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Je něco špatně v tomto záznamu ?
Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
KM. Johannesen, Y. Liu, M. Koko, CE. Gjerulfsen, L. Sonnenberg, J. Schubert, CD. Fenger, A. Eltokhi, M. Rannap, NA. Koch, S. Lauxmann, J. Krüger, J. Kegele, L. Canafoglia, S. Franceschetti, T. Mayer, J. Rebstock, P. Zacher, S. Ruf, M. Alber, K....
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
K23 NS107646
NINDS NIH HHS - United States
UM1 HG008895
NHGRI NIH HHS - United States
U01 HG009088
NHGRI NIH HHS - United States
K08 NS097633
NINDS NIH HHS - United States
K02 NS112600
NINDS NIH HHS - United States
U54 NS108874
NINDS NIH HHS - United States
U54 HD086984
NICHD NIH HHS - United States
UL1 TR001878
NCATS NIH HHS - United States
NLK
Free Medical Journals
od 1996 do Před 1 rokem
Open Access Digital Library
od 1996-01-01
PubMed
34431999
DOI
10.1093/brain/awab321
Knihovny.cz E-zdroje
- MeSH
- blokátory sodíkových kanálů terapeutické užití MeSH
- epilepsie generalizovaná * farmakoterapie genetika MeSH
- epileptické syndromy * farmakoterapie genetika MeSH
- genetické asociační studie MeSH
- kojenec MeSH
- lidé MeSH
- mentální retardace * genetika MeSH
- mutace MeSH
- napěťově řízený sodíkový kanál, typ 6 * genetika MeSH
- prognóza MeSH
- záchvaty farmakoterapie genetika MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
'L Sacco' Department of Biomedical and Clinical Sciences University of Milan 20157 Milan Italy
1 M Sechenov 1st Moscow State Medical University 100000 Moscow Russia
Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA 02108 USA
Center for Pediatric Neurology Cleveland Clinic Cleveland OH 44102 USA
Child Neurology and Clinical Neurophysiology Unit Padova University Hospital 35100 Padova Italy
Child Neurology and Psychiatry Unit Children's Hospital G Salesi 60121 Ancona Italy
Child Neurology Center for Pediatric and Teenage Health Care 53757 Sankt Augustin Germany
Child Neuropsychiatric Unit Civilian Hospital 25100 Brescia Italy
Children's Department Swiss Epilepsy Centre Clinic Lengg 8001 Zurich Switzerland
Clinique de Génétique Guy Fontaine CHU Lille 59000 Lille France
Cologne Center for Genomics University of Cologne 50667 Cologne Germany
Comprehensive Epilepsy Center Ludwig Maximilian University of Munich 80331 Munich Germany
Département de Neuropédiatrie INSERM CHU Montpellier 34000 Montpellier France
Department of Child Neurology 5 Buzzi Children's Hospital 20125 Milan Italy
Department of Clinical Diagnostics Ambry Genetics Aliso Viejo CA 92637 USA
Department of Clinical Medicine University of Copenhagen 2200 Copenhagen Denmark
Department of Genetics Boston Children's Hospital Boston MA 02108 USA
Department of Medical Genetics Institute of Mother and Child 00 034 Warsaw Poland
Department of Neurology Aarhus University Hospital 8000 Aarhus Denmark
Department of Neurology Boston Children's Hospital and Harvard Medical School Boston MA 02108 USA
Department of Neuropediatrics Kiel University 24105 Kiel Germany
Department of Neuropediatrics Klinikum Weiden Kliniken Nordoberpfalz AG 92637 Weiden Germany
Department of Neuropediatrics Universitätsklinikum Schleswig Holstein Campus Kiel 24106 Kiel Germany
Department of Neuropediatrics University Hospital Bonn 53229 Bonn Germany
Department of Pediatric Neurology Hospital Italiano de Buenos Aires C1428 Buenos Aires Argentina
Department of Pediatrics Copenhagen University Hospital Rigshospitalet 2200 Copenhagen Denmark
Department of Pediatrics Division of Pediatric Neurology Gent University Hospital 9042 Gent Belgium
Department of Pediatrics Oestfold Hospital 1712 Graalum Norway
Department of Pediatrics St Jacques Hospital 25000 Besançon France
Department of Pediatrics University of Melbourne Royal Children's Hospital 3052 Parkville Australia
Department of Woman's and Child's Health Padova University Hospital 35100 Padova Italy
Division of Neurology Children's Hospital of Philadelphia Philadelphia PA 19104 USA
Epilepsy Center Kleinwachau 01454 Dresden Radeberg Germany
Epilepsy Center Neurological Institute Cleveland Clinic Cleveland OH 44102 USA
Epilepsy Genetics Program Boston Children's Hospital Boston MA 02108 USA
Finnish Institute for Molecular Medicine University of Helsinki 320 Helsinki Finland
Geisinger Autism and Developmental Medicine Institute Lewisburg PA 17837 USA
Genetics Department CHRU Strasbourg 67000 Strasbourg France
Genetics Department CHU Côte de Nacre 14118 Caen France
Genomed Ltd 100000 Moscow Russia
Genomic Medicine Institute Lerner Research Institute Cleveland Clinic Cleveland OH 44102 USA
