Repeat expansions in gene in refractory chronic cough.

Introduction: Refractory chronic cough (RCC), persisting despite addressing contributory diagnoses, is likely underpinned by neurally mediated cough hypersensitivity. disorders are genetic neurodegenerative conditions caused by biallelic repeat expansion sequences, commonly presenting with cough, followed by neurological features including cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). The prevalence and identifying clinical characteristics of repeat-expansion disorders in patients with RCC are unknown.

Methods: Consecutive patients with RCC underwent genotyping, cough severity visual analogue scale (VAS) and cough-specific health status assessment (Leicester Cough Questionnaire (LCQ)). Participants with biallelic repeat expansions (RFC1) also underwent nerve conduction studies, brain imaging (MRI) and cough reflex sensitivity testing.

Results: 51 participants with RCC were recruited; 36 (71%) female, median (IQR) age 65 (56-70) years, duration of cough 12.8 (6.9-20.0) years. Four (8%) were RFC1, five (10%) monoallelic carriers (RFC1) and 42 (82%) of wild-type genotype (RFC1). No difference was observed in age, sex, cough duration, spirometry, VAS or LCQ scores between RFC1 and RFC1 subjects (p>0.05). The symptom of pins and needles was more frequent in RFC1 (n=4, 100%) compared to RFC1 (n=12, 33%) (p=0.01). RFC1 participants had impaired sensory action potentials, and one had cerebellar atrophy. RFC1 participants had heightened cough reflex sensitivity to capsaicin, similar to previous CANVAS and RCC studies.

Conclusion: Biallelic RFC1 repeat expansions (RFC1) were present in 8% of RCC patients. RFC1 participants demonstrated features of cough reflex hypersensitivity. RFC1 chronic cough had few identifying features, although symptoms of pins and needles were more common.