Abstract
BACKGROUND AND OBJECTIVES: SCN8A-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. METHODS: In this study, we harmonized electronic medical record data from 82 individuals with SCN8A-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. RESULTS: Compared with the cohort of other known or presumed genetic epilepsies, those with SCN8A-related disorders (mean age = 8.3 years, 52% female) had >10-fold odds of bilateral tonic-clonic seizures as early as at 1 year (p = 1.70 × 10(-14), OR 10.56, CI 5.85-18.90). Individuals carrying gain-of-function (GOF) SCN8A variants had particularly high seizure risk at 6 months (p = 0.007/p(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 (p = 0.002/p(threshold) = 4.72 × 10(-5), OR 5.67, CI 1.74-20.23) when compared with the broader SCN8A cohort. Individuals with loss-of-function variants were more likely to have atypical absence seizures, most prominently at 4.25 years (p = 0.013/p(threshold) = 7.08 × 10(-4), OR 32.71, CI 1.44-2,193.51). Compared with the broader SCN8A 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 SCN8A epilepsy in individuals carrying GOF variants and those whose variants have not been functionally characterized, suggesting that many unstudied SCN8A variants may have GOF mechanisms. DISCUSSION: SCN8A-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 SCN8A-related disorders, paving the way for future precision medicine approaches.