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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Katrine M. Johannesen - , The Danish Epilepsy Center (Autor:in)
  • Yuanyuan Liu - , Universitätsklinikum Tübingen (Autor:in)
  • Mahmoud Koko - , Universitätsklinikum Tübingen (Autor:in)
  • Cathrine E. Gjerulfsen - , The Danish Epilepsy Center (Autor:in)
  • Lukas Sonnenberg - , Universitätsklinikum Tübingen (Autor:in)
  • Julian Schubert - , Universitätsklinikum Tübingen (Autor:in)
  • Christina D. Fenger - , The Danish Epilepsy Center (Autor:in)
  • Ahmed Eltokhi - , Universitätsklinikum Tübingen (Autor:in)
  • Maert Rannap - , Universitätsklinikum Tübingen (Autor:in)
  • Nils A. Koch - , Universitätsklinikum Tübingen (Autor:in)
  • Stephan Lauxmann - , Universitätsklinikum Tübingen (Autor:in)
  • Johanna Krüger - , Universitätsklinikum Tübingen (Autor:in)
  • Josua Kegele - , Universitätsklinikum Tübingen (Autor:in)
  • Laura Canafoglia - , IRCCS Fondazione Istituto Neurologico Carlo Besta - Milano (Autor:in)
  • Silvana Franceschetti - , IRCCS Fondazione Istituto Neurologico Carlo Besta - Milano (Autor:in)
  • Thomas Mayer - , Epilepsy Center Kleinwachau (Autor:in)
  • Johannes Rebstock - , Epilepsy Center Kleinwachau (Autor:in)
  • Pia Zacher - , Epilepsy Center Kleinwachau (Autor:in)
  • Susanne Ruf - , Universitäts-Kinderspital Zürich – Eleonorenstiftung (Autor:in)
  • Michael Alber - , Universitäts-Kinderspital Zürich – Eleonorenstiftung (Autor:in)
  • Katalin Sterbova - , Universitätskrankenhaus Motol (Autor:in)
  • Petra Lassuthová - , Universitätskrankenhaus Motol (Autor:in)
  • Marketa Vlckova - , Universitätskrankenhaus Motol (Autor:in)
  • Johannes R. Lemke - , Universitätsklinikum Leipzig (Autor:in)
  • Konrad Platzer - , Universitätsklinikum Leipzig (Autor:in)
  • Ilona Krey - , Universitätsklinikum Leipzig (Autor:in)
  • Constanze Heine - , Universitätsklinikum Leipzig (Autor:in)
  • Dagmar Wieczorek - , Odessa National Medical University (Autor:in)
  • Judith Kroell-Seger - , Universitätsklinikum Münster (Autor:in)
  • Caroline Lund - , Universitätsklinikum Oslo (Autor:in)
  • Karl Martin Klein - , University of Calgary (Autor:in)
  • P. Y. Billie Au - , University of Calgary (Autor:in)
  • Jong M Rho - , University of Calgary (Autor:in)
  • Alice W. Ho - , University of Calgary (Autor:in)
  • Silvia Masnada - , V. Buzzi Children's Hospital (Autor:in)
  • Pierangelo Veggiotti - , V. Buzzi Children's Hospital (Autor:in)
  • Lucio Giordano - , Civilian Hospital (Autor:in)
  • Patrizia Accorsi - , Civilian Hospital (Autor:in)
  • Christina E Hoei-Hansen - , Copenhagen University Hospitals (Autor:in)
  • Pasquale Striano - , University of Genoa (Autor:in)
  • Federico Zara - , IRCCS Istituto Giannina Gaslini - Genova (Autor:in)
  • Helene Verhelst - , Ghent University Hospital (Autor:in)
  • Judith S. Verhoeven - , Akademisches Krankenhaus Maastricht (UMC+) (Autor:in)
  • Hilde M. H. Braakman - , Radboud University Medical Center (Autor:in)
  • Bert van der Zwaag - , Utrecht University (Autor:in)
  • Aster V. E. Harder - , Utrecht University (Autor:in)
