RNA Foci in Two bi‐Allelic RFC1 Expansion Carriers

Abstract

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late‐onset, autosomal recessive neurodegenerative disorder caused by biallelic AAGGG/ACAGG repeat expansion (AAGGG‐exp/ACAGG‐exp) in RFC1. The recent identification of patients with CANVAS exhibiting compound heterozygosity for AAGGG‐exp and truncating variants supports the loss‐of‐function of RFC1 in CANVAS patients. We investigated the pathological changes in 2 autopsied patients with CANVAS harboring biallelic ACAGG‐exp and AAGGG‐exp. RNA fluorescence in situ hybridization of the 2 patients revealed CCTGT‐ and CCCTT‐containing RNA foci, respectively, in neuronal nuclei of tissues with neuronal loss. Our findings suggest that RNA toxicity may be involved in the pathogenesis of CANVAS. ANN NEUROL 2023