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

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.

Early Diagnosis in Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS) by Focusing on Major Clinical Clues: Beyond Ataxia and Vestibular Impairment

“…Indeed, most of our patients had been initially considered to have an immune-mediated sensory ataxic neuronopathy, which prompted us to look for Sjögren’s disease, paraneoplastic sensory neuronopathy or ganglionopathy linked to anti-FGFR3 antibodies [ 15 ]. However, as recently emphasized, the partial or complete sparing of tendon reflexes in our patients is a typical feature of CANVAS [ 16 , 17 ]. Therefore, it must be kept in mind that sensory neuronopathy with positive sensory symptoms, even with an initial asymmetrical distribution, might be encountered in CANVAS.…”

Head impulse testing in bilateral vestibulopathy in patients with genetically defined CANVAS

“…Three of the 20 patients displayed isolated bilateral vestibulopathy and one-third of the examined patients did not suffer from cerebellar ataxia at the first visit albeit an average disease duration of 7 years, representing a similar distribution compared to CANVAS cohorts published to date (Cortese et al, 2020;Dominik et al, 2021;Traschütz et al, 2021). Of note, due to the lack of nerve conduction studies at the time point of the first examination, the presence of neuropathy Together, our data encourage (i) screening for RFC1 mutations not only in late-ataxia cohorts but also in patients with isolated bilateral vestibulopathy as this approach possibly allows earlier detection of the disease, (ii) investigating distinct vestibular functions separately (semicircular canals, otoliths) as well as the vertical vestibular-ocular reflex in a prospective study design as this might detect even earlier vestibular manifestations, and (iii) longitudinal analyses including comprehensive nerve conduction studies to decipher whether somatosensory neuropathy and bilateral vestibulopathy develop at the same time possibly reflecting that bilateral vestibulopathy is another manifestation of ganglionopathy in CANVAS (Palla et al, 2009).…”

“…Three of the 20 patients displayed isolated bilateral vestibulopathy and one‐third of the examined patients did not suffer from cerebellar ataxia at the first visit albeit an average disease duration of 7 years, representing a similar distribution compared to CANVAS cohorts published to date (Cortese et al., 2020 ; Dominik et al., 2021 ; Traschütz et al., 2021 ). Of note, due to the lack of nerve conduction studies at the time point of the first examination, the presence of neuropathy had to be defined in most cases by clinical signs only.…”

“…IN an attempt to characterize the natural course of bilateral vestibulopathy in CANVAS, we related its most representative and easily accessible sign, that is, the abnormal video head impulse test, of biallelic RFC1 expansion carriers (all of them with BV) to disease duration and other CANVAS symptoms. In contrast to the recent studies on the clinical phenotype of RFC1 mutation carriers with various but inconsistent methods of vestibular testing (Cortese et al., 2020 ; Dominik et al., 2021 ; Traschütz et al., 2021 ), we focused on the horizontal high‐frequency vestibulo‐ocular reflex quantified by video head impulse testing as it is applicable in many outpatient clinics.…”

Cognitive Dysfunction in Repeat Expansion Diseases: A Review

“…Recently, the pathogenic gene, a biallelic intronic repeat expansion in the replication factor complex subunit 1 (RFC1), was identified, adding a new member to the list of REDs (Cortese et al, 2019 ). The pentanucleotide is generally repeated 11 times, often <15 repeats, while in the patients with CANVAS, the repeat numbers expanded from several hundred to over 2,000 (Gisatulin et al, 2020 ; Dominik et al, 2021 ). The mean onset for any neurological sign of CANVAS (cough excluded) is 52 years, albeit the onset might range between 19 and 76 years (Sullivan et al, 2021 ).…”