THE PHENOTYPIC SPECTRUM RELATED TO THE HUMAN EPILEPSY SUSCEPTIBILITY GENE EJM1

Linkage studies of families ascertained through patients with juvenile myoclonic epilepsy (JME) suggest that an HLA-linked susceptibility ge ne on chromosome 6, designated ''EJM1,'' predisposes to a group of idi opathic generalized epilepsies (IGEs) comprising JME, juvenile absence epilepsy (JAE), childhood absence epilepsies (CAE), and epilepsies wi th generalized tonic-clonic seizures (GTCS). To explore the EJM1-relat ed phenotypic spectrum, we conducted linkage studies with HLA-DQ alpha restriction fragment length polymorphisms in 44 families ascertained through patients with CAE or JAE. Our results for the entire group of families provide evidence against a major susceptibility locus for idi opathic absence epilepsies and broader spectra of IGEs in the HLA regi on. Lod scores less than -2 were obtained for a region from 10 cM up t o 23 cM on either side of the HLA-DQ alpha locus, depending on the ass umed trait model. Suggestive evidence for linkage was found only for a subgroup of families with JME patients assuming an autosomal dominant mode of inheritance with 70% penetrance. A maximum lod score was obta ined when family members with JME, JAE, CAE, and idiopathic GTCS were included into the affection status. Our results demonstrate that (1) t he genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs is heterogeneous, (2) the gene effect of EJM1 depends on the familial genetic background, and (3) EJM1 confers genetic susc eptibility to idiopathic absence epilepsies and broader spectra of IGE s in the presence of family members with JME.