Genetics of the Epilepsies

Abstract

Summary: Recent molecular insights into the human idiopathic epilepsies have suggested the central role of ligand-gated and voltage-gated ion channels in their etiology. So far, genes coding for sodium and potassium channel subunits as well as a nicotinic cholinergic receptor subunit have been identified for mendelian idiopathic epilepsies. In vitro and in vivo studies of mutations demonstrate functional changes, allowing new insights into mechanisms underlying hyperexcitability. Similarly, spontaneous murine epilepsy models have been associated with calcium channel molecular defects. The major challenge before us in understanding the genetics of the epilepsies is to identify genes for common forms of epilepsy following complex inheritance. Once such genes are discovered, the gene-gene-environmental interactions producing specific epilepsy syndromes can be explored.

Benign Familial Infantile Convulsions: Linkage to Chromosome 16p12‐q12 in 14 Families

“…According to a databank gene scan performed in this region (UCSC: http://www.genome.ucsc.edu, NCBI: http://www.ncbi.nlm.nih.gov, GDB: http://www.gdb.org), we could not identify any sequence susceptible to an ion channel gene, as found previously in other forms of idiopathic epilepsies (5–11). Several sodium glucose cotransporters and hypothetical genes with similarity to a carboanhydrase were identified, and might be interesting candidates.…”

“…In some of the rare idiopathic epilepsies with a mendelian inheritance, the causative mutations could be identified. With one exception, all these mutations were found in ligand‐ or voltage‐gated ion channel genes (5–11). Such findings augment our knowledge about the pathophysiologic concepts of epilepsy and may help to identify new targets for pharmacotherapy, as was recently shown for the novel anticonvulsant drug retigabine (RGB), which activates neuronal KCNQ potassium channels mutated in benign familial neonatal convulsions (12).…”

Focal epilepsy in the Belgian shepherd: evidence for simple Mendelian inheritance

“…A genetic aetiology is increasingly being identified for generalised and focal (partial) epilepsies in both human beings and canines (Prasad and others 1999, Gargus 2003, Bercovic and Scheffer 2004, Andermann and others 2005, Lohi and others 2005, Chandler 2006). In dogs, the beagle, Keeshond, Labrador retriever, Bernese mountain dog, Shetland sheep dog, Irish wolfhound, English springer spaniel, Lagotto Romagnolo and Belgian shepherd, among others, are believed to have an increased risk of epilepsy with a suspected genetic background (van der Velden 1968, Bielfelt and others 1971, Hall and Wallace 1996, Famula and others 1997, Famula and Oberbauer 1998, 2000, Jaggy and others 1998, Kathmann and others 1999, Berendt and others 2002, Morita and others 2002, Oberbauer and others 2003, Patterson and others 2005, Casal and others 2006, Jokinen and others 2007).…”

Epilepsy

“…30 generalized epilepsies associated with ion-channel mutations inheritance pattern and are associated with singlegene mutations (Table 1). [42][43][44] Almost all these mutations have been found in genes encoding ionchannel proteins (Fig. 2).…”