Clinical trial NCT04703595: Chronic Cough and CANVAS (Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome)
Official title: Chronic Cough and CANVAS (Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome): Screening for Mutations in Subunit 1 of the Replication Factor Complex: Initial Pilot Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cough
Cerebellar Ataxia
Gastroesophageal Reflux
Keywords: Cerebellar Ataxia
chronic cough
CANVAS
Lead sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
Sponsor class: OTHER
First posted: 2021-01-11
Enrollment: 50
Sex: ALL
Minimum age (years): 30
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: A total of 50 patients, non-smokers, aged between 30 and 99 years, with chronic and / or refractory cough as the only manifestation or associated with gastroesophageal reflux, who have signed the informed consent will be included.

Chronic cough will be defined as cough lasting more than 8 weeks that is not related to an acute (3 weeks) or subacute (3-8 weeks) process.

Brief summary: Chronic cough is a frequent cause of Pneumology consultations. CANVAS syndrome (Cerebellar Ataxia with Neuropathy and bilateral Vestibular Areflexia Syndrome) is a progressive and disabling neurological disease that very frequently occurs with chronic cough. This cough invariably appears as a prodromal symptom that precedes neurological symptoms. The biallelic expansion of AAGGG in RFC1, a causal mutation in CANVAS syndrome, appears with high frequency in the general population. Objectives: Main: To determine the presence of biallelic expansion of AAGGG in RFC1 in patients with chronic cough, regardless of the presence of neurological symptoms. Secondary: Describe the phenotypic, functional and inflammatory characteristics of these patients. and Know the relationship between gastroesophageal reflux and chronic cough in patients with CANVAS. Method: A descriptive cross-sectional pilot study including 50 non-smoking patients between the ages of 30 and 99 years with chronic and / or refractory cough as the only manifestation or associated with gastroesophageal reflux. All patients will undergo the pertinent studies for the diagnosis of chronic cough, those who meet criteria for suspicion of gastroesophageal reflux will be requested an esophageal phmetry and esophageal manometry. Peripheral venous blood sample will be obtained for subsequent genetic analysis. Vibration sensitivity will be studied in all patients regardless of the presence of mutation. Those with alterations in vibratory sensitivity or mutations in RFC1 will be referred to the Neurology Service for a complementary neurological evaluation. For the molecular study of the DNA sample of the patients, two techniques will be used: standard Polymerase chain reaction amplification with primers flanking the intron 2 fragment of the RFC1 gene and amplification using Repeated Primed Polymerase chain reaction in 3 independent reactions.

Detailed description: A descriptive cross-sectional pilot study that included 50 non-smoking patients between the ages of 30 and 99 years with chronic and / or refractory cough as the only manifestation or associated with gastroesophageal reflux.

All patients will undergo the pertinent studies for the diagnosis of chronic cough, those who meet criteria for suspected gastroesophageal reflux will be asked for an esophageal phmetry and esophageal manometry, according to the usual clinical practice.

Peripheral venous blood sample will be obtained for subsequent genetic analysis.

Vibration sensitivity will be studied in all patients regardless of the presence of mutation.

Those with alterations in vibratory sensitivity or mutations in RFC1 will be referred to the Neurology Service for a complementary neurological evaluation. For the molecular study of the DNA sample of the patients, two techniques will be used: standard Polymerase chain reaction amplification with primers flanking the intron 2 fragment of the RFC1 gene and amplification using Repeated Primed Polymerase chain reaction in 3 independent reactions.

Eligibility criteria: Inclusion Criteria:

* Non-smokers
* Aged between 30 and 99 years
* with chronic and / or refractory cough as the only manifestation or associated with gastroesophageal reflux, who have signed the informed consent will be included.

Exclusion Criteria:

* Other causes of cough other than gastroesophageal reflux: pneumological diseases (asthma, Chronic obstructive pulmonary disease, bronchiectasis, tracheomalacia, cystic fibrosis, residual pleural diseases, interstitial diseases, infectious diseases.)
* Upper airway pathologies (rhinitis, sinusitis)
* Foreign bodies
* Smokers or ex-smokers
* Symptoms of associated respiratory allergies
* Severe associated comorbidity.
* Autoimmune disease or systemic inflammatory disease.
* Active immunodeficiency.
* Neoplastic disease.

Primary outcomes:
measure: Presence of biallelic expansion of AAGGG in RFC1 in patients with chronic cough, regardless of the presence of neurological symptoms
timeFrame: 6 months
Secondary outcomes:
measure: Phenotypic, functional and inflammatory characteristics of these patients
timeFrame: 12 months
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau. Carrer Mas Casanovas 90.
Study officials:
affiliation: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
name: Astrid Crespo, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Infante J, Garcia A, Serrano-Cardenas KM, Gonzalez-Aguado R, Gazulla J, de Lucas EM, Berciano J. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) with chronic cough and preserved muscle stretch reflexes: evidence for selective sparing of afferent Ia fibres. J Neurol. 2018 Jun;265(6):1454-1462. doi: 10.1007/s00415-018-8872-1. Epub 2018 Apr 25.
citation: Szmulewicz DJ, McLean CA, MacDougall HG, Roberts L, Storey E, Halmagyi GM. CANVAS an update: clinical presentation, investigation and management. J Vestib Res. 2014;24(5-6):465-74. doi: 10.3233/VES-140536.
citation: Scriba CK, Beecroft SJ, Clayton JS, Cortese A, Sullivan R, Yau WY, Dominik N, Rodrigues M, Walker E, Dyer Z, Wu TY, Davis MR, Chandler DC, Weisburd B, Houlden H, Reilly MM, Laing NG, Lamont PJ, Roxburgh RH, Ravenscroft G. A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. Brain. 2020 Oct 1;143(10):2904-2910. doi: 10.1093/brain/awaa263.
citation: Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Zuchner S, Reilly MM, Houlden H. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019 Apr;51(4):649-658. doi: 10.1038/s41588-019-0372-4. Epub 2019 Mar 29.