{"doi":"10.1093/brain/awab321","title":"Genotype-phenotype correlations in <i>SCN8A</i> -related disorders reveal prognostic and therapeutic implications","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.","journal":"Brain","year":2021,"id":147696,"datarank":2.9211823330427023,"base_score":5.0106352940962555,"endowment":5.0106352940962555,"self_citation_contribution":0.7515952941144385,"citation_network_contribution":2.1695870389282637,"self_endowment_contribution":0.7515952941144385,"citer_contribution":2.1695870389282637,"corpus_percentile":null,"corpus_rank":null,"citation_count":149,"citer_count":88,"citers_with_citation_signal":59,"citers_with_endowment":59,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.7101,"is_data_producer":true,"deposit_databanks":{"figshare":["10.6084/m9.figshare.15141018"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":510090,"name":"Yuanyuan Liu","orcid":"0000-0001-9865-1378","position":1,"is_corresponding":false},{"id":211034,"name":"Mahmoud Koko","orcid":"0000-0001-9512-0184","position":2,"is_corresponding":false},{"id":628340,"name":"Cathrine E. Gjerulfsen","orcid":"0000-0002-3419-3133","position":3,"is_corresponding":false},{"id":628341,"name":"Lukas Sonnenberg","orcid":"0000-0002-3657-6146","position":4,"is_corresponding":false},{"id":629426,"name":"Julian Schubert","orcid":null,"position":5,"is_corresponding":false},{"id":296363,"name":"Christina Fenger","orcid":"0009-0001-7288-4787","position":6,"is_corresponding":false},{"id":628342,"name":"Ahmed Eltokhi","orcid":"0000-0001-9067-5017","position":7,"is_corresponding":false},{"id":629427,"name":"Maert Rannap","orcid":null,"position":8,"is_corresponding":false},{"id":628343,"name":"Nils A. Koch","orcid":"0000-0002-8478-8717","position":9,"is_corresponding":false},{"id":629428,"name":"Stephan Lauxmann","orcid":null,"position":10,"is_corresponding":false},{"id":628344,"name":"Johanna Krüger","orcid":"0000-0003-4346-1133","position":11,"is_corresponding":false},{"id":628345,"name":"Josua Kegele","orcid":"0000-0002-0126-7466","position":12,"is_corresponding":false},{"id":493619,"name":"Laura Canafoglia","orcid":"0000-0002-5385-761X","position":13,"is_corresponding":false},{"id":628346,"name":"Silvana Franceschetti","orcid":"0000-0002-1921-6755","position":14,"is_corresponding":false},{"id":629429,"name":"Thomas Mayer","orcid":null,"position":15,"is_corresponding":false},{"id":629430,"name":"Johannes Rebstock","orcid":null,"position":16,"is_corresponding":false},{"id":456144,"name":"Pia Zacher","orcid":"0000-0002-0211-5763","position":17,"is_corresponding":false},{"id":629431,"name":"Susanne Ruf","orcid":null,"position":18,"is_corresponding":false},{"id":629432,"name":"Michael Alber","orcid":null,"position":19,"is_corresponding":false},{"id":299871,"name":"Katalin Štěrbová","orcid":null,"position":20,"is_corresponding":false},{"id":297294,"name":"Petra Laššuthová","orcid":"0000-0003-1726-5868","position":21,"is_corresponding":false},{"id":297292,"name":"Markéta Vlčková","orcid":"0000-0002-1496-392X","position":22,"is_corresponding":false},{"id":456160,"name":"Johannes R. Lemke","orcid":"0000-0002-4435-6610","position":23,"is_corresponding":false},{"id":456161,"name":"Konrad Platzer","orcid":"0000-0001-6127-6308","position":24,"is_corresponding":false},{"id":628347,"name":"Ilona Krey","orcid":"0000-0002-9168-7615","position":25,"is_corresponding":false},{"id":629433,"name":"Constanze Heine","orcid":null,"position":26,"is_corresponding":false},{"id":28512,"name":"Dagmar Wieczorek","orcid":"0000-0003-2812-6492","position":27,"is_corresponding":false},{"id":629434,"name":"Judith Kroell-Seger","orcid":null,"position":28,"is_corresponding":false},{"id":628348,"name":"Caroline