Institute for Molecular and Behavioral Neuroscience University of Cologne 50667 Cologne Germany
Institute for Neurobiology University of Tuebingen 72072 Tuebingen Germany
Institute for Pathology and Genetics 6040 Gosselies Belgium
Institute for Regional Health Services University of Southern Denmark 5230 Odense Denmark
Institute of Clinical Molecular Biology Kiel University 24105 Kiel Germany
Institute of Human Genetics University Clinic Heinrich Heine University 40210 Düsseldorf Germany
Institute of Human Genetics University of Leipzig Hospitals and Clinics 4275 Leipzig Germany
IRCCS 'G Gaslini' Institute 16121 Genoa Italy
IRCCS Stella Maris 56121 Pisa Italy
Justin Neurosciences Center Cook Children's Medical Center Fort Worth TX 76101 USA
Luxembourg Centre for Systems Biomedicine University Luxembourg L 4243 Esch sur Alzette Luxembourg
McLaughlin Centre and Department of Molecular Genetics University of Toronto Toronto ON 66777 Canada
Murdoch Children's Research Institute 3052 Parkville Australia
National Centre for Rare Epilepsy Related Disorders Oslo University Hospital 0001 Oslo Norway
Neurology Department The Royal Children's Hospital Melbourne 3002 Melbourne Australia
Pediatric Neurology and Development Center Shamir Medical Center Be'er Ya'akov Israel
Pediatric Neurology Marie Curie Hospital CHU Charleroi 6032 Charleroi Belgium
Pediatric Neurology Unit Vittore Buzzi Hospital ASST Fatebenefratelli Sacco 20100 Milan Italy
Research Centre for Medical Genetics 115522 Moscow Russia
Research Institute 'Rehabilitation Transition Palliation' PMU Salzburg 5020 Salzburg Austria
Russian Medical Academy of Continuous Professional Education 100000 Moscow Russia
Sackler Faculty of Medicine Tel Aviv University 5296001 Tel Aviv Israel
Service de Génétique Centre Hospitalier Universitaire de Poitiers 86021 Poitiers France
Service de Génétique Médicale CHU Nantes 44093 Nantes France
Stanley Center for Psychiatric Research Broad Institute of Harvard and M 1 T Cambridge MA 02138 USA
Svt Luka's Institute of Child Neurology and Epilepsy 100000 Moscow Russia
The Epilepsy Neurogenetics Initiative Children's Hospital of Philadelphia Philadelphia PA 19104 USA
University of Copenhagen 2200 Copenhagen Denmark
Citace poskytuje Crossref.org
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- $a Johannesen, Katrine M $u Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark $u Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark $1 https://orcid.org/0000000273563109
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- $a Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications / $c KM. Johannesen, Y. Liu, M. Koko, CE. Gjerulfsen, L. Sonnenberg, J. Schubert, CD. Fenger, A. Eltokhi, M. Rannap, NA. Koch, S. Lauxmann, J. Krüger, J. Kegele, L. Canafoglia, S. Franceschetti, T. Mayer, J. Rebstock, P. Zacher, S. Ruf, M. Alber, K. Sterbova, P. Lassuthová, M. Vlckova, JR. Lemke, K. Platzer, I. Krey, C. Heine, D. Wieczorek, J. Kroell-Seger, C. Lund, KM. Klein, PYB. Au, JM. Rho, AW. Ho, S. Masnada, P. Veggiotti, L. Giordano, P. Accorsi, CE. Hoei-Hansen, P. Striano, F. Zara, H. Verhelst, JS. Verhoeven, HMH. Braakman, B. van der Zwaag, AVE. Harder, E. Brilstra, M. Pendziwiat, S. Lebon, M. Vaccarezza, NM. Le, J. Christensen, S. Grønborg, SW. Scherer, J. Howe, W. Fazeli, KB. Howell, R. Leventer, C. Stutterd, S. Walsh, M. Gerard, B. Gerard, S. Matricardi, CM. Bonardi, S. Sartori, A. Berger, D. Hoffman-Zacharska, M. Mastrangelo, F. Darra, A. Vøllo, MM. Motazacker, P. Lakeman, M. Nizon, C. Betzler, C. Altuzarra, R. Caume, A. Roubertie, P. Gélisse, C. Marini, R. Guerrini, F. Bilan, D. Tibussek, M. Koch-Hogrebe, MS. Perry, S. Ichikawa, E. Dadali, A. Sharkov, I. Mishina, M. Abramov, I. Kanivets, S. Korostelev, S. Kutsev, KE. Wain, N. Eisenhauer, M. Wagner, JM. Savatt, K. Müller-Schlüter, H. Bassan, A. Borovikov, MC. Nassogne, A. Destrée, AS. Schoonjans, M. Meuwissen, M. Buzatu, A. Jansen, E. Scalais, S. Srivastava, WH. Tan, HE. Olson, T. Loddenkemper, A. Poduri, KL. Helbig, I. Helbig, MP. Fitzgerald, EM. Goldberg, T. Roser, I. Borggraefe, T. Brünger, P. May, D. Lal, D. Lederer, G. Rubboli, HO. Heyne, G. Lesca, UBS. Hedrich, J. Benda, E. Gardella, H. Lerche, RS. Møller
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- $a We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1-3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1-3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
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- $a Liu, Yuanyuan $u Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany
