This multicenter retrospective study examined the clinical characteristics and outcomes of 26 patients with sodium channel protein type 8 subunit alpha (SCN8A)-related epilepsy and/or neurodevelopmental disorders across the Gulf region. Data were collected from August 2024 to January 2025. Most patients (80.77%) experienced epilepsy onset within the first year of life, with a mean onset age of 8.25 months. Common features included developmental delay (69.57%), epileptic encephalopathy (73.08%), intellectual disability (46.15%), and movement disorders (34.62%). Genetic testing identified SCN8A mutations, primarily loss-of-function variants (65.38%), with missense mutations being most frequent. Seizure types varied, with generalized tonic-clonic (53.84%) and focal seizures (42.31%) being common. Levetiracetam and sodium channel blockers were the most used treatments. A seizure reduction of >50% was achieved in 65.38% of patients, and 26.92% became seizure-free. Loss-of-function mutations were linked to better outcomes. The study underscores the clinical variability of SCN8A disorders and the importance of personalized genetic diagnosis and targeted therapy.
TalwarDHammerMF. SCN8A Epilepsy, developmental encephalopathy, and related disorders. Pediatr Neurol. 2021;122:76–83. doi:10.1016/J.PEDIATRNEUROL.2021.06.011
2.
BurgessDLKohrmanDCGaltJ, et al.Mutation of a new sodium channel gene, Scn8a, in the mouse mutant ‘motor endplate disease’. Nat Genet. 1995;10(4):461–465. doi:10.1038/NG0895-461
3.
FuxJEMehtaAMoffatJSpaffordJD. Eukaryotic voltage-gated sodium channels: on their origins, asymmetries, losses, diversification and adaptations. Front Physiol. 2018;9:1406. doi:10.3389/FPHYS.2018.01406
4.
KrzemienDSchallerKRock LevinsonSCaldwellJ. Immunolocalization of sodium channel isoform NaCh6 in the nervous system. J Comp Neurol. 2000;420(1):70–83. doi:10.1002/(SICI)1096-9861(20000424)420:1<70::AID-CNE5>3.0.CO;2-P
5.
CaldwellJHSchallerKLLasherRSPelesELevinsonSR. Sodium channel Na(v)1.6 is localized at nodes of Ranvier, dendrites, and synapses. Proc Natl Acad Sci U S A. 2000;97(10):5616–5620. doi:10.1073/PNAS.090034797
SatamHJoshiKMangroliaU, et al.Next-generation sequencing technology: current trends and advancements. Biol. 2023;12(7):997. doi:10.3390/BIOLOGY12070997
8.
VeeramahKRO’BrienJEMeislerMH, et al.De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet. 2012;90(3):502–510. doi:10.1016/J.AJHG.2012.01.006
9.
JohannesenKMLiuYKokoM, et al.Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain. 2022;145(9):2991–3009. doi:10.1093/brain/awab321
10.
Morrison-LevyNBorlotFJainPWhitneyR. Early-onset developmental and epileptic encephalopathies of infancy: an overview of the genetic basis and clinical features. Pediatr Neurol. 2021;116:85–94. doi:10.1016/J.PEDIATRNEUROL.2020.12.001
11.
WagnonJLMeislerMH. Recurrent and non-recurrent mutations of SCN8A in epileptic encephalopathy. Front Neurol. 2015;6:104. Published 2015 May 15. doi:10.3389/fneur.2015.00104
12.
MeislerMHKearneyJEscaygAMacDonaldBTSprungerLK. Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. Neuroscientist. 2001;7(2):136–145. doi:10.1177/107385840100700208
13.
MitsuiYSatoHTogiSUraHNiidaY. A case of SCN8A-related developmental epileptic encephalopathy diagnosed by clinical speculation driven targeted DNA sequencing and remission of epilepsy by sodium channel blockers combination therapy. Brain Dev Case Rep. 2024;2(2):100015. doi:10.1016/J.BDCASR.2024.100015
14.
HebbarMAl-TaweelNGillI, et al.Expanding the genotype-phenotype spectrum in SCN8A-related disorders. BMC Neurol. 2024;24(31):1–7. doi:10.1186/S12883-023-03478-Y/FIGURES/1
15.
GardellaEMøllerRS. Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes. Epilepsia. 2019;60(Suppl 3):S77–S85. doi:10.1111/EPI.16319
16.
O’BrienJEMeislerMH. Sodium channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability. Front Genet. 2013;4(4):213. doi:10.3389/FGENE.2013.00213
17.
