CANVAS Syndrome: Definition, Diagnosis, and Management
What is CANVAS Syndrome?
CANVAS (Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome) is a late-onset autosomal recessive neurodegenerative disorder caused by biallelic AAGGG repeat expansions in intron 2 of the RFC1 gene, presenting with the classic triad of progressive cerebellar ataxia, bilateral vestibular areflexia, and sensory neuropathy or neuronopathy. 1, 2
Core Clinical Features
The syndrome typically manifests in middle age with:
- Progressive imbalance from combined cerebellar, proprioceptive, and vestibular system impairment 1, 3
- Oscillopsia (visual blurring with head movement) due to bilateral vestibular loss 1
- Sensory disturbance from sensory neuropathy or ganglionopathy 1, 4
- Chronic dry cough that often precedes neurological symptoms by years and serves as a critical diagnostic clue 1, 3
Expanded Phenotypic Spectrum
Beyond the classic triad, CANVAS frequently includes:
- Dysautonomia with blood pressure instability, bowel/bladder dysfunction 2, 4
- Neurogenic pain (radicular or neuropathic) 4
- Chronic cough present in the majority of cases 2, 4
- Site-restricted variants affecting only sensory nerves, cerebellum, or vestibular system in isolation 1, 3
Diagnostic Approach
Clinical Examination Priorities
The key to diagnosis is systematic assessment of all three affected systems plus recognition of chronic cough. 1
Cerebellar System Assessment
- Wide-based gait with truncal instability that does NOT worsen with eye closure (distinguishing from sensory ataxia) 5
- Dysmetria on finger-to-nose and heel-to-shin testing 5
- Dysdiadochokinesia and dyssynergia 5
- Ataxic dysarthria with scanning speech 5
- Ocular dysmetria (saccadic overshooting) 5
Vestibular System Assessment
- Bilateral vestibular areflexia on bedside head impulse testing 1, 4
- Impaired visuo-vestibulo-ocular reflex (VVOR) - a characteristic deficit due to impaired slow stabilizing eye movements 4
- Oscillopsia reported during head movement 1
Sensory Neuropathy Assessment
- Sensory neuropathy or neuronopathy with distal sensory loss 1, 4
- Decreased or absent reflexes (areflexia) 4
- Proprioceptive deficits contributing to imbalance 3
- Neuropathological studies demonstrate diffuse ganglionopathy affecting both sensory and vestibular systems 4
Associated Features to Document
- Chronic cough - ask specifically about this symptom as it often precedes neurological manifestations 1, 3
- Dysautonomia signs (orthostatic symptoms, bowel/bladder changes) 2, 4
- Pain patterns (neuropathic, radicular) 4
Genetic Testing
RFC1 genetic testing for biallelic AAGGG repeat expansions is the definitive diagnostic test. 1, 2
Genetic Findings
- Biallelic (AAGGG)n expansions in RFC1 intron 2 are found in 100% of familial cases and 92% of sporadic cases with complete triad 4
- Alternative pathogenic expansion (ACGGG)n also causes CANVAS 3
- Truncating variants in RFC1 coding region (e.g., c.1267C>T, c.2876del) can occur in trans with (AAGGG)n expansion 6
- Full RFC1 sequencing is recommended in typical CANVAS cases carrying only monoallelic (AAGGG)n expansions to detect second truncating variants 6
Pathomechanism
- Pathogenic expansions disrupt RFC1 function via secondary structures (G-quadruplexes) 2
- Truncating variants cause nonsense-mediated mRNA decay with reduced RFC1 transcript and protein, supporting a loss-of-function mechanism 6
Neuroimaging
MRI of the head without IV contrast is the preferred initial imaging modality. 5, 7
Expected MRI Findings
- Cerebellar atrophy affecting hemispheres and vermis 5, 7
- Signal abnormalities in cerebellum and brainstem 5
- Early imaging may be normal or subtly abnormal, with progressive changes on follow-up 7
Additional Imaging Considerations
- MRI of cervical and thoracic spine should be obtained when spinal cord signs (motor spasticity, sensory ataxia) are present to evaluate for spinal cord atrophy 7
- Spine imaging helps exclude alternative diagnoses and may show cord atrophy correlating with symptom severity 7
Differential Diagnosis
Key Distinguishing Features
- Negative Romberg test (unsteadiness does NOT worsen with eye closure) distinguishes CANVAS from sensory ataxia 5, 8
- Bilateral vestibular areflexia distinguishes from other spinocerebellar ataxias 1, 4
- Chronic cough is highly specific and not typical of other ataxias 1, 3
Conditions to Exclude
- Other spinocerebellar ataxias (SCA1-48, Friedreich ataxia) - typically lack vestibular areflexia and chronic cough 7
- Miller Fisher syndrome - presents with ataxia, areflexia, and ophthalmoplegia (not vestibular areflexia), acute/subacute onset 9, 7
- Posterior circulation stroke - acute onset, not progressive 7
- Cerebellar tumors - must be excluded with imaging 7
- Inflammatory/paraneoplastic cerebellar degeneration - different tempo and associated features 9, 7
Clinical Epidemiology
RFC1 disease is probably the most common cause of recessive ataxia. 1
- Typical onset in middle age (40s-60s) 1, 2
- Slowly progressive course over years to decades 1, 2
- Autosomal recessive inheritance pattern 2, 4
- Phenotypic spectrum expanding to include isolated neuronopathy, cerebellar-only, or vestibular-only presentations 1, 3
Management
Current Treatment Limitations
There is no disease-modifying therapy for CANVAS; management is entirely supportive and rehabilitative. 1, 2
Rehabilitation Strategies
Based on general cerebellar ataxia management principles:
- Balance training programs to improve stability 5
- Postural training for trunk control 5
- Task-oriented upper limb training for reaching and fine motor control 5
- Assistive devices and orthoses (canes, walkers) to improve balance and mobility 5
Symptomatic Management
- Chronic cough management (though specific effective therapies not well-established) 1, 2
- Neuropathic pain treatment with standard agents 4
- Dysautonomia management (orthostatic hypotension measures, bowel/bladder support) 2, 4
Monitoring
- Serial neurological examinations to track progression 1, 2
- Follow-up MRI may demonstrate progressive cerebellar atrophy 7
Critical Diagnostic Pitfalls
- Missing chronic cough as a diagnostic clue - always ask about this symptom specifically 1, 3
- Failing to test vestibular function - bilateral vestibular areflexia is essential for diagnosis 1, 4
- Assuming all progressive ataxia is benign hereditary disease - always exclude tumors, inflammatory conditions, and paraneoplastic syndromes first 7
- Stopping genetic testing after finding monoallelic RFC1 expansion - proceed to full RFC1 sequencing to detect truncating variants 6
- Overlooking site-restricted phenotypes - isolated sensory neuropathy or cerebellar ataxia may be RFC1-related 1, 3