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- $a Koch, Nils A $u Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany
- 700 1_
- $a Lauxmann, Stephan $u Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany $u Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany
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- $a Krüger, Johanna $u Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany
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- $a Giordano, Lucio $u Child Neuropsychiatric Unit, Civilian Hospital, 25100 Brescia, Italy
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Mastrangelo, Massimo $u Pediatric Neurology Unit, Vittore Buzzi Hospital, ASST Fatebenefratelli Sacco, 20100 Milan, Italy
- 700 1_
- $a Darra, Francesca $u Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37121 Verona, Italy
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Betzler, Cornelia $u Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik, 83569 Vogtareuth, Germany $u Research Institute 'Rehabilitation, Transition, Palliation', PMU Salzburg, 5020 Salzburg, Austria
- 700 1_
- $a Altuzarra, Cecilia $u Department of Pediatrics, St. Jacques Hospital, 25000 Besançon, France
- 700 1_
- $a Caume, Roseline $u Clinique de Génétique Guy Fontaine, CHU Lille, 59000, Lille, France
- 700 1_
- $a Roubertie, Agathe $u Département de Neuropédiatrie, INSERM, CHU Montpellier, 34000 Montpellier, France
- 700 1_
- $a Gélisse, Philippe $u Département de Neuropédiatrie, INSERM, CHU Montpellier, 34000 Montpellier, France
- 700 1_
- $a Marini, Carla $u Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, 50131 Florence, Italy
- 700 1_
- $a Guerrini, Renzo $u IRCCS Stella Maris, 56121 Pisa, Italy
- 700 1_
- $a Bilan, Frederic $u Service de Génétique, Centre Hospitalier Universitaire de Poitiers, 86021 Poitiers, France
- 700 1_
- $a Tibussek, Daniel $u Child Neurology, Center for Pediatric and Teenage Health Care, 53757 Sankt Augustin, Germany
- 700 1_
- $a Koch-Hogrebe, Margarete $u Vestische Kinder- und Jugendklinik, 45711 Datteln, Germany
- 700 1_
- $a Perry, M Scott $u Justin Neurosciences Center, Cook Children's Medical Center, Fort Worth, TX 76101, USA
- 700 1_
- $a Ichikawa, Shoji $u Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA 92637, USA
- 700 1_
- $a Dadali, Elena $u Research Centre for Medical Genetics, 115522 Moscow, Russia $u Veltischev Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, 125412 Moscow, Russia
- 700 1_
- $a Sharkov, Artem $u Veltischev Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, 125412 Moscow, Russia $u Genomed Ltd., 100000 Moscow, Russia
- 700 1_
- $a Mishina, Irina $u Research Centre for Medical Genetics, 115522 Moscow, Russia
- 700 1_
- $a Abramov, Mikhail $u Veltischev Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, 125412 Moscow, Russia
- 700 1_
- $a Kanivets, Ilya $u Svt. Luka's Institute of Child Neurology & Epilepsy, 100000 Moscow, Russia $u Russian Medical Academy of Continuous Professional Education, 100000 Moscow, Russia
- 700 1_
- $a Korostelev, Sergey $u Svt. Luka's Institute of Child Neurology & Epilepsy, 100000 Moscow, Russia $u I.M. Sechenov First Moscow State Medical University, 100000 Moscow, Russia
- 700 1_
- $a Kutsev, Sergey $u Research Centre for Medical Genetics, 115522 Moscow, Russia
- 700 1_
- $a Wain, Karen E $u Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA
- 700 1_
- $a Eisenhauer, Nancy $u Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA
- 700 1_
- $a Wagner, Monisa $u Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA
- 700 1_
- $a Savatt, Juliann M $u Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA
- 700 1_
- $a Müller-Schlüter, Karen $u Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School, 16816 Neuruppin, Germany
- 700 1_
- $a Bassan, Haim $u Pediatric Neurology & Development Center, Shamir Medical Center (Assaf Harofe), Be'er Ya'akov, Israel $u Sackler Faculty of Medicine, Tel Aviv University, 5296001 Tel Aviv, Israel
- 700 1_
- $a Borovikov, Artem $u Research Centre for Medical Genetics, 115522 Moscow, Russia
- 700 1_
- $a Nassogne, Marie Cecile $u Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1000 Brussels, Belgium
- 700 1_
- $a Destrée, Anne $u Institute for Pathology and Genetics, 6040 Gosselies, Belgium
- 700 1_
- $a Schoonjans, An Sofie $u Department of Pediatrics and Pediatric Neurology, Antwerp University Hospital, University of Antwerp, 2650 Edegem, Belgium
- 700 1_
- $a Meuwissen, Marije $u Pediatric Neurology, Marie Curie Hospital-CHU Charleroi, 6032 Charleroi, Belgium