Lund","orcid":"0009-0000-5122-0116","position":29,"is_corresponding":false},{"id":297295,"name":"Karl Martin Klein","orcid":"0000-0002-6654-1665","position":30,"is_corresponding":false},{"id":629435,"name":"P Y Billie Au","orcid":null,"position":31,"is_corresponding":false},{"id":430123,"name":"Jong M. Rho","orcid":"0000-0001-9886-9924","position":32,"is_corresponding":false},{"id":628349,"name":"Alice Ho","orcid":"0000-0002-8699-635X","position":33,"is_corresponding":false},{"id":628350,"name":"Silvia Masnada","orcid":"0000-0003-3850-8849","position":34,"is_corresponding":false},{"id":236853,"name":"Pierangelo Veggiotti","orcid":"0000-0003-2851-3441","position":35,"is_corresponding":false},{"id":628351,"name":"Lucio Giordano","orcid":"0000-0002-6736-4330","position":36,"is_corresponding":false},{"id":628352,"name":"Patrizia Accorsi","orcid":"0000-0002-8801-5498","position":37,"is_corresponding":false},{"id":628353,"name":"Christina Engel Hoei‐Hansen","orcid":"0000-0002-6191-694X","position":38,"is_corresponding":false},{"id":52257,"name":"Pasquale Striano","orcid":null,"position":39,"is_corresponding":false},{"id":473779,"name":"Federico Zara","orcid":"0000-0001-9744-5222","position":40,"is_corresponding":false},{"id":424225,"name":"Hélène Verhelst","orcid":"0000-0001-9433-7998","position":41,"is_corresponding":false},{"id":629436,"name":"J. Verhoeven","orcid":null,"position":42,"is_corresponding":false},{"id":494159,"name":"Hilde M. H. Braakman","orcid":"0000-0001-8053-5918","position":43,"is_corresponding":false},{"id":629437,"name":"Bert van der Zwaag","orcid":null,"position":44,"is_corresponding":false},{"id":628354,"name":"Aster V. E. Harder","orcid":"0000-0002-5477-7232","position":45,"is_corresponding":false},{"id":286588,"name":"Eva H. Brilstra","orcid":"0000-0001-5793-9623","position":46,"is_corresponding":false},{"id":297302,"name":"Manuela Pendziwiat","orcid":"0000-0001-8942-8334","position":47,"is_corresponding":false},{"id":629438,"name":"Sebastian Lebon","orcid":null,"position":48,"is_corresponding":false},{"id":629439,"name":"María Vaccarezza","orcid":null,"position":49,"is_corresponding":false},{"id":629440,"name":"Ngọc Minh Lê","orcid":null,"position":50,"is_corresponding":false},{"id":367696,"name":"Jakob Christensen","orcid":"0000-0002-9385-6435","position":51,"is_corresponding":false},{"id":628355,"name":"Sabine Grønborg","orcid":"0000-0002-2113-9023","position":52,"is_corresponding":false},{"id":441431,"name":"Stephen W. Scherer","orcid":"0000-0002-8326-1999","position":53,"is_corresponding":false},{"id":40238,"name":"Jennifer Howe","orcid":null,"position":54,"is_corresponding":false},{"id":628356,"name":"Walid Fazeli","orcid":"0000-0002-9425-5535","position":55,"is_corresponding":false},{"id":628357,"name":"Katherine B. Howell","orcid":"0000-0002-5469-8411","position":56,"is_corresponding":false},{"id":325754,"name":"Richard J. Leventer","orcid":"0000-0003-0362-5607","position":57,"is_corresponding":false},{"id":332841,"name":"Chloe Stutterd","orcid":null,"position":58,"is_corresponding":false},{"id":629441,"name":"Sonja Walsh","orcid":null,"position":59,"is_corresponding":false},{"id":628358,"name":"Marion Gérard","orcid":"0000-0003-2319-0305","position":60,"is_corresponding":false},{"id":628359,"name":"Bénédicte Gérard","orcid":"0000-0002-0015-7425","position":61,"is_corresponding":false},{"id":628360,"name":"Sara Matricardi","orcid":"0000-0002-4403-6342","position":62,"is_corresponding":false},{"id":628361,"name":"Claudia Bonardi","orcid":"0000-0002-6266-3665","position":63,"is_corresponding":false},{"id":628362,"name":"Stefano Sartori","orcid":"0000-0002-0012-6848","position":64,"is_corresponding":false},{"id":628363,"name":"Andrea