Clinical Importance of Carrier Status of Recessive Gene Mutations in Myopathy (CICS)

Recessive Gene Myopathies Clinical Trial

— CICS  

Official title:

Clinical Importance of Carrier Status of Recessive Gene Mutations in Myopathy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02897921
• Other study ID #: H-16035677
• Status: Active, not recruiting
• Start date: October 2016
• Est. completion date: August 2021

Study information

• Verified date: May 2018
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Many myopathies are inherited in a recessive manner, but in some of these recessively inherited disorders, clinical manifestations may potentially manifest in carriers of just a single mutation.

The aim of the study is to describe the clinical characteristics of single mutation carriers of recessive myopathy, through measuring serum creatine kinase, muscle strength, muscle degeneration (by MRI) and heart affection. The investigators will do this by blood sampling, Biodex 4 Isokinetic Dynamometer, MRI analysis, ECG, Holter monitoring, and echocardiography.

The aim is further to describe whether these characteristics are found primarily with specific mutations.

Description:

Background:

Many myopathies are inherited in a recessive manner, but in some of these recessively inherited disorders, clinical manifestations may potentially manifest in carriers of just a single mutation. This has recently been demonstrated by researchers for the recessively inherited limb girdle muscle dystrophy (LGMD) type 2A, where carriers of single mutations can also be symptomatic. In X-linked recessively inherited dystrophinopathies caused by mutations in the DMD gene on chromosome Xp21, female mutation carriers may also manifest with disease, although this is often milder than affected men. In the recently discovered LGMD2L, manifesting carriers are also suspected. Thus, according to statistics, too many persons evaluated for myopathy carry a single LGMD2L mutation.

Some previous studies have looked into the significance of being a single mutation carrier in recessive muscle disease. In dystrophinopathy, it was reported that 5 % of female DMD carriers reported myalgia and cramps, 17 % experienced mild-to-moderate muscle weakness and 8 % experienced dilated cardiomyopathy, with a mean onset age of approximately 30 years. Another study found that echocardiographic examination was abnormal in up to 38% of DMD female carriers - some with dilated cardiomyopathy, and some with left ventricle dilatation.

Overall, however significance of carrying a single mutation of recessive myopathy is widely unexplored. No study has yet investigated the characteristics of single mutation carriers of recessive myopathy in an observational, cross-sectional study.

Aim:

In this study, clinical characteristics of single mutation carriers of recessive myopathies will be investigated. The investigation will include sceletal muscle degeneration and strength, as well as cardiac status.

Recruitment and Methods:

Estimated total of subjects recruited is 200 with known recessive gene mutations, and 40 healthy controls. In former studies 40 healthy volunteers have already been investigated, thereby giving a total of 80 healthy controls. Recessive gene carrier recruits will be obtained via the Department of Clinical Genetics and Copenhagen Neuromuscular Center, Rigshospitalet, thus only including carriers aware of their carrier status.

2 days of testing per participant. Day one: Measuring S-creatine kinase level (blood sampling), muscle strength (Biodex 4 Isokinetic Dynamometer), ECG, and Holter monitor device application.

Day two: Holter monitor device removal, Dixon MRI analysis with gadolinium contrast medium, and echocardiography.

Healthy controls will take part in MRI-scanning and isokinetic dynamometer testing.

Trials are expected to be carried out between October 2016 and May 2020.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 240
• Est. completion date: August 2021
• Est. primary completion date: May 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Single mutation carriers of recessive myopathy:

Inclusion Criteria:

• Verified carrier status of recessive myopathy mutation before entry into the study

• Age of 18 years or older

Exclusion Criteria:

• Contraindications for MRI (pacemaker or other internal metal or magnetic devices)

• Claustrophobia

• Pregnancy at the time of MRI

• After investigators judgement

Healthy controls:

Inclusion Criteria:

• Age of 18 years or older

Exclusion Criteria:

• Contraindications for MRI (pacemaker or other internal metal or magnetic devices)

• Claustrophobia

• Pregnancy at the time of MRI

• After investigators judgement

Related Conditions & MeSH terms

• Muscular Diseases
• Recessive Gene Myopathies

Locations

Country	Name	City	State
Denmark	Copenhagen Neuromuscular Center, Rigshospitalet, 3342	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

References & Publications (4)

Flanigan KM. Oxford Textbook of Neuromuscular Disorders chapter 22 "The dystrophinopathies". Oxford University Press 2014, first edition.

Hoogerwaard EM, van der Wouw PA, Wilde AA, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF, van Essen AJ, Leschot NJ, de Visser M. Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy. Neuromuscul Disord. 1999 Jul;9(5):347-51. — View Citation

Lee SH, Lee JH, Lee KA, Choi YC. Clinical and Genetic Characterization of Female Dystrophinopathy. J Clin Neurol. 2015 Jul;11(3):248-51. doi: 10.3988/jcn.2015.11.3.248. Epub 2015 May 28. — View Citation

Vissing J, Barresi R, Witting N, Van Ghelue M, Gammelgaard L, Bindoff LA, Straub V, Lochmüller H, Hudson J, Wahl CM, Arnardottir S, Dahlbom K, Jonsrud C, Duno M. A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy. Brain. 2016 Aug;139(Pt 8):2154-63. doi: 10.1093/brain/aww133. Epub 2016 Jun 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cardiac status	We will use MRI with a contrast agent (gadolinium). Kidney function and contrast allergy status will be tested prior to use of contrast agent, and avoided if the participant is not suitable for contrast injection.	MRI of cardiac status and muscles takes around 1,5 hours
Primary	Muscle tissue quality	Muscle tissue cross sectional area and fat percent will be investigated and measured by Dixon MRI scan.	MRI of cardiac status and muscles takes around 1,5 hours
Secondary	Serum CK-levels	Blood sampling	Estimated time 5 minutes.
Secondary	Muscle strength	Investigated by an isokinetic dynamometer (Biodex 4).	Testing takes around 10-20 minutes
Secondary	ECG	ECG electrodes will be places on the subject's chest, and an electrocardigram will be measured.	Estimated time: 5 minutes.
Secondary	Holter monitor	The electrodes will be places on the chest and the monitor attached in a line around the neck. 24-48 hours of electrocardiogram will be measured.	A Holter monitor device will be attached on test day 1, and worn until test day 2 (24-48 hours)