Abstracts

The neuronal voltage-gated sodium channel is an important molecular target for several antiepileptic drugs (AEDs). Fundamental channel properties are conferred by a single [alpha]-subunit, which also contains the AED binding site. The Na[sub]v[/sub]1.2 subunit is the most widely expressed sodium channel [alpha]-subunit in human brain. Single nucleotide polymorphisms (SNPs) in the gene ([italic]SCN2A[/italic]) encoding this subunit have the potential to influence the properties of the channel and its sensitivity to blockade by AEDs. We have investigated the prevalence of a specific SNP (R19K) in exon 1 of the [italic]SCN2A[/italic] gene in responders and non-responders to AED treatment. A total of 400 patients attending a specialist epilepsy clinic were recruited. Of these, 118 had idiopathic generalised epilepsy, 269 had localisation related epilepsy and in 13 patients, the epilepsy was unclassified. Genomic DNA was extracted from venous blood and a 400bp fragment of the [italic]SCN2A[/italic] gene containing the site of the R19K polymorphism was amplified by PCR. Presence of the R19K SNP was determined by restriction digest with ScrF1 endonuclease. Patients were categorised as responders (seizure free for 6 months) or non-responders by review of case notes and seizure diaries. Allele and genotype frequencies in each group were compared by logistic regression analysis. A total of 170 (42%) patients were classified as responders and 230 (58%) as non-responders. Genotype frequencies in the cohort were 88% GG, 11% GA and 1% AA. Variant genotypes (GA and AA) were present in 8% of responders and 16% of non-responders (OR 2.07, 95% CI 1.08-3.97, p=0.024). The A allele was present in 5% of responders and 8% of non-responders (OR 1.71, 95% CI 0.95-3.09, p=0.067). Sub-analysis on the basis of seizure classification did not influence the findings. As a diagnostic test for uncontrolled epilepsy, the variant genotype had a sensitivity of 16% and specificity of 92%, with test efficiency of 48%. The R19K polymorphism in [italic]SCN2A[/italic] is more prevalent in patients with uncontrolled epilepsy than in those with well-controlled epilepsy. The predictive power of the variant genotype is poor owing to low frequency of the polymorphic allele and the undoubtedly limited contribution of a single SNP to drug response. Identification of several SNPs correlating with response to drug treatment could provide sufficient predictive power to achieve the goal of genotype-based therapy.