Berger","orcid":"0000-0001-5557-4114","position":65,"is_corresponding":false},{"id":628364,"name":"Dorota Hoffman‐Zacharska","orcid":"0000-0001-7367-512X","position":66,"is_corresponding":false},{"id":629442,"name":"Massimo Mastrangelo","orcid":null,"position":67,"is_corresponding":false},{"id":628365,"name":"Francesca Darra","orcid":"0000-0002-1062-8438","position":68,"is_corresponding":false},{"id":629443,"name":"Arve Vøllo","orcid":null,"position":69,"is_corresponding":false},{"id":628366,"name":"M. Mahdi Motazacker","orcid":"0000-0002-2283-7405","position":70,"is_corresponding":false},{"id":628367,"name":"Phillis Lakeman","orcid":"0000-0001-6385-1804","position":71,"is_corresponding":false},{"id":242584,"name":"Mathilde Nizon","orcid":"0000-0003-2170-4210","position":72,"is_corresponding":false},{"id":629444,"name":"Cornelia Betzler","orcid":null,"position":73,"is_corresponding":false},{"id":629445,"name":"Cécilia Altuzarra","orcid":null,"position":74,"is_corresponding":false},{"id":629446,"name":"Roseline Caume","orcid":null,"position":75,"is_corresponding":false},{"id":628368,"name":"Agathe Roubertie","orcid":"0000-0002-8180-4857","position":76,"is_corresponding":false},{"id":628369,"name":"Philippe Gélisse","orcid":"0000-0001-9296-1957","position":77,"is_corresponding":false},{"id":483029,"name":"Carla Marini","orcid":"0000-0002-9212-2691","position":78,"is_corresponding":false},{"id":52251,"name":"Renzo Guerrini","orcid":"0000-0002-7272-7079","position":79,"is_corresponding":false},{"id":463265,"name":"Frédéric Bilan","orcid":"0000-0001-8589-6018","position":80,"is_corresponding":false},{"id":628370,"name":"Daniel Tibussek","orcid":"0000-0001-5114-3173","position":81,"is_corresponding":false},{"id":629447,"name":"Margarete Koch‐Hogrebe","orcid":null,"position":82,"is_corresponding":false},{"id":154465,"name":"M. Scott Perry","orcid":"0000-0002-1825-846X","position":83,"is_corresponding":false},{"id":628371,"name":"Shoji Ichikawa","orcid":"0000-0001-6477-0520","position":84,"is_corresponding":false},{"id":473774,"name":"Е. Л. Дадали","orcid":"0000-0001-5602-2805","position":85,"is_corresponding":false},{"id":628372,"name":"Artem Sharkov","orcid":"0000-0002-0980-2638","position":86,"is_corresponding":false},{"id":629448,"name":"Irina Mishina","orcid":null,"position":87,"is_corresponding":false},{"id":629449,"name":"M. O. Abramov","orcid":null,"position":88,"is_corresponding":false},{"id":628373,"name":"Ilya Kanivets","orcid":"0000-0001-5821-9783","position":89,"is_corresponding":false},{"id":628374,"name":"С. А. Коростелев","orcid":"0000-0002-3816-8031","position":90,"is_corresponding":false},{"id":230653,"name":"Sergey I. Kutsev","orcid":"0000-0002-3133-8018","position":91,"is_corresponding":false},{"id":628375,"name":"Karen E. Wain","orcid":"0000-0002-3711-7670","position":92,"is_corresponding":false},{"id":629450,"name":"Nancy Eisenhauer","orcid":null,"position":93,"is_corresponding":false},{"id":629451,"name":"Monisa Wagner","orcid":null,"position":94,"is_corresponding":false},{"id":400188,"name":"Juliann M. Savatt","orcid":"0000-0001-6444-1962","position":95,"is_corresponding":false},{"id":629452,"name":"Karen Müller‐Schlüter","orcid":null,"position":96,"is_corresponding":false},{"id":628376,"name":"Haim Bassan","orcid":"0000-0003-1627-8069","position":97,"is_corresponding":false},{"id":473771,"name":"Artem Borovikov","orcid":"0000-0001-5871-8005","position":98,"is_corresponding":false},{"id":628377,"name":"Marie‐Cécile Nassogne","orcid":"0000-0001-6936-1611","position":99,"is_corresponding":false},{"id":628339,"name":"Katrine M. Johannesen","orcid":"0000-0002-7356-3109","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T23:42:35.448762Z","pmid":"34431999","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}