Deciphering the dynamic clinical patterns in SCN8A-related disorders using real-world data

Background and ObjectivesSCN8A-related disorders encompass a range of neurodevelopmental and epilepsy phenotypes. However, despite representing one of the most common epilepsy-associated channelopathies, the longitudinal progression of its clinical features remains largely uncharacterized. MethodsHere, we harmonized electronic medical record data of 82 individuals with SCN8A-related disorders. Clinical data was mapped to the standardized language of the Human Phenotype Ontology to reconstruct the natural history of SCN8A-related disorders in comparison to a cohort of 2,833 individuals with known or presumed genetic epilepsies. ResultsCompared to other known or presumed genetic epilepsies, those with SCN8A-related disorders had earlier generalized seizures, including a ten-fold risk for generalized-onset seizures at 9 months (P = 4.98 x 10-17, OR 10.65, CI 6.07-18.77) and >40-fold risk bilateral tonic-clonic seizures at 1 year (P = 1.76 x 10-8, OR 46.09, CI 10.72-275.01). Individuals carrying gain-of-function SCN8A variants had particularly high generalized seizure risk at 9 months (P = 0.005, OR 3.85, CI 1.35-11.55), as well as an increased risk for global developmental delay as early as 3 months (P = 0.002, OR 5.67, CI 1.74-20.23) when compared to the broader SCN8A cohort. Individuals with loss-of-function variants were more likely to experience absence seizures, most prominently at 4.25 years (P = 0.013, OR 32.71, CI 1.44-2193.51). Compared to the wider SCN8A cohort, individuals with the recurrent p.Arg850Gln variant were more likely to have infantile spasms at 6 months (P = 0.016, OR 12.02, CI 1.20-164.23), those with variants at the p.Arg1872Trp/Gln/Leu hotspot were more likely to have neonatal seizures (P = 0.025, OR 16.84, CI 0.99-291.58). Individuals with the recurrent p.Gly1475Arg variant were more likely to have active epilepsy after 5 years of age. Focal seizures in later childhood were more prominent in individuals with the recurrent p.Arg1617Gln variant. DiscussionSCN8A-related disorders distinguish themselves from other genetic epilepsies by the frequent generalized-onset seizures in infancy, prominent early epileptic and developmental features in gain-of-function variant carriers, and unique seizure phenotypes in those with recurrent variants. Our study provides a longitudinal perspective on this genetic condition, paving the way for the future precision medicine approaches.