Chronic Cough and CANVAS (Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome)

Gastroesophageal Reflux Clinical Trial

— CANVAS  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04703595
• Other study ID #: IIBSP-TOS-2020-143
• Status: Completed
• Start date: January 1, 2022
• Est. completion date: September 30, 2023

Study information

• Verified date: July 2022
• Source: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: September 30, 2023
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 99 Years

Eligibility

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.

Related Conditions & MeSH terms

• Ataxia
• Bilateral Vestibulopathy
• Cerebellar Ataxia
• Cough
• Gastroesophageal Reflux

Intervention

Genetic:
• To determine the presence of biallelic expansion of AAGGG in RFC1 in patients with chronic cough, regardless of the presence of neurological symptoms.
To determine the presence of biallelic expansion of AAGGG in RFC1 in patients with chronic cough, regardless of the presence of neurological symptoms. 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.

Locations

Country	Name	City	State
Spain	Hospital de la Santa Creu i Sant Pau. Carrer Mas Casanovas 90.	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Country where clinical trial is conducted

Spain, 

References & Publications (4)

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. Erratum In: Nat Genet. 2019 May;51(5):920. — View 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. — View 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. Erratum In: Brain. 2021 Jun 22;144(5):e51. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Presence of biallelic expansion of AAGGG in RFC1 in patients with chronic cough, regardless of the presence of neurological symptoms	Study of the DNA sample of the patients with two techniques: 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.	6 months
Secondary	Phenotypic, functional and inflammatory characteristics of these patients	The tests of the usual clinical practice will be carried out for the study of chronic cough	12 months