Liège, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], AP-HP Hôpital universitaire Robert-Debré [Paris], 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Robert Debré, Sorbonne Université (SU), University of Edinburgh, Supported by grants from the European Leukodystrophy Association (ELA 2012-008l1), the European Research Council (GA 309449 and 786142-E-T1IFNs), ERA-NET Neuron (MR/M501803/1), and the French National Research Agency (ANR-10-IAHU-01 and CE17001002). Medications were provided by GlaxoSmithKline and ViiV Healthcare., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris], CHU Toulouse [Toulouse], Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Gene Expression, Pilot Projects, Nervous System Malformations/drug therapy, Medicine, MESH: Interferons, ComputingMilieux_MISCELLANEOUS, Cerebrovascular Circulation/drug effects, MESH: Zidovudine, General Medicine, MESH: Cerebrovascular Circulation, 3. Good health, Drug Combinations, MESH: Dideoxynucleosides, Lamivudine, Cerebrovascular Circulation, Autoimmune Diseases of the Nervous System/drug therapy, Reverse Transcriptase Inhibitors, [SDV.IMM]Life Sciences [q-bio]/Immunology, France, Zidovudine, MESH: Lamivudine, Interferons/genetics, Reverse Transcriptase Inhibitors/therapeutic use, MESH: Gene Expression, [SDV.IMM] Life Sciences [q-bio]/Immunology, Zidovudine/therapeutic use, Encephalopathy, Gene Expression/drug effects, Nervous System Malformations, MESH: Nervous System Malformations, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, Humans, Lamivudine/therapeutic use, MESH: Drug Combinations, MESH: Humans, business.industry, Dideoxynucleosides/therapeutic use, medicine.disease, MESH: Pilot Projects, Virology, Dideoxynucleosides, Reverse transcriptase, MESH: Autoimmune Diseases of the Nervous System, MESH: France, 030104 developmental biology, Nucleic acid, Aicardi–Goutières syndrome, Interferons, MESH: Reverse Transcriptase Inhibitors, business
Abstract

International audience; To the Editor:The Aicardi–Goutières syndrome is a genetic encephalopathy that is associated with childhood illness and death. The syndrome is hypothesized to be due to misidentification of self-derived nucleic acids as nonself and the subsequent induction of a type I interferon–mediated response that simulates an antiviral reaction.1 Endogenous retroelements, mobile genetic elements that can be transcribed to RNA and then to DNA by reverse transcription, constitute 40% of the human genome and represent a potential source of immunostimulatory nucleic acid in patients with this syndrome.2

Published
2018
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24. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients

Author

Rolph Pfundt, Sarju G. Mehta, Amy Lawson Yuen, Gunnar Houge, Marie-Cécile Nassogne, Nicola S. Cooper, Bjørn Ivar Haukanes, Ingvild Aukrust, Siren Berland, Pradeep Vasudevan, Mónica Roselló, Stéphanie Moortgat, Nina Powell-Hamilton, Charlotte von der Lippe, Barbara van Loon, Ruth Newbury-Ecob, Alain Verloes, Laura A. Baker, Trine Prescott, Andrew O.M. Wilkie, Emma Wakeling, Ddd Study, Isabelle Maystadt, Francisco Martínez, Laurence Faivre, Alfonso Caro-Llopis, Karen J. Low, Emma Kivuva, François-Guillaume Debray, Thatjana Gardeitchik, Louise C. Wilson, Christine Verellen-Dumoulin, Valérie Benoit, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie pédiatrique

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, X-linked intellectual disability, Ubiquitin-Protein Ligases, Mutation, Missense, Short stature, Article, Craniosynostosis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Intellectual Disability, Intellectual disability, Obligate carrier, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), X chromosome, Genes, Dominant, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Tumor Suppressor Proteins, Genetic Diseases, X-Linked, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Dermatology, 030104 developmental biology, Speech delay, Female, medicine.symptom, business
Abstract

Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.

Published
2018

25. Mitochondrial encephalomyopathy with cytochrome c oxidase deficiency caused by a novel mutation in the MTCO1 gene

Author

Kim Vancampenhaut, Joél Smet, François-Guillaume Debray, Michel Gonce, Laurent Weekers, Elettra Bianchi, Rudy Van Coster, Sara Seneca, and François Boemer

Subjects
Mitochondrial encephalomyopathy, Adolescent, Biopsy, Nonsense mutation, Respiratory chain, Cytochrome-c Oxidase Deficiency, Biology, DNA, Mitochondrial, Frameshift mutation, Electron Transport Complex IV, Mitochondrial Encephalomyopathies, medicine, Humans, Missense mutation, Cytochrome c oxidase, Frameshift Mutation, Myopathy, Molecular Biology, Muscles, High-Throughput Nucleotide Sequencing, Cell Biology, medicine.disease, Molecular biology, Codon, Nonsense, Mutation, biology.protein, Molecular Medicine, Female, medicine.symptom
Abstract

Cytochrome c oxidase (COX) deficiency is one of the most common respiratory chain deficiencies. A woman was presented at the age of 18 y with acute loss of consciousness, non-convulsive status epilepticus, slow neurological deterioration, transient cortical blindness, exercise intolerance, muscle weakness, hearing loss, cataract and cognitive decline. Muscle biopsy revealed ragged-red fibers, COX negative fibers and a significant decreased activity of complex IV in a homogenate. Using next generation massive parallel sequencing of the mtDNA, a novel heteroplasmic mutation was identified in MTCO1, m.7402delC, causing frameshift and a premature termination codon. Single fiber PCR showed co-segregation of high mutant load in COX negative fibers. Mutation in mitochondrially encoded complex IV subunits should be considered in mitochondrial encephalomyopathies and COX negative fibers after the common mtDNA mutations have been excluded.

Published
2014
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26. Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3′ end of FBN1 gene

Author

Uwe Kornak, Bert Callewaert, Alain Verloes, Lionel Van Maldergem, Frederic Lebrun, Anne De Paepe, Jacques Lombet, Gérald Pierard, Sofie Symoens, François-Guillaume Debray, Adeline Jacquinet, Paul Coucke, Peter N. Robinson, and Christine Coremans

Subjects
Marfan syndrome, endocrine system, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pathology, Adolescent, Lipodystrophy, Fibrillin-1, DNA Mutational Analysis, Molecular Sequence Data, Biology, Fibrillins, Progeroid syndromes, Marfan Syndrome, Frameshift mutation, Diagnosis, Differential, Exon, Progeria, Internal medicine, Genetics, medicine, Humans, Amino Acid Sequence, Genetics (clinical), Fetal Growth Retardation, Base Sequence, Microfilament Proteins, Marfanoid, General Medicine, medicine.disease, Phenotype, Endocrinology, Molecular Diagnostic Techniques, Female, Differential diagnosis, Fibrillin
Abstract

We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann–Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid–progeroid–lipodystrophy syndrome) and frameshift mutations at the 3′ end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes.

