[en] 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 could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 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 DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no (11) or unclassifiable (6) epilepsy; only three had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of 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 LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
Centre de recherche :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Génétique & processus génétiques Neurologie
Auteur, co-auteur :
Johannesen, Katrine M.
Liu, Yuanyuan
Koko, Mahmoud
Gjerulfsen, Cathrine E.
Sonnenberg, Lukas
Schubert, Julian
Fenger, Christina D.
Eltokhi, Ahmed
Rannap, Maert
Koch, Nils A.
Lauxmann, Stephan
Krüger, Johanna
Kegele, Josua
Canafoglia, Laura
Franceschetti, Silvana
Mayer, Thomas
Rebstock, Johannes
Zacher, Pia
Ruf, Susanne
Alber, Michael
Sterbova, Katalin
Lassuthová, Petra
Vlckova, Marketa
Lemke, Johannes R.
Platzer, Konrad
Krey, Ilona
Heine, Constanze
Wieczorek, Dagmar
Kroell-Seger, Judith
Lund, Caroline
Klein, Karl Martin
Billie Au, P. Y.
Rho, Jong M.
Ho, Alice W.
Masnada, Silvia
Veggiotti, Pierangelo
Giordano, Lucio
Accorsi, Patrizia
Hoei-Hansen, Christina E.
Striano, Pasquale
Zara, Federico
Verhelst, Helene
Verhoeven, Judith S.
van der Zwaag, Bert
Harder, Aster V. E.
Brilstra, Eva
Pendziwiat, Manuela
Lebon, Sebastian
Vaccarezza, Maria
Minh Le, Ngoc
Christensen, Jakob
Grønborg, Sabine
Scherer, Stephen W.
Howe, Jennifer
Fazeli, Walid
Howell, Katherine B.
Leventer, Richard
Stutterd, Chloe
Walsh, Sonja
Gerard, Marion
Gerard, Bénédicte
Matricardi, Sara
Bonardi, Claudia M.
Sartori, Stefano
Berger, Andrea
Hoffman-Zacharska, Dorota
Mastrangelo, Massimo
Darra, Francesca
Vøllo, Arve
Motazacker, M. Mahdi
Lakeman, Phillis
Nizon, Mathilde
Betzler, Cornelia
Altuzarra, Cecilia
Caume, Roseline
Roubertie, Agathe
Gélisse, Philippe
Marini, Carla
Guerrini, Renzo
Bilan, Frederic
Tibussek, Daniel
Koch-Hogrebe, Margarete
Perry, M. Scott
Ichikawa, Shoji
Dadali, Elena
Sharkov, Artem
Mishina, Irina
Abramov, Mikhail
Kanivets, Ilya
Korostelev, Sergey
Kutsev, Sergey
Wain, Karen E.
Eisenhauer, Nancy
Wagner, Monisa
Savatt, Juliann M.
Müller-Schlüter, Karen
Bassan, Haim
Borovikov, Artem
Nassogne, Marie-Cecile
Destrée, Anne
Schoonjans, An-Sofie
Meuwissen, Marije
Buzatu, Marga
Jansen, Anna
Scalais, Emmanuel
Srivastava, Siddharth
Tan, Wen-Hann
Olson, Heather E.
Loddenkemper, Tobias
Poduri, Annapurna
Helbig, Katherine L.
Helbig, Ingo
Fitzgerald, Mark P.
Goldberg, Ethan M.
Roser, Timo
Borggraefe, Ingo
Brünger, Tobias
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
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