Abstracts

Rationale: Pathogenic variants in SCN8A encoding the Na_v1.6 voltage-gated sodium channel contribute to various neurological phenotypes, including developmental epileptic encephalopathy, benign familial infantile epilepsy, and movement disorders. While considerable research has been conducted on genotype-phenotype correlations in these conditions, the longitudinal landscape of SCN8A-related disorders remains unexplored.

Methods: Combining the electronic medical record data from a local SCN8A cohort and the Ciitizen^® platform, we performed an analysis of 82 individuals with SCN8A-related disorders. We leveraged the Human Phenotype Ontology, a standardized biomedical dictionary, to map clinical features. We reconstructed seizure trajectories, medication histories, and developmental milestones. To contrast SCN8A-related disorders with other epilepsies, we compared it to a local epilepsy cohort (n=2,833).

Results: Compared to other epilepsies, those with SCN8A-related disorders were 10 times more likely to have generalized-onset seizures and 3 times more likely to have bilateral tonic-clonic seizures in the first year of life. Individuals carrying gain-of-function SCN8A variants had a three-fold increased risk for generalized-onset seizures and a four-fold increased risk for global developmental delay within the first year of life when compared to the rest of the SCN8A cohort. In contrast, individuals with loss-of-function variants had a 12 times higher frequency of absence seizures with later onset at 4 years of age. Compared to the remainder of the SCN8A cohort, individuals with p.Arg850Gln were 11 times more likely to have infantile spasms, those with p.Arg1872Trp/Gln/Leu were 17 times more likely to have neonatal seizures, those with p.Gly1475Arg were 27 times more likely to have bilateral tonic-clonic seizures at 0.75 years old and 14 times more likely to have active epilepsy after 5 years of age, and those with p.Arg1617Gln were 15 times more likely to have focal seizures at 7 years old. Lamotrigine and ketogenic diet were most effective in reducing seizure frequency, while oxcarbazepine, topiramate, and phenytoin were superior in maintaining seizure freedom.

Conclusions: Through a rigorous analysis of clinical features over time, we reconstructed the clinical history of SCN8A-related disorders. They stand out among epilepsies with presumed genetic basis due to the high frequency generalized-onset and bilateral tonic-clonic seizures in infancy, prominent early epileptic and developmental features in individuals with gain-of-function variants, and unique seizure phenotypes in those with recurrent variants. Finally, we present real-world retrospective data as evidence for the efficacy of sodium channel blockers in seizure management for SCN8A epilepsy. Our study provides a comprehensive perspective on this genetic condition, paving the way for the future precision medicine approaches.

Funding: National Institute of Neurological Disorders and Stroke; CURE Epilepsy Rare Epilepsy Partnership Award; The Cute Syndrome Foundation