Impact of the intronic RFC1 expansion size in CANVAS phenotype: an oculomotor study

Abstract

The identification of the RFC1 homozygous intronic expansion in cerebellar ataxia neuropathy and vestibular areflexia syndrome (CANVAS) highlighted that genetically determined CANVAS patients exhibit a wide range of clinical presentations and natural course. Previous studies suggested a link between disease severity and the size of the intronic expansion. The aim of our study was to obtain quantitative data related to vestibular and cerebellar impairments using oculomotor recordings to provide further evidence of a link between RFC1 intronic expansion size and the phenotype. This study recruited 26 genetically determined CANVAS patients in whom the size of the pathological intronic expansion was measured on both alleles. In addition to clinical data, we also recorded the Overall Neuropathy Limitation Scale (ONLS) and conducted objective oculomotor testing. According to the median expansion length on one allele, the patients were divided in a longer intronic repeat subgroup and a shorter intronic repeat subgroup. Given the homozygous nature of this disease, this analysis was carried out for the smallest and for the longest allele. We found for the smallest allele that vestibular deficit and cerebellar impairment were significantly more frequent and mean ONLS, smooth pursuit, pendular visually enhanced vestibulo-ocular reflex, and head impulse vestibulo-ocular reflex gains were significantly more impaired in the subgroup of patients with the long intronic repeat. This work provides objective evidence for a functional impact of the pathological intronic expansion size in CANVAS and highlights the interest of oculomotor assessment in research and clinical practice both for diagnostic and potentially prognostic purposes.