Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Abstract

Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.

Fig. 1.

Visualization showing the contribution of ion channels to genetic epilepsy.

Fig. 2.

Schematic illustrating a path to the development of targeted therapeutic strategies in genetic epilepsy. Genetic screening is identifying large numbers of causative mutations. For ion channels, functional analysis usually involves electrophysiological recordings. Knock-in mice based on human mutations provide good preclinical models on which disease mechanisms can be determined and on which treatments can be tested. This can lead to the development of various targeted therapies that can be based on small molecules or newer molecular techniques.

Fig. 3.

Cartoon illustrating the known expression patterns of ion channels implicated in genetic epilepsy. Gene groups are represented by different colors.