Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
Authors: Johannesen Katrine M , Liu Yuanyuan , Gjerulfsen Cathrine E , Koko Mahmoud , 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 , Krey Ilona , Heine Constanze , Wieczorek Dagmar , Kroell-Seger Judith , Lund Caroline , Klein Karl Martin , Au PY 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 , S.Verhoeven Judith , van der Zwaag Bert , Harder Aster V. E. , Brilstra Eva , Pendziwiat Manuela , Lebon Sebastian , Vaccarezza Maria , Le Ngoc Minh , Christensen Jakob , Schmidt-Petersen Mette U , 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 , Lesca Gaetan , Hedrich Ulrike BS , Benda Jan , Gardella Elena , Lerche Holger , Møller Rikke S 
Published: March 2021

We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. 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 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two 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 therapeutic treatment option in early onset SCN8A-related focal epilepsy.