CANVAS as example of genetic and clinical complexity of RFC1-related disorders

Abstract

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a late-onset, autosomal recessive neurodegenerative disorder characterised by the triad of cerebellar ataxia, bilateral vestibular areflexia, and sensory neuropathy. First identified more than 30 years ago, its clinical phenotype has since expanded to include chronic cough, dysautonomia, and pain, with isolated neuronopathy reported in some cases. The discovery of biallelic AAGGG repeat expansions in intron 2 of the RFC1 gene in 2019 established the genetic basis for CANVAS, with the pathogenic expansions disrupting gene function via secondary structures such as G-quadruplexes. Despite this breakthrough, the precise pathophysiological mechanisms behind CANVAS remain elusive, necessitating further research into the molecular, clinical, and genetic aspects of this disease. This review consolidates the current understanding of CANVAS, encompassing the expanding spectrum of RFC1-related disorders, clinical manifestations, molecular underpinnings, and epidemiology, while exploring future directions for diagnostics and therapeutic advancements.

Keywords: AAGGG repeat expansion; RFC1 gene; bilateral vestibular areflexia; cerebellar ataxia; sensory neuropathy.