RFC1 -Related Disease

Abstract

In 2019, a biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) was reported as a cause of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). In addition, biallelic expansions were shown to account for up to 22% of cases with late-onset ataxia. Since this discovery, the phenotypic spectrum reported to be associated with RFC1 expansions has extended beyond the initial conditions to include pure cerebellar ataxia, isolated somatosensory impairment, combinations of the 2, and parkinsonism, leading to a potentially broad differential diagnosis. Genetic studies suggest RFC1 expansions may be the most common genetic cause of ataxia and are likely underdiagnosed. This review summarizes the current molecular and clinical knowledge of RFC1-related disease, with a focus on the evaluation of recent phenotype associations and highlighting the current challenges in clinical pathways to diagnosis and molecular testing.

Cranial Nerve Thinning Distinguishes RFC1‐Related Disorder from Other Late‐Onset Ataxias

“…[44][45][46] However, neuronal depletion has not been depicted as severe as that seen in RFC1/CANVAS. 47 MSA-C is primarily an oligodendrogliopathy and the major pathological burden of the disease falls on the basal ganglia, brainstem and cerebellum. 48 Prominent cranial nerve involvement has not been reported in the available necropsy studies of patients with MSA-C. [48][49][50] Altogether, these data suggest that the neuroimaging abnormalities herein reported somehow recapitulate the pathological signature not only of RFC1/CANVAS, but also of the other late-onset degenerative ataxias.…”

“…SCA2 and SCA3 may present similar pathological features, particularly regarding the vestibulo‐cochlear nerve and nuclei 44–46 . However, neuronal depletion has not been depicted as severe as that seen in RFC1/CANVAS 47 . MSA‐C is primarily an oligodendrogliopathy and the major pathological burden of the disease falls on the basal ganglia, brainstem and cerebellum 48 .…”

A novel intronic GAA repeat expansion inFGF14causes autosomal dominant adult-onset ataxia (SCA50, ATX-FGF14)

“…For example, they are rarely observed in RFC1-mediated disease 51,52 , which is thought to be the most common inherited cause of CA. 53 The identification and high prevalence of FGF14 (GAA)n-mediated ataxia, a novel RE mutation mechanism in a gene previously known to cause a related phenotype, may account for a significant proportion of unresolved individuals with ataxia and fill this diagnostic vacuum. A noteworthy feature of our study is that several participants partially fulfilled criteria for CANVAS with cerebellar ataxia and vestibulopathy, some with additional cough and autonomic failure but all lacking large fibre sensory neuropathy.…”

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