Candidate gene analysis of the succinic semialdehyde dehydrogenase gene (ALDH5A1) in patients with idiopathic generalized epilepsy and photosensitivity

Succinic semialdehyde dehydrogenase (SSADH) is involved in the degradation of the inhibitory neurotransmitter GABA and about 50% of patients with SSADH deficiency suffer from seizures. The gene encoding SSADH (gene symbol: ALDH5A1) maps in proximity to susceptibility loci for juvenile myoclonic epilepsy (JME) and photosensitivity on chromosome 6p22. The present study tested whether variation of the ALDH5A1 gene confers susceptibility to common syndromes of idiopathic generalized epilepsy (IGE) and an abnormal photoparoxysmal response (PPR). Mutation screening of the ALDH5A1 coding sequence of 35IGE/PPR patients and four healthy control subjects identified 17 sequence variants, of which three resulted in an exchange of amino acids (H180Y, P182L, A237S). Association analysis was carried out for six single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (TNR, intron 1), covering the genomic ALDH5A1 sequence. The study sample comprised 566 unrelated German IGE patients, including 218 JME and 95 photosensitive IGE patients, 78 PPR probands without IGE, and 662 German population controls. None of the investigated ALDH5H1 polymorphisms showed evidence for an allelic or genotypic association with either IGE, JME, or PPR, when corrected for multiple tests. A tentative haplotypic association of the two-marker haplotype (rs1883415-TNR) covering the 5'-regulatory region in IGE patients (chi2=11.65, d.f.=3, P=0.009) warrants further replication studies. The present results do not provide evidence that any ALDH5A1 missense variant itself contributes a common and substantial susceptibility effect (RR>2) to IGE syndromes or an increased liability to visually-induced cortical synchronization.