Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.

Autor:	Johannesen KM; Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark.; Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark., Liu Y; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Koko M; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Gjerulfsen CE; Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark., Sonnenberg L; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany.; Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany., Schubert J; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Fenger CD; Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark., Eltokhi A; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Rannap M; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Koch NA; Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany., Lauxmann S; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany.; Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany., Krüger J; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Kegele J; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Canafoglia L; Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologio Carlo Besta, 20125 Milan, Italy., Franceschetti S; Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologio Carlo Besta, 20125 Milan, Italy., Mayer T; Epilepsy Center Kleinwachau, 01454 Dresden-Radeberg, Germany., Rebstock J; Epilepsy Center Kleinwachau, 01454 Dresden-Radeberg, Germany., Zacher P; Epilepsy Center Kleinwachau, 01454 Dresden-Radeberg, Germany., Ruf S; Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tuebingen, Germany., Alber M; Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, 72072 Tuebingen, Germany., Sterbova K; Department of Child Neurology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, 10000 Prague, Czech Republic., Lassuthová P; Department of Child Neurology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, 10000 Prague, Czech Republic., Vlckova M; Department of Child Neurology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, 10000 Prague, Czech Republic., Lemke JR; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 4275 Leipzig, Germany., Platzer K; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 4275 Leipzig, Germany., Krey I; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 4275 Leipzig, Germany., Heine C; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 4275 Leipzig, Germany., Wieczorek D; Institute of Human Genetics, University Clinic, Heinrich-Heine-University, 40210 Düsseldorf, Germany., Kroell-Seger J; Children's Department, Swiss Epilepsy Centre, Clinic Lengg, 8001 Zurich, Switzerland., Lund C; National Centre for Rare Epilepsy-Related Disorders, Oslo University Hospital, 0001 Oslo, Norway., Klein KM; Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2P 0A1, Canada., Au PYB; Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, AB T6G 2T4, Canada., Rho JM; Section of Pediatric Neurology, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, AB T2P 0A1, Canada., Ho AW; Section of Pediatric Neurology, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, AB T2P 0A1, Canada., Masnada S; Department of Child Neurology, V. Buzzi Children's Hospital, 20125 Milan, Italy., Veggiotti P; Department of Child Neurology, V. Buzzi Children's Hospital, 20125 Milan, Italy.; 'L. Sacco' Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy., Giordano L; Child Neuropsychiatric Unit, Civilian Hospital, 25100 Brescia, Italy., Accorsi P; Child Neuropsychiatric Unit, Civilian Hospital, 25100 Brescia, Italy., Hoei-Hansen CE; Department of Pediatrics, Copenhagen University Hospital Rigshospitalet, 2200 Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark., Striano P; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16121 Genova, Italy.; IRCCS 'G. Gaslini' Institute, 16121 Genoa, Italy., Zara F; IRCCS 'G. Gaslini' Institute, 16121 Genoa, Italy., Verhelst H; Department of Pediatrics, Division of Pediatric Neurology, Gent University Hospital, 9042 Gent, Belgium., Verhoeven JS; Academic Center for Epileptology, Kempenhaeghe/Maastricht University Medical Center, 5591 Heeze, The Netherlands., Braakman HMH; Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, 6525 Nijmegen, The Netherlands., van der Zwaag B; Department of Genetics, University Medical Center Utrecht, Utrecht University, 3553 Utrecht, The Netherlands., Harder AVE; Department of Genetics, University Medical Center Utrecht, Utrecht University, 3553 Utrecht, The Netherlands., Brilstra E; Department of Genetics, University Medical Center Utrecht, Utrecht University, 3553 Utrecht, The