Abstracts

Rationale: Familial adult myoclonic epilepsy (FAME) is an autosomal dominant epilepsy syndrome which is characterized by the triad of cortical tremor, multifocal myoclonus and generalized tonic-clonic seizures (GTCS). Linkage to loci on chromosome 2, 3, 5 and 8 have been reported. Mutations in the a2-adrenergic receptor subtype B (ADRA2B) gene have been described in autosomal dominant cortical myoclonus and epilepsy. This is a clinically similar condition and linked to the same chromosome 2 locus. The causative gene in FAME has not been identified yet. Here, we report a new FAME family that is consistent with linkage to chromosome 2. We aim to identify the molecular cause by exome sequencing. Methods: A large Sephardi Jewish family originating from Egypt with affected individuals over 5 generations was recruited and phenotyped. Linkage analysis was performed using SNP genotyping microarrays. ADRA2B was Sanger sequenced and whole exome sequencing was performed in two affected individuals. Results: Seventeen family members were reported to have had tremor, myoclonus and/or GTCS. Of these, detailed phenotypic information was available in 10 individuals. Tremor was present in eight family members who were considered to have FAME. Myoclonus was present in 6/8 and GTCS in 3/8 family members with FAME. Two family members were considered to be phenocopies as they did not have tremor. These were categorized as having unknown affected status for the linkage analysis. Linkage analysis revealed peaks with positive LOD scores (1.77-1.78) on chromosome 2p12-q12.3, chromosome 3q25.33-q26.31, chromosome 5pter-p15.32, chromosome 11p12-q14.3, chromosome 13q32.3-qter and chromosome 22q12.1-q13.1. The region on chromosome 2 included the previously reported FAME locus. The other regions did not overlap with any previously reported locus for FAME. Sanger sequencing of ADRA2B did not reveal any mutations. Exome sequencing in two affected individuals did not show any promising variants within the linkage regions. Conclusions: Linkage analysis in this large FAME family was consistent with linkage to the previously reported locus on chromosome 2. Sanger sequencing of the candidate gene ADRA2B as well as exome sequencing did not identify a possibly causative mutation. Further analyses in FAME families are required to discover the responsible gene. Funding: This study was supported by the Deutsche Forschungsgemeinschaft (HE 5415/3-1) within the EuroEPINOMICS project, the P. E. Kempkes foundation (05/2013), the Christian-Albrechts-University Kiel and the Philipps-University Marburg.