Gain of function SCN1A disease-causing variants: expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

The boundaries of SCN1A-disorders are wide and still expanding. In our cohort, more than 50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and non-familial, focal epilepsies. Alternative, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium-channel-blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate ASM.