  • Eva Brilstra - , Utrecht University (Autor:in)
  • Manuela Pendziwiat - , Universitätsklinikum Schleswig-Holstein Campus Kiel (Autor:in)
  • Sebastian Lebon - , Centre Hospitalier Universitaire Vaudois (Autor:in)
  • Maria Vaccarezza - , Hospital Italiano de Buenos Aires (Autor:in)
  • Ngoc Minh Le - , Charité – Universitätsmedizin Berlin (Autor:in)
  • Jakob Christensen - , Aarhus University Hospital (AUH) (Autor:in)
  • Sabine Grønborg - , Copenhagen University Hospitals (Autor:in)
  • Stephen W. Scherer - , University of Toronto (Autor:in)
  • Jennifer Howe - , Universitätsklinikum Bonn (Autor:in)
  • Walid Fazeli - , Deutsche Sporthochschule Köln (Autor:in)
  • Katherine B. Howell - , Royal Children's Hospital Melbourne (Autor:in)
  • Richard Leventer - , Royal Children's Hospital Melbourne (Autor:in)
  • Chloe Stutterd - , Murdoch Children's Research Institute (Autor:in)
  • Sonja Walsh - , Klinik und Poliklinik für Kinder- und Jugendmedizin, Abteilung für Neuropädiatrie (Autor:in)
  • Marion Gerard - , Forest Research Institute (Autor:in)
  • Bénédicte Gerard - , Forest Research Institute (Autor:in)
  • Sara Matricardi - , Children's Hospital G. Salesi (Autor:in)
  • Claudia M. Bonardi - , Azienda Ospedaliera di Padova (Autor:in)
  • Stefano Sartori - , Azienda Ospedaliera di Padova (Autor:in)
  • Andrea Berger - , Kliniken Nordoberpfalz – Klinikum Weiden (Autor:in)
  • Dorota Hoffman-Zacharska - , Institute of Mother and Child (Autor:in)
  • Massimo Mastrangelo - , Vittore Buzzi Hospital (Autor:in)
  • Francesca Darra - , University of Verona (Autor:in)
  • Arve Vøllo - , Oestfold Hospital (Autor:in)
  • M. Mahdi Motazacker - , University of Amsterdam (Autor:in)
  • Phillis Lakeman - , University of Amsterdam (Autor:in)
  • Mathilde Nizon - , CHU de Nantes (Autor:in)
  • Cornelia Betzler - , Schön Klinik Vogtareuth (Autor:in)
  • Cecilia Altuzarra - , St. Jacques Hospital (Autor:in)
  • Roseline Caume - , Clinique de Génétique Guy Fontaine (Autor:in)
  • Agathe Roubertie - , Département de Neuropédiatrie (Autor:in)
  • Philippe Gélisse - , Département de Neuropédiatrie (Autor:in)
  • Carla Marini - , Università degli Studi di Firenze (Autor:in)
  • Renzo Guerrini - , IRCCS Fondazione Stella Maris (Autor:in)
  • Frederic Bilan - , CHU de Poitiers (Autor:in)
  • Daniel Tibussek - , Asklepios Kinderklinik Sankt Augustin (Autor:in)
  • Margarete Koch-Hogrebe - , Vestische Kinder- und Jugendklinik Datteln (Autor:in)
  • M. Scott Perry - , Justin Neurosciences Center (Autor:in)
  • Shoji Ichikawa - , Ambry Genetics (Autor:in)
  • Elena Dadali - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Artem Sharkov - , Pirogov Russian National Research Medical University (Autor:in)
  • Irina Mishina - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Mikhail Abramov - , Pirogov Russian National Research Medical University (Autor:in)
  • Ilya Kanivets - , Svt. Luka's Institute of Child Neurology & Epilepsy (Autor:in)
  • Sergey Korostelev - , Svt. Luka's Institute of Child Neurology & Epilepsy (Autor:in)
