Repeat expansions in RFC1 gene in refractory chronic cough

Barnaby Hirons; Peter S.P. Cho; Katie Rhatigan; Joe Shaw; Riccardo Curro; Bianca Rugginini; Natalia Dominik; Richard D. Turner; Ewan Mackay; James H. Hull; Hisham Abubakar-Waziri; Harini Kesavan; Caroline Jolley; Robert D. Hadden; Andrea Cortese; Surinder S. Birring

doi:10.1183/23120541.00584-2024

Repeat expansions in RFC1 gene in refractory chronic cough

Barnaby Hirons, Peter S.P. Cho, Katie Rhatigan, Joe Shaw, Riccardo Curro, Bianca Rugginini, Natalia Dominik, Richard D. Turner, Ewan Mackay, James H. Hull, Hisham Abubakar-Waziri, Harini Kesavan, Caroline Jolley, Robert D. Hadden, Andrea Cortese, Surinder S. Birring^*

^*Corresponding author for this work

Centre for Human & Applied Physiological Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	00584-2024
Journal	ERJ Open Research
Volume	11
Issue number	1
DOIs	https://doi.org/10.1183/23120541.00584-2024
Publication status	Published - Jan 2025

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Hirons, B., Cho, P. S. P., Rhatigan, K., Shaw, J., Curro, R., Rugginini, B., Dominik, N., Turner, R. D., Mackay, E., Hull, J. H., Abubakar-Waziri, H., Kesavan, H., Jolley, C., Hadden, R. D., Cortese, A., & Birring, S. S. (2025). Repeat expansions in RFC1 gene in refractory chronic cough. ERJ Open Research, 11(1), Article 00584-2024. https://doi.org/10.1183/23120541.00584-2024

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title = "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.",

author = "Barnaby Hirons and Cho, {Peter S.P.} and Katie Rhatigan and Joe Shaw and Riccardo Curro and Bianca Rugginini and Natalia Dominik and Turner, {Richard D.} and Ewan Mackay and Hull, {James H.} and Hisham Abubakar-Waziri and Harini Kesavan and Caroline Jolley and Hadden, {Robert D.} and Andrea Cortese and Birring, {Surinder S.}",

note = "Publisher Copyright: {\textcopyright} The authors 2025.",

year = "2025",

month = jan,

doi = "10.1183/23120541.00584-2024",

language = "English",

volume = "11",

journal = "ERJ Open Research",

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publisher = "European Respiratory Society",

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T1 - Repeat expansions in RFC1 gene in refractory chronic cough

AU - Hirons, Barnaby

AU - Cho, Peter S.P.

AU - Rhatigan, Katie

AU - Shaw, Joe

AU - Curro, Riccardo

AU - Rugginini, Bianca

AU - Dominik, Natalia

AU - Turner, Richard D.

AU - Mackay, Ewan

AU - Hull, James H.

AU - Abubakar-Waziri, Hisham

AU - Kesavan, Harini

AU - Jolley, Caroline

AU - Hadden, Robert D.

AU - Cortese, Andrea

AU - Birring, Surinder S.

PY - 2025/1

Y1 - 2025/1

N2 - 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.

AB - 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.

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U2 - 10.1183/23120541.00584-2024

DO - 10.1183/23120541.00584-2024

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Repeat expansions in RFC1 gene in refractory chronic cough

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