Genetics of Familial Adult Myoclonus Epilepsy: From linkage studies to non-coding repeat expansions

Abstract

Familial Adult Myoclonus Epilepsy (FAME) is a genetic epilepsy syndrome that for many years, withstood revealing its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of non-coding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A and RAPGEF2). FAME occurs worldwide, however repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade-off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors, such as maternal or paternal inheritance, parental age and repeat length alone have been suggested to influence repeat variation however further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress towards a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci and development of cell and animal models.