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1. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author

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.

Subjects
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.]

Published
2021
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2. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Author

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.

Subjects
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.

Published
2020

3. EpiNet as a way of involving more physicians and patients in epilepsy research: Validation study and accreditation process

Author

Bergin, P. S., Beghi, E., Sadleir, L. G., Brockington, A., Tripathi, M., Richardson, M. P., Bianchi, E., Srivastava, K., Jayabal, J., Legros, B., Ossemann, M., Mcgrath, N., Verrotti, A., Tan, H. J., Beretta, S., Frith, R., Iniesta, I., Whitham, E., Wanigasinghe, J., Ezeala-Adikaibe, B., Striano, P., Rosemergy, I., Walker, E. B., Alkhidze, M., Rodriguez-Leyva, I., Ramirez Gonzalez, J. A., D'Souza, W. J., Calle, A., Palacios, C., Cairns, A., Carney, P., Craig, D., Gill, D., Gupta, S., Lander, C., Laue-Gizzi, H., Hitchens, N., Kiley, M., Lawn, N., Reyneke, E., Riney, K., Tan, M., Thieban, M., Wong, C., van Rijckevorsel, G., Ferrari Strang, A. G., Gifoni, A., Helio, L., Monnerat, B., Brna, P., Donner, E., Jacques, S., Jette, N., Mclachlan, R., Mohamed, I., Tran, T. P. Y., Bo, X., Fan, S., Guang, Y., Li, M., Wang, K., Zhang, S., Ladino, L., Christensen, J., Kӧlmel, M. S., Nikanorova, M., Uusitalo, A., Vieira, P., Auvin, S., Ediberidze, T., Gogatishvili, N., Jishkariani, T., Dennig, D., Grimmer, A., Michaelis, R., Schubert-Bast, S., Stephani, C., Stodieck, S., Vollbrandt, M., Zellner, A., Zafeiriou, D., Fogarasi, A., Halasz, P., Chaurasia, R. N., Jain, S., Nair, R., Passi, P., Rajadhyaksha, S., Sattaluri, S. J., Shah, H., Udani, V., Costello, D., Aguglia, U., Bartocci, A., Benna, P., Ferlazzo, E., Laino, D., Spalice, A., Zanchi, C., Ali, A., Lim, K. S., Ramirez, A., Anderson, N., Barber, A., Cariga, P., Cleland, J., Child, N., Davis, S., Dayal, V., Dickson, C., Doran, J., Duncan, R., Giri, P., Herd, M., Hutchinson, D., Jones, B., Kao, J., Kilfoyle, D., Mottershead, J., Muir, C., Nolan, M., Pereira, J., Ranta, A., Sadani, S., Simpson, M., Spooner, C., Timmings, P., Walker, E., Wei, D., Willoughby, E., Wong, E., Wu, T., Olusola, T., Mahmud, H., Mogul, Z., Espinoza, J., Vizarreta, J. H., Baeta, E. M., Teotonio, R., Jocic-Jakubi, B., Lukic, S., Korosec, M., Zgur, T., Eguilaz, M. G., Asztely, F., Sithinamsuwan, P., Anderson, J., Auce, P., Desurkar, A., Hamandi, K., Kelso, A., Sanchez, V., Sidra, A., Smith, P., Wehner, T., Winston, G., Andrade, E., Bensalem-Owen, M., Boudreau, M., Caller, T., Chapman, K., Chari, G., Davis, K., Droker, B., El-Hagrassy, M., Eliashiv, D., Eze, C., Heck, C., Kabir, A., Kolesnik, D., Lam, A., Lopez, J., Maamoon, T., Cohen, J. M., Maganti, R., Nwankwo, C., Park, K., Proteasa, S., Sandok, E., Seinfield, S., Toub, J., Wirrell, E., Arbildi, M., Thien, T. T., UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (MGD) Service de neurologie

Subjects
0301 basic medicine, medicine.medical_specialty, Validation study, education, Alternative medicine, Multicenter collaboration, Diagnostic accuracy, Accreditation, 03 medical and health sciences, Epilepsy, Clinical trials, 0302 clinical medicine, Clinical Trials, Multicentre Collaboration, medicine, health care economics and organizations, Kappa value, business.industry, medicine.disease, Invited Original Research, Clinical trial, 030104 developmental biology, Neurology, Family medicine, Etiology, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study, Biomedical engineering
Abstract