Netherlands., Pendziwiat M; Department of Neuropediatrics, Universitätsklinikum Schleswig Holstein Campus Kiel, 24106 Kiel, Germany., Lebon S; Pediatric Neurology and Neurorehabilitation Unit, Woman Mother Child Department, Lausanne University Hospital (CHUV), 1000 Lausanne, Switzerland.; University of Lausanne, 1000 Lausanne, Switzerland., Vaccarezza M; Department of Pediatric Neurology, Hospital Italiano de Buenos Aires, C1428 Buenos Aires, Argentina., Le NM; Center for Pediatric Neurology, Cleveland Clinic, Cleveland, OH 44102, USA., Christensen J; Department of Neurology, Aarhus University Hospital, 8000 Aarhus, Denmark., Grønborg S; Center for Rare Diseases, Department of Pediatrics and Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, 2200 Copenhagen, Denmark., Scherer SW; McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, ON 66777, Canada.; The Centre for Applied Genomics and Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON 66777, Canada., Howe J; Department of Neuropediatrics, University Hospital Bonn, 53229 Bonn, Germany., Fazeli W; Institute for Molecular and Behavioral Neuroscience, University of Cologne, 50667 Cologne, Germany.; Neurology Department, The Royal Children's Hospital Melbourne, 3002 Melbourne, Australia., Howell KB; Neurology Department, The Royal Children's Hospital Melbourne, 3002 Melbourne, Australia.; Murdoch Children's Research Institute, 3052 Parkville, Australia.; Department of Pediatrics, University of Melbourne, Royal Children's Hospital, 3052 Parkville, Australia., Leventer R; Neurology Department, The Royal Children's Hospital Melbourne, 3002 Melbourne, Australia.; Murdoch Children's Research Institute, 3052 Parkville, Australia.; Department of Pediatrics, University of Melbourne, Royal Children's Hospital, 3052 Parkville, Australia., Stutterd C; Murdoch Children's Research Institute, 3052 Parkville, Australia.; Department of Pediatrics, University of Melbourne, Royal Children's Hospital, 3052 Parkville, Australia., Walsh S; Department of Neuropediatrics, Children's Hospital, University Hospital Carl Gustav Carus, Technical University, 1099 Dresden, Germany., Gerard M; Genetics Department, CHU Côte de Nacre, 14118 Caen, France., Gerard B; Genetics Department, CHRU Strasbourg, 67000 Strasbourg, France., Matricardi S; Child Neurology and Psychiatry Unit, Children's Hospital G. Salesi, 60121 Ancona, Italy., Bonardi CM; Department of Woman's and Child's Health, Padova University Hospital, 35100 Padova, Italy., Sartori S; Child Neurology and Clinical Neurophysiology Unit, Padova University Hospital, 35100 Padova, Italy., Berger A; Department of Neuropediatrics, Klinikum Weiden, Kliniken Nordoberpfalz AG, 92637 Weiden, Germany., Hoffman-Zacharska D; Department of Medical Genetics, Institute of Mother and Child, 00-034 Warsaw, Poland., Mastrangelo M; Pediatric Neurology Unit, Vittore Buzzi Hospital, ASST Fatebenefratelli Sacco, 20100 Milan, Italy., Darra F; Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37121 Verona, Italy., Vøllo A; Department of Pediatrics, Oestfold Hospital, 1712 Graalum, Norway., Motazacker MM; Laboratory of Genome Diagnostics, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1019 Amsterdam, Netherlands., Lakeman P; Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, 1019 Amsterdam, Netherlands., Nizon M; Service de Génétique Médicale, CHU Nantes, 44093 Nantes, France., Betzler C; Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik, 83569 Vogtareuth, Germany.; Research Institute 'Rehabilitation, Transition, Palliation', PMU Salzburg, 5020 Salzburg, Austria., Altuzarra C; Department of Pediatrics, St. Jacques Hospital, 25000 Besançon, France., Caume R; Clinique de Génétique Guy Fontaine, CHU Lille, 59000, Lille, France., Roubertie A; Département de Neuropédiatrie, INSERM, CHU Montpellier, 34000 Montpellier, France., Gélisse P; Département de Neuropédiatrie, INSERM, CHU Montpellier, 34000 Montpellier, France., Marini C; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, 50131 Florence, Italy., Guerrini R; IRCCS Stella Maris, 56121 Pisa, Italy., Bilan F; Service de Génétique, Centre Hospitalier Universitaire de Poitiers, 86021 Poitiers, France., Tibussek D; Child Neurology, Center for Pediatric and Teenage Health Care, 53757 Sankt Augustin, Germany., Koch-Hogrebe M; Vestische Kinder- und Jugendklinik, 45711 Datteln, Germany., Perry MS; Justin Neurosciences Center, Cook Children's Medical Center, Fort Worth, TX 76101, USA., Ichikawa S; Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, CA 92637, USA., Dadali E; Research Centre for Medical Genetics, 115522 Moscow, Russia.; Veltischev Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, 125412 Moscow, Russia., Sharkov A; Veltischev Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, 125412 Moscow, Russia.; Genomed Ltd., 100000 Moscow, Russia., Mishina I; Research Centre for Medical Genetics, 115522 Moscow, Russia., Abramov M; Veltischev Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, 125412 Moscow, Russia., Kanivets I; Svt. 