CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

Natalia Dominik,Henry Houlden,Andrea Cortese,Valentina Galassi Deforie

doi:10.1007/s00415-020-10183-0

Natalia Dominik, Henry Houlden + Show 2 more

Open Access

https://doi.org/10.1007/s00415-020-10183-0

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Abstract

The ataxias are a group of disorders that manifest with balance, movement, speech and visual problems. They can arise due to dysfunction of the cerebellum, the vestibular system and/or the sensory neurons. Genetic defects are a common cause of chronic ataxia, particularly common are repeat expansions in this group of conditions. Co-occurrence of cerebellar ataxia with neuropathy and vestibular areflexia syndrome has been termed CANVAS. Although CANVAS is a rare syndrome, on discovery of biallelic expansions in the second intron of replication factor C subunit 1 (RFC1) gene, we and others have found the phenotype is broad and RFC1 expansions are a common cause of late-onset progressive ataxia.We aim to provide a review and update on recent developments in CANVAS and populations, where the disorder has been reported. We have also optimised a protocol for RFC1 expansion screening which is described herein and expanded phenotype after analysing late-onset ataxia patients from around the world.

Highlights

Late-onset ataxia is a common neurological condition, where failure of systems controlling motor coordination occurs
CANVAS is a common cause of late-onset progressive ataxia and the CANVAS patients suffer from ataxia, sensory neuronopathy or neuropathy as well as vestibular dysfunction [5]
A sensory neuropathy was identified as a common feature in all cases carrying biallelic AAGGG replication factor C subunit 1 (RFC1) expansions

Summary

Introduction

Late-onset ataxia is a common neurological condition, where failure of systems controlling motor coordination occurs This can lead to falls because of gait and stance ataxia and severe limitations in daily life. CANVAS is a common cause of late-onset progressive ataxia and the CANVAS patients suffer from ataxia, sensory neuronopathy or neuropathy as well as vestibular dysfunction [5]. A sensory neuropathy was identified as a common feature in all cases carrying biallelic AAGGG RFC1 expansions. The cough is reported up to 30 years before neurological onset [6, 7], and it is hypothesised to be arising either as hypersensitivity syndrome due to a peripheral mechanism, where dysfunction of C fibres at level of upper way or oesophagus occurs; or due to cerebellar circuitry impairment [7]. Clinical diagnosis of CANVAS may be difficult and genetic investigations should follow

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