Repeat expansions in RFC1 gene in refractory chronic cough

Abstract

Introduction: Refractory chronic cough (RCC), persisting despite addressing contributory diagnoses, is likely underpinned by neurally mediated cough hypersensitivity. RFC1 disorders are genetic neurodegenerative conditions caused by biallelic RFC1 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 RFC1 repeat-expansion disorders in patients with RCC are unknown.

Methods: Consecutive patients with RCC underwent RFC1 genotyping, cough severity visual analogue scale (VAS) and cough-specific health status assessment (Leicester Cough Questionnaire (LCQ)). Participants with biallelic RFC1 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.

FIGURE 1

Duration of cough in patients with refractory chronic cough and biallelic (RFC1⁺⁺), monoallelic (RFC1⁺⁻) or no (RFC1⁻⁻) repeat expansions in the RFC1 gene. Data are displayed as median (IQR).