Objective: This study aims to clinically characterize a Swedish cohort of patients featuring RFC1 CANVAS/spectrum disorders.

Background: Biallelic pentanucleotide expansions in the RFC1 gene are associated with a wide, multisystemic spectrum disorder, which includes Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome (CANVAS).

Method: A retrospective analysis was conducted on patients from a tertiary center in Sweden, incorporating clinical records, genetic data, and phenotypic assessments (n=30). Neurological evaluations included nerve conduction studies (NCS, n=27), electromyography (n=7), quantitative sensory testing (n=18), and brain MRI (n=29). Additionally, 21 patients underwent vestibular and eye motor assessments, including videooculography (n=19), video head impulse testing (vHIT, n=16), caloric testing (n=19), and cervical/ocular vestibular evoked myogenic potentials (n=18).

Results: In total we analyzed data from 30 patients with biallelic pentanucleotide expansions in RFC1, 22 of which met the diagnostic criteria for CANVAS. The mean age of onset was 52 years (range 20-70 years), with a disease duration of 13 years (±11). Symptoms and signs aligned with the CANVAS triad, though multisystemic involvement was observed in 76%, primarily as dysautonomia (77%), dyskinesia with chorea and dystonia (36%), and bradykinesia (17%). Some patients exhibited MSA-C-like features, including frequent falls and severe dysautonomia with syncope triggered by bowel movements or coughing, while others mimic mitochondrial ataxia disorders. Notably, one symptomatic patient did not meet neuropathy criteria on NCS, a novel finding, further expanding the RFC1 phenotype. Disease progression was 0.3 points per year (Spinocerebellar Degeneration Functional Score) and 1.4 points per year (Scale for the Assessment and Rating of Ataxia). Eye motor abnormalities primarily affected saccades and induced central nystagmus without clear correlation with cerebellar atrophy or ataxia. Vestibular testing suggested impairment of the vestibulo-ocular reflex at higher frequencies in early disease stages, potentially serving as an early CANVAS marker.

Conclusion: This study confirms and expands the RFC1 phenotypic spectrum, providing novel insights into its clinical features. Our findings suggest an early vestibular marker for CANVAS and highlight the need to consider RFC1 disease in patients with cerebellar or vestibular dysfunction, even in the absence of neuropathy.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-findings-in-a-swedish-rfc1-related-disorder-cohort/