  • Sergey Kutsev - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Karen E. Wain - , Geisinger Medical Center (Autor:in)
  • Nancy Eisenhauer - , Geisinger Medical Center (Autor:in)
  • Monisa Wagner - , Geisinger Medical Center (Autor:in)
  • Juliann M. Savatt - , Geisinger Medical Center (Autor:in)
  • Karen Müller-Schlüter - , Universitätsklinikum Ruppin-Brandenburg (Autor:in)
  • Haim Bassan - , Shamir Medical Center (Assaf Harofe) (Autor:in)
  • Artem Borovikov - , Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Marie Cecile Nassogne - , Pediatric Neurology Unit (Autor:in)
  • Anne Destrée - , Institute Pathology Et De Génétique (Autor:in)
  • An Sofie Schoonjans - , University of Antwerp (Autor:in)
  • Marije Meuwissen - , CHU de Charleroi (Autor:in)
  • Marga Buzatu - , CHU de Charleroi (Autor:in)
  • Anna Jansen - , Pediatric Neurology Unit (Autor:in)
  • Emmanuel Scalais - , Center Hospitalier de Luxembourg (Autor:in)
  • Siddharth Srivastava - , Boston Children's Hospital (Autor:in)
  • Wen Hann Tan - , Boston Children's Hospital (Autor:in)
  • Heather E. Olson - , Boston Children's Hospital (Autor:in)
  • Tobias Loddenkemper - , Boston Children's Hospital (Autor:in)
  • Annapurna Poduri - , Boston Children's Hospital (Autor:in)
  • Katherine L. Helbig - , Children's Hospital of Philadelphia (CHOP) (Autor:in)
  • Ingo Helbig - , Children's Hospital of Philadelphia (CHOP) (Autor:in)
  • Mark P. Fitzgerald - , Children's Hospital of Philadelphia (CHOP) (Autor:in)
  • Ethan M. Goldberg - , Children's Hospital of Philadelphia (CHOP) (Autor:in)
  • Timo Roser - , Ludwig-Maximilians-Universität München (LMU) (Autor:in)
  • Ingo Borggraefe - , Ludwig-Maximilians-Universität München (LMU) (Autor:in)
  • Tobias Brünger - , University of Luxembourg (Autor:in)
  • Patrick May - , Rady Children's Institute for Genomic Medicine (Autor:in)
  • Dennis Lal - , University of Luxembourg (Autor:in)
  • Damien Lederer - , Institute Pathology Et De Génétique (Autor:in)
  • Guido Rubboli - , The Danish Epilepsy Center (Autor:in)
  • Henrike O. Heyne - , Universitätsklinikum Leipzig (Autor:in)
  • Gaetan Lesca - , Hospices civils de Lyon (Autor:in)
  • Ulrike B. S. Hedrich - , Universitätsklinikum Tübingen (Autor:in)
  • Jan Benda - , Universitätsklinikum Tübingen (Autor:in)
  • Elena Gardella - , The Danish Epilepsy Center (Autor:in)
  • Holger Lerche - , Universitätsklinikum Tübingen (Autor:in)
  • Rikke S. Møller - , The Danish Epilepsy Center (Autor:in)

Abstract

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)2991-3009
Seitenumfang19
FachzeitschriftBrain : a journal of neurology
Jahrgang145
Ausgabenummer9
PublikationsstatusVeröffentlicht - 14 Sept. 2022
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC10147326
Scopus 85138447351

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Epilepsy, Generalized/drug therapy, Epileptic Syndromes/drug therapy, Genetic Association Studies, Humans, Infant, Intellectual Disability/genetics, Mutation, NAV1.6 Voltage-Gated Sodium Channel/genetics, Prognosis, Seizures/drug therapy, Sodium Channel Blockers/therapeutic use

Bibliotheksschlagworte