CANVAS

CANVAS, or cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (OMIM #614575), is a progressive and disabling neurological disorder characterized by ataxia, sensory neuropathy, and bilateral vestibular dysfunction. Sensory neuropathy is a central feature of the disease and is often the initial manifestation. Although the clinical entity has been recognized for several years, it is only recently that a biallelic pentanucleotide expansion in the RFC1 gene has been identified as responsible for the majority of cases. Nevertheless, the pathogenic mechanisms underlying this disease remain unknown. This project proposes:

• Molecular characterization of genetic variations in RFC1 in patients with cryptogenic sensory neuropathy or CANVAS, assessing the number of known pentanucleotide expansions and possible new alleles in our population (novel expansion conformations and point variants).

• Detailed clinical characterization of patients with phenotypes associated with pathogenic RFC1 variations, and the establishment of a registry on the GenRaRE platform to enable natural history studies.

• Creation of a CANVAS biorepository within the CIBERER Biobank through the collection of biological samples from patients with pathogenic RFC1 variations.

• Generation of new study models to structurally and functionally characterize the dynamic mutation and to determine the epigenetic marks associated with the repeat.

• To deepen the understanding of the pathogenic mechanism of the disease.