Published
2014
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27. Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

Author

Nicole Revencu, François-Guillaume Debray, Catherine Wanty, Willy Lissens, Sara Seneca, Joél Smet, Laurent Weekers, Boel De Paepe, Julie Harvengt, Christine Sempoux, Rudy Van Coster, Etienne Sokal, Clinical sciences, Reproduction and Genetics, and Medical Genetics

Subjects
Pathology, medicine.medical_specialty, Mitochondrial disease, Hepatosplenomegaly, Respiratory chain, Gaucher disease, Biology, Endocrinology, Medicine and Health Sciences, Genetics, medicine, Oculomotor apraxia, MPV17, Molecular Biology, Neurohepatic, lcsh:QH301-705.5, Cytopenia, lcsh:R5-920, mtDNA depletion, neurohepatic, Enzyme replacement therapy, medicine.disease, mtDNA, mitochondrial DNA, Transplantation, ERT, enzyme replacement therapy, mitochondrial disease, lcsh:Biology (General), medicine.symptom, lcsh:Medicine (General), Research Paper
Abstract

A 1-year-old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19 months. Subsequent partial splenectomy for persistent cytopenia showed the presence of foamy cells, and Gaucher disease was confirmed by homozygosity for the p.Leu483Pro mutation in the GBA gene. She was treated by enzyme replacement therapy (ERT). Clinical follow-up showed mild developmental delay, strabismus, nystagmus and oculomotor apraxia. Biochemical studies revealed multiple respiratory chain deficiencies and a mosaic pattern of deficient complex IV immunostaining in liver and fibroblast. Molecular analysis identified a mtDNA depletion syndrome due to the homozygous p.Pro98Leu mutation in MPV17. A younger sister unaffected by mtDNA depletion, presented with pancytopenia and hepatosplenomegaly. ERT for Gaucher disease resulted in visceral normalization without any neurological symptom. A third sister, affected by both conditions, had marked developmental delay, strabismus and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs in MPV17-related disease. The combined pathological effect of Gaucher and mitochondrial diseases can negatively impact neurological and liver functions and influence the outcome in consanguineous families. The immunocytochemical staining of OXPHOS protein in tissues and cultured cells is a powerful tool revealing mosaic pattern of deficiency pointing to mtDNA-related mitochondrial disorders.

Published
2014

28. Changing facial phenotype in Cohen syndrome

Author

Bernard Aral, Nadège Gigot, François-Guillaume Debray, Alice Masurel-Paulet, Patrick Rump, Christel Thauvin-Robinet, Frédéric Huet, Muriel Holder-Espinasse, Marlène Rio, Laurence Duplomb, Patrick Callier, Edward Blair, Anne-Marie Frances, Salima El Chehadeh-Djebbar, Anne Moncla, and Laurence Faivre

Subjects
Male, Microcephaly, Developmental Disabilities, FEATURES, facial phenotype, Vesicular Transport Proteins, Myopia, CRITERIA, HETEROGENEITY, Child, Genetics (clinical), Genetics, Cohen syndrome, Retinal Degeneration, Hypotonia, VPS13B, Phenotype, medicine.anatomical_structure, Child, Preschool, Muscle Hypotonia, Female, medicine.symptom, medicine.medical_specialty, changing phenotype, Genetic counseling, Biology, Article, Fingers, Intellectual Disability, medicine, Humans, Abnormalities, Multiple, Obesity, Short philtrum, Auricle, NATURAL-HISTORY, medicine.disease, Dermatology, MUTATIONAL SPECTRUM, GENE, DELETIONS, stomatognathic diseases, Early Diagnosis, Face, Mutation, Square face, VPS13B gene
Abstract

Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is generally raised after school age, when visual disturbances lead to CRD diagnosis and to VPS13B gene testing. This relatively late diagnosis precludes accurate genetic counselling. The aim of this study was to analyse the evolution of CS facial features in the early period of life, particularly before school age (6 years), to find clues for an earlier diagnosis. Photographs of 17 patients with molecularly confirmed CS were analysed, from birth to preschool age. By comparing their facial phenotype when growing, we show that there are no special facial characteristics before 1 year. However, between 2 and 6 years, CS children already share common facial features such as a short neck, a square face with micrognathia and full cheeks, a hypotonic facial appearance, epicanthic folds, long ears with an everted upper part of the auricle and/or a prominent lobe, a relatively short philtrum, a small and open mouth with downturned corners, a thick lower lip and abnormal eye shapes. These early transient facial features evolve to typical CS facial features with aging. These observations emphasize the importance of ophthalmological tests and neutrophil count in children in preschool age presenting with developmental delay, hypotonia and the facial features we described here, for an earlier CS diagnosis.

Published
2013
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29. Are heterozygous carriers for hereditary fructose intolerance predisposed to metabolic disturbances when exposed to fructose?

Author

Katarina Damjanovic, Lauréane Mittaz-Crettol, Robin Rosset, Luc Tappy, Luisa Bonafé, Jean-Pascal De Bandt, Frédéric Barbey, Olivier Braissant, Christel Tran, Clothilde Roux, Nicolas Paquot, and François-Guillaume Debray

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Heterozygote, Hereditary fructose intolerance, Medicine (miscellaneous), 030209 endocrinology & metabolism, Fructose, Carbohydrate metabolism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Lipid oxidation, Metabolic Diseases, Internal medicine, Medicine, Humans, Hyperuricemia, Nutrition and Dietetics, business.industry, medicine.disease, Lipid Metabolism, Fructose Intolerance, Uric Acid, 030104 developmental biology, Postprandial, Endocrinology, chemistry, Creatinine, Uric acid, Carbohydrate Metabolism, Female, business
Abstract

High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin resistance and dyslipidemia in the general population. In patients with hereditary fructose intolerance, fructose consumption is associated with acute hypoglycemia, renal tubular acidosis, and hyperuricemia. We investigated whether asymptomatic carriers for hereditary fructose intolerance (HFI) would have a higher sensitivity to adverse effects of fructose than would the general population. Eight subjects heterozygous for HFI (hHFI; 4 men, 4 women) and 8 control subjects received a low-fructose diet for 7 d and on the eighth day ingested a test meal, calculated to provide 25% of the basal energy requirement, containing 13C-labeled fructose (0.35 g/kg), glucose (0.35 g/kg), protein (0.21 g/kg), and lipid (0.22 g/kg). Glucose rate of appearance (GRa, calculated with [6,6-2H2]glucose), fructose, net carbohydrate, and lipid oxidation, and plasma triglyceride, uric acid, and lactate concentrations were monitored over 6 h postprandially. Postprandial GRa, fructose, net carbohydrate, and lipid oxidation, and plasma lactate and triglyceride concentrations were not significantly different between the 2 groups. Postprandial plasma uric acid increased by 7.2% compared with fasting values in hHFI subjects (P

