Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications
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; Billie Au, P Y; 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; van der Zwaag, Bert; Harder, Aster V E; Brilstra, Eva; Pendziwiat, Manuela; Lebon, Sebastian; Vaccarezza, Maria; Minh Le, Ngoc; 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
(2022) Brain : a journal of neurology, volume 145, issue 9, pp. 2991 - 3009
(Article)
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);
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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.
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Keywords: Epilepsy, Generalized/drug therapy, Epileptic Syndromes/drug therapy, Genetic Association Studies, Humans, Infant, Intellectual Disability/genetics, Mutation, NAV1.6 Voltage-Gated Sodium Channel/genetics, Prognosis, SCN8A, Seizures/drug therapy, Sodium Channel Blockers/therapeutic use, epilepsy, genetics, personalized medicine, General Medicine, Journal Article
ISSN: 0006-8950
Publisher: Oxford University Press
Note: Funding Information: This work was supported by the German Research Foundation and the Fonds Nationale de la Recherche in Luxembourg (Research Unit FOR-2715, DFG grants Le1030/15-1 and/16-1 to H.L., He8155/1-1 to U.B.S.H., He5415/7-1 to I.H., FNR grant INTER/DFG/17/11583046 to P.M.), the German Federal Ministry for Education and Research (BMBF, Treat-ION, 01GM1907A to H.L., D.L. and P.M.), the foundation no epilep (to H.L. to partially support L.S.), the Medical Faculty of the University of Tuebingen (the Fortune program 2430-00 to SL). K.S., P.L. and M.V. were funded by grant: MH CR AZV NU20-04-00279. Epi25 was supported by the National Human Genome Research Institute (NHGRI) grants UM1 HG008895 and 5U01HG009088-02 and the Stanley Center for Psychiatric Research at the Broad Institute. S.I. was employed by and received a salary from Ambry Genetics. S.S. hold the GlaxoSmithKline Endowed Chair in Genome Sciences at the Hospital for Sick Children and University of Toronto. P.S. has received speaker fees and participated at advisory boards for Biomarin, Zogenyx and GW Pharmaceuticals and has received research funding from ENECTA BV, GW Pharmaceuticals, Kolfarma Srl. and Eisai. E.M. was funded by a grant NIH NINDS K08 NS097633 and the Foerderer Award for Excellence from The Children's Hospital of Philadelphia Research Institute. P.V. received a speaker fee from Nutricia GmbH, Dr Schär AG/SPA, Eisai, Nestle, Pediatrica. F.Z. and P.S. developed this work within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016). I.H. was also supported by The Hartwell Foundation through an Individual Biomedical Research Award. This work was also supported by the National Institute for Neurological Disorders and Stroke (K02 NS112600), including support through the Center Without Walls on ion channel function in epilepsy ('Channelopathy-associated Research Center', U54 NS108874), the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Intellectual and Developmental Disabilities Research Center (IDDRC) at the Children's Hospital of Philadelphia and the University of Pennsylvania (U54 HD086984) and by intramural funds from the Children's Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN). Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001878. This project was also supported in part by the Institute for Translational Medicine and Therapeutics' (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics at the Perelman School of Medicine of the University of Pennsylvania. H.E.O. was funded by K23 NS107646-03, PI Olson. Publisher Copyright: © 2022 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
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