Follow-up Study on Female Carriers With DMD Gene Variants

Background Duchenne and Becker muscular dystrophies are X-linked recessive allelic disorders caused by mutations of the dystrophin gene on chromosome Xp21. Female carriers may pass on the pathogenic variant to their daughters, resulting in a significant number of female carriers of pathogenic DMD variants. There was a large variability in the severity of symptoms with some being asymptomatic and some having severe symptoms. Skewed X-Chromosome Inactivation (XCI) might explain some of this variability. But now, the underlying cause of the large variability in phenotype is therefore uncertain.AimTo describe the change over a 6-year follow-up period in the structure and function of the heart and in function and muscle fat fraction in skeletal muscle of DMD/BMD carriers.To explain the relationship between the XCI and the severity of the disease (phenotype).To compare cardiac affection of female carriers of DMD/BMD to patients with BMD using new cardiac MRI techniques (spectroscopy and Dixon sequences).MethodsThis study contains three parts:Part 1 is a 6-year follow-up on 53 genetically verified female carriers of pathogenic DMD variants initially investigated in 2016-2018 at Copenhagen Neuromuscular Center, Rigshospitalet (Ethical journal no. H-16035677). In this part, the same 53 females will be investigated with the same measurements as 6 years ago to describe the progression of symptoms. All the follow-up results from this study will be compared to the results from 6 years ago.In Part 2 a muscle biopsy will be taken from 1-3 muscles (see "3.3.3 Description of outcomes) to investigate the XCI. To correlate the XCI to the phenotype, these patients will also undergo a muscle MRI and a Medical Research Council scale score for muscle strength (MRC).In Part 3 The cardiac structure and function in patients with BMD will be investigated using a cardiac MRI to compare the findings with that of female carriers. An MRC will carried out to investigate if the heart affection correlates to the muscle affection.Female carriers can decide whether to participate in Part 1, Part 2, or both. Patient with BMD can only participate in Part 3.

Part 1:Criteria of inclusion:Female genderVerified carrier of DMD gene mutations through genetic testing.Age of 18 years or moreParticipation in the study 6 years agoCriteria of exclusion from MRI:Contraindications to MRI (pacemaker or other internal metal or magnetic devices)Claustrophobia.Pregnant or nursing women.Competing disorders and other muscle disorders, which may alter measurements of i.e., muscle strength. The investigator will decide whether or not the competing disorder can significantly influence the results.Patients will be investigated with all other measurements than MRI if not eligible for MRI.Part 2:Criteria of inclusion:Female genderVerified carrier of DMD gene mutations through genetic testing.Age of 18 years or moreCriteria of exclusion:• Anticoagulating medicine that cannot be paused due to health reasonsPart 3:Criteria of inclusion:Genetically verified patient with BMDAge of 18 years or moreCriteria of exclusion:Contraindications to MRI (pacemaker or other internal metal or magnetic devices)Claustrophobia.Atrial fibrillationCompeting disorders and other muscle disorders, which may alter measurements of i.e., muscle strength. The investigator will decide whether or not the competing disorder can significantly influence the results.