Genetics of the epilepsies

Purpose of review This article reviews the most significant advances in the field of genetics of the epilepsies during the past year, with emphasis on newly identified genes and functional studies leading to new insights into the pathophysiology of epilepsy. Recent findings Mutations in the chloride channel gene CLCN2 have been associated with the most common forms of idiopathic generalized epilepsies. A mutation in the ATP1A2 sodium potassium ATPase pump gene has been described in a family in which familial hemiplegic migraine and benign familial infantile convulsions partly co-segregate. The leucine-rich, glioma-inactivated 1 gene (LGI1) (also known as epitempin) was found to be responsible for autosomal-dominant lateral temporal lobe epilepsy in additional families. The serine-threonine kinase 9 gene (STK9) was identified as the second gene associated with X-linked infantile spasms. Mutations in the Aristaless-related homeobox gene (ARX) have been recognized as a cause of X-linked infantile spasms and sporadic cryptogenic infantile spasms. A second gene underlying progressive myoclonus epilepsy of Lafora, NHLRC1, was shown to code for a putative E3 ubiquitin ligase. Summary Genes associated with idiopathic generalized epilepsies remain within the ion channel family. Mutations in non-ion channel genes are responsible for autosomal-dominant lateral temporal lobe epilepsy, a form of idiopathic focal epilepsy, malformations of cortical development, and syndromes that combine X-linked mental retardation and epilepsy. Most genetic epilepsies have a complex mode of inheritance, and genes identified so far account only for a minority of families and sporadic cases. Functional studies are leading to a better understanding of the mechanisms underlying hyperexcitability and seizures.