Recent advances in benign adult familial myoclonus epilepsy

Benign adult familial myoclonus epilepsy (BAFME), also called familial cortical myoclonic tremor and epilepsy (FCMTE), autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME), and familial adult myoclonic epilepsy (FAME) is a disorder characterized by infrequent generalized seizures and tremulous myoclonus with an autosomal dominant mode of inheritance. The diagnosis of BAFME was previously based on clinical features and electrophysiological findings, but genetic analysis is now increasingly becoming important in the diagnosis after identification of repeat expansions; BAFME is caused by expansions of TTTCA and TTTTA repeats in SAMD12 (BAFME1), STARD7 (BAFME2), MARCHF6 (BAFME3), YEATS2 (BAFME4), TNRC6A (BAFME6), or RAPGEF2 (BAFME7). The findings strongly support a concept of "repeat motif-phenotype correlation" which we have proposed previously. Pathologically, BAFME1 patients carrying heterozygous expansions of TTTCA and TTTTA repeats do not show any obvious abnormal neuropathological findings in the central nervous system. These pathological findings, in addition to electrophysiological studies, suggest a dysfunctional neuronal circuit that causes enhanced excitability of the sensorimotor cortex. Autopsied brains of BAFME1 patients showed RNA foci consisting of UUUCA repeats in cortical neurons and cerebellar Purkinje cells. These findings suggest that RNA toxicity caused by UUUCA repeat expansions is involved in the pathogenesis of BAFME. Since our discovery of the causative gene for BAFME1, progress has been made in genetic studies of each type of BAFME, as well as in pathogenetic mechanisms of BAFME caused by TTTCA and TTTTA expansions. Here, we present a comprehensive review on recent advances focusing on expanded TTTCA and TTTTA repeats in BAFME.