SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications

A large number of cases with Dravet syndrome (DS) has been attributed to SCN1A loss of function (LOF), whereas SCN1A gain-of-function (GOF) causes early infantile developmental and epileptic encephalopathy (EIDEE) and familial hemiplegic migraine 3. We retrospectively analyzed 37 individuals with SCN1A pathogenic variants at our institute between January 2012 and October 2024 to investigate phenotype-function correlations. Variant functions were classified as LOF, GOF, or mixed, based on existing patch-clamp data, paralog sodium channel experimental findings, and in silico prediction tools. Clinical characteristics, antiseizure medication (ASM) responses, and variant location were compared. Nine variants were novel. One variant with insufficient data for functional prediction was excluded. Of the 36 cases with predictable functions, five cases (14%) were classified as GOF/mixed (DS = 4, EIDEE = 1) and 31 (86%) as LOF (DS = 31). GOF/mixed-DS had earlier epilepsy onset but otherwise resembled LOF-DS. Sodium channel blocking ASMs (SCB-ASMs) did not exacerbate seizures in GOF/mixed DS cases, with carbamazepine reducing seizures in one case. GOF/mixed variants clustered in the intracellular S6 segment, whereas LOF variants clustered in the S5-S6 pore loop. These findings highlight a potential GOF effect for certain DS cases, suggesting that SCB-ASMs may be effective for GOF/mixed DS. This underscores the importance of functional characterization for tailored therapy, warranting further research to confirm and extend these results. PLAIN LANGUAGE SUMMARY: Dravet syndrome is a severe epilepsy that usually begins in infancy and is linked to changes in a gene called SCN1A. Most cases are caused by gene changes that reduce function, but in some cases, the gene may become overactive. In this study, we found that some patients with Dravet syndrome had these overactive changes and still showed typical symptoms. We found that people with overactive SCN1A function might respond differently to certain medications.