作者
Katrine M Johannesen,Yuanyuan Liu,Mahmoud Koko,Cathrine E Gjerulfsen,Lukas Sonnenberg,Julian Schubert,Christina Fenger,Ahmed Eltokhi,Maert Rannap,Nils A Koch,Stephan Lauxmann,Johanna Krüger,Josua Kegele,Laura Canafoglia,Silvana Franceschetti,Thomas U. Mayer,Johannes Rebstock,Pia Zacher,Susanne Ruf,Michael Alber,Katalin Sterbova,Petra Laššuthová,Marketa Vlckova,Johannes R. Lemke,Konrad Platzer,Ilona Krey,Constanze Heine,Dagmar Wieczorek,Judith Kroell-Seger,Caroline Lund,Karl Martin Klein,P Y Billie Au,Jong M. Rho,Alice W Ho,Silvia Masnada,Pierangelo Veggiotti,Lucio Giordano,Patrizia Accorsi,Christina E. Hoei-Hansen,Pasquale Striano,Federico Zara,Helene Verhelst,Judith S. Verhoeven,Bert van der Zwaag,Aster V. E. Harder,Eva H. Brilstra,Manuela Pendziwiat,Sebastian Lebon,María Vaccarezza,Ngoc Minh Le,Jakob Christensen,Sabine Grønborg,Stephen W. Scherer,Jennifer L. Howe,Walid Fazeli,Katherine B. Howell,Richard J. Leventer,Chloe A Stutterd,Sonja Walsh,Marion Gérard,Bénédicte Gérard,Sara Matricardi,Claudia M Bonardi,Stefano Sartori,Andrea Berger,Dorota Hoffman-Zacharska,Massimo Mastrangelo,Francesca Darra,Arve Vøllo,M. Mahdi Motazacker,Phillis Lakeman,Mathilde Nizon,Cornelia Betzler,Cecilia Altuzarra,Roseline Caume,Agathe Roubertie,Philippe Gelisse,Carla Marini,Renzo Guerrini,Frederic Bilan,Daniel Tibussek,Margarete Koch-Hogrebe,M Scott Perry,Shoji Ichikawa,Elena L. Dadali,A. A. Sharkov,Irina Mishina,Mikhail Abramov,Ilya V. Kanivets,Sergey Korostelev,Sergey Kutsev,Karen E. Wain,Nancy Eisenhauer,Monisa D. Wagner,Juliann M. Savatt,Karen Müller-Schlüter,Haim Bassan,Artem Borovikov,Marie-Cécile Nassogne,Anne Destrée
摘要
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.