Ion channels and epilepsy

摘要

During the past 10 years, there has been an upsurge in the discovery of epilepsy-causing mutations in genes encoding ion channel proteins. Good genotype-phenotype correlation is possible in BFNC, BFNIS and ADNFLE, where little intrafamilial variability is seen. However, in GEFS+ and epilepsy caused by CLCN2 mutations, the clinical phenotype can be highly variable. This has led to the hypothesis of channel mutations as risk factors only when expressed on the correct inherited genetic background, in the presence of polymorphisms or a mutation in another gene. However, digenic inheritance is very rare. Little is known about the control of gene expression of ion channels. There are conceivably many modifying genes that are completely unknown at present. In the future, when such mechanisms have been elucidated, we will have a greater understanding of the role of ion channel gene mutations and epileptogenesis. Perhaps the variable penetrance and clinical phenotype depends on the availability of alternative ion channel subunits to replace those which are dysfunctional. The differing severities of these syndromes may represent the non-redundancy of multiple ion-channel subunits in distinct channel types, so that (for example) an α_1 subunit could be replaced by an α_2 subunit. Even in syndromes with little phenotypic variability, there remains genetic heterogeneity (e.g. ADNFLE), with no obvious clinical correlates to indicate which gene is affected, making molecular diagnosis difficult. This suggests that dysfunction of a single ion channel type per se does not lead to the seizure phenotype; rather, it is due to a more general effect on neuronal excitability. Our understanding of epileptogenesis in ion channel diseases may lie in the elucidation of the final common pathway in neuronal signalling, downstream to the individual neurone.