10 results on '"Moller, R."'
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2. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy
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Wolking, S., Moreau, C., Mccormack, M., Krause, R., Krenn, M., Berkovic, S., Cavalleri, G. L., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P. C., Kunz, W. S., Lerche, H., Marson, A. G., O'Brien, T. J., Petrovski, S., Sander, J. W., Sills, G. J., Striano, P., Zara, F., Zimprich, F., Sisodiya, S. M., Girard, S. L., Cossette, P., Avbersek, A., Leu, C., Heggeli, K., Demurtas, R., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Berghuis, B., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Auce, P., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Hutton, J., Muhle, H., Klein, K. M., Moller, R. S., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Craig, J., and Stefansson, H.
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0301 basic medicine ,Male ,Candidate gene ,Drug Resistant Epilepsy ,Neurology [D14] [Human health sciences] ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Drug resistance ,Bioinformatics ,Polymorphism, Single Nucleotide ,Whole Exome Sequencing ,Cohort Studies ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Exome Sequencing ,medicine ,Humans ,Polymorphism ,RC346-429 ,Gene ,Exome sequencing ,Research Articles ,Genetic Association Studies ,Neurologie [D14] [Sciences de la santé humaine] ,business.industry ,General Neuroscience ,Genetic variants ,Genetic Variation ,Single Nucleotide ,medicine.disease ,DEPDC5 ,Female ,030104 developmental biology ,Cohort ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,business ,030217 neurology & neurosurgery ,RC321-571 ,Research Article - Abstract
Annals of Clinical and Translational Neurology 8(7), 1376-1387 (2021). doi:10.1002/acn3.51374, Published by Wiley, Chichester [u.a.]
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- 2021
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3. Mowat-Wilson syndrome:growth charts
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Ivanovski I., Djuric O., Broccoli S., Caraffi S. G., Accorsi P., Adam M. P., Avela K., Badura-Stronka M., Bayat A., Clayton-Smith J., Cocco I., Cordelli D. M., Cuturilo G., Di Pisa V., Dupont Garcia J., Gastaldi R., Giordano L., Guala A., Hoei-Hansen C., Inaba M., Iodice A., Nielsen J. E. K., Kuburovic V., Lazalde-Medina B., Malbora B., Mizuno S., Moldovan O., Moller R. S., Muschke P., Otelli V., Pantaleoni C., Piscopo C., Poch-Olive M. L., Prpic I., Marin Reina P., Raviglione F., Ricci E., Scarano E., Simonte G., Smigiel R., Tanteles G., Tarani L., Trimouille A., Valera E. T., Schrier Vergano S., Writzl K., Callewaert B., Savasta S., Street M. E., Iughetti L., Bernasconi S., Giorgi Rossi P., Garavelli L., HUSLAB, Clinicum, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Ivanovski I., Djuric O., Broccoli S., Caraffi S.G., Accorsi P., Adam M.P., Avela K., Badura-Stronka M., Bayat A., Clayton-Smith J., Cocco I., Cordelli D.M., Cuturilo G., Di Pisa V., Dupont Garcia J., Gastaldi R., Giordano L., Guala A., Hoei-Hansen C., Inaba M., Iodice A., Nielsen J.E.K., Kuburovic V., Lazalde-Medina B., Malbora B., Mizuno S., Moldovan O., Moller R.S., Muschke P., Otelli V., Pantaleoni C., Piscopo C., Poch-Olive M.L., Prpic I., Marin Reina P., Raviglione F., Ricci E., Scarano E., Simonte G., Smigiel R., Tanteles G., Tarani L., Trimouille A., Valera E.T., Schrier Vergano S., Writzl K., Callewaert B., Savasta S., Street M.E., Iughetti L., Bernasconi S., Giorgi Rossi P., and Garavelli L.
