GENETIC-MAPPING OF A MAJOR SUSCEPTIBILITY LOCUS FOR JUVENILE MYOCLONIC EPILEPSY ON CHROMOSOME 15Q

The epilepsies are a group of disorders characterised by recurrent sei zures caused by episodes of abnormal neuronal hyperexcitability involv ing the brain, Up to 60 million people are affected worldwide and gene tic factors may contribute to the aetiology in up to 40% of patients, The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of det ectable structural or metabolic abnormalities, Juvenile myoclonic epil epsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is en tirely unknown, but a mutation in the gene CHRNA4, encoding the alpha 4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), wa s recently identified in a rare Mendelian variety of idiopathic epilep sy, Chromosomal regions harbouring genes for nAChR subunits were there fore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha 7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.6 5; Z(all) = 2.94, P = 0.0005), This major locus contributes to genetic susceptibility to JME in a majority of the families studied.