CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions
- PDF / 972,810 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 37 Downloads / 157 Views
NEUROLOGICAL UPDATE
CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions Natalia Dominik1 · Valentina Galassi Deforie1 · Andrea Cortese1,2 · Henry Houlden1 Received: 6 May 2020 / Revised: 19 August 2020 / Accepted: 20 August 2020 © The Author(s) 2020
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. Keywords Late-onset ataxia · CANVAS · RFC1 · Repeat expansion · Southern blot
Phenotype 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. The disorder can be acquired, hereditary or non-hereditary; and up to 60% of familial and 19% of sporadic cases could have a genetic basis [1–3] and in most patients, it can present without an obvious familial background [4]. 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]. Efforts have been made to piece together the syndromic clinical features of CANVAS with the genetic information to allow for more accurate clinical diagnosis. Recently, Cortese et al. reported the clinical features in the first 100 genetically confirmed * Natalia Dominik [email protected] * Henry Houlden [email protected] 1
Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
2
RFC1 CANVAS cases [6]. The mean age of onset appears to be just over 50 years. Progressive unsteadiness was the most common complaint at disease onset and universally present during disease progression. A sensory neuropathy was identified as a common feature in all cases carrying biallelic AAGGG RFC1 expansions. There is often intrafamilial variability in age at onset and severity in clinical features but we have not seen extreme differences. The repeat sizing on Southern blot does not allow accurate expansion size comparison although as numbers of
Data Loading...
