Insights into familial adult myoclonus epilepsy pathogenesis: How the same repeat expansion in six unrelated genes may lead to cortical excitability

Abstract

Familial adult myoclonus epilepsy (FAME) results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes encoding proteins with different subcellular localizations and very different functions, which poses the issue of what causes the neurobiological disturbances that lead to the clinical phenotype. Postmortem and electrophysiological studies have pointed to cortical hyperexcitability as well as dysfunction and neurodegeneration of both the cortex and cerebellum of FAME subjects. FAME expansions, contrary to the same expansion in DAB1 causing spinocerebellar ataxia type 37, seem to have no or limited impact on their recipient gene expression, which suggests a pathophysiological mechanism independent of the gene and its function. Current hypotheses include toxicity of the RNA molecules carrying UUUCA repeats, or toxicity of polypeptides encoded by the repeats, a mechanism known as repeatassociated non-AUG translation. The analysis of postmortem brains of FAME1 expansion (in SAMD12) carriers has revealed the presence of RNA foci that could be formed by the aggregation of RNA molecules with abnormal UUUCA repeats, but evidence is still lacking for other FAME subtypes. Even when the expansion is located in a gene ubiquitously expressed, expression of repeats remains undetectable in peripheral tissues (blood, skin). Therefore, the development of appropriate cellular models (induced pluripotent stem cell-derived neurons) or the study of affected tissues in patients is required to elucidate how FAME repeat expansions located in unrelated genes lead to disease.

Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions

“…There remain families in which known loci were excluded by linkage, or direct molecular tests for the known repeat expansions, suggesting additional FAME genes are yet to be discovered 28,39,43,48–50 . The questions of what modifies the correlation between repeat length and disease onset and which factors influence germline and somatic instability also remain open and will require new cell and animal preclinical models to uncover 51 …”

A solved puzzle: Familial adult myoclonus epilepsy is a new expansion repeats disorder

“…FAME treatment is so far symptomatic and often elusive, as discussed by Coppola et al 11 Elucidating the pathogenesis of this condition is essential to provide further insight into therapeutic options aiming at precision medicine that would not be possible otherwise 12 …”

“…These aspects are discussed by Corbett et al 9 and Silveira et al 10 FAME treatment is so far symptomatic and often elusive, as discussed by Coppola et al 11 Elucidating the pathogenesis of this condition is essential to provide further insight into therapeutic options aiming at precision medicine that would not be possible otherwise. 12 We heartily thank Dr. Mike Sperling, Editor of Epilepsia, for the generous offer to publish this supplement issue, which may serve as a helpful guide for epileptologists as well as for medical students and residents who want to learn more about the pathophysiology, epidemiology, and potential treatment of this intriguing epileptic disorder.…”

Familial adult myoclonus epilepsy: Neuroimaging and neuropathological findings

“…The condition is usually slowly progressive, although the disease course is milder compared to progressive myoclonus epilepsies. FAME, with autosomal dominant inheritance, results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes 7 …”

“…FAME, with autosomal dominant inheritance, results from the same pathogenic TTTTA/TTTCA pentanucleotide repeat expansion in six distinct genes. 7 Here, we address the specific conventional and advanced imaging and pathology findings in FAME. Moreover, we discuss how these findings relate to (1) clinical and neurophysiological findings in FAME, (2) other pentanucleotide repeat disorders, and (3) other movement and epileptic disorders.…”