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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; Lassuthova, Petra; Vlckova, Marketa; Lemke, Johannes R.; Platzer, Konrad; Krey, Ilona; Heine, Constanze; Wieczorek, Dagmar; Kroell-Seger, Judith; Lund, Caroline; Klein, Karl Martin; 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; Verhelst, Helene; Verhoeven, Judith S.; Braakman, Hilde M. H.; Zwaag, Bert van der; Harder, Aster V. E.; Brilstra, Eva; Pendziwiat, Manuela; Lebon, Sebastian; Vaccarezza, Maria; Ngoc, Minh Le; Christensen, Jakob; Gronborg, Sabine; Scherer, Stephen W.; Howe, Jennifer; Fazeli, Walid; Howell, Katherine B.; Leventer, Richard; Stutterd, Chloe; Walsh, Sonja; Gerard, Marion; Gerard, Benedicte; Matricardi, Sara; 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; 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; Destree, 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; Brunger, Tobias; May, Patrick; Lal, Dennis; Lederer, Damien; Rubboli, Guido; Heyne, Henrike O.; Lesca, Gaetan; Hedrich, Ulrike B. S.; Benda, Jan; Gardella, Elena; Lerche, Holger and Moller, Rikke S. (2022): Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. In: Brain, Vol. 145, No. 9: pp. 2991-3009

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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.

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