WagnonJLBarkerBSOttoliniM, et al.Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet. 2017;3(4):e170. doi:10.1212/NXG.0000000000000170
18.
RichardsSAzizNBaleS, et al.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. doi:10.1038/GIM.2015.30
19.
SchreiberJMTochenLBrownM, et al.A multi-disciplinary clinic for SCN8A-related epilepsy. Epilepsy Res. 2020;159:106261. doi:10.1016/J.EPLEPSYRES.2019.106261
20.
EncinasACMooreIKWatkinsJCHammerMF. Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort. Epilepsia. 2019;60(8):1711–1720. doi:10.1111/EPI.16288
DymentDATétreaultMBeaulieuCL, et al.Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: a retrospective study. Clin Genet. 2015;88(1):34–40. doi:10.1111/CGE.12464
23.
BoermaRSBraunKPvan de BroekMPH, et al.Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach. Neurotherapeutics. 2016;13(1):192–197. doi:10.1007/S13311-015-0372-8
24.
BlanchardMGWillemsenMHWalkerJB, et al.De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J Med Genet. 2015;52(5):330–337. doi:10.1136/JMEDGENET-2014-102813
25.
ConeckerGXiaMYHeckerJ, et al.Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders. Epilepsia. 2024;65(8):2322–2338. doi:10.1111/epi.17992. doi:10.1016/J.NBD.2014.05.017
26.
Mercimek-MahmutogluSPatelJCordeiroD, et al.Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. Epilepsia. 2015;56(5):707–716. doi:10.1111/EPI.12954
27.
MalcolmsonJKleynerRTegayD, et al.SCN8A mutation in a child presenting with seizures and developmental delays. Cold Spring Harb Mol Case Stud. 2016;2(5):a001073. doi:10.1101/MCS.A001073
28.
LarsenJCarvillGLGardellaE, et al.The phenotypic spectrum of SCN8A encephalopathy. Neurology. 2015;84(5):480–489. doi:10.1212/WNL.0000000000001211
29.
de KovelCGFMeislerMHBrilstraEH, et al.Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res. 2014;108(9):1511–1518. doi:10.1016/J.EPLEPSYRES.2014.08.020
MeislerMHHelmanGHammerMF, et al.SCN8A encephalopathy: research progress and prospects. Epilepsia. 2016;57(7):1027. doi:10.1111/EPI.13422
32.
HackJBHorningKJuroske ShortDMSchreiberJMWatkinsJCHammerMF. Distinguishing loss-of-function and gain-of-function SCN8A variants using a random forest classification model trained on clinical features. Neurol Genet. 2023;9(4):e200060. doi:10.1212/NXG.0000000000200060
33.
WagnonJLBarkerBSOttoliniM, et al.Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet. 2017;3(4):e170. doi:10.1212/NXG.0000000000000170
34.
JohannesenKMLiuYKokoM, et al.Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain. 2022;145(9):2991–3009. doi:10.1093/BRAIN/AWAB321
35.
BereckiGHowellKBHeighwayJ, et al.Functional correlates of clinical phenotype and severity in recurrent SCN2A variants. Commun Biol. 2022;5(1):475. doi:10.1038/S42003-022-03454-1
36.
CuttsASavoieHHammerMF, et al.Clinical characteristics and treatment experience of individuals with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE): findings from an online caregiver survey. Seizure. 2022;97:50–57. doi:10.1016/j.seizure.2022.03.008
37.
GardellaEMøllerRS. Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes. Epilepsia. 2019;60(Suppl 3):S77–S85. doi:10.1111/EPI.16319
38.
GardellaEMariniCTrivisanoM, et al.The phenotype of SCN8A developmental and epileptic encephalopathy. Neurology. 2018;91(12):E1112–E1124. doi:10.1212/WNL.0000000000006199
39.
KimHJYangDKimSH, et al.Genetic and clinical features of SCN8A developmental and epileptic encephalopathy. Epilepsy Res. 2019;158:106222. doi:10.1016/J.EPLEPSYRES.2019.106222
40.
LarsenJCarvillGLGardellaE, et al.The phenotypic spectrum of SCN8A encephalopathy. Neurology. 2015;84(5):480. doi:10.1212/WNL.0000000000001211
41.
HammerMFWagnonJLMeffordHCMeislerMH. SCN8A-related epilepsy and/or neurodevelopmental disorders. GeneReviews®. Published April 6, 2023.
