Abstracts

Rationale: Dravet Syndrome is a rare, catastrophic childhood epileptic encephalopathy, involving a de novo loss of function mutation in the SCN1A gene in 70-80% of cases. More recently, other genes have been implicated, including GABRG2. While treatment for SCN1A-associated Dravet Syndrome has been extensively studied, establishing more effective (e.g. Stiripentol) and potentially exacerbating (e.g. sodium channel blockade) therapies, treatment of GABRG2-associated Dravet Syndrome is less well-characterized. We present a case of Dravet Syndrome associated with a novel GABRG2 variant, with highly favorable response to clobazam. Methods: A 2 year-old girl born term without complication, presenting at 6 months with onset of intractable epilepsy manifesting as multifocal status epilepticus, associated with significant and prolonged developmental stagnation. Presenting seizures were febrile focal dyscognitive, usually with right or left hemibody convulsions, lasting up to three hours, evolving into both febrile and afebrile seizures after 1 year of age. Physical exam revealed mixed language delay, but was otherwise unremarkable. She was initially treated with levetiracetam (maximum 124mg/kg/day), later in combination with zonisamide (maximum 11.5mg/kg/day), during which she continued to experience frequent episodes of status epilepticus every 1-4 weeks requiring emergency care. Significant seizure control was subsequently achieved with adjunctive clobazam (maximum 0.65mg/kg/day), providing 6 months of seizure-freedom, with recent breakthrough in the setting of a 2kg weight increase. She has remained seizure-free following weight-based dose adjustment. Results: Video EEGs were initially normal, but repeat study at 33 months demonstrated occasional generalized epileptiform discharges in sleep pseudo-lateralized to the right frontotemporal region, mild excessive bifrontotemporal theta-delta slowing, and excessive diffuse beta frequencies. 3T MRI brain was unremarkable. Genetic testing failed to demonstrate any known pathogenic mutations referable to Dravet or other epilepsy syndromes, but did revealed a heterozygous missense variant in the GABRG2 gene (R323W). The variant was reported as a non-conservative amino acid substitution with inconsistent in silico analysis. The variant was not present in parents, thus demonstrating a de novo mutation. Subsequent whole-genome oligonucleotide array CGH+SNP failed to reveal any pathogenic abnormalities. Therefore, we concluded that the Dravet phenotype was likely referable to the R323W GABRG2 variant. Conclusions: This case presents non-SCN1A Dravet Syndrome associated with a de novo GABRG2 gene variant (R323W). Although likely referable, experimental validation is needed to more fully implicate this variant as pathogenic. This case also highlights >90% seizure reduction with submaximal adjunctive clobazam in the setting of pharmacoresistance to optimized doses of levetiracetam and zonisamide. Therefore, we postulate that clobazam may help mitigate loss of function associated with a potential GABRG2 mutation, and thus may prove an effective agent for GABRG2-associated Dravet Syndrome. Funding: None