Follow-up Study on Female Carriers With DMD Gene Variants

Condition(s) studied

Investigational drug(s) / intervention(s)

No intervention: No intervention

Study summary

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.

Aim

1. To 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.
2. To explain the relationship between the XCI and the severity of the disease (phenotype).
3. To compare cardiac affection of female carriers of DMD/BMD to patients with BMD using new cardiac MRI techniques (spectroscopy and Dixon sequences).

Methods

This 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.

Eligibility

Primary outcome measure(s)

• Change in fat fraction — 30 minutes
  Change in fat fraction (in %) in leg muscles from baseline to 6-year follow-up
• Change in fibrosis in the heart — 1 hour
  Change in fibrosis (in %) in the heart from baseline to 6-year follow-up
• Change in LVEF/GLS-score — 1 hour
  Change in LVEF/GLS-score (in %) in the heart from baseline to 6-year follow-up
• Correlation between XCI and phenotype — 1 hour
  Correlation between XCI (ratio of healthy vs mutant X chromosome) and phenotype (from fat fraction and clinical symptoms). Correlation measured using linear regression.
• Cardiac status in patients with BMD vs carriers of variants in the DMD gene — 1 hour
  Correlation between cardiac structure and function (measured through Dixon and spectroscopy from cardiac MRI) between patients with BMD and carriers of genetic variants of the DMD gene.

Trial sites (1)

More Copenhagen University Hospital, Rigshospitalet trials in Denmark

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