Johannesen, Katrine M., Liu, Yuanyuan, Koko, Mahmoud ORCID: 0000-0001-9512-0184, Gjerulfsen, Cathrine E., Sonnenberg, Lukas, Schubert, Julian, Fenger, Christina D., Eltokhi, Ahmed ORCID: 0000-0001-9067-5017, Rannap, Maert, Koch, Nils A., Lauxmann, Stephan, Krueger, Johanna, Kegele, Josua, Canafoglia, Laura, Franceschetti, Silvana, Mayer, Thomas, Rebstock, Johannes, Zacher, Pia, Ruf, Susanne, Alber, Michael, Sterbova, Katalin, Lassuthova, Petra, Vlckova, Marketa, Lemke, Johannes R., Platzer, Konrad, Krey, Ilona, Heine, Constanze, Wieczorek, Dagmar, Kroell-Seger, Judith, Lund, Caroline, Klein, Karl Martin ORCID: 0000-0002-6654-1665, 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 ORCID: 0000-0001-9744-5222, 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, Christensen, Jakob ORCID: 0000-0002-9385-6435, Gronborg, Sabine, Scherer, Stephen W. ORCID: 0000-0002-8326-1999, Howe, Jennifer, Fazeli, Walid, Howell, Katherine B., Leventer, Richard, Stutterd, Chloe, Walsh, Sonja, Gerard, Marion, Gerard, Benedicte, Matricardi, Sara ORCID: 0000-0002-4403-6342, Bonardi, Claudia M., Sartori, Stefano, Berger, Andrea, Hoffman-Zacharska, Dorota, Mastrangelo, Massimo, Darra, Francesca, Vollo, Arve, Motazacker, M. Mahdi, Lakeman, Phillis, Nizon, Mathilde, Betzler, Cornelia, Altuzarra, Cecilia, Caume, Roseline, Roubertie, Agathe, Gelisse, Philippe, Marini, Carla, Guerrini, Renzo ORCID: 0000-0002-7272-7079, Bilan, Frederic, Tibussek, Daniel, Koch-Hogrebe, Margarete, Perry, M. Scott, Ichikawa, Shoji, Dadali, Elena ORCID: 0000-0001-5602-2805, Sharkov, Artem, Mishina, Irina, Abramov, Mikhail, Kanivets, Ilya, Korostelev, Sergey, Kutsev, Sergey, Wain, Karen E., Eisenhauer, Nancy, Wagner, Monisa, Savatt, Juliann M., Muller-Schluter, Karen, Bassan, Haim ORCID: 0000-0003-1627-8069, Borovikov, Artem ORCID: 0000-0001-5871-8005, Nassogne, Marie-Cecile, Destree, Anne, Schoonjans, An-Sofie, Meuwissen, Marije, Buzatu, Marga, Jansen, Anna ORCID: 0000-0002-3835-2824, Scalais, Emmanuel, Srivastava, Siddharth, Tan, Wen-Hann ORCID: 0000-0002-1593-6149, Olson, Heather E., Loddenkemper, Tobias, Poduri, Annapurna, Helbig, Katherine L., Helbig, Ingo, Fitzgerald, Mark P., Goldberg, Ethan M., Roser, Timo, Borggraefe, Ingo, Brunger, Tobias, May, Patrick ORCID: 0000-0001-8698-3770, Lal, Dennis, Lederer, Damien, Rubboli, Guido ORCID: 0000-0002-5309-2514, Heyne, Henrike O., Lesca, Gaetan ORCID: 0000-0001-7691-9492, Hedrich, Ulrike B. S., Benda, Jan, Gardella, Elena, Lerche, Holger and Moller, Rikke S. ORCID: 0000-0002-9664-1448 . Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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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 Na(v)1.6, 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 Na(v)1.6 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Johannesen, Katrine M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, YuanyuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koko, MahmoudUNSPECIFIEDorcid.org/0000-0001-9512-0184UNSPECIFIED
Gjerulfsen, Cathrine E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sonnenberg, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schubert, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fenger, Christina D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eltokhi, AhmedUNSPECIFIEDorcid.org/0000-0001-9067-5017UNSPECIFIED
Rannap, MaertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, Nils A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauxmann, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kegele, JosuaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Canafoglia, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franceschetti, SilvanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayer, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rebstock, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zacher, PiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruf, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alber, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sterbova, KatalinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lassuthova, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vlckova, MarketaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Platzer, KonradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krey, IlonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heine, ConstanzeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wieczorek, DagmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kroell-Seger, JudithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lund, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, Karl MartinUNSPECIFIEDorcid.org/0000-0002-6654-1665UNSPECIFIED
Au, P. Y. BillieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rho, Jong M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ho, Alice W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masnada, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veggiotti, PierangeloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giordano, LucioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Accorsi, PatriziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoei-Hansen, Christina E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, PasqualeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zara, FedericoUNSPECIFIEDorcid.org/0000-0001-9744-5222UNSPECIFIED
