Young-Adulthood Onset Chronic Cough as a Three Decades Prodrome of RFC1-related Autonomic and Sensory Neuropathy
Objective:
To inform about CANVAS, a rare overlooked progressive neurodegenerative disorder with various clinical and genetic phenotypes.
Background:
RFC1-related disease spans a spectrum from full cerebellar ataxia-neuropathy-vestibular areflexia syndrome (CANVAS) to isolated sensory or autonomic neuropathy. CANVAS is due to AAGGG repeat expansion in the second intron of replication factor-C subunit-1 (RFC1) gene. In addition to autonomic dysfunction symptoms as the most prevalent, sensory neuropathy/neuronopathy manifestations with/without overt vestibular dysfunction vary in presentation and severity. Two-thirds of affected individuals report a dry spasmodic cough that may antedate neurologic signs by decades, yet the link is often missed, highlighting cough as an overlooked prodrome.
Design/Methods:
Searched PubMed literature (2000–2025) for RFC1-disease.
Results:
A 57-year-old woman had a refractory dry cough from young adulthood. In her 5th decade she developed cold feet with paraesthesias, unsteady gait and orthostatic light-headedness. Examination with length-dependent loss of light touch, vibration and proprioception. Autonomic review revealed heat intolerance, anhidrosis and mottled acral skin. Nerve-conduction studies demonstrated absent SNAPs in legs and reduced in arms consistent with sensory neuronopathy. Brain-MRI demonstrated mild parenchymal atrophy and nonspecific periventricular FLAIR-hyperintensities without cerebellar tonsillar descent. Repeat-primed PCR detected biallelic RFC1 AAGGG expansions, establishing an RFC1-related disorder in the spectrum of CANVAS. Chronic cough was therefore recognized as the inaugural symptom, preceding neuropathy by three decades.
Conclusions:
Refractory chronic cough can represent the sole manifestation of CANVAS for decades. Autonomic dysfunction may be related to a ganglioneuropathy. There is no specific treatment. Neurologists should query for a lifetime chronic cough in late-onset neuropathy even without overt vestibular involvement. Timely recognition enables targeted genetic testing, counselling, appropriate management of symptoms and avoidance of unnecessary immunotherapies. Genetic testing with repeat-primed PCR to detect intronic expansions in RFC1 should be performed in cases with suspicion of CANVAS and/or in case of whole-exome sequencing negative hereditary sensory and autonomic neuropathy.
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