Abstracts

Rationale: Clinical and molecular genetic analysis of large families showing Mendelian inheritance of epilepsies has been enormously fruitful in characterizing new epilepsy syndromes and identifying their underlying genes. Familial Adult Myoclonic Epilepsy (FAME) is a dominant syndrome with the clinical triad of cortical tremor, myoclonus and epilepsy. Families from Japan and Europe map to loci on chromosomes 8 (8q23.3-q24.11, FAME1) and 2 (2p11.1-2q12.2, FAME2) respectively, but the relevant genes remain unknown. Methods: A large FAME family, descended from an Austrian ancestor, was ascertained from New Zealand and Australia. Structured clinical histories, videotaped neurological examinations and neurophysiological data were obtained from affected individuals, together with DNA samples for linkage analysis. Linkage analysis was performed using a commercial 250K SNP platform (Affymetrix). Results: 57 affected individuals from a 6 generational pedigree were studied. Onset of postural tremor affecting the hands typically occurred in adolescence (median age of 15.5 years, range 4-60). Tremor was also variably present in eyelids, face, voice and legs. Proximal myoclonus was present in 46/57 (81%) of individuals and had later onset than tremor (median 19.5 yrs, range 8-60). Tremor and myoclonus were responsive to anitmyoclonic agents (sodium valproate, clonazepam, diazepam), though benefit from beta blockers was also reported in 4 of 5 individuals who tried them. Tremor and myoclonus were slowly progressive, but usually caused minor disability only, with affected individuals reporting spilling drinks and having difficulty with fine tasks such as needlework or using a screwdriver. Generalized tonic-clonic seizures were seen in only 8/57 (14%) individuals, most often commencing in middle age (range 18-76 yrs, median 49.5). EEG was available in 37 affected people though epileptiform abnormalities were present in only 2 (5%), both showing generalized spike wave. Somatosensory evoked potentials (SSEPs) showed positive long loop reflexes at rest, though giant SSEPs were not seen. EMG-EEG back-averaging demonstrated consistent positive premyoclonic cortical potentials, confirming a cortical origin of myoclonus. Linkage analysis defines a region overlapping the existing FAME2 locus. Further refinement with microsatellite markers is ongoing. Conclusions: We describe clinical and electrographic features of the largest FAME family to date and demonstrate linkage to chromosome 2. Comparison to other FAME2 linked families reveals significantly fewer individuals with generalized tonic-clonic seizures or epileptiform EEG abnormalities in this new family, despite a similar age of tremor onset. This may be due to a weaker FAME2 allele than in previously reported families. This very large family holds promise for narrowing the FAME2 locus and identifying its underlying gene.