| Title: |
Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications |
| Authors: |
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; Lassuthová,Petra; Vlckova,Marketa; Lemke,Johannes R; Platzer,Konrad; Krey,Ilona; Heine,Constanze; Wieczorek,Dagmar; Kroell-Seger,Judith; Lund,Caroline; Klein,Karl Martin; Billie Au,P Y; 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; van der Zwaag, Bert; Harder,Aster V E; Brilstra, Eva; Pendziwiat,Manuela; Lebon,Sebastian; Vaccarezza,Maria; Minh Le,Ngoc; Christensen,Jakob; Grønborg,Sabine; Scherer,Stephen W; Howe,Jennifer; Fazeli,Walid; Howell,Katherine B; Leventer,Richard; Stutterd,Chloe; Walsh,Sonja; Gerard,Marion; Gerard,Bénédicte; Matricardi,Sara; Bonardi,Claudia M; Sartori,Stefano; Berger,Andrea; Hoffman-Zacharska,Dorota; Mastrangelo,Massimo; Darra,Francesca; Vøllo,Arve; Motazacker,M Mahdi; Lakeman,Phillis; Nizon,Mathilde; Betzler,Cornelia; Altuzarra,Cecilia; Caume,Roseline; Roubertie,Agathe; Gélisse,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; Destrée,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; Brünger,Tobias; May,Patrick; Lal,Dennis; Lederer,Damien; Rubboli,Guido; Heyne,Henrike O; Lesca,Gaetan; Hedrich,Ulrike B S; Benda,Jan; Gardella,Elena; Lerche,Holger; Møller,Rikke S; Genetica Sectie Genoomdiagnostiek; Child Health; Genetica Klinische Genetica; Brain |
| Publication Year: |
2022 |
| Subject Terms: |
Epilepsy; Generalized/drug therapy; Epileptic Syndromes/drug therapy; Genetic Association Studies; Humans; Infant; Intellectual Disability/genetics; Mutation; NAV1.6 Voltage-Gated Sodium Channel/genetics; Prognosis; SCN8A; Seizures/drug therapy; Sodium Channel Blockers/therapeutic use; genetics; personalized medicine; Taverne; General Medicine; Journal Article |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
text/plain |
| Language: |
English |
| ISSN: |
0006-8950 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/443446 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/443446 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.547AADA1 |
| Database: |
BASE |