Abstracts

Rationale: Childhood absence epilepsy (CAE) is a common pediatric epilepsy syndrome, for which virtually all neurologists would choose either ethosuximide (ETX) or valproic acid (VPA) as first line medication, as these drugs had roughly equivalent efficacy in a 2010 randomized control trial. ETX and VPA both act on aspects of the thalamocortical network; however, ETX is a fairly specific T-type calcium channel inhibitor while VPA mainly acts through GABA agonistic effects. The primary aim of this study was to determine the frequency of rare variants in genes encoding subunits of calcium channels or GABA receptors in patients treated with both ETX and VPA, and to determine whether the presence of such variants predicted medication response. Specifically, we hypothesized that rare variants in calcium channel genes would be less frequent in ETX-responsive patients and that rare variants in GABA receptor genes would be less frequent in VPA-response patients. Methods: Patients with absence epilepsy who had received therapeutic trials of both VPA and ETX were recruited. The clinical response to VPA and ETX was determined from clinical notes, and categorized as clear positive response (complete or near complete control of seizures) or no clear positive response (little to no reduction in seizures or seizures worsened). All patients provided blood samples for whole exome sequencing. We identified all rare non-synonymous variants (defined as allele frequency (AF) < 0.01 in the gnomAD database) in genes encoding subunits of calcium channels (CACNA1A, CACNA1G, CACNA1H and CACNA1I) and GABA receptors (GABRA1, GABRB1, GABRB3 and GABRG2). In a secondary analysis, we compared the frequency of rare variants in our population of absence epilepsy patients with the large control population in gnomAD. Results: Sixty-two patients were included in the study: 12 were ETX-responsive, 14 were VPA-responsive, and the remaining 36 did not show a clear positive response to either medication.  For calcium channel genes, rare variants in CACNA1H and CACNA1A were seen more often in ETX-unresponsive patients (12/50 (24%) vs 1/12 (8%) for CACNA1H, and 4/50 (8%) vs 0/12 (0%) for CACNA1A) but neither difference reached statistical significance (p = 0.2 and p = 0.5, respectively).  There was no significant difference in the frequency of rare variants for GABA receptor genes between VPA-responsive and non-responsive groups. However, we did find that rare variants in GABA receptor genes were more frequent in our absence epilepsy population when compared to controls (p = 0.002).  A similar trend was noted for calcium channel genes, but did not meet statistical significance (p = 0.10).  Notably, one of the rare GABRB3 variants (c.C31T:p.P11S, rs25409) was present in 3 of our patients, including one homozygote – an AF of 0.032 versus 0.0030 in gnomAD.  There were four other recurrent rare variants, all found in two patients each: CACNA1G c.G3704A:p.R1235Q; CACNA1G c.G1367A:p.R456Q; CACNA1H c.G3792T:p.Q1264H; and CACNA1H c.A2354T:p.K785M.  Conclusions: Rare variants in GABA receptor genes may be enriched in patients with absence epilepsy who fail at least one of VPA or ETX (due to lack of efficacy or side effects), suggesting subtle GABA receptor dysfunction may underly the pathophysiology of absence epilepsy in these more difficult-to-treat individuals. However, the presence of these rare variants does not have clear clinical utility in guiding choice of initial therapy. Funding: Citizens United for Research in Epilepsy - Taking Flight Award