Deciphering the Natural History of <i>SCN8A</i>-Related Disorders.

Abstract

<i>SCN8A</i>-related disorders encompass a range of neurodevelopmental and epilepsy phenotypes. However, despite representing one of the most common epilepsy-associated channelopathies, its longitudinal phenotypes remain largely uncharacterized. In this study, we harmonized electronic medical record data from 82 individuals with <i>SCN8A</i>-related disorders to reconstruct the natural history of the disorder in comparison with a cohort of 2,833 individuals with known or presumed genetic epilepsies. Compared with the cohort of other known or presumed genetic epilepsies, those with <i>SCN8A</i>-related disorders (mean age = 8.3 years, 52% female) had >10-fold odds of bilateral tonic-clonic seizures as early as at 1 year (<i>p</i> = 1.70 × 10^-14, OR 10.56, CI 5.85-18.90). Individuals carrying gain-of-function (GOF) <i>SCN8A</i> variants had particularly high seizure risk at 6 months (<i>p</i> = 0.007/<i>p</i>_threshold = 4.25 × 10^-4, OR 4.71, CI 1.36-21.25) and an increased risk of global developmental delay as early as at 3 months (<i>p</i> = 0.002/<i>p</i>_threshold = 4.72 × 10^-5, OR 5.67, CI 1.74-20.23) when compared with the broader <i>SCN8A</i> cohort. Individuals with loss-of-function variants were more likely to have atypical absence seizures, most prominently at 4.25 years (<i>p</i> = 0.013/<i>p</i>_threshold = 7.08 × 10^-4, OR 32.71, CI 1.44-2,193.51). Compared with the broader <i>SCN8A</i> cohort, individuals with the recurrent p.Arg850Gln variant were more likely to have infantile spasms at 6 months and those with variants at the p.Arg1872Trp/Gln/Leu hotspot were more likely to have neonatal seizures. Individuals with the recurrent p.Gly1475Arg variant were more likely to have active epilepsy after 5 years of age. In later childhood, focal seizures were more prominent in individuals with the recurrent p.Arg1617Gln variant while generalized-onset seizures were more prominent with the p.Asn1877Ser variant. We also established the effectiveness of sodium channel blockers in managing <i>SCN8A</i> epilepsy in individuals carrying GOF variants and those whose variants have not been functionally characterized, suggesting that many unstudied <i>SCN8A</i> variants may have GOF mechanisms. <i>SCN8A</i>-related disorders distinguish themselves from other genetic epilepsies by the frequent bilateral tonic-clonic seizures in infancy, prominent early epileptic and developmental features in GOF variant carriers, and unique seizure phenotypes in those with recurrent variants. Our study provides a longitudinal perspective on <i>SCN8A</i>-related disorders, paving the way for future precision medicine approaches.