Abstracts

Clobazam (CLB) is effective in SCN1A-related epilepsy, but its role in other pediatric genetic drug-resistant epilepsies (DRE) remains unclear. This study examined whether non-SCN1A variants influence clobazam response.

We reviewed pediatric genetic DRE cases treated with CLB between 2014 and 2024, and assessed improvement in daily seizures (IDS) in relation to their pathogenic variants.

We included 263 patients (52% male), with a mean age of 10 years and a mean epilepsy duration of 7 years. Genetic testing identified 187 variants: 43% pathogenic or likely pathogenic, 36% VUS, and 19% negative. A CLB dose of 1–2 mg/kg/day was used in 60% of cases. IDS was seen in 115 patients (44%), consistent across dosing and genetic epilepsy syndromes, including Dravet. IDS appeared across seizure types without clear patterns; however, when pathogenic variants were considered,  the likelihood of IDS was significant (OR = 2.5, p < 0.05). STRING analysis of genes linked to IDS revealed functional clusters, including ion channelopathies (SCN1A, CACNA1A), synaptic and transcriptional regulators (MECP2, CDKL5), mTOR pathway genes (DEPDC5, TSC2), and lysosomal genes (CLN6, TPP1). Novel responses were observed in understudied genes (UGDH, CERT1, TMX2), suggesting CLB may be effective across a broad spectrum of genetic epilepsies, including those not traditionally associated with GABAergic dysfunction.