TY - JOUR

T1 - Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

AU - Johannesen, Katrine M.

AU - Liu, Yuanyuan

AU - Koko, Mahmoud

AU - Gjerulfsen, Cathrine E.

AU - Sonnenberg, Lukas

AU - Schubert, Julian

AU - Fenger, Christina D.

AU - Eltokhi, Ahmed

AU - Rannap, Maert

AU - Koch, Nils A.

AU - Lauxmann, Stephan

AU - Krüger, Johanna

AU - Kegele, Josua

AU - Canafoglia, Laura

AU - Franceschetti, Silvana

AU - Mayer, Thomas

AU - Rebstock, Johannes

AU - Zacher, Pia

AU - Ruf, Susanne

AU - Alber, Michael

AU - Sterbova, Katalin

AU - Lassuthová, Petra

AU - Vlckova, Marketa

AU - Lemke, Johannes R.

AU - Platzer, Konrad

AU - Krey, Ilona

AU - Heine, Constanze

AU - Wieczorek, Dagmar

AU - Kroell-Seger, Judith

AU - Lund, Caroline

AU - Klein, Karl Martin

AU - Au, P. Y.Billie

AU - Rho, Jong M.

AU - Ho, Alice W.

AU - Masnada, Silvia

AU - Veggiotti, Pierangelo

AU - Giordano, Lucio

AU - Accorsi, Patrizia

AU - Hoei-Hansen, Christina E.

AU - Striano, Pasquale

AU - Zara, Federico

AU - Verhelst, Helene

AU - Verhoeven, Judith S.

AU - Braakman, Hilde M.H.

AU - van der Zwaag, Bert

AU - Harder, Aster V.E.

AU - Brilstra, Eva

AU - Pendziwiat, Manuela

AU - Lebon, Sebastian

AU - Vaccarezza, Maria

AU - Le, Ngoc Minh

AU - Christensen, Jakob

AU - Grønborg, Sabine

AU - Scherer, Stephen W.

AU - Howe, Jennifer

AU - Fazeli, Walid

AU - Howell, Katherine B.

AU - Leventer, Richard

AU - Stutterd, Chloe

AU - Walsh, Sonja

AU - Gerard, Marion

AU - Gerard, Bénédicte

AU - Matricardi, Sara

AU - Bonardi, Claudia M.

AU - Sartori, Stefano

AU - Berger, Andrea

AU - Hoffman-Zacharska, Dorota

AU - Mastrangelo, Massimo

AU - Darra, Francesca

AU - Vøllo, Arve

AU - Motazacker, M. Mahdi

AU - Lakeman, Phillis

AU - Nizon, Mathilde

AU - Betzler, Cornelia

AU - Altuzarra, Cecilia

AU - Caume, Roseline

AU - Roubertie, Agathe

AU - Gélisse, Philippe

AU - Marini, Carla

AU - Guerrini, Renzo

AU - Bilan, Frederic

AU - Tibussek, Daniel

AU - Koch-Hogrebe, Margarete

AU - Perry, M. Scott

AU - Ichikawa, Shoji

AU - Dadali, Elena

AU - Sharkov, Artem

AU - Mishina, Irina

AU - Abramov, Mikhail

AU - Kanivets, Ilya

AU - Korostelev, Sergey

AU - Kutsev, Sergey

AU - Wain, Karen E.

AU - Eisenhauer, Nancy

AU - Wagner, Monisa

AU - Savatt, Juliann M.

AU - Müller-Schlüter, Karen

AU - Bassan, Haim

AU - Borovikov, Artem

AU - Nassogne, Marie Cecile

AU - Destrée, Anne

AU - Schoonjans, An Sofie

AU - Meuwissen, Marije

AU - Buzatu, Marga

AU - Jansen, Anna

AU - Scalais, Emmanuel

AU - Srivastava, Siddharth

AU - Tan, Wen Hann

AU - Olson, Heather E.

AU - Loddenkemper, Tobias

AU - Poduri, Annapurna

AU - Helbig, Katherine L.

AU - Helbig, Ingo

AU - Fitzgerald, Mark P.

AU - Goldberg, Ethan M.

AU - Roser, Timo

AU - Borggraefe, Ingo

AU - Brünger, Tobias

AU - May, Patrick

AU - Lal, Dennis

AU - Lederer, Damien

AU - Rubboli, Guido

AU - Heyne, Henrike O.

AU - Lesca, Gaetan

AU - Hedrich, Ulrike B.S.

AU - Benda, Jan

AU - Gardella, Elena

AU - Lerche, Holger

AU - Møller, Rikke S.

N1 - Publisher Copyright: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - epilepsy

KW - genetics

KW - personalized medicine

KW - SCN8A

U2 - 10.1093/brain/awab321

DO - 10.1093/brain/awab321

M3 - Journal article

C2 - 34431999

AN - SCOPUS:85138447351

VL - 145

SP - 2991

EP - 3009

JO - Brain

JF - Brain

SN - 0006-8950

IS - 9

ER -