Genotype-phenotype correlations in SCN8A -related disorders reveal prognostic and therapeutic implications
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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.
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Seizure onset under age 3 months in SCN2A DEEs and 6 months in SCN8A DEEs is associated with GOF, and SCBs are efficacious in these phenotypes.
“Seizure onset under age 3 months in SCN2A DEEs and 6 months in SCN8A DEEs, is associated with GOF 34,35 , and SCBs are efficacious in these phenotypes 34 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [35]
The phenotype-correlations discussion (p. 25) reports an approximately three-month GOF/LOF onset boundary for SCN2A, but describes overlapping onset ages for SCN8A rather than a six-month boundary. The treatment-effects results (p. 22) find better responses to sodium-channel blockers in SCN8A GOF carriers; they do not establish efficacy for SCN2A DEE in this paper. (LLM, conf=0.86)
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- Authors
- Johannesen, K. M., Liu, Y., Koko, M., Gjerulfsen, C. E., Sonnenberg, L., Schubert, J., Fenger, C. D., Eltokhi, A., Rannap, M., Koch, N. A., Lauxmann, S., Krüger, J., Kegele, J., Canafoglia, L., Franceschetti, S., Mayer, T., Rebstock, J., Zacher, P., Ruf, S., Alber, M., Sterbova, K., Lassuthová, P., Vlckova, M., Lemke, J. R., Platzer, K., Krey, I., Heine, C., Wieczorek, D., Kroell-Seger, J., Lund, C., Klein, K. M., Au, P. Y. B., Rho, J. M., Ho, A. W., Masnada, S., Veggiotti, P., Giordano, L., Accorsi, P., Hoei-Hansen, C. E., Striano, P., Zara, F., Verhelst, H., Verhoeven, J. S., Braakman, H. M. H., van der Zwaag, B., Harder, A. V. E., Brilstra, E., Pendziwiat, M., Lebon, S., Vaccarezza, M., Le, N. M., Christensen, J., Grønborg, S., Scherer, S. W., Howe, J., Fazeli, W., Howell, K. B., Leventer, R., Stutterd, C., Walsh, S., Gerard, M., Gerard, B., Matricardi, S., Bonardi, C. M., Sartori, S., Berger, A., Hoffman-Zacharska, D., Mastrangelo, M., Darra, F., Vøllo, A., Motazacker, M. M., Lakeman, P., Nizon, M., Betzler, C., Altuzarra, C., Caume, R., Roubertie, A., Gélisse, P., Marini, C., Guerrini, R., Bilan, F., Tibussek, D., Koch-Hogrebe, M., Perry, M. S., Ichikawa, S., Dadali, E., Sharkov, A., Mishina, I., Abramov, M., Kanivets, I., Korostelev, S., Kutsev, S., Wain, K. E., Eisenhauer, N., Wagner, M., Savatt, J. M., Müller-Schlüter, K., Bassan, H., Borovikov, A., Nassogne, M. C., Destrée, A., Schoonjans, A. S., Meuwissen, M., Buzatu, M., Jansen, A., Scalais, E., Srivastava, S., Tan, W. H., Olson, H. E., Loddenkemper, T., Poduri, A., Helbig, K. L., Helbig, I., Fitzgerald, M. P., Goldberg, E. M., Roser, T., Borggraefe, I., Brünger, T., May, P., Lal, D., Lederer, D., Rubboli, G., Heyne, H. O., Lesca, G., Hedrich, U. B. S., Benda, J., Gardella, E., Lerche, H., & Møller, R. S.
- Affiliations
- University of Southern Denmark (DK)
- Hertie Institute for Clinical Brain Research (DE)
- Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Center , 4293 Dianalund , Denmark
- University of Tübingen (DE)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Epilepsiezentrum Kleinwachau Gemeinnützige (DE)
- University Children's Hospital Tübingen (DE)
- Department of Child Neurology, 2nd Faculty of Medicine, Charles University and University Hospital Motol , 10000 Prague , Czech Republic
- University Hospital Leipzig (DE)
- Heinrich Heine University Düsseldorf (DE)
- Swiss Epilepsy Center (CH)
- Oslo University Hospital (NO)
- University of Calgary (CA)
- Ospedale dei Bambini Vittore Buzzi (IT)
- University of Milan (IT)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- Department of Pediatrics, Copenhagen University Hospital Rigshospitalet , 2200 Copenhagen , Denmark
- Istituto Giannina Gaslini (IT)
- Department of Pediatrics, Division of Pediatric Neurology, Gent University Hospital , 9042 Gent , Belgium
- Maastricht University (NL)
- Radboud University Medical Center (NL)
- Department of Genetics, University Medical Center Utrecht, Utrecht University , 3553 Utrecht , The Netherlands
- Utrecht University (NL)
- University Hospital Schleswig-Holstein (DE)
- Centre Hospitalier Universitaire Vaudois (CH)
- Hospital Italiano de Buenos Aires (AR)
- Center for Pediatric Neurology, Cleveland Clinic , Cleveland, OH 44102 , USA
- Aarhus University Hospital (DK)
- Copenhagen University Hospital (DK)
- University of Toronto (CA)
- University Hospital Bonn (DE)
- Royal Children's Hospital (AU)
- University Hospital Carl Gustav Carus (DE)
- Genetics Department, CHU Côte de Nacre , 14118 Caen , France
- Genetics Department, CHRU Strasbourg , 67000 Strasbourg , France
- Fondazione Ospedale Salesi (IT)
- University of Padua (IT)
- Klinikum Weiden (DE)
- Department of Medical Genetics, Institute of Mother and Child , 00-034 Warsaw , Poland