Objective\ud \ud EpiNet was established to encourage epilepsy research. EpiNet is used for multicenter cohort studies and investigator‐led trials. Physicians must be accredited to recruit patients into trials. Here, we describe the accreditation process for the EpiNet‐First trials.\ud Methods\ud \ud Physicians with an interest in epilepsy were invited to assess 30 case scenarios to determine the following: whether patients have epilepsy; the nature of the seizures (generalized, focal); and the etiology. Information was presented in two steps for 23 cases. The EpiNet steering committee determined that 21 cases had epilepsy. The steering committee determined by consensus which responses were acceptable for each case. We chose a subset of 18 cases to accredit investigators for the EpiNet‐First trials. We initially focused on 12 cases; to be accredited, investigators could not diagnose epilepsy in any case that the steering committee determined did not have epilepsy. If investigators were not accredited after assessing 12 cases, 6 further cases were considered. When assessing the 18 cases, investigators could be accredited if they diagnosed one of six nonepilepsy patients as having possible epilepsy but could make no other false‐positive errors and could make only one error regarding seizure classification.\ud Results\ud \ud Between December 2013 and December 2014, 189 physicians assessed the 30 cases. Agreement with the steering committee regarding the diagnosis at step 1 ranged from 47% to 100%, and improved when information regarding tests was provided at step 2. One hundred five of the 189 physicians (55%) were accredited for the EpiNet‐First trials. The kappa value for diagnosis of epilepsy across all 30 cases for accredited physicians was 0.70.\ud Significance\ud \ud We have established criteria for accrediting physicians using EpiNet. New investigators can be accredited by assessing 18 case scenarios. We encourage physicians with an interest in epilepsy to become EpiNet‐accredited and to participate in these investigator‐led clinical trials.

Published
2017
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4. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Author

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

Subjects
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

Published
2019

5. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author

Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, 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), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), 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-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 d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), 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), 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-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.

Subjects
0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Published
2018
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6. Effectiveness of antiepileptic therapy in patients with PCDH19 mutations

Author

Simona Pellacani, Pasquale Striano, Christian Mühe, Kurt Schlachter, Tobias Loddenkemper, Christine Makowski, Peter Borusiak, Antonietta Coppola, Marina Nikanorova, Joost Nicolai, Reinhard Keimer, Biayna G. Sukhudyan, Helle Hjalgrim, Sunny Philip, András Fogarasi, Thomas Bast, Susanne Ruf, Michaela Linder-Lucht, Irene Graneß, Gerhard Kluger, Tanja Weisbrod, Steffen Leiz, Christian Korff, Iván Sánchez Fernández, J Lotte, Gerhard Kurlemann, J. Helen Cross, Bernd Wilken, Deyana Valcheva, R. Jeroen Vermeulen, Renzo Guerrini, Petia Dimova, Philipp Wolf, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: FHML non-thematic output, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Lotte, J., Bast, T., Borusiak, P., Coppola, A., Cross, J. H., Dimova, P., Fogarasi, A., Graneß, I., Guerrini, R., Hjalgrim, H., Keimer, R., Korff, C. M., Kurlemann, G., Leiz, S., Linder-Lucht, M., Loddenkemper, T., Makowski, C., Mühe, C., Nicolai, J., Nikanorova, M., Pellacani, S., Philip, S., Ruf, S., Sánchez Fernández, I., Schlachter, K., Striano, P., Sukhudyan, B., Valcheva, D., Vermeulen, R. J., Weisbrod, T., Wilken, B., Wolf, P., and Kluger, G.

Subjects
0301 basic medicine, Pediatrics, Clobazam, Epilepsy, 0302 clinical medicine, Surveys and Questionnaires, Young adult, Child, media_common, Age Factors, General Medicine, Cadherins, Treatment Outcome, Neurology, Child, Preschool, Anticonvulsants, Female, medicine.drug, Adult, Drug, medicine.medical_specialty, Adolescent, media_common.quotation_subject, Antiepileptic drugs, Clinical Neurology, Long-term effectiveness, Young Adult, 03 medical and health sciences, medicine, Humans, In patient, Retrospective Studies, business.industry, Retrospective cohort study, PCDH19 mutation, Treatment, Neurology (clinical), medicine.disease, Red Cross, Protocadherins, 030104 developmental biology, Multicenter study, Pharmacogenetics, Mutation, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Purpose PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations. Methods We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2–27 years (mean age 10.6 years). Results The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year. Significance The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered.

Published
2016

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