Published
2017

30. POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism

Author

Arnaud Besse, Kate Craig, Emma L. Blakely, Juliette Piard, Pierre Hella, Boel De Paepe, Patrice Laloux, Giovanni Stevanin, François-Guillaume Debray, Robert W. Taylor, Eric Mormont, Vivek Appadurai, Marion Gaussen, Langping He, Lionel Van Maldergem, Rudy Van Coster, Margaret M. Humble, Jean-Jacques Martin, William C. Copeland, Penelope E. Bonnen, UCL - (MGD) Service de neurologie, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/MONT - Pôle Mont Godinne, Centre Hospitalier Universitaire de Liège (CHU-Liège), Baylor College of Medicine (BCM), Baylor University, Department of Pediatrics, Ghent University Hospital, Newcastle University [Newcastle], National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH), Centre hospitalier de Namur, Instituut Born-Bunge, Universiteit Antwerpen, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Centre Hospitalier Universitaire de Liège ( CHU-Liège ), Baylor College of Medicine ( BCM ), Baylor College of Medicine, National Institute of Environmental Health Sciences, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), PSL Research University ( PSL ), Universiteit Antwerpen = University of Antwerpen [Antwerpen], and 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)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Mitochondrial DNA, Ataxia, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, POLYMERASE GAMMA-SUBUNITS, Mitochondrion, VARIANTS, PATIENT, DISEASE, TWINKLE, 03 medical and health sciences, 0302 clinical medicine, Medicine and Health Sciences, Medicine, Dementia, Cognitive decline, Cerebellar ataxia, business.industry, MUTATIONS, General Neuroscience, Parkinsonism, DEMENTIA, medicine.disease, OPHTHALMOPLEGIA, 3. Good health, 030104 developmental biology, Peripheral neuropathy, MAINTENANCE, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MITOCHONDRIAL-DNA DELETIONS, Human medicine, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Research Article
Abstract

International audience; Objective: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome. Methods: Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted. Results: Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mito-chondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells. Interpretation: This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicompo-nent syndrome provides further evidence for a major role of mitochondrial dys-function in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders.

Published
2016
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31. Neonatal Liver Cirrhosis Without Iron Overload Caused by Gestational Alloimmune Liver Disease

Author

Virginie de Halleux, Philippe Goyens, Nancy Detrembleur, Xiaomin Pan, François-Guillaume Debray, Ornella Guidi, Stephanie Gaillez, Peter F. Whitington, and Léon Rausin

Subjects
Liver Cirrhosis, Pathology, medicine.medical_specialty, Cirrhosis, Biopsy, Iron, Ultrasonography, Prenatal, Autoimmune Diseases, Diagnosis, Differential, Liver disease, Pregnancy, medicine, Neonatal hemochromatosis, Humans, Liver injury, Fetus, medicine.diagnostic_test, business.industry, Liver Diseases, medicine.disease, Pregnancy Complications, Liver, Liver biopsy, Pediatrics, Perinatology and Child Health, Female, Siderosis, Liver function tests, business, Follow-Up Studies, Hepatomegaly
Abstract

Gestational alloimmune liver disease has emerged as the major cause of antenatal liver injury and failure. It usually manifests as neonatal liver failure with hepatic and extrahepatic iron overload, a clinical presentation called neonatal hemochromatosis. We report on a newborn in whom fetal hepatomegaly was detected during pregnancy and who presented at birth with liver cirrhosis and mild liver dysfunction. Liver biopsy showed the absence of iron overload but strong immunostaining of hepatocytes for the C5b-9 complex, the terminal complement cascade neoantigen occurring specifically during complement activation by the immunoglobulin G-mediated classic pathway, which established the alloimmune nature of the hepatocyte injury. The infant survived with no specific therapy, and follow-up until 36 months showed progressive normalization of all liver parameters. This case report expands the recognized clinical spectrum of congenital alloimmune liver disease to include neonatal liver disease and cirrhosis, even in the absence of siderosis. Such a diagnosis is of utmost importance regarding the necessity for immunotherapy in further pregnancies to avoid recurrence of alloimmune injury.

Published
2012
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32. Temple-Baraitser syndrome: A rare and possibly unrecognized condition

Author

Geert Mortier, Jean Paul Misson, Lionel Van Maldergem, Marion Gérard, Léon Rausin, Michael T. Gabbett, Adeline Jacquinet, François-Guillaume Debray, Alain Verloes, and Björn Menten

Subjects
Adult, Male, medicine.medical_specialty, Inheritance Patterns, Rare Diseases, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Family, In patient, Abnormal thumbs, Copy-number variation, Child, Genetics (clinical), business.industry, Infant, De novo mutation, Aplasia, Middle Aged, Toes, medicine.disease, Dermatology, body regions, Thumb, Female, business, Temple Baraitser syndrome, Comparative genomic hybridization
Abstract

Temple-Baraitser syndrome, previously described in two unrelated patients, is the association of severe mental retardation and abnormal thumbs and great toes. We report two additional unrelated patients with Temple-Baraitser syndrome, review clinical and radiological features of previously reported cases and discuss mode of inheritance. Patients share a consistent pattern of anomalies: hypo or aplasia of the thumb and great toe nails and broadening and/or elongation of the thumbs and halluces, which have a tubular aspect. All patients were born to unrelated parents and occurred as a single occurrence in multiple sibships, suggesting sporadic inheritance from a de novo mutation mechanism. Comparative genomic hybridization in Patients 1, 2 and 3 did not reveal any copy number variations. We confirm that Temple-Baraitser syndrome represents a distinct syndrome, probably unrecognized, possibly caused by a de novo mutation in a not yet identified gene.

Published
2010
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33. BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects

Author

Florence Dastot-Le-Moal, Pierre Bitoun, Kathreen Johnston, François-Guillaume Debray, Nobuhiko Okamoto, Beverly N. Hay, Jennifer J. Johnston, Leslie G. Biesecker, Chiharu Torii, Odile Boute, Marion Gérard, Josiane Martin, Sylvie Manouvrier, Rahat Perveen, Michel Goossens, Hiroshi Kohara, Emma Hilton, Kenjiro Kosaki, Anthony T. Moore, Graeme C.M. Black, Michael Lyons, Yoshikazu Hatsukawa, David R. FitzPatrick, Irina Giurgea, Johannes Lemke, Juntaro Nishio, John W. Belmont, Deborah Bartholdi, Sandra Whalen, Kim Jenny, Caroline J Law, Albert Schinzel, Seiji Mizuno, Tanya Bardakjian, Alain Verloes, Florence Fellmann, and Yoshiko Hirano

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Heart Diseases, BCL-6 Corepressor, medicine.disease_cause, Microphthalmia, Article, Cohort Studies, Intellectual Disability, Proto-Oncogene Proteins, Genetics, medicine, Animals, Humans, Microphthalmos, Genetics(clinical), Eye Abnormalities, Allele, Child, Alleles, Genetics (clinical), Aged, Mutation, business.industry, Infant, Newborn, Genetic Diseases, X-Linked, Syndrome, Middle Aged, medicine.disease, Phenotype, eye diseases, Repressor Proteins, Developmental disorder, Lenz microphthalmia syndrome, Child, Preschool, Female, Oculofaciocardiodental syndrome, business
Abstract

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked (‘Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

Published
2009
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34. Reduced brain choline in homocystinuria due to remethylation defects

Author

Anne Lortie, M. S. Roy, J. Orquin, Y. Boulanger, C.A.J.M. Jakobs, Nanda M. Verhoeven, François-Guillaume Debray, Henk J. Blom, A. Khiat, Jean-Claude Décarie, E. Levy, Marie Lambert, F. Ramos, Grant A. Mitchell, Eduard A. Struys, Laboratory Medicine, and Neuroscience Campus Amsterdam 2008

Subjects
Adult, Male, S-Adenosylmethionine, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Adolescent, Central nervous system, Homocystinuria, Homocysteine S-Methyltransferase, Creatine, Methylation, Choline, Central nervous system disease, chemistry.chemical_compound, Internal medicine, medicine, Humans, Child, Brain Chemistry, Aspartic Acid, Lenticular nucleus, Brain, Isolated brain, medicine.disease, Choline Deficiency, Endocrinology, medicine.anatomical_structure, chemistry, Child, Preschool, Female, Neurology (clinical), Transmethylation
Abstract

To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects.Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ((1)H MRSI). Brain N-acetylaspartate, choline-containing compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine.MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units +/- SD, patients vs controls): frontal white matter (0.051 +/- 0.010 vs 0.064 +/- 0.010; p = 0.001), lenticular nucleus (0.056 +/- 0.011 vs 0.069 +/- 0.009; p0.001), and thalamus (0.063 +/- 0.010 vs 0.071 +/- 0.007; p = 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p0.005) concentrations were observed.Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.