- University of Verona (IT)
- Østfold Hospital Trust (NO)
- Amsterdam University Medical Centers (NL)
- Centre Hospitalier Universitaire de Nantes (FR)
- Schön Klinik Vogtareuth (DE)
- Department of Pediatrics, St. Jacques Hospital , 25000 Besançon , France
- Centre Hospitalier Universitaire de Lille (FR)
- Inserm (FR)
- Meyer Children's Hospital (IT)
- IRCCS Stella Maris , 56121 Pisa , Italy
- Service de Génétique, Centre Hospitalier Universitaire de Poitiers , 86021 Poitiers , France
- Child Neurology, Center for Pediatric and Teenage Health Care , 53757 Sankt Augustin , Germany
- Vestische Kinder- und Jugendklinik , 45711 Datteln , Germany
- Cook Children's Medical Center (US)
- Ambry Genetics (United States) (US)
- Research Centre for Medical Genetics , 115522 Moscow , Russia
- Pirogov Russian National Research Medical University (RU)
- Research Centre for Medical Genetics (RU)
- Russian Medical Academy of Continuous Professional Education (RU)
- Sechenov University (RU)
- Autism & Developmental Medicine Institute (US)
- Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School , 16816 Neuruppin , Germany
- Tel Aviv University (IL)
- Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain , 1000 Brussels , Belgium
- Institute for Pathology and Genetics , 6040 Gosselies , Belgium
- University of Antwerp (BE)
- Hôpital Civil de Charleroi (BE)
- Vrije Universiteit Brussel (BE)
- Centre Hospitalier de Luxembourg (LU)
- Boston Children's Hospital (US)
- Children's Hospital of Philadelphia (US)
- Ludwig-Maximilians-Universität München (DE)
- Luxembourg Centre for Systems Biomedicine (LU)
- Cleveland Clinic (US)
- Broad Institute (US)
- Institute of Pathology and Genetics (BE)
- University of Copenhagen (DK)
- Department of Medical Genetics, Groupement Hospitalier Est and ERN EpiCARE, University Hospitals of Lyon (HCL) , 69001 Lyon , France
- Corresponding author
- Lerche, Holger
- Møller, Rikke S
- ORCID
- Johannesen, Katrine M
- Liu, Yuanyuan
- Koko, Mahmoud
- Gjerulfsen, Cathrine E
- Sonnenberg, Lukas
- Fenger, Christina D
- Eltokhi, Ahmed
- Koch, Nils A
- Lauxmann, Stephan
- Krüger, Johanna
- Kegele, Josua
- Canafoglia, Laura
- Franceschetti, Silvana
- Zacher, Pia
- Alber, Michael
- Lemke, Johannes R
- Platzer, Konrad
- Krey, Ilona
- Wieczorek, Dagmar
- Lund, Caroline
- Klein, Karl Martin
- Au, P Y Billie
- Rho, Jong M
- Ho, Alice W
- Masnada, Silvia
- Veggiotti, Pierangelo
- Giordano, Lucio
- Accorsi, Patrizia
- Striano, Pasquale
- Zara, Federico
- Braakman, Hilde M H
- Harder, Aster V E
- Brilstra, Eva
- Pendziwiat, Manuela
- Christensen, Jakob
- Grønborg, Sabine
- Scherer, Stephen W
- Fazeli, Walid
- Howell, Katherine B
- Leventer, Richard
- Matricardi, Sara
- Bonardi, Claudia M
- Sartori, Stefano
- Darra, Francesca
- Motazacker, M Mahdi
- Lakeman, Phillis
- Nizon, Mathilde
- Roubertie, Agathe
- Gélisse, Philippe
- Marini, Carla
- Guerrini, Renzo
- Tibussek, Daniel
- Perry, M Scott
- Ichikawa, Shoji
- Sharkov, Artem
- Kanivets, Ilya
- Korostelev, Sergey
- Kutsev, Sergey
- Wain, Karen E
- Savatt, Juliann M
- Bassan, Haim
- Borovikov, Artem
- Schoonjans, An Sofie
- Meuwissen, Marije
- 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
- May, Patrick
- Lal, Dennis
- Lederer, Damien
- Rubboli, Guido
- Heyne, Henrike O
- Hedrich, Ulrike B S
- Benda, Jan
- Gardella, Elena
- Lerche, Holger
- Møller, Rikke S
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-08-25
- Volume
- 145
- Issue
- 9
- Pages
- 2991-3009
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC10147326
- OpenAlex
- W3194416265
- Cited by
- 147
- References
- 54
- Citations by year
- 2026: 24 · 2025: 31 · 2024: 36 · 2023: 35 · 2022: 16 · 2021: 5
- FWCI
- 16.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nd)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- Florence Research (University of Florence) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- IRIS (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion, cc-by-nd)
- SERVAL (Université de Lausanne) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- German Research Foundation and the Fonds Nationale de la Recherche in Luxembourg (FOR-2715)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- SCN8A, Nav1.6, voltage-gated sodium channels, genotype-phenotype correlation, developmental and epileptic encephalopathy, generalized epilepsy, intellectual disability, gain-of-function mutations, loss-of-function mutations, neuronal firing rate, steady-state activation, fast inactivation
- MeSH terms
- Epileptic Syndromes, Epilepsy, Generalized, Humans, Infant, Intellectual Disability, Mutation, Prognosis, Seizures, Sodium Channel Blockers, Genetic Association Studies, NAV1.6 Voltage-Gated Sodium Channel
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