Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) typically presents in middle life with a combination of neuropathy, ataxia and vestibular disease, with patients reporting progressive imbalance, oscillopsia, sensory disturbance and a dry cough. Examination identifies a sensory neuropathy or neuronopathy and bilaterally impaired vestibulo-ocular reflex. The underlying genetic basis is of biallelic AAGGG expansions in the second intron of replication factor complex subunit 1 (RFC1). The frequency and phenotype spectrum of RFC1 disease is expanding, ranging from typical CANVAS to site-restricted variants affecting the sensory nerves, cerebellum and/or the vestibular system. Given the wide phenotype spectrum of RFC1, the differential diagnosis is broad. RFC1 disease due to biallelic AAGGG expansions is probably the most common cause of recessive ataxia. The key to suspecting the disease (and prompt genetic testing) is a thorough clinical examination assessing the three affected systems and noting the presence of chronic cough.
- cerebellar ataxia
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Contributors AC, MMR and HH designed the study. AC, RC, EV and WYY drafted the manuscript. All authors revised and approved the manuscript.
Funding AC thanks the Medical Research Council (MRC) (MR/T001712/1), the Fondazione CARIPLO (2019–1836), the Italian Ministry of Health Ricerca Corrente 2018–2019 and 2020, the Inherited Neuropathy Consortium and the Fondazione Regionale per la Ricerca Biomedica for grant support. HH and MMR thank the MRC, the Wellcome Trust, the MDA, MD UK, Ataxia UK, The MSA Trust, the Rosetrees Trust and the NIHR UCLH BRC for grant support.
Competing interests None declared.
Provenance and peer review Provenance and peer review. Commissioned. Externally peer reviewed by Simon Hammans, Southampton, UK.
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