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Male ,0301 basic medicine ,BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences ,Pediatrics ,Microcephaly ,FEATURES ,lcsh:Medicine ,CHILDREN ,030105 genetics & heredity ,Head circumference ,DISEASE ,0302 clinical medicine ,Intellectual disability ,Medicine and Health Sciences ,Genetics(clinical) ,Pharmacology (medical) ,Mowat-Wilson syndrome ,Child ,Genetics (clinical) ,Body mass index ,ZEB2 ,2. Zero hunger ,education.field_of_study ,0303 health sciences ,BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti ,Mowat-Wilson syndrome, ZEB2, Growth charts, Weight, Length, Height, Head circumference, Body mass index, BM ,1184 Genetics, developmental biology, physiology ,General Medicine ,STATISTICS ,3. Good health ,MORFOMETRIA ,Italy ,030220 oncology & carcinogenesis ,Female ,medicine.medical_specialty ,Mowat–Wilson syndrome ,Length ,Population ,BMI ,Growth charts ,Height ,Weight ,Growth chart ,03 medical and health sciences ,AGE ,Intellectual Disability ,medicine ,Humans ,In patient ,Hirschsprung Disease ,education ,Zinc Finger E-box Binding Homeobox 2 ,030304 developmental biology ,Homeodomain Proteins ,Physical development ,MUTATIONS ,business.industry ,Research ,lcsh:R ,Infant, Newborn ,Facies ,Infant ,medicine.disease ,Repressor Proteins ,DELINEATION ,INDIVIDUALS ,030104 developmental biology ,3111 Biomedicine ,business - Abstract
Background: Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2,865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children.Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.
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- 2020
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4. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load
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Perucca, P., Anderson, A., Jazayeri, D., Hitchcock, A., Graham, J., Todaro, M., Tomson, T., Battino, D., Perucca, E., Ferri, M. M., Rochtus, A., Lagae, L., Canevini, M. P., Zambrelli, E., Campbell, E., Koeleman, B. P. C., Scheffer, I. E., Berkovic, S. F., Kwan, P., Sisodiya, S. M., Goldstein, D. B., Petrovski, S., Craig, J., Vajda, F. J. E., O'Brien, T. J., Leu, C., Wolking, S., Peter, S., Weber, Y. G., Weckhuysen, S., Moller, R. S., Nikanorova, M., Muhle, H., Avbersek, A., Heggeli, K., Striano, P., Gambardella, A., Langley, S. R., Krenn, M., Klein, K. M., Mccormack, M., Borghei, M., Willis, J., Berghuis, B., Jorgensen, A., Auce, P., Francis, B., Srivastava, P., Sonsma, A. C. M., Sander, Jw., Zimprich, F., Depondt, C., Johnson, M. M., Marson, A. G., Sills, G. J., Kunz, W. S., Cavalleri, G. L., Delanty, N., Zara, F., Krause, R., Lerche, H., Andrade, D., Sen, A., Bazil, C. W., Boland, M., Cavalleri, G., Choi, H., Colombo, S., Costello, D., Devinsky, O., Doherty, C. P., Dugan, P., Frankel, W., Heinzen, E., Johnson, M., Marson, T., Mikati, M., Ottman, R., Pandolfo, M., Radtke, R., Rees, M., Sadoway, T., Valley, N., Walley, N., Wood, N., and Zuberi, S.
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Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,DNA Copy Number Variations ,Polymorphism, Single Nucleotide ,Paternal Age ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Pregnancy ,Polymorphism (computer science) ,medicine ,Humans ,Exome ,Copy-number variation ,Indel ,business.industry ,Confounding ,Infant, Newborn ,Abnormalities, Drug-Induced ,Genetic Variation ,DNA ,medicine.disease ,Genetic load ,Exact test ,Teratogens ,030104 developmental biology ,Neurology ,Anticonvulsants ,Female ,Neurology (clinical) ,Genetic Load ,business ,030217 neurology & neurosurgery - Abstract
OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism which we investigated. METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data. RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children [median dnSNV/indel number/child (range): 3 (0-7) vs 3 (1-5), p = 0.50]. Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counselling. This article is protected by copyright. All rights reserved.