- 700 1_
- $a Buzatu, Marga $u Pediatric Neurology, Marie Curie Hospital-CHU Charleroi, 6032 Charleroi, Belgium
- 700 1_
- $a Jansen, Anna $u Pediatric Neurology Unit, Department of Pediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, 1050 Brussels, Belgium
- 700 1_
- $a Scalais, Emmanuel $u Pediatric Neurology Unit, Department of Pediatrics, Centre Hospitalier de Luxembourg, 1313 Luxembourg, Luxembourg
- 700 1_
- $a Srivastava, Siddharth $u Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02108, USA
- 700 1_
- $a Tan, Wen Hann $u Department of Genetics, Boston Children's Hospital, Boston, MA 02108, USA
- 700 1_
- $a Olson, Heather E $u Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02108, USA $u Epilepsy Genetics Program, Boston Children's Hospital, Boston, MA 02108, USA
- 700 1_
- $a Loddenkemper, Tobias $u Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02108, USA
- 700 1_
- $a Poduri, Annapurna $u Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02108, USA $u Epilepsy Genetics Program, Boston Children's Hospital, Boston, MA 02108, USA
- 700 1_
- $a Helbig, Katherine L $u Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA $u The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- 700 1_
- $a Helbig, Ingo $u Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA $u The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA $u Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104USA $u Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104USA $u Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany $u Department of Neuropediatrics, Kiel University, 24105 Kiel, Germany
- 700 1_
- $a Fitzgerald, Mark P $u Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA $u The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA $u Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104USA $u Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany
- 700 1_
- $a Goldberg, Ethan M $u Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA $u The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- 700 1_
- $a Roser, Timo $u Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Children's Hospital, Ludwig-Maximilian-University of Munich, 80331 Munich, Germany
- 700 1_
- $a Borggraefe, Ingo $u Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Haunersches Children's Hospital, Ludwig-Maximilian-University of Munich, 80331 Munich, Germany $u Comprehensive Epilepsy Center, Ludwig-Maximilian- University of Munich, 80331 Munich, Germany
- 700 1_
- $a Brünger, Tobias $u Luxembourg Centre for Systems Biomedicine (LCSB), University Luxembourg, L-4243 Esch-sur-Alzette, Luxembourg
- 700 1_
- $a May, Patrick $u Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44102, USA
- 700 1_
- $a Lal, Dennis $u Luxembourg Centre for Systems Biomedicine (LCSB), University Luxembourg, L-4243 Esch-sur-Alzette, Luxembourg $u Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44102, USA $u Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T ., Cambridge, MA 02138, USA $u Cologne Center for Genomics (CCG), University of Cologne, 50667 Cologne, Germany
- 700 1_
- $a Lederer, Damien $u Institute for Pathology and Genetics, 6040 Gosselies, Belgium
- 700 1_
- $a Rubboli, Guido $u Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark $u University of Copenhagen, 2200 Copenhagen, Denmark
- 700 1_
- $a Heyne, Henrike O $u Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 4275 Leipzig, Germany $u Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, 320 Helsinki, Finland $u Program for Medical and Population Genetics/Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA $u Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02108, USA
- 700 1_
- $a Lesca, Gaetan $u Department of Medical Genetics, Groupement Hospitalier Est and ERN EpiCARE, University Hospitals of Lyon (HCL), 69001 Lyon, France $u Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, 69001 Lyon, France
- 700 1_
- $a Hedrich, Ulrike B S $u Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany
- 700 1_
- $a Benda, Jan $u Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany
- 700 1_
- $a Gardella, Elena $u Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark $u Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark
- 700 1_
- $a Lerche, Holger $u Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany
- 700 1_
- $a Møller, Rikke S $u Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark $u Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark
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