Serotonin Transporter Gene Variation and Prediction of Pharmacoresistance in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis

KAUFFMAN MARCELO; CONSALVO DAMIAN; GONZALEZ MORON DOLORES; AGUIRRE FLORENCIA; D ALESSIO LUCIANA; KOCHEN SILVIA

Chicago, EEUU

Congreso; 60 Annual Meeting of the American Academy of Neurology; 2008

American Academy of Neurology

Background and Aims: About a 70% of the patients with a diagnosis of Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTE-HS) are refractory to antiepileptic drug (AED) treatment. Genetic factors could be involved in the phenomenon of pharmacoresistance. Recent evidence supports the role of serotoninergic neurotransmission in epileptogenic modulatory mechanisms. The serotonin transporter gene (SLC6A4) exhibits a functional VNTR polymorphism in intron 2. Since, pharmacogenetic prediction of response is one possibility for improving the efficiency of AED treatment we performed a molecular epidemiology study in a population of MTE-HS patients in order to investigate the role of the VNTR intron 2 polymorphism in the prediction of AED treatment response. Methods: We included a population of 111 MTE-HS patients. The cohort was stratified according to individual response to AED. Subjects with optimal treatment having more than 2 seizures in the month were defined as refractory (n=67). A VNTR in the intron 2 of SLC6A4 gene was genotyped by means of a PCR- agarose electrophoresis assay.  The effect of the genetic variant was estimated by logistic regression. Results: Subjects homozygotes for alleles with 12 repetitions are thrice more likely to be refractory (OR 2.82 CI 95% 1.21 – 6.56; LR X2=6; p=0.0143; pearson goodness of fit, p=0.63). 29.5% of subjects responding to AED were homozygotes for allele 12, whereas 53.7% of refractory patients were homozygotes for this allele. In order to analyze SLC6A4 intron 2 VNTR genotyping as a potential predictive diagnostic tool of AED response, we estimate the specificity of the test (genotype 12/12 as positive test) in 70.5% (CI 95% 54.8% - 83.2%), the positive predictive value in 73.5% (CI 95% 58.9% - 85.1%) and the positive likelihood ratio in 1.82. Considering that in our population the pretest probability of refractoriness was of 60.4%, being able to know SLC6A4 intron 2 VNTR genotype at moment of diagnosis modify the odds (prediction) of response to AED a 33 % to 82 %. Conclusion: Genetic variation in SLC6A4 gene modifies the odds of response to AED treatment in MTE-HS patients.