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- 2020
5. De novo variants in neurodevelopmental disorders with epilepsy
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Heyne, H. O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Moller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S., Afawi, Z., De Kovel, C., Dimova, P., Djemie, T., Endziniene, M., Hoffman-Zacharska, D., Jahn, J., Korff, C., Lehesjoki, A. -E., Marini, C., Muller, S. H., Pal, D., Schwarz, N., Selmer, K., Serratosa, J., Stephani, U., Sterbova, K., Suls, A., Syrbe, S., Talvik, I., Von Spiczak, S., Zara, F., Poduri, A., Weber, Y. G., Weckhuysen, S., Sisodiya, S. M., Daly, M. J., Helbig, I., Lal, D., Lemke, J. R., Children's Hospital, Lastenneurologian yksikkö, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Research Programme for Molecular Neurology, Neuroscience Center, HUS Children and Adolescents, Genomics of Neurological and Neuropsychiatric Disorders, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Korff, Christian, and EuroEPINOMICS RES Consortium
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Exome/genetics ,Male ,0301 basic medicine ,ILAE COMMISSION ,Joint analysis ,Neurodevelopmental Disorders/genetics ,Bioinformatics ,Epilepsy/genetics ,Epilepsy ,0302 clinical medicine ,Intellectual disability ,SEQUENCE VARIANTS ,Missense mutation ,Epilepsy is a frequent feature ,Exome ,TERMINOLOGY ,Disease gene ,0303 health sciences ,ddc:618 ,medicine.diagnostic_test ,Genetic Predisposition to Disease/genetics ,Neurodevelopmental disorders ,1184 Genetics, developmental biology, physiology ,HUMAN-DISEASE ,PREVALENCE ,3. Good health ,Genetic Variation/genetics ,De novo variants ,Female ,Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] ,Genetic Testing/methods ,Disease Association ,Biology ,CLASSIFICATION ,03 medical and health sciences ,Intellectual Disability ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Limited evidence ,030304 developmental biology ,Genetic testing ,business.industry ,MUTATIONS ,AUTISM SPECTRUM DISORDER ,Genetic Variation ,medicine.disease ,Intellectual Disability/genetics ,030104 developmental biology ,Neurodevelopmental Disorders ,epilepsy ,KCNQ2 ENCEPHALOPATHY ,Human medicine ,3111 Biomedicine ,business ,Genetic diagnosis ,030217 neurology & neurosurgery - Abstract
Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.
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- 2018
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6. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine
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Berghuis, B., Stapleton, C., Sonsma, A. C. M., Hulst, J., de Haan, G. -J., Lindhout, D., Demurtas, R., Krause, R., Depondt, C., Kunz, W. S., Zara, F., Striano, P., Craig, J., Auce, P., Marson, A. G., Stefansson, H., O'Brien, T. J., Johnson, M. R., Sills, G. J., Wolking, S., Lerche, H., Sisodiya, S. M., Sander, J. W., Cavalleri, G. L., Koeleman, B. P. C., Mccormack, M., Avbersek, A., Leu, C., Heggeli, K., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Delanty, N., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Petrovski, S., Hutton, J., Zimprich, F., Krenn, M., Muhle, H., Martin Klein, K., Moller, R., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Berghuis, Bianca, Stapleton, Caragh, Sonsma, Anja C. M., Hulst, Janic, de Haan, Gerrit-Jan, Lindhout, Dick, Demurtas, Rita, Krause, Roland, Depondt, Chantal, Kunz, Wolfram S., Zara, Federico, Striano, Pasquale, Craig, John, Auce, Paul, Marson, Anthony G., Stefansson, Hreinn, O'Brien, Terence J., Johnson, Michael R., Sills, Graeme J., Wolking, Stefan, Lerche, Holger, Sisodiya, Sanjay M., Sander, Josemir W., Cavalleri, Gianpiero L., Koeleman, Bobby P. C., Mccormack, Mark, Weckhuysen, Sarah, EpiPGX Consortium, Imperial College Healthcare NHS Trust- BRC Funding, and Commission of the European Communities
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medicine.medical_specialty ,hyponatremia ,Clinical Neurology ,Gastroenterology ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,adverse effects ,antiepileptic drugs ,EpiPGX Consortium ,GWAS ,antiepileptic drug ,Internal medicine ,adverse effect ,medicine ,Oxcarbazepine ,Adverse effect ,030304 developmental biology ,0303 health sciences ,business.industry ,Généralités ,Carbamazepine ,medicine.disease ,3. Good health ,Neurology ,Cohort ,Full‐length Original Research ,Phenobarbital ,Human medicine ,Neurology (clinical) ,Hyponatremia ,business ,030217 neurology & neurosurgery ,Drug metabolism ,medicine.drug - Abstract
Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2019
7. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy
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Mignot, C., von Stulpnage, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G., Rastetter, A., Gachet, B., Marie, Y., Korenke, G. C., Borggraefe, I., Hoffmann-Zacharska, D., Szczepanik, E., Rudzka-Dybala, M., Uluc, Yis, Caglayan, H., Isapof, A., Marey, I., Panagiotakaki, E., Korff, C., Rossier, E., Riess, A., Beck-Woedl, S., Rauch, A., Zweier, C., Hoyer, J., Reis, A., Mironov, M., Bobylova, M., Mukhin, K., Hernandez-Hernandez, L., Maher, B., Sisodiya, S., Kuhn, M., Glaeser, D., Wechuysen, S., Myers, C. T., Mefford, H. C., Hortnagel, K., Biskup, S., Lemke, J. R., Heron, D., Kluger, G., Depienne, C., Craiu, D., De Jonghe, P., Helbig, I., Guerrini, R., Lehesjoki, A. -E., Marini, C., Muhle, H., Moller, R. S., Neubauer, B., Pal, D., Selmer, K., Stephani, U., Sterbova, K., Striano, P., Talvik, T., von Spiczak, S., Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-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), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Université de Lyon, Klinikum Oldenburg [Oldenburg], Zentrum für Kinder- und Jugendmedizin, Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich], University of Munich, Department of Medical Genetics, Institute of Mother and Child, Division of Child Neurology, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Dpt of Molecular Biology and Genetics Istanbul, Boǧaziçi üniversitesi = Boğaziçi University [Istanbul], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève], Hôpitaux Universitaires de Genève (HUG), Institute of Human Genetics [Tuebingen], University of Tuebingen, Institute of Medical Genetics and Applied Genomics [Tübingen], University of Tübingen, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Svt. Luka's Institute of Child Neurology and Epilepsy, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Genetikum, Neurogenetics Group, Division of Genetic Medicine [Seattle], University of Washington [Seattle], CeGaT GmbH, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Mignot, Cyril, von Stülpnagel, Celina, Korff, Christian, EuroEPINOMICS-RES MAE Working Grp, HAL-UPMC, Gestionnaire, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), 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), Groupement Hospitalier Lyon-Est (GHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Boğaziçi University [Istanbul], CHU Trousseau [APHP], and Universität Heidelberg [Heidelberg] = Heidelberg University
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0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Encephalopathy ,Myoclonic Jerk ,SYNGAP1 ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,fluids and secretions ,Medizinische Fakultät ,Intellectual disability ,mental disorders ,Genetics ,medicine ,ddc:610 ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Exome ,Genetics (clinical) ,reproductive and urinary physiology ,ddc:618 ,business.industry ,medicine.disease ,Hypotonia ,3. Good health ,030104 developmental biology ,Autism ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Human medicine ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Mae Euroepinomics-Res Mae; International audience; Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.
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- 2016
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8. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia
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Hardies, K., De Kovel, C. G. F., Weckhuysen, S., Asselbergh, B., Geuens, T., Deconinck, T., Azmi, A., May, P., Brilstra, E., Becker, F., Barisic, N., Craiu, D., Braun, K. P. J., Lal, D., Thiele, H., Schubert, J., Weber, Y., Van 'T Slot, R., Nurnberg, P., Balling, R., Timmerman, V., Lerche, H., Maudsley, S., Helbig, I., Suls, A., Koeleman, B. P. C., De Jonghe, P., Afawi, Z., Baulac, S., Caglayan, H., Lopez, R. G., Guerrini, R., Hjalgrim, H., Jahn, J., Klein, K. M., Leguern, E., Lemke, J., Marini, C., Muhle, H., Rosenow, F., Serratosa, J., Sterbova, K., Moller, R. S., Striano, P., Zara, F., and EuroEPINOMICS RES Consortium
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Male ,medicine.medical_specialty ,Adolescent ,anaplerosis ,epileptic encephalopathy ,NaCT ,recessive disorder ,SLC13A5 ,teeth hypoplasia ,medicine.medical_treatment ,Developmental Disabilities ,Mutant ,Genes, Recessive ,Biology ,medicine.disease_cause ,Citric Acid ,Epilepsy ,Internal medicine ,medicine ,Journal Article ,Humans ,Genetic Predisposition to Disease ,Child ,Gene ,Anodontia ,Genetics ,Mutation ,Brain Diseases ,Symporters ,Citrate transport ,medicine.disease ,Hypoplasia ,Pedigree ,Endocrinology ,HEK293 Cells ,Epilepsy syndromes ,Female ,Neurology (clinical) ,Human medicine ,Ketogenic diet - Abstract
The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder.
