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

Katrine M Johannesen, Yuanyuan Liu, Mahmoud Koko, Cathrine E Gjerulfsen, Lukas Sonnenberg, Julian Schubert, Christina D Fenger, Ahmed Eltokhi, Maert Rannap, Nils A Koch, Stephan Lauxmann, Johanna Krüger, Josua Kegele, Laura Canafoglia, Silvana Franceschetti, Thomas Mayer, Johannes Rebstock, Pia Zacher, Susanne Ruf, Michael AlberKatalin Sterbova, Petra Lassuthová, 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 Brilstra, Manuela Pendziwiat, Sebastian Lebon, Maria Vaccarezza, Ngoc Minh Le, Jakob Christensen, Sabine Grønborg, Stephen W Scherer, Jennifer Howe, Walid Fazeli, Katherine B Howell, Richard Leventer, Chloe Stutterd, Sonja Walsh, Marion Gerard, Bénédicte Gerard, 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 Gélisse, Carla Marini, Renzo Guerrini, Frederic Bilan, Daniel Tibussek, Margarete Koch-Hogrebe, M Scott Perry, Shoji Ichikawa, Elena Dadali, Artem Sharkov, Irina Mishina, Mikhail Abramov, Ilya Kanivets, Sergey Korostelev, Sergey Kutsev, Karen E Wain, Nancy Eisenhauer, Monisa Wagner, Juliann M Savatt, Karen Müller-Schlüter, Haim Bassan, Artem Borovikov, Marie-Cecile Nassogne, Anne Destrée, An-Sofie Schoonjans, Marije Meuwissen, Marga Buzatu, Anna Jansen, Emmanuel Scalais, Siddharth Srivastava, Wen-Hann Tan, Heather E Olson, Tobias Loddenkemper, Annapurna Poduri, Katherine L Helbig, Ingo Helbig, Mark P Fitzgerald, Ethan M Goldberg, Timo Roser, Ingo Borggraefe, Tobias Brünger, Patrick May, Dennis Lal, Damien Lederer, Guido Rubboli, Henrike O Heyne, Gaetan Lesca, Ulrike B S Hedrich, Jan Benda, Elena Gardella, Holger Lerche, Rikke S Møller

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2991-3009
Number of pages19
Issue number9
Early online date25 Aug 2021
Publication statusPublished - 14 Sep 2022

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© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email:


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