Published
2008
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35. Pyruvate Dehydrogenase Deficiency Presenting as Intermittent Isolated Acute Ataxia

Author

Marie Lambert, Rachel Laframboise, R. Gagne, François-Guillaume Debray, Grant A. Mitchell, B. H. Robinson, N. MacKay, and Bruno Maranda

Subjects
Male, medicine.medical_specialty, Ataxia, Encephalopathy, Pyruvate Dehydrogenase Complex, Diagnosis, Differential, Fatal Outcome, Basal Ganglia Diseases, Internal medicine, medicine, Humans, Pyruvate Dehydrogenase (Lipoamide), Lactic Acid, Child, Pyruvate Dehydrogenase Complex Deficiency Disease, Episodic ataxia, Dystonia, Binding Sites, Movement Disorders, Muscle Weakness, Brain Diseases, Metabolic, business.industry, Infant, General Medicine, medicine.disease, Pyruvate dehydrogenase complex, Pyruvate dehydrogenase deficiency, Endocrinology, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Thiamine, Neurology (clinical), Thiamine Pyrophosphate, medicine.symptom, business, Thiamine pyrophosphate binding
Abstract

Objective: The aim of this study is to report and emphasize unusual presentations of pyruvate dehydrogenase (PDH) deficiency (OMIM 312170). Methods: PDH activity and PDHA1 gene were studied in two siblings presenting with intermittent ataxia in childhood. Similar presentations in reported PDH-deficient patients were searched for using the Medline database. Results: Both patients had PDH deficiency caused by a new mutation (G585C) in the PDHA1 gene, which is predicted to replace a highly conserved glycine at codon 195 by alanine. Although this mutation lies within the thiamine pyrophosphate binding domain, there was no thiamine responsiveness in vivo. The patients presented recurrent episodes of acute isolated ataxia in infancy. Both had normal blood and CSF lactate levels. Although symptoms initially resolved between episodes during the first decade, both patients subsequently worsened and developed progressive and severe encephalopathy, leading to death in their twenties. The spectrum of intermittent presentations in PDH deficiency includes episodic ataxia, intermittent peripheral weakness, recurrent dystonia and extrapyramidal movement disorders. Conclusions: PDH deficiency should be considered in patients with unexplained intermittent and recurrent acute neurological symptoms. Long-term prognosis and outcome remain uncertain. PDH deficiency can occur even with normal CSF lactate concentration.

Published
2008
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36. Long-term Outcome and Clinical Spectrum of 73 Pediatric Patients With Mitochondrial Diseases

Author

François-Guillaume Debray, Marie Lambert, Brian H. Robinson, Isabelle Chevalier, Grant A. Mitchell, Eric A. Shoubridge, Yves Robitaille, and Jean-Claude Décarie

Subjects
Male, medicine.medical_specialty, Mitochondrial Diseases, Time Factors, DNA Fragmentation, Optic Atrophy, Hereditary, Leber, MELAS syndrome, DNA, Mitochondrial, Severity of Illness Index, Cohort Studies, Mitochondrial myopathy, Mitochondrial Encephalomyopathies, Cause of Death, Internal medicine, MELAS Syndrome, medicine, Humans, Child, Probability, Proportional Hazards Models, Retrospective Studies, business.industry, Mortality rate, Infant, Newborn, Infant, Mitochondrial Myopathies, Retrospective cohort study, medicine.disease, Survival Analysis, Functional Independence Measure, Surgery, Child, Preschool, Pediatrics, Perinatology and Child Health, Cohort, Female, business, Follow-Up Studies, Cohort study
Abstract

OBJECTIVES. We sought to determine the clinical spectrum, survival, and long-term functional outcome of a cohort of pediatric patients with mitochondrial diseases and to identify prognostic factors. METHODS. Medical charts were reviewed for 73 children diagnosed between 1985 and 2005. The functional status of living patients was assessed prospectively by using the standardized Functional Independence Measure scales. RESULTS. Patients fell into 7 phenotypic categories: neonatal-onset lactic acidosis (10%), Leigh syndrome (18%), nonspecific encephalopathy (32%), mitochondrial (encephalo)myopathy (19%), intermittent neurologic (5%), visceral (11%), and Leber hereditary optic neuropathy (5%). Age at first symptoms ranged from prenatal to 16 years (median: 7 months). Neurologic symptoms were the most common (90%). Visceral involvement was observed in 29% of the patients. A biochemical or molecular diagnosis was identified for 81% of the patients as follows: deficiency of complex IV (27%), of pyruvate dehydrogenase or complex I (25% each), of multiple complexes (13%), and of pyruvate carboxylase (5%) or complexes II+III (5%). A mitochondrial DNA mutation was found in 20% of patients. At present, 46% of patients have died (median age: 13 months), 80% of whom were 5 years (n = 32), 62% had Functional Independence Measure quotients of >0.75. CONCLUSIONS. Mitochondrial diseases in children span a wide range of symptoms and severities. Age at first symptoms is the strongest predictor mortality. Despite a high mortality rate in the cohort, 62% of patients aged >5 years have only mild impairment or normal functional outcome.

Published
2007
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37. Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1

