Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
Authors: 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 , Au P Y Billie , 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 , Braakman Hilde M H , van der Zwaag Bert , Harder Aster V E , Brilstra Eva , Pendziwiat Manuela , Lebon Sebastian , Vaccarezza Maria , Le Ngoc Minh , 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 , Lal Dennis , Lederer Damien , Rubboli Guido , Heyne Henrike O , Lesca Gaetan , Hedrich Ulrike B S , Benda Jan , Gardella Elena , Lerche Holger , Møller Rikke S 
Published: August 2021

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.