Clinical short communication| Volume 446, 120565, March 15, 2023

RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit

Published:January 27, 2023DOI:


      • Pathogenic RFC1 expansions cause a heterogenic disorder beyond CANVAS syndrome.
      • Peripheral nervous system involvement is a hallmark of multisystemic RFC1 disease.
      • RFC1 expansions are a frequent cause of sensory neuropathy of unexplained aetiology.
      • Identification of key features can improve selection criteria for genetic testing.



      Pathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system.


      We recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed.


      Biallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients.


      Pathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.



      CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome), DRG (dorsal root ganglia), CIAP (chronic idiopathic axonal polyneuropathies), PNS (peripheral nervous system), RFC1 (repat factor complex 1), PCR (polymerase chain reaction), NCS (nerve conduction studies), ANS (autonomic nervous system), SSEPs (somatosensory evoked potentials), CMAP (compound muscle action potential), VEMP (vestibular evoked myogenic potential), CSF (cerebrospinal fluid)
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