Abstracts

Irreversible visual field constriction due to the anticonvulsant vigabatrin (VGB) is reported in 14-78% of patients. Data from our cohort of 93 patients exposed to VGB suggests this effect is unrelated to maximum dose, duration or cumulative dose. We hypothesised that genetic factors may play a role and investigated if polymorphic variation in the genes involved in the pharmacology of vigabatrin predisposed to retinal toxicity We identified six candidate genes involved in the pharmacology of VGB ([italic]GABRR1, GABRR2, ABAT, GAT1, GAT2[/italic]and [italic]GAT3[/italic]We used a haplotype tagging single nucleotide polymorhism (SNP) approach and identified 31 tagging SNPs sufficient to capture common variation (minor allele frequency [gt]5%) across these genes. Patients on a stable dose of VGB for at least one year, with reliable Goldmann visual fields (N=67), were enrolled. Visual constriction was estimated by calculating the mean radial degrees (MRD). Values less than 48.7 degrees were considered constricted. The relationship between tSNPs and MRD was assessed using linear regression at a single SNP and haplotype level No SNP or haplotype was found to clearly predispose to visual field constriction on VGB, although a significant association was found between a tSNP in Rho 2 subunit of GABA[sub]C [/sub]receptor (rs2273508 C/T) and development of constriction(homozygous major allele: MRD=45.7 degrees; heterozygous: MRD=37.7 degrees; homozygous minor: MRD=57.1 but only one patient with this genotype. p=0.027) Given that multiple tests were carried out, the association found should be regarded as tentative and may represent a false positive. We are therefore replicating the study in a separate UK patient cohort of greater size. Biologically the association could be plausable as high dose GABA induced by VGB accumulation in the retina could reverse chloride currents at GABA receptors causing toxicity. Variation in one of the subunits of the GABA[sub]C[/sub] receptor may alter resistance to this effect. Also, familial cases of Retinitis Pigmentosa have been linked to this region on chromosome 6.