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Sechenov First Moscow State Medical University, 100000 Moscow, Russia., Kutsev S; Research Centre for Medical Genetics, 115522 Moscow, Russia., Wain KE; Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA., Eisenhauer N; Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA., Wagner M; Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA., Savatt JM; Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA 17837, USA., Müller-Schlüter K; Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School, 16816 Neuruppin, Germany., Bassan H; Pediatric Neurology & Development Center, Shamir Medical Center (Assaf Harofe), Be'er Ya'akov, Israel.; Sackler Faculty of Medicine, Tel Aviv University, 5296001 Tel Aviv, Israel., Borovikov A; Research Centre for Medical Genetics, 115522 Moscow, Russia., Nassogne MC; Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1000 Brussels, Belgium., Destrée A; 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Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02108, USA., Poduri A; Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02108, USA.; Epilepsy Genetics Program, Boston Children's Hospital, Boston, MA 02108, USA., Helbig KL; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Helbig I; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104USA.; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104USA.; Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany.; Department of Neuropediatrics, Kiel University, 24105 Kiel, Germany., Fitzgerald MP; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19104USA.; Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany., Goldberg EM; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.; The Epilepsy Neurogenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Roser T; 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., Borggraefe I; 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.; Comprehensive Epilepsy Center, Ludwig-Maximilian- University of Munich, 80331 Munich, Germany., Brünger T; Luxembourg Centre for Systems Biomedicine (LCSB), University Luxembourg, L-4243 Esch-sur-Alzette, Luxembourg., May P; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44102, USA., Lal D; Luxembourg Centre for Systems Biomedicine (LCSB), University Luxembourg, L-4243 Esch-sur-Alzette, Luxembourg.; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44102, USA.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T ., Cambridge, MA 02138, USA.; Cologne Center for Genomics (CCG), University of Cologne, 50667 Cologne, Germany., Lederer D; Institute for Pathology and Genetics, 6040 Gosselies, Belgium., Rubboli G; Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark.; University of Copenhagen, 2200 Copenhagen, Denmark., Heyne HO; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 4275 Leipzig, Germany.; Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, 320 Helsinki, Finland.; Program for Medical and Population Genetics/Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02108, USA., Lesca G; Department of Medical Genetics, Groupement Hospitalier Est and ERN EpiCARE, University Hospitals of Lyon (HCL), 69001 Lyon, France.; Institut Neuromyogène, CNRS UMR 5310 - INSERM U1217, Université de Lyon, Université Claude Bernard Lyon 1, 69001 Lyon, France., Hedrich UBS; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Benda J; Institute for Neurobiology, University of Tuebingen, 72072 Tuebingen, Germany., Gardella E; Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark.; Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark., Lerche H; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72072 Tuebingen, Germany., Møller RS; Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center, 4293 Dianalund, Denmark.; Institute for Regional Health Services, University of Southern Denmark, 5230 Odense, Denmark.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2022 Sep 14; Vol. 145 (9), pp. 2991-3009.
DOI:	10.1093/brain/awab321
Abstrakt:	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. (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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