Author

Patrick Niaudet, François Nobili, Guylhène Bourdat-Michel, Estelle Colin, Karin Dahan, Brigitte Gilbert-Dussardier, Claire Rigothier, Robert Novo, Dominique Martin-Coignard, Justine Bacchetta, Karim Bouchireb, Rémi Salomon, Thierry Hannedouche, Ariela Vergara-Jaque, Chantal Loirat, Dominique Chauveau, Pascal Houillier, Stéphane Burtey, Nicole Van Regemorter, Lamisse Mansour-Hendili, Sandrine Lemoine, Xavier Jeunemaitre, Muriel Holder-Espinasse, Michel Fischbach, Denis Morin, François-Guillaume Debray, S. Benoit, Valérie Leroy, Gilles Morin, Marie Alice Macher, Andreas Schleich, Mathilde Cailliez, Hassan Izzedine, Isabelle Roncelin, Gwenaëlle Roussey-Kesler, Cyrielle Treard, Claire Cartery, Hubert Nivet, Stéphane Lourdel, Véronique Baudouin, Pierre Cochat, Bertrand Knebelmann, Anne Blanchard, Wendy González, Estelle Desport, Tim Ulinski, Stella Dieguez, Marco Janner, Rosa Vargas-Poussou, Laurence Faivre, Alexandre Karras, Nelly Le Pottier, Francesco Emma, Philippe Vanhille, Renaud de la Faille, Anne Laure Sellier-Leclerc, J. Fourcade, Olivier Devuyst, Denis Fouque, Kenza Soulami, Aurélien Tiple, Etienne Bérard, Laurenne Dehoux, Marie Pierre Lavocat, Hélène François, Gérard Champion, Gerard Cardon, Georges Deschênes, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-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), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Univ Talca, Escuela Ingn Bioinfomat, Talca, Chile, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des maladies rénales rares Néphrogones [CHU-HCL, Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice)-Fondation LENVAL-Hopital pour Enfants, Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Néphrologie et Immunopathologie Clinique, Centre Hospitalier Universitaire de Toulouse, PRES Université de Toulouse, Département de Pédiatrie, Hôpital Edouard Herriot [CHU - HCL], Service de Néphrologie-Transplantation-Dialyse, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Liège (CHU-Liège), Unité de Néphrologie Pédiatrique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Division of Nephrology, Université catholique de Louvain Medical school, Université Catholique de Louvain = Catholic University of Louvain (UCL), Department of Nephrology and Urology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma]-IRCCS, Service de Néphrologie pédiatrique [Hôpital de Hautepierre, Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Human-machine spoken dialogue (CORDIAL), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-INRIA Rennes, Institut National de Recherche en Informatique et en Automatique (Inria)-École Nationale Supérieure des Sciences Appliquées et de Technologie (ENSSAT), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Service de Physiologie [Georges-Pompidou], 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)-Université Paris Descartes - Paris 5 (UPD5), Service de Néphrologie [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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de néphrologie adultes [CHU Necker], Sciences pour l'environnement (SPE), Centre National de la Recherche Scientifique (CNRS)-Université Pascal Paoli (UPP), Service de néphrologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Métal, Travaux et recherches archéologiques sur les cultures, les espaces et les sociétés (TRACES), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie, Hôpital de Clocheville, Service de néphrologie pédiatrique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Unité Néphrologie Pédiatrique [CHRU Lille], Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Nephrology, Transplantation and Dialysis, Bordeaux, Hospices Civils de Lyon (HCL), Service de Néphrologie Dialyse Transplantation, CHU Ibn Rochd [Casablanca], CHU Clermont-Ferrand, Service de néphrologie et pédiatrie générale [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de médecine interne et néphrologie, CH Valenciennes, Centre de Génétique de Bruxelles, Université libre de Bruxelles (ULB), Service de Génétique [CHU HEGP], 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), French Ministry of Health (Plan Maladies Rares), European Community FP7EUNEFRON 201590 and EURenOmics 2012‐305608, The Chilean PIA‐Conycit program (grant ACT‐1104), The Swiss National Science Foundation project (grant 310030_146490), RADIZ, Rare Diseases Initiative Zürich, a KFSP of the University of Zurich., Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Médecine interne et immunopathologie clinique [CHU Toulouse], Pôle IUCT [CHU Toulouse], Institut National de la Recherche Agronomique (INRA)-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), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-INRIA Rennes, Université Pascal Paoli (UPP)-Centre National de la Recherche Scientifique (CNRS), École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Ministère de la Culture et de la Communication (MCC)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Max Planck Institute for Biophysical Chemistry (MPI-BPC), Max-Planck-Gesellschaft, Service de Génétique [AP-HP Hôpital Européen Georges Pompidou, Paris], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Université Catholique de Louvain (UCL), IRCCS-IRCCS Ospedale Pediatrico Bambino Gesù [Roma], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Service de néphrologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de nephrologie pédiatrique, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP]-Sorbonne Université (SU), Free University of Brussels (BELGIUM), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), 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), Néphrologie, Centre Hospitalier Universitaire (CHU), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Male, chloride channel, renal failure, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Dent Disease, ClC-5, medicine.disease_cause, Cohort Studies, Mice, 0302 clinical medicine, Missense mutation, MESH: Animals, MESH: DNA Mutational Analysis, low molecular weight proteinuria, Genetics (clinical), Genetics, Mice, Knockout, 0303 health sciences, Mutation, biology, MESH: Genetic Predisposition to Disease, MESH: Anion Transport Proteins, Phenotype, 3. Good health, Pedigree, Chloride Channels/chemistry/*genetics/metabolism, Dent Disease/*genetics/metabolism, Nephrocalcinosis, MESH: Bartter Syndrome, MESH: Mutation, Knockout, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 03 medical and health sciences, Tubulopathy, Chloride Channels, medicine, Animals, Humans, Genetic Association Studies, 030304 developmental biology, MESH: Humans, CLCN5, MESH: Chloride Channels, Dent disease 1, medicine.disease, Bartter syndrome, biology.protein, OCRL, CLC family of chloride transporters and channels
Abstract

International audience; Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

Published
2015
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38. Une forme particulière d'anémie constitutionnelle chez un nourrisson de deux mois : l'elliptocytose

Author

Christophe Chantrain, S. Ilunga, Bénédicte Brichard, Jean-Marie Scheiff, Christiane Vermylen, and François-Guillaume Debray

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Reticulocytosis, medicine.drug_class, Antibiotics, Disease, Haemolysis, medicine.disease, Elliptocytosis, Pediatrics, Perinatology and Child Health, Immunology, Medicine, Septic arthritis, Spectrin, Differential diagnosis, medicine.symptom, business
Abstract

We report the case of a 2.5-month-old infant with severe anaemia discovered fortuitously during an acute febrile illness. The patient was admitted because of a septic arthritis of the knee. Initial biology showed a 3.5 g/dl haemoglobin concentration. The anaemia was microcytic and hypochromic, with obvious haemolysis and reticulocytosis. Standard analysis was not contributive. Further investigations allowed the diagnosis of elliptocytosis. The patient was treated by antibiotics, orthopaedic measures and iterative transfusions. Now, 18 months from the initial episode, she is in good health. With this history, we discuss the clinical process facing severe anaemia during infancy and review the particularities of such uncommon congenital anaemia. Elliptocytosis is a haemolytic anaemia caused by congenital anomalies of the erythrocyte membrane. Diagnosis requires morphological studies of the red blood cells on peripheral blood smear. The disease is often overlooked by membrane protein electrophoresis. The condition is heterogeneous concerning clinical, biochemical and genetic aspects. Most of the cases are linked to mutations of the alpha-spectrin gene, in autoassociation regions. Search of spectrin and protein 4.1 genes mutations can confirm the diagnosis but is not routinely performed. (C) 2004 Elsevier SAS. Tous droits reserves.

