Why the study?
To investigate pathological changes in CANVAS patients harboring biallelic ACAGG-exp and AAGGG-exp, given recent evidence supporting RFC1 loss-of-function.
The identification of RNA foci in neuronal nuclei suggests that RNA toxicity may be involved in the pathogenesis of CANVAS.
RNA toxicity may contribute to CANVAS; leaves open confirmation and therapeutic targeting in larger cohorts.
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 2024;95:607-613.
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Wada et al. (2023) studied this question.
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