Clinical and molecular characterization of Becker muscular dystrophy

Background: Becker muscular dystrophy (BMD) is an X-linked muscle disease caused by mutations in the DMD gene, encoding the dystrophin protein. The clinical picture of this progressive neuromuscular disease is variable, including myalgias, limb-girdle weakness leading to wheelchair dependency usually after the age of 16 years or isolated elevation of serum creatine kinase without overt muscle weakness. Other rare BMD phenotypes are characterized by isolated dilated cardiomyopathy. Objective: This multicentre retrospective study aims at collecting demographic, clinical and genetic information in a large cohort of BMD patients in order to describe the natural history and relevant milestones of the disease. Materials and methods: Retrospective data were collected from 917 patients followed by 16 Italian Neuromuscular Centres. Statistical methods were used to describe the cohort of patients by examining patients’ demographics, main signs and symptoms at BMD onset, neuropsychiatric comorbidities, age at loss of ambulation (LoA), cardiac left ventricular ejection fraction (LVEF), pulmonary forced vital capacity (FVC) and the effect of glucocorticoid (GC) therapy. DMD mutations were collected and disease milestones were analysed in specific DMD mutational groups. Results: At last assessment, 12.70% of patients had lost the ability to walk at a mean age of 34.99 years. The estimated median age at LoA was 70 years. The patients were further grouped according to the reading frame retention and mutational subtypes of DMD gene. Out-of-frame mutations (10.01%) (p<0.0001) and deletions in the exons 45-49 (p<0.0001) and 45-47 (HR: 2.90, p=0.0370) were associated with earlier LoA, instead deletions in the exons 45-55 (p=0.018) correlated with later LoA. Finally, GC treatment (p<0.0001) seemed to be associated with earlier LoA. On average, LVEF% was 55.94% and FVC% was 93.45% in the entire cohort. Using LVEF%<55% and FVC%<50% as threshold measures, 29.07% and 2.15% of patients presented left ventricular impairment and respiratory involvement. Deletions in the exons 45-48 (p=0.002) or in the N-terminal domain (p<0.020) were linked to decreased left ventricular systolic function. Moreover, deletions in the exons 45-55 (p=0.048) were identified to induce a lowered risk of developing a pathological LVEF%. Conclusions: Our results contribute to better describe the natural history of BMD. The knowledge of the natural history in subsets of BMD patients carrying homogenous DMD mutation will serve as an in vivo model for the identification of successful therapies in Duchenne muscular dystrophy.