DUCHENNE MUSCULAR DYSTROPHY - GENETICS: P.217Duchenne and Becker muscular dystrophy carrier mothers: characterization of skeletal and cardiac muscle compared to healthy controls

Abstract

The risks of developing dystrophinopathy symptoms in female carriers have been linked to skewed X-chromosome inactivation with over-representation of the affected allele in the target tissue. Clinical manifestations reported include cardiomyopathy, skeletal muscle weakness and elevated creatine kinase (CK). The reported incidence of such abnormalities varies depending on the method of detection. We aim to prospectively assess the prevalence and extent of skeletal and cardiac muscle impairment in mothers of patients with Duchenne and Becker muscular dystrophy (DMD) in comparison to age-matched healthy controls. This longitudinal observational study characterizes skeletal and cardiac impairment in three cohorts: somatic carrier mothers, non-somatic mothers and age-matched healthy controls. Subjects from all cohorts are assessed at baseline and annually thereafter. To date, 95 subjects have been enrolled: 51 somatic carrier mothers, 18 non-somatic mothers and 26 healthy controls with mean ages of 43.1, 40.2 and 42.3 years respectively. Skeletal muscle weakness on manual muscle testing was detected in 25% of the somatic carriers compared to 17% in non-somatic mothers. Objective weakness was documented through reduced quantified knee extension strength (MVICT) only in the somatic mothers (p<0.005). Elevated CK was seen in 41% of somatic carriers. Late-gadolinium enhancement on cardiac MRI studies suggestive of myocardial fibrosis was observed in nearly half (46%) of the somatic carriers. Enrollment is continuing and additional data will be presented. This study corroborates reports of skeletal muscle weakness in manifesting carriers and provides greater detail than previously reported using cardiac MRI, permitting early detection of cardiomyopathy in somatic carriers. This novel study design is the first to assess all DMD/BMD mothers, carriers and non-carriers, with a healthy control arm to help distinguish manifestations due to age and daily burden of a caregiver.