Published
2005
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39. Rapid prenatal diagnosis of fetal Zellweger syndrome by biochemical tests, complementation studies, and molecular analyses

Author

Ronald J.A. Wanders, Karin Segers, M. C. Retz, Stephanie Gaillez, Geneviève Pierquin, François-Guillaume Debray, Malek Tebache, Sacha Ferdinandusse, Katty Delbecque, and Hans R. Waterham

Subjects
Complementation, Zellweger syndrome, Fetus, Pathology, medicine.medical_specialty, business.industry, Obstetrics and Gynecology, Medicine, Prenatal diagnosis, business, medicine.disease, Genetics (clinical)
Published
2013
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40. Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy

Author

Adeline Jacquinet, Linlin Ma, Ben Cristofori-Armstrong, Lachlan D. Rash, Serhat Guler, Cas Simons, David Miller, Michael T. Gabbett, John G. Cleary, Gozde Yesil, Yasemin Alanay, Glenn F. King, Kelin Ru, Gregory J. Baillie, Joseph J. Shen, Julie McGaughran, Ryan J. Taft, Sean M. Grimmond, Joanna Crawford, Adnan Yuksel, François-Guillaume Debray, Alain Verloes, and YEŞİL, Gözde

Subjects
Male, Protein Conformation, Recombinant Fusion Proteins, Molecular Sequence Data, Mutation, Missense, Nails, Malformed, Biology, medicine.disease_cause, Epilepsy, Xenopus laevis, Simons C., Rash L. D. , Crawford J., Ma L., Cristofori-Armstrong B., Miller D., Ru K., Baillie G. J. , Alanay Y., Jacquinet A., et al., -Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy-, NATURE GENETICS, cilt.47, ss.73-0, 2015, Dravet syndrome, Intellectual Disability, Genetics, medicine, Missense mutation, Animals, Humans, Amino Acid Sequence, Child, Conserved Sequence, Mutation, Sequence Homology, Amino Acid, Mosaicism, Infant, Voltage-gated potassium channel, Exons, medicine.disease, Hypoplasia, Ether-A-Go-Go Potassium Channels, Developmental disorder, HEK293 Cells, Thumb, Child, Preschool, Oocytes, Hallux, Female, Temple Baraitser syndrome
Abstract

Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe1, 2. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether a go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports3, 4, 5, 6, 7, 8, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.

Published
2015

41. Use of sapropterin dihydrochloride in maternal phenylketonuria. A European experience of eight cases

Author

Fritz Friedrich Trefz, Amelie S. Lotz-Havla, Francjan J. van Spronsen, Alexandra Puchwein-Schwepcke, François-Guillaume Debray, Ma Atem Beatrice Fofou-Caillierez, François Feillet, Ania C. Muntau, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Pédiatrie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Department of Molecular Pediatrics [Dr. von Hauner Children’s Hospital], Ludwig-Maximilians-Universität München (LMU), Centre Hospitalier Universitaire de Liège (CHU-Liège), Service de Biochimie et Biologie Moléculaire, Nutrition et Métabolisme [CHRU Nancy], Beatrix Children's Hospital/University Medical Center Groningen, University of Tuebingen, and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
Adult, HYPERPHENYLALANINEMIA, Pediatrics, medicine.medical_specialty, Phenylketonuria, Maternal, Side effect, Offspring, Phenylalanine, [SDV]Life Sciences [q-bio], TETRAHYDROBIOPTERIN DEFICIENCY, Nutritional Status, DIAGNOSIS, PHENYLALANINE-HYDROXYLASE DEFICIENCY, 03 medical and health sciences, 0302 clinical medicine, Hyperphenylalaninemia, Pregnancy, Genetics, PREGNANCIES, Medicine, Humans, Tetrahydrobiopterin deficiency, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Fetus, business.industry, Infant, Newborn, Pregnancy Outcome, Gestational age, medicine.disease, Fetal Blood, Biopterin, 3. Good health, Pterins, GENOTYPE, Europe, Pregnancy Complications, Metabolic control analysis, PKU, Female, business, 030217 neurology & neurosurgery
Abstract

International audience; Sapropterin dihydrochloride (SD) is the first drug treatment for phenylketonuria (PKU), but due to the lack of data, its use in maternal PKU must be undertaken with caution as noted in the FDA and EMEA labels. We collected data from eight pregnancies in PKU women treated with SD and we analysed the phenotypes of these patients, their tetrahydrobiopterin (BH4) responsiveness, the indications for SD treatment, the efficacy (metabolic control, phenylalanine (Phe) tolerance and offspring outcome) and the safety data. Results showed that in the seven patients known to be responsive to BH4, the use of SD during pregnancy was efficient in terms of metabolic control and Phe tolerance. The indications for giving SD included the failure of the low-Phe diet (n = 3), the fact that some of these women had never experienced the low Phe diet (n = 2), one unexpected pregnancy in a woman currently on SD and one pregnancy where the foetus was known to have PKU. The offspring of these seven pregnancies were all normal babies with normal birth measurements and outcomes. No side effect related to SD was observed in these seven cases. In the eighth case, SD was prescribed as a rescue treatment without previous knowledge of the BH4 responsiveness to a woman who was already 8 weeks pregnant without diet. The birth occurred at 33 weeks of gestational age with Potter syndrome (probably related to the absence of metabolic control during the first trimester) and the baby died in the first hours of life. In conclusion, the data presented here provides the first evidence that treatment with pharmacological doses of SD appears to be efficient and safe in women with PKU during pregnancy. Its use should, however, be restricted to those women previously identified to be clear responders to BH4.

Published
2014
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42. Reproduction, Smell, and Neurodevelopmental Disorders: Genetic Defects in Different Hypogonadotropic Hypogonadal Syndromes

Author

François-Guillaume Debray, Mariana Tomé Fernández-Ladreda, Vincent Bours, Matilde Rubio Almanza, Albert Beckers, and Hernan Valdes-Socin

Subjects
Leptin, medicine.medical_specialty, Kallmann syndrome, Endocrinology, Diabetes and Metabolism, Olfaction, Review Article, Biology, lcsh:Diseases of the endocrine glands. Clinical endocrinology, FSHB, reproduction, kisspeptin, Olfaction Disorders, Kisspeptin, Endocrinology, male, Hypogonadotropic hypogonadism, Internal medicine, medicine, genetics, Kisspeptins, lcsh:RC648-665, Hypogonadism, Fibroblast growth factor receptor 1, GNRHR, hypogonadotropic hypogonadism, Kallmann Syndrome, medicine.disease, Kallman syndrome, Congenital Hypogonadotropic Hypogonadism, olfaction
Abstract

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations (Kallmann syndrome) and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). Kallmann syndrome (KS) is a heterogeneous disorder affecting 1 in 5000 males, with a 3-5 fold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental and genetic aspects of HH in human pathology.

Published
2014

43. Eccentric Training for Elbow Hypermobility

Author

François-Guillaume Debray, François Delvaux, Jean-François Kaux, Bénédicte Forthomme, Jean-Michel Crielaard, Jean-Louis Croisier, and Marguerite Foidart-Dessalle

Subjects
musculoskeletal diseases, Joint hypermobility, medicine.medical_specialty, Rehabilitation, Proprioception, business.industry, Elbow hypermobility, medicine.medical_treatment, Elbow, Physical Therapy, Sports Therapy and Rehabilitation, General Medicine, Wrist, medicine.disease, Omics, body regions, medicine.anatomical_structure, Physical medicine and rehabilitation, Eccentric training, Physical therapy, Eccentric, Medicine, Orthopedics and Sports Medicine, Range of motion, business
Abstract

