CANVAS, a frequently underrecognized cause of late-onset progressive ataxia: a case report

Abstract

Case Presentation: J.A.D.S., a 72-year-old man with a history of atrial fibrillation and prior chronic alcohol use, presented with progressive gait ataxia for 12 years with dysphagia and recurrent cough. Neurological examination revealed dysarthria, bilaterally impaired vestibulo-ocular reflex (VOR), lower-limb areflexia, distal pallhypesthesia in the lower limbs, axial and gait ataxia. Laboratory evaluation for reversible causes of ataxia was unremarkable. Lower-limb electroneuromyography demonstrated severe axonal sensory polyneuropathy compatible with chronic ganglionopathy. Brain magnetic resonance imaging showed mild microangiopathic changes (Fazekas 1). Cerebrospinal fluid analysis was normal. Video head impulse testing (vHIT) demonstrated VOR hypofunction at high-frequency stimulation in the lateral and anterior semicircular canals bilaterally. A panel for common spinocerebellar ataxias (SCAs) was negative. Targeted molecular testing for Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome (CANVAS) subsequently identified biallelic pathogenic expansions in intron 2 of the RFC1 gene, confirming the diagnosis. The patient was adopted and had no available information regarding his biological parents, preventing family history assessment. Discussion: CANVAS is a rare late-onset neurodegenerative disorder often underrecognized. It is classically characterized by the triad of cerebellar ataxia, sensory neuronopathy, and bilateral vestibular areflexia, and is often associated with chronic cough and autonomic dysfunction. Since the identification of biallelic intronic repeat expansions in RFC1 as the genetic basis of the syndrome, many previously undiagnosed cases have been recognized, expanding awareness of the disease. In the present case, the patient remained without a definitive diagnosis for more than a decade, due to the insidious course and heterogeneous clinical manifestations. The presence of unexplained cough raises the possibility of vagal sensory fiber involvement, leading to cough reflex hypersensitivity. The neurophysiological findings, consistent with sensory ganglionopathy, showed predominant sensory impairment with relative preservation of motor function, contrasting with the pattern more commonly observed in typical polyneuropathies. The absence of significant abnormalities in complementary investigations and in the diagnostic panels performed is also relevant, as it helped exclude other important causes of late-onset ataxia. Final Comments: This case highlights the diagnostic complexity of late-onset ataxias and underscores the importance of recognizing clinical features suggestive of CANVAS, particularly the association of progressive ataxia, sensory neuronopathy, and chronic cough. Recognition of this clinical phenotype may reduce diagnostic delay and more appropriately guide genetic testing, given the central role of RFC1 expansion analysis in diagnostic confirmation. Earlier recognition may improve counseling and multidisciplinary rehabilitation.