Abstract
Objective: To explore fat replacement, muscle strength, and clinical features in women heterozygous for a pathogenic DMD variant, we prospectively examined 53 women, assuming that some of these women—despite of the recessive X-linked inheritance—manifested clinical symptoms.Methods: We performed a cross-sectional observational study using MRI and stationary dynamometry of lower extremities, extracted blood muscle biomarkers, and investigated subjective complaints. Results were compared with 19 healthy women.Results:DMD variant carriers were weaker and had higher fat fractions than controls in all investigated muscle groups (p < 0.02). Fat fractions were 18% in carriers vs. 11% in controls in thighs (p = 0.008), and 15 vs. 11% in calf muscles (p = 0.032). Seventy-two percent had fat fractions deviating from controls by two standard deviations (SDs) in one or more of the 16 investigated muscle groups. On strength testing, 40% of the carriers had results deviating from control muscle strength by two SDs in one or more dynamometry assessments. Forty-three carriers (81%) had either reduced muscle strength (<2 SDs from control mean) and/or elevated muscle fat fraction (>2 SDs from control mean). Thirty of these had subjective symptoms. Blood creatine kinase and myoglobin were elevated in 57% of the carriers.Conclusion: Using quantitative methods, this study shows that both clinically symptomatic and asymptomatic women with pathogenic DMD variants show a high prevalence of muscle affection. Longitudinal studies in female carriers of pathogenic DMD variants are needed to follow the evolution of these changes.
Highlights
Duchenne (DMD) and Becker (BMD) muscular dystrophies are two of the most common inherited disorders of muscle, caused by X-linked recessively inherited mutations in the dystrophin gene (DMD) [1, 2]
All 53 were genetically verified carriers of pathogenic Duchenne muscular dystrophy (DMD) variants, and all had relatives diagnosed with either DMD or Becker muscular dystrophy (BMD), except for three sporadic de novo variant carriers who had DMD variants most likely to cause a Duchenne phenotype in men and were categorized as such in this study
Of the 53 participants, 33 had DMD variants predicted to produce a Duchenne phenotype in men (DMD-associated), and 20 a Becker phenotype in men (BMD-associated). These assumptions were based on male relatives’ diagnosis or predicted pathogenicity according to database records in the three participants with no affected male relatives
Summary
Duchenne (DMD) and Becker (BMD) muscular dystrophies are two of the most common inherited disorders of muscle, caused by X-linked recessively inherited mutations in the dystrophin gene (DMD) [1, 2]. One in 5,000 boys are born with pathogenic DMD mutations [3, 4]. The point prevalence of DMD is approximately 8.3/100,000 and 7.3/100,000 for BMD [5], making them two of the most common inherited disorders of muscle. Two-thirds of the pathogenic variants in affected boys are inherited from their mother, and one third are caused by de novo variants [2]
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