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Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by cortical myoclonic tremor and seizures. FAME has been mapped to chromosomes (chr) 2, 3, 5 and 8, but the cause has remained elusive for more than a decade. An expansion of intronic TTTTA and TTTCA repeats in SAMD12 was identified as the cause of FAME1 in Japanese families linked to chr 8 in 2018. This discovery triggered the identification of identical repeat expansions at five additional loci (FAME2: STARD7; FAME3: MARCHF6; FAME4: YEATS2; FAME6: TNRC6A and FAME7: RAPGEF2). These genes encode proteins with different functions and subcellular localizations and their expression is unaltered in available peripheral tissues, suggesting that the expansion is pathogenic independently of the gene itself. The pathophysiological mechanisms are not yet known but possibly include toxicity at the RNA level or translation of toxic polypeptides from the repeats, a mechanism known as repeat-associated non-AUG (RAN) translation. FAME is a paradigm of human genetic disorder caused by a non-coding expansion unrelated to the gene where it occurs.

Noncoding repeat expansions are a well-known cause of genetic disorders mainly affecting the central nervous system. Missed by most standard technologies used in routine diagnosis, pathogenic noncoding repeat expansions have to be searched for using specific techniques such as repeat-primed PCR or specific bioinformatics tools applied to genome data, such as ExpansionHunter. In this review, we focus on GC-rich repeat expansions, which represent at least one third of all noncoding repeat expansions described so far. GC-rich expansions are mainly located in regulatory regions (promoter, 5′ untranslated region, first intron) of genes and can lead to either a toxic gain-of-function mediated by RNA toxicity and/or repeat-associated non-AUG (RAN) translation, or a loss-of-function of the associated gene, depending on their size and their methylation status. We herein review the clinical and molecular characteristics of disorders associated with these difficult-to-detect expansions.

The cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset and recessively inherited ataxia. For many years, CANVAS has been diagnosed based on the clinical phenotype. Only recently, a large biallelic pentanucleotide repeat expansion in the replication factor C subunit 1 (RFC1) gene has been identified as the underlying genetic cause for the large majority of CANVAS cases. Subsequently, other phenotypes such as ataxia with chronic cough, incomplete CANVAS and MSA-C-like phenotypes have been associated with biallelic RFC1 repeat expansions. Because of this heterogeneity it has been suggested to change the name of the disease to “RFC1 disease”. Chronic cough is characteristic and can precede neurological symptoms by years or decades. In the neurological examination signs of cerebellar, sensory, and vestibular ataxia are frequently observed. Nerve conduction studies usually show absent or markedly reduced sensory nerve action potentials. On brain MRI cerebellar degeneration and spinal cord alterations are common. In later disease stages more widespread neurodegeneration with additional involvement of the brainstem and basal ganglia is possible. As yet, the exact incidence of RFC1-associated neurological diseases remains uncertain although first studies suggest that RFC1-related ataxia is common. Moreover, the pathophysiological mechanisms caused by the large biallelic pentanucleotide repeat expansions in RFC1 remain elusive. Future molecular and genetic research as well as natural history studies are highly desirable to pave the way towards personalized treatment approaches.