Introduction: Joint hypermobility involves an increased range of motion compared to normal amplitudes for the same age, sex and ethnic group. Patients with hypermobility suffer from joints problems and chronic pain is the most frequently reported symptom. Eccentric muscle strengthening could be very important to protect hypermobile joints. Case report: An Ehler-Danlos syndrome patient presented pain in the right elbow and the right wrist after a season of tennis. Her physiotherapy (18 sessions, 3 times a week) consisted of wrist prono-supination and flexion-extension muscle group reinforcement and proprioceptive training. To protect the wrist against excessive load, the eccentric strengthening exercises of prono-supinator and flexor-extensor muscles of elbow and wrist were undertaken gradually, at increasing speeds [30°/s, 60°/s, and 90°/s] within a limited range of motion in flexion and extension, on an isokinetic device after an evaluation. She was also given an ortheosis restricting the joint range of motion of the wrist. The patient rapidly noted a decrease in pain and an increase in the stability of her right arm even when playing tennis. Isokinetic evaluation objectified an improvement in maximal torque of 20 to 25% in flexion-extension muscles of the right elbow. She was also given individualized home exercises. Conclusion: The goal of rehabilitation is to avoid hypermobility by using the muscles as a protective brake in the control of joint positioning. Muscles can be reinforced in eccentric mode with starting position at the maximum length of these muscles when unstreched. The exercises can be carried out safely on an isokinetic device, at slow speed and limited range of joint motion to avoid risk of luxation. Thus, in this case report, the eccentric exercises using an isokinetic device were effective to safely reinforce the muscles as a protective brake for joint hypermobility.

Published
2013
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44. Hepatocyte transplantation using the domino concept in a child with Tetrabiopterin non-responsive phenylketonuria

Author

G. Sana, Pierre Goffette, Tatiana Tondreau, Etienne Sokal, Xavier Stéphenne, Mustapha Najimi, François Boemer, Nawal Jazouli, François-Guillaume Debray, Roland Schoos, Søren W. Gersting, Françoise Smets, Renaud Menten, Philippe Goyens, Ania C. Muntau, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, and UCL - (SLuc) Service de radiologie

Subjects
Male, medicine.medical_specialty, Phenylalanine hydroxylase, Phenylalanine, Biomedical Engineering, Cell- and Tissue-Based Therapy, lcsh:Medicine, Glycogen Storage Disease Type I, chemistry.chemical_compound, Liver Function Tests, Oral administration, Internal medicine, Phenylketonurias, medicine, Humans, Phenylketonuria (PKU), Child, Transplantation, medicine.diagnostic_test, biology, Glycogen, business.industry, lcsh:R, Infant, Phenylalanine Hydroxylase, Cell Biology, Tetrahydrobiopterin, medicine.disease, Malnutrition, Endocrinology, chemistry, biology.protein, Hepatocytes, Female, Liver function tests, business, medicine.drug, Half-Life
Abstract

Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and severe psychosocial burden. Oral administration of tetrahydrobiopterin can increase residual enzyme activity, but most patients with severe clinical phenotypes are nonresponders. We performed liver cell transplantation in a 6-year-old boy with severe tetrahydrobiopterin nonresponsive phenylketonuria who failed to comply with diet prescriptions. The transplanted hepatocytes were obtained in part from an explanted glycogen storage type 1b liver. Following two infusions, blood phenylalanine levels returned within the therapeutic target while the phenylalanine half-life assessed by loading tests decreased from 43 to 19 h. However, 3 months later, blood phenylalanine concentrations increased and the phenylalanine intake had to be reduced. Cell-based therapy is a promising therapeutic option in phenylketonuria, and the domino concept may solve the issue of cell sources for hepatocyte transplantation.

Published
2012

45. LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency

Author

François-Guillaume Debray, Annie Janvier, Bruno Maranda, Yves Robitaille, Charles Morin, Grant A. Mitchell, Brian H. Robinson, Rachel Laframboise, Josée Villeneuve, Marie Lambert, Jean-Claude Décarie, and Jacques Lacroix

Subjects
Male, medicine.medical_specialty, Adolescent, Fulminant, Cytochrome-c Oxidase Deficiency, Congenital lactic acidosis, Gastroenterology, Central nervous system disease, Mitochondrial Proteins, Young Adult, Internal medicine, Diabetes mellitus, Genetics, medicine, Cytochrome c oxidase, Humans, Leigh disease, Child, Genetics (clinical), Retrospective Studies, biology, business.industry, Homozygote, Infant, Membrane Proteins, medicine.disease, Neoplasm Proteins, Endocrinology, Logistic Models, Phenotype, Lactic acidosis, Child, Preschool, Failure to thrive, Mutation, biology.protein, Acidosis, Lactic, Female, medicine.symptom, Leigh Disease, business, Follow-Up Studies
Abstract

The natural history of all known patients with French-Canadian Leigh disease (Saguenay-Lac-St-Jean cytochrome c oxidase deficiency, MIM220111, SLSJ-COX), the largest known cohort of patients with a genetically homogeneous, nuclear encoded congenital lactic acidosis, was studied.55 of 56 patients were homozygous for the A354V mutation in LRPPRC. One was a genetic compound (A354V/C1277Xdel8). Clinical features included developmental delay, failure to thrive, characteristic facial appearance and, in 90% of patients, acute crises that have not previously been detailed, either metabolic (fulminant lactic acidosis) and/or neurological (Leigh syndrome and/or stroke-like episodes). Survival ranged from 5 days to30 years. 46/56 patients (82%) died, at a median age of 1.6 years. Of 73 crises, 38 (52%) were fatal. The immediate causes of death were multiple organ failure and/or Leigh disease. Major predictors of mortality during crises (p0.005) were hyperglycaemia, hepatic cytolysis, and altered consciousness at admission. Compared to a group of SURF1-deficient Leigh syndrome patients assembled from the literature, SLSJ-COX is distinct by the occurrence of metabolic crises, leading to earlier and higher mortality (p=0.001).SLSJ-COX is clinically distinct, with acute fatal acidotic crises on a backdrop of chronic moderate developmental delay and hyperlactataemia. Leigh syndrome is common. Stroke-like episodes can occur. The Leigh syndrome of SLSJ-COX differs from that of SURF1-related COX deficiency. SLSJ-COX has a different spectrum of associated abnormalities, acidotic crises being particularly suggestive of LRPPRC related Leigh syndrome. Even among A354V homozygotes, pronounced differences in survival and severity occur, showing that other genetic and/or environmental factors can influence outcome.

Published
2011

46. Low citrulline in Leigh disease: still a biomarker of maternally inherited Leigh syndrome

Author

Pierre Allard, Grant A. Mitchell, Marie-Hélène Lambert, and François-Guillaume Debray

Subjects
Adult, Male, Mitochondrial DNA, Genotype, Mitochondrial disease, Encephalopathy, DNA Mutational Analysis, Respiratory chain, Biology, Argininosuccinate Synthase, Cohort Studies, medicine, Humans, Genetic Testing, Leigh disease, Genetics, Citrullinemia, Infant, medicine.disease, Maternally inherited Leigh syndrome, Heteroplasmy, Lactic acidosis, Child, Preschool, Pediatrics, Perinatology and Child Health, Immunology, Citrulline, Female, Neurology (clinical), Leigh Disease, Biomarkers
Abstract

Two siblings presented with encephalopathy, lactic acidosis, and hypocitrullinemia. Muscle and liver biopsies were considered for respiratory chain studies, but because of hypocitrullinemia, molecular analysis for maternally inherited Leigh syndrome was first performed, revealing in both siblings the mitochondrial DNA T8993G mutation (95% heteroplasmy), allowing to avoid tissue biopsies. Hypocitrullinemia, an occasional finding in mitochondrial diseases, has been specifically associated with T8993G mutation. However, only few patients have been reported, and the prevalence of hypocitrullinemia in 8993 mitochondrial DNA mutations is unknown. In a small series of 16 Leigh syndrome patients, sensitivity and specificity of hypocitrullinemia (≤12 μmol/L) for 8993 mitochondrial DNA mutations were 66% and 85%, respectively. Although studies in larger cohorts are necessary, we suggest considering T8993G mutation early in the diagnostic evaluation of infantile mitochondrial diseases with hypocitrullinemia, which minimizes the need for invasive procedures associated with a small but nonnegligible risk of complications and incorrect diagnosis.

