Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS)

Abstract

The syndrome of cerebellar ataxia with neuropathy and bilateral vestibular areflexia (CANVAS) has emerged progressively during the last 30 years. It was first outlined by the neurootology/neurophysiology community in the vestibular areflexic patients, through the description of patients slowly developing late-onset cerebellar ataxia and bilateral vestibulopathy. The characteristic deficit of visuo-vestibulo-ocular reflex (VVOR) due to the impaired slow stabilizing eye movements was put forward and a specific disease subtending this syndrome was suggested. The association to a peripheral sensory axonal neuropathy was described later on, with neuropathological studies demonstrating that both sensory neuropathy and vestibular areflexia were diffuse ganglionopathy. Clinical and electrophysiological criteria of CANVAS were then proposed in 2016. Besides the classical triad, frequent chronic cough, signs of dysautonomia and neurogenic pains were frequently observed. From the beginning of published cohorts, sporadic as well as familial cases were reported, the last suggestive of an autosomal recessive mode of transmission. The genetic disorder was discovered in 2019, under the form of abnormal biallelic expansion in the replication factor C subunit 1 (RFC1) in a population of late-onset ataxia. This pathological expansion was found in 100% of the familial form and 92% of sporadic ones when the triad was complete. But using the genetic criteria, the phenotype of CANVAS seems to expand, for exemple including patients with isolated neuronopathy. We propose here to review the clinical, electrophysiological, anatomical, genetic aspect of CANVAS in light of the recent discovery of the genetic aetiology, and discuss differential diagnosis, neuropathology and physiopathology.

Review Article “Spotlight on Ultrasonography in the Diagnosis of Peripheral Nerve Disease: The Evidence to Date”

“…CANVAS is an adult-onset disorder caused by mutation in the RFC1 gene. A sensory neuronopathy is universally seen in patients with CANVAS, 176 and can be detected on ultrasound as a reduction in CSA of the median, ulnar, tibial, and sural nerves. 177 A reduced median and ulnar nerve CSA < 5 mm 2 in the mid-forearm or mid-humerus demonstrate a sensitivity of 79–93%, specificity 100% and area under the curve (AUC) of 0.97–0.99 178 for distinguishing CANVAS from healthy controls.…”

RFC1 gene intronic repeat expansion and unexplained chronic cough: A pathophysiological conundrum

“…[10] As brainstem and cerebellum functions are impaired in CANVAS, including in neurologically asymptomatic patients, an early impairment of central networks of cough may be hypothesized. [13][14] Chronic cough is a common medical problem, with a 10% prevalence in the general adult population. [15] Tobacco use, angiotensin-converting enzyme inhibitors, reflux and esophageal dysmotility, asthma, chronic respiratory diseases and rhinosinusitis are major causes of chronic cough.…”

Canvas: A case report

“…5,6 This pathological expansion was found in 100% of the familial form, and 92% of seemimgly sporadic ones when the triad was complete. 7 This mutation has been identified as a major cause of late-onset ataxia, which affects the cerebellum, sensory ganglia including the vestibular system, and explaining the pathology of CANVAS. 5,8 Case report DLSS, 69 years old, female, started with dizziness in 2012, previously diagnosed with PPPD (persistent perceptual postural dizziness), due to the dizzying condition associated with great emotional stress, provoked by the death of her mother.…”