clinical importance of carrier status of recessive gene mutations in myopathy (cics)

Conditions: Recessive Gene Myopathies

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.

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.

Eligibility criteria:
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