Genetic basis of Levetiracetam pharmacoresistance and side effects in human epilepsy

Coordinator:    Prof. Dr. Susanne Schoch McGovern
Institution: Institut für Neuropathologie, Bonn
Pharmacoresistance and side effects of anti-epileptic drugs (AEDs) represent serious problems in epilepsy treatment. With the identification of the synaptic vesicle protein SV2A as high-affinity binding site for the AED Levetiracetam (LEV), the presynapse has come into focus as a target for AEDs. For many patients, LEV is be a promising AED. However, serious behavioral side effects occur in up to 8% of LEV-treated patients, resulting in discontinuation of treatment. In this project, we have studied the genetic basis for a priori pharmacoresistance and behavioral side effects of LEV. Our main results are the following: Sequence analysis of the SV2A gene revealed that there is no association with regard to a priori LEV pharmacoresponse. A genome-wide search identified an allelic variant associated with the risk of psychiatric side-effects of LEV. Furthermore, this approach revealed several allelic variants, which are correlated with the a priori pharmacoresponse of LEV. Together with the projects of Becker, Beck, Nöthen and Cichon we detected changes in the levels of distinct mRNAs associated with a priori LEV pharmacoresponse in hippocampal tissue obtained through epilepsy-surgery. These changes were found predominantly in synapse-associated genes. In addition, allelic variants were identified that are directly correlated with mRNA expression (eQTLs). The results of our studies might form the basis for the development of novel drug targets and thereby more therapy- and cost-effective perspectives for epilepsy patients.
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