@article{8759574,
  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.}},
  author       = {{Johannesen, Katrine M. and Liu, Yuanyuan and Koko, Mahmoud and Gjerulfsen, Cathrine E. and Sonnenberg, Lukas and Schubert, Julian and Fenger, Christina D. and Eltokhi, Ahmed and Rannap, Maert and Koch, Nils A. and Lauxmann, Stephan and Krueger, Johanna and Kegele, Josua and Canafoglia, Laura and Franceschetti, Silvana and Mayer, Thomas and Rebstock, Johannes and Zacher, Pia and Ruf, Susanne and Alber, Michael and Sterbova, Katalin and Lassuthova, Petra and Vlckova, Marketa and Lemke, Johannes R. and Platzer, Konrad and Krey, Ilona and Heine, Constanze and Wieczorek, Dagmar and Kroell-Seger, Judith and Lund, Caroline and Klein, Karl Martin and Au, P. Y. Billie and Rho, Jong M. and Ho, Alice W. and Masnada, Silvia and Veggiotti, Pierangelo and Giordano, Lucio and Accorsi, Patrizia and Hoei-Hansen, Christina E. and Striano, Pasquale and Zara, Federico and Verhelst, Helene and Verhoeven, Judith S. and Braakman, Hilde M. H. and van der Zwaag, Bert and Harder, Aster V. E. and Brilstra, Eva and Pendziwiat, Manuela and Lebon, Sebastian and Vaccarezza, Maria and Ngoc Minh Le, Ngoc Minh Le and Christensen, Jakob and Gronborg, Sabine and Scherer, Stephen W. and Howe, Jennifer and Fazeli, Walid and Howell, Katherine B. and Leventer, Richard and Stutterd, Chloe and Walsh, Sonja and Gerard, Marion and Gerard, Benedicte and Matricardi, Sara and Bonardi, Claudia M. and Sartori, Stefano and Berger, Andrea and Hoffman-Zacharska, Dorota and Mastrangelo, Massimo and Darra, Francesca and Vollo, Arve and Motazacker, M. Mahdi and Lakeman, Phillis and Nizon, Mathilde and Betzler, Cornelia and Altuzarra, Cecilia and Caume, Roseline and Roubertie, Agathe and Gelisse, Philippe and Marini, Carla and Guerrini, Renzo and Bilan, Frederic and Tibussek, Daniel and Koch-Hogrebe, Margarete and Perry, M. Scott and Ichikawa, Shoji and Dadali, Elena and Sharkov, Artem and Mishina, Irina and Abramov, Mikhail and Kanivets, Ilya and Korostelev, Sergey and Kutsev, Sergey and Wain, Karen E. and Eisenhauer, Nancy and Wagner, Monisa and Savatt, Juliann M. and Muller-Schluter, Karen and Bassan, Haim and Borovikov, Artem and Nassogne, Marie-Cecile and Destree, Anne and Schoonjans, An-Sofie and Meuwissen, Marije and Buzatu, Marga and Jansen, Anna and Scalais, Emmanuel and Srivastava, Siddharth and Tan, Wen-Hann and Olson, Heather E. and Loddenkemper, Tobias and Poduri, Annapurna and Helbig, Katherine L. and Helbig, Ingo and Fitzgerald, Mark P. and Goldberg, Ethan M. and Roser, Timo and Borggraefe, Ingo and Brunger, Tobias and May, Patrick and Lal, Dennis and Lederer, Damien and Rubboli, Guido and Heyne, Henrike O. and Lesca, Gaetan and Hedrich, Ulrike B. S. and Benda, Jan and Gardella, Elena and Lerche, Holger and Moller, Rikke S.}},
  issn         = {{0006-8950}},
  journal      = {{BRAIN}},
  keywords     = {{SODIUM-CHANNEL SCN8A,EPILEPTIC ENCEPHALOPATHY,DE-NOVO-SCN8A MUTATION,SEIZURES,ATAXIA,MOUSE,ONSET,CLASSIFICATION,INTERNEURONS,CHILDREN,SCN8A,epilepsy,genetics,personalized medicine}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{2991--3009}},
  title        = {{Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications}},
  url          = {{http://dx.doi.org/10.1093/brain/awab321}},
  volume       = {{145}},
  year         = {{2022}},
}

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