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- 2015
- Full Text
- View/download PDF
9. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes
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Schubert, J., Siekierska, A., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., de Kovel, C. G. F., Thiele, H., Konrad, K., Kawalia, A., Toliat, M. R., Sander, T., Ruschendorf, F., Caliebe, A., Nagel, I., Kohl, B., Kecskes, A., Jacmin, M., Hardies, K., Weckhuysen, S., Riesch, E., Dorn, T., Brilstra, E. H., Baulac, S., Moller, R. S., Hjalgrim, H., Koeleman, B. P. C., Jurkat-Rott, K., Lehman-Horn, F., Roach, J. C., Glusman, G., Hood, L., Galas, D. J., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nurnberg, P., Crawford, A. D., Esguerra, C. V., Weber, Y. G., Lerche, H., Euro, Epinomics R. E. S. Consortium, EuroEPINOMICS RES Consortium, [GIN] Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Institute for Systems Biology [Seattle] (ISB), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurogenetics Group, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Cologne Center for Genomics (CCG), University of Cologne, Department of Molecular and Developmental Genetics (VIB11), Flanders institute of biotechnology, 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), 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), Medical Genetics Laboratory, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratory of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences Lueven Belgium, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Center for Genomics and Transcriptomics (CEGAT), Antwerp University Hospital [Edegem] (UZA), Children’s Hospital of Philadelphia (CHOP ), Cologne Center for Genomics, University of Cologne, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Heidelberg [Heidelberg] = Heidelberg University, 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)
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Male ,Genetic Linkage ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Syntaxin 1 ,medicine.disease_cause ,Epilepsy/genetics ,Cohort Studies ,Epilepsy ,0302 clinical medicine ,Syntaxin 1/genetics ,Missense mutation ,Exome ,ComputingMilieux_MISCELLANEOUS ,In Situ Hybridization, Fluorescence ,Zebrafish ,Genetics ,0303 health sciences ,Mutation ,Comparative Genomic Hybridization ,Temperature ,PAROXYSMAL KINESIGENIC DYSKINESIA SYNAPTIC VESICLE FUSION DE-NOVO MUTATIONS FEBRILE SEIZURES INFANTILE CONVULSIONS GENERALIZED EPILEPSY PRRT2 MUTATIONS GENERATION DISORDERS ZEBRAFISH ,Pedigree ,Phenotype ,Codon, Nonsense ,Female ,Molecular Sequence Data ,Biology ,Polymorphism, Single Nucleotide ,Seizures, Febrile ,03 medical and health sciences ,SCN1B ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Seizures, Febrile/genetics ,Generalized epilepsy ,030304 developmental biology ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Sequence Analysis, DNA ,Paroxysmal dyskinesia ,medicine.disease ,Epilepsy syndromes ,Human medicine ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Gene Deletion - Abstract
Febrile seizures affect 2-4% of all children(1) and have a strong genetic component(2). Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)(3-5) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B(6), that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees(7,8) identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.
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- 2014
- Full Text
- View/download PDF
10. Influence of drugs on the bilirubin UDP-glucuronyltransferase activity and the concentration of Y and Z acceptor proteins in rat liver
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Klinger W, D Gmyrek, Moller R, Grimmer I, and Gross J
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Drug ,Male ,Cytoplasm ,Methylphenobarbital ,Bilirubin ,media_common.quotation_subject ,Nikethamide ,Mephobarbital ,Pharmacology ,Fatty Acid-Binding Proteins ,chemistry.chemical_compound ,Bilirubin UDP-Glucuronyltransferase ,medicine ,Animals ,Glucuronosyltransferase ,media_common ,biology ,Intracellular Signaling Peptides and Proteins ,Rats, Inbred Strains ,Stereoisomerism ,Acceptor ,Enzyme assay ,Stimulation, Chemical ,Rats ,Drug Combinations ,Biochemistry ,chemistry ,Liver ,Rat liver ,Phenobarbital ,Pediatrics, Perinatology and Child Health ,biology.protein ,Carrier Proteins ,Developmental Biology ,medicine.drug - Abstract
The aim of this paper is to report on the influence of phenobarbital, the combination of phenobarbital/nicethamide, the racemate and (+) isomer of methylphenobarbital on the activity of bilirubin UDP-glucuronyltransferase and the concentration of intrahepatic Y and Z protein in rats. The activity of bilirubin UDP-glucuronyltransferase increased after the treatment in all groups. Pretreatment with phenobarbital/nicethamide resulted in the highest enzyme activity, using wet weight as reference. (+) Methylphenobarbital isomer as well as the racemate showed effects similar to those of phenobarbital. The concentration of hepatic Y acceptor protein increased in all pretreated groups by about 30%. The drugs did not increase the concentration of Z protein. The (+) isomer of methylphenobarbital seems better suited as an inductive drug in the prophylaxis of hyperbilirubinemia and in the treatment of nonconjugated hyperbilirubinemia than phenobarbital or phenobarbital/nicethamide since it has no sedative effect.
- Published
- 1981
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