Verhelst, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verhoeven, Judith S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braakman, Hilde M. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Zwaag, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harder, Aster V. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brilstra, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pendziwiat, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lebon, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaccarezza, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christensen, JakobUNSPECIFIEDorcid.org/0000-0002-9385-6435UNSPECIFIED
Gronborg, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scherer, Stephen W.UNSPECIFIEDorcid.org/0000-0002-8326-1999UNSPECIFIED
Howe, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fazeli, WalidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Howell, Katherine B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leventer, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stutterd, ChloeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walsh, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerard, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerard, BenedicteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matricardi, SaraUNSPECIFIEDorcid.org/0000-0002-4403-6342UNSPECIFIED
Bonardi, Claudia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sartori, StefanoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berger, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffman-Zacharska, DorotaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mastrangelo, MassimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Darra, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vollo, ArveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motazacker, M. MahdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lakeman, PhillisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nizon, MathildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Betzler, CorneliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altuzarra, CeciliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caume, RoselineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roubertie, AgatheUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gelisse, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marini, CarlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrini, RenzoUNSPECIFIEDorcid.org/0000-0002-7272-7079UNSPECIFIED
Bilan, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tibussek, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch-Hogrebe, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perry, M. ScottUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ichikawa, ShojiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dadali, ElenaUNSPECIFIEDorcid.org/0000-0001-5602-2805UNSPECIFIED
Sharkov, ArtemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mishina, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abramov, MikhailUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kanivets, IlyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korostelev, SergeyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kutsev, SergeyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wain, Karen E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eisenhauer, NancyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MonisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savatt, Juliann M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muller-Schluter, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bassan, HaimUNSPECIFIEDorcid.org/0000-0003-1627-8069UNSPECIFIED
Borovikov, ArtemUNSPECIFIEDorcid.org/0000-0001-5871-8005UNSPECIFIED
Nassogne, Marie-CecileUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Destree, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoonjans, An-SofieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meuwissen, MarijeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buzatu, MargaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jansen, AnnaUNSPECIFIEDorcid.org/0000-0002-3835-2824UNSPECIFIED
Scalais, EmmanuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Srivastava, SiddharthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tan, Wen-HannUNSPECIFIEDorcid.org/0000-0002-1593-6149UNSPECIFIED
Olson, Heather E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loddenkemper, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poduri, AnnapurnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, Katherine L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fitzgerald, Mark P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldberg, Ethan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roser, TimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borggraefe, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunger, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lederer, DamienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rubboli, GuidoUNSPECIFIEDorcid.org/0000-0002-5309-2514UNSPECIFIED
Heyne, Henrike O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lesca, GaetanUNSPECIFIEDorcid.org/0000-0001-7691-9492UNSPECIFIED
Hedrich, Ulrike B. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benda, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardella, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDorcid.org/0000-0002-9664-1448UNSPECIFIED
URN: urn:nbn:de:hbz:38-699507
DOI: 10.1093/brain/awab321
Journal or Publication Title: Brain
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SODIUM-CHANNEL SCN8A; EPILEPTIC ENCEPHALOPATHY; DE-NOVO-SCN8A MUTATION; SEIZURES; ATAXIA; MOUSE; ONSET; CLASSIFICATION; INTERNEURONS; CHILDRENMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69950

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