Published
2010

47. Long-term outcome of Leigh syndrome caused by the NARP-T8993C mtDNA mutation

Author

Grant A. Mitchell, Michel Vanasse, Marie Lambert, Anne Lortie, and François-Guillaume Debray

Subjects
Adult, Male, Ataxia, Adolescent, Neurological examination, Biology, Bioinformatics, DNA, Mitochondrial, Retinitis pigmentosa, Genetics, medicine, Humans, Point Mutation, Leigh disease, Genetics (clinical), medicine.diagnostic_test, Point mutation, Neurodegenerative Diseases, Maternally inherited Leigh syndrome, medicine.disease, Heteroplasmy, Mutation (genetic algorithm), Female, medicine.symptom, Leigh Disease, Follow-Up Studies
Abstract

Mutations at mitochondrial DNA (mtDNA) nucleotide 8993 can cause neurogenic weakness, ataxia and retinitis pigmentosa (NARP syndrome), or maternally inherited Leigh syndrome (LS), with a correlation between the amount of mutant mtDNA and the severity of the neurological disease. The T8993C mutation is generally considered to be clinically milder than the T8993G mutation but when the level of heteroplasmy exceeds 90%, progressive neurodegeneration has been found. We report on a long-term follow-up of a patient who presented at 4 years of age with typical LS but showed an unexpected resolution of his symptoms and a favorable outcome. At 18 years of age, his neurological examination was near normal, with neither peripheral neuropathy nor retinopathy. mtDNA analysis identified the presence of T8993C mutation at high level (>95%) in the patient's blood leukocytes. This case report and literature review emphasizes the variability of the phenotypic expression of the T8993C mutation and the need for caution in predictive counseling in such patients. (c) 2007 Wiley-Liss, Inc.

Published
2007

48. Acute tubular dysfunction with Fanconi syndrome: a new manifestation of mitochondrial cytopathies

Author

François-Guillaume Debray, Grant A. Mitchell, Marie Lambert, Pierre Brochu, Aicha Merouani, Brian H. Robinson, and Chantal Bernard

Subjects
De Toni-Debre-Fanconi Syndrome, Renal tubule, medicine.medical_specialty, Pathology, Mitochondrial Diseases, business.industry, Infant, Newborn, Fanconi syndrome, Infant, Mitochondrion, medicine.disease, Fanconi Syndrome, Endocrinology, Tubulopathy, Nephrology, Aminoaciduria, Internal medicine, Acute Disease, Medicine, Humans, Female, business, Follow-Up Studies
Published
2007

49. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis

Author

Brian H. Robinson, Grant A. Mitchell, James A. Hanley, François-Guillaume Debray, Pierre Allard, and Marie Lambert

Subjects
Male, medicine.medical_specialty, Pathology, Mitochondrial Diseases, Mitochondrial disease, Clinical Biochemistry, Congenital lactic acidosis, Gastroenterology, Sensitivity and Specificity, Diagnosis, Differential, chemistry.chemical_compound, Internal medicine, Pyruvic Acid, medicine, Humans, Lactic Acid, Child, Pyruvate Dehydrogenase Complex Deficiency Disease, Acidosis, Retrospective Studies, business.industry, Biochemistry (medical), Metabolic disorder, medicine.disease, Pyruvate dehydrogenase complex, Hospitals, Pediatric, Pyruvate dehydrogenase deficiency, Lactic acid, chemistry, ROC Curve, Acidosis, Lactic, Female, Differential diagnosis, medicine.symptom, business
Abstract

Background: Although the blood lactate-to-pyruvate (L:P) molar ratio is used to distinguish between pyruvate dehydrogenase deficiency (PDH-D) and other causes of congenital lactic acidosis (CLA), its diagnostic accuracy for differentiating between these 2 types of CLA has not been evaluated formally. Methods: We conducted a retrospective study of all patients followed for mitochondrial diseases between 1985 and 2005 in a tertiary care pediatric hospital. Results: At the recommended cut point of ∼25, individual median L:P ratio demonstrated low sensitivity and specificity (77% and 91%, respectively) for differentiating between patients with enzymatically proven PDH-D (n = 11) and those with mitochondrial disease but normal pyruvate dehydrogenase (PDH) activity (non-PDH; n = 35). We observed a strong positive association between L:P ratio and blood lactate in non-PDH CLA, whereas this association was weak in PDH-D CLA. Consequently, patient classification based on median L:P ratio showed improved diagnostic accuracy at higher lactate concentrations: for lactate 2.5 mmol/L. In the 2.5 to 5.0 mmol/L lactate category, the sensitivity and specificity at an optimal cut point of 18.4 were 93% (95% CI, 77%–99%) and 71% (95% CI, 20%–96%), respectively; for lactate >5.0 mmol/L, with an optimal cut point of 25.8, sensitivity and specificity were 96% (95% CI, 77%–99%) and 100% (95% CI, 59%–100%), respectively. Conclusion: Usefulness of the L:P ratio for differentiating non-PDH and PDH-D types of CLA increases at higher lactate concentrations.

Published
2007

50. Recurrent pancreatitis in mitochondrial cytopathy

Author

Marie Lambert, François-Guillaume Debray, Jacques L. Michaud, Denise Herzog, Laurent Garel, Éric Drouin, Grant A. Mitchell, and Anne Lortie

Subjects
Male, medicine.medical_specialty, Pancreatic disease, Pancreatic pseudocyst, Adolescent, Mitochondrial disease, DNA Mutational Analysis, Kearns-Sayre Syndrome, Mitochondrion, Biology, Gastroenterology, DNA, Mitochondrial, Kearns–Sayre syndrome, Recurrent pancreatitis, Recurrence, Internal medicine, Pancreatic Pseudocyst, Genetics, medicine, Humans, Genetics (clinical), Sequence Deletion, medicine.disease, Endocrinology, Pancreatitis, Acute Disease, Acute pancreatitis, Tomography, X-Ray Computed
Abstract

Diabetes mellitus and exocrine insufficiency are the commonest pancreatic manifestations of mitochondrial diseases. In contrast, pancreatitis has rarely been described in mitochondrial syndromes. We report on a patient with Kearns-Sayre syndrome and recurrent episodes of acute pancreatitis for which no explanation could be found other than the associated mitochondrial dysfunction. Interestingly, pharmacological disruption of mitochondrial metabolism in various models as well as in patients can cause pancreatitis, further supporting this association. A diagnosis of pancreatitis should be considered in any patients with mitochondrial disease and recurrent abdominal pain.

Published
2006

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