Abstracts

Rationale: The Temporal Lobe Epilepsy (TLE) caused by mesial sclerosis is probably a multifactorial disease influenced by genetic and environmental factors. The aim of this study is to evaluate genes potentially associated with susceptibility to the development of TLE through the search for DNA polymorphisms in promoter and coding regions of genes potentially involved in the etiology of TLE. The called "susceptibility genes" contributes a small effect that, individually, is not sufficient or necessary to determine the disease phenotype. Have been described more than 60 association studies in TLE involving over 30 different genes, however, still remain uncertainties in the associations and failures in replication. Methods: By the time we selected 50 patients with TLE and 50 controls without personal and family history of neurological and psychiatric diseases. The search for new polymorphisms is initially done in silico and, once validated, is experimentally investigated by direct sequencing of DNA. Results: Initially we selected 115 genes involved in different biochemical pathways that lead to hyper or hypo-neuronal excitation, of ion channels function or their subunits, neurogenesis, metabolism, plasticity and neuronal migration. We have studied 39 polymorphisms in 26 genes, of which 16 SNPs were validated experimentally on 12 different genes (TMEM1, EFHC1, ME2, BRD2, BDNF, CHRNA2, RTN4, SCN1A, CLCN2, JRK, RELN, KCNQ2). The NRG1 gene, has shown potential association with pathology. The T allele (rs35641374 [C/T]) seems to have a significant protective role (controls = 15.3%, patients = 4,2%). The PLXNA2 gene (SNP rs2782948, [C/T]) also showed association with TLE, where again the polymorphic allele seems to have a protective role (controls = 38%, patients = 30%; P 0,001). Conclusions: Polymorphisms in the NRG1 gene (Neuregulin 1), involved in neuronal growth and differentiation, and PLXNA2 (plexin A2), active in axon guidance during nervous system development, have shown allele frequencies different when comparing patients and respective controls, indicating a role potential in the development of TLE. The number of polymorphisms in these genes and the number of patients investigated should be increased in order to evaluate which one (s) possible (s) haplotype (s) would be associated with TLE, in addition to the replication of results. The purpose of this study was to broaden the knowledge about the molecular events that predispose to TLE. With the molecular characterization of TLE we intend to contribute to a better understanding of the complex pathways that characterize the neuronal hyper-excitability. Financial Support: FAPESP and ABADHS.