In recent years, growing evidence has indicated that genetic predisposition appears to be an important causal factor of TLE, but positive linkage was obtained only in one form characterized by auditory seizures, which led to the identification of the underlying gene. The difficulty of identifying genes involved in TLE rests mainly on the fact that TLE, like most epileptic diseases, is typically a complex disorder in which more than one gene, with or without the influence of acquired factors, act in a multifactorial fashion and result in the specific clinical problems that clinicians attempt to unravel and treat in any given patient. There is now good evidence that allelic variants rather then harmful mutations play a major role in such multifatcorial disorders including sporadic TLE.
On this topic, association studies seem to be a more powerful approach to identify genes implicated in complex multietiological diseases such as TLE. Accordingly, recent association studies in patients with TLE illustrated that polymorphisms of some genes, such as the interleukin-1b gene or ApoE epsilon gene, may influence the occurrence of hippocampal sclerosis, or the silent interval before the onset of TLE, respectively. In addition, another study has illustrated that a functional polymorphism in the prodinorphin gene promotor is a significant risk factor for TLE. More recently, it has been shown that a prion protein variant was highly associated with medically untreatable TLE due to hippocampal sclerosis. Using a candidate gene approach, we have recently illustrated (Gambardella et al. GABA(B) Receptor 1 Polymorphism (G1465A) is Associated with Temporal Lobe Epilepsy. Neurology 2003;60:560-563) that the G1465A polymorphism in the GABA(B(1)) gene is a strong risk factor for non-lesional TLE. Moreover, we also demonstrated that such a polymorphism seems to influence the severity of this common epileptic disorder. Overall, the results of these studies, including ours, reinforce the belief that since the proximate causes and predisposing factors contributing to TLE are many, other independent genetic factors will be identified, leading to a better understanding of such a complex disorder.
To discover these susceptibility genes through allele-polymorphism association studies represents the next frontier in the genetics of the epilepsy and should provide clues to its pathogenesis, treatment, and prevention.
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