Channelopathies as a genetic cause of epilepsy : Current Opinion in Neurology (original) (raw)

Seizure disorders

Mulley, John C.a; Scheffer, Ingrid E.b; Petrou, Stevenc; Berkovic, Samuel F.b

aCentre for Medical Genetics, Department of Laboratory Genetics, Women's and Children's Hospital, and Department of Molecular Biosciences, University of Adelaide, South Australia; bEpilepsy Research Institute and Department of Medicine (Neurology), University of Melbourne, and Austin & Repatriation Medical Centre, Heidelberg, Victoria; and cDepartment of Physiology, University of Melbourne, Victoria, Australia

Correspondence to John Mulley PhD, Department of Laboratory Genetics, Women's and Children's Hospital, 72 King William Rd, North Adelaide 5006, Australia Tel: +61 8 8161 6304; fax +61 8 8161 7342; e-mail: [email protected]

Abbreviations

ARX: Aristaless related homeobox

BFNIS: benign familial neonatal infantile seizures

BFNS: benign familial neonatal seizures (formerly BFNC)

CACNA1A: α1A subunit of the voltage-gated calcium channel

CACNB4: β4 subunit of the voltage-gated calcium channel

CHRNA4: nicotinic acetylcholine receptor, α4 subunit

CHRNB2: nicotinic acetylcholine receptor, β2 subunit

GABRA1: GABAA receptor, α1 subunit

GABRG2: GABAA receptor, γ2 subunit

GEFS+: generalized epilepsy with febrile seizures plus

KCNQ2: potassium channel, KQT-like, subunit 2

KCNQ3: potassium channel, KQT-like, subunit 3

LGI1: leucine-rich, glioma inactivated 1 gene

SCN1A: sodium channel, α1 subunit

SCN2A: sodium channel, α2 subunit

SCN1B: sodium channel, β1 subunit

SMEI: severe myoclonic epilepsy of infancy

Abstract

Purpose of review

This review describes the significant number of new gene associations with epilepsy syndromes that have emerged during the past year, together with additional mutations and new electrophysiological data relating to previously known gene associations.

Recent findings

Autosomal dominant juvenile myoclonic epilepsy was demonstrated to be a channelopathy associated with a GABAA receptor, α1 subunit mutation. Benign familial neonatal infantile seizures were delineated as another channelopathy of infancy, by molecular characterization of sodium channel, α2 subunit defects. A sodium channel, α2 subunit defect was previously found to be associated with generalized epilepsy with febrile seizures plus. Similarly, the clinical spectrum associated with potassium channel, KQT-like mutations was extended to include the channelopathy myokymia and neonatal epilepsy. Mutations in the non-ion channel genes, leucine-rich, glioma inactivated 1 gene and Aristaless related homeobox gene, have emerged as important causes of their specific syndromes, with mutations in the latter gene frequently underlying X-linked mental retardation with epilepsy.

Summary

All but one of the idiopathic epilepsies with a known molecular basis are channelopathies. Where the ion channel defects have been identified, however, they generally account for a minority of families and sporadic cases with the syndrome in question. The data suggest that ion channel mutations of large effect are a common cause of rare monogenic idiopathic epilepsies, but are rare causes of common epilepsies. Additive effects of genetic variation, perhaps within the same ion channel gene families, are likely to underlie the common idiopathic generalized epilepsies with complex inheritance. The genetics of epilepsy is progressing rapidly toward a more detailed molecular dissection and definition of syndromes.