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

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.

OriginalsprogEngelsk
TidsskriftBrain
Vol/bind145
Udgave nummer9
Sider (fra-til)2991-3009
Antal sider19
ISSN0006-8950
DOI
StatusUdgivet - 14 sep. 2022

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