Natural history of Becker muscular dystrophy: DMD gene mutations predict clinical severity
Authors: Gorgoglione Domenico , Sabbatini Daniele , Riguzzi Pietro , Capece Giuliana , Pane Marika , Servidei Serenella , Briganti Marta , Sancricca Cristina , Bruschi Fabio , Ardissone Anna , Masson Riccardo , Gallone Annamaria , Maggi Lorenzo , Picillo Esther , Politano Luisa , Petrosino Angela , Vianello Sara , Penzo Martina , Villa Matteo , Sframeli Maria , Allegra Cosimo , Barp Andrea , Di Bari Alessandra , Salmin Francesca , Albamonte Emilio , Colacicco Giovanni , Panicucci Chiara , Traverso Monica , Palermo Concetta , Lerario Alberto , Velardo Daniele , D'Angelo Maria G , Berardinelli Angela , Gardani Alice , Nicotra Roberta , Parravicini Stefano , Siciliano Gabriele , Ricci Giulia , Torri Francesca , Gadaleta Giulio , Urbano Guido , Rolle Enrica , Ricci Federica , D'Amico Adele , Catteruccia Michela , Pini Antonella , Giannotta Melania , Battini Roberta , Marinella Gemma , Previtali Stefano C , Zambon Alberto A , Ferlini Alessandra , Fortunato Fernanda , Magri Francesca , Mongini Tiziana E , Sansone Valeria A , Bruno Claudio , Messina Sonia , Nigro Vincenzo , Moroni Isabella , Mercuri Eugenio , Bello Luca , Pegoraro Elena 
Published: November 2024

Abstract

Background
Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease due to mutations in the DMD gene, leading to a deficient and less functional dystrophin mainly in skeletal and cardiac muscle. Understanding the natural history of BMD is crucial for optimizing patient care and developing targeted treatments.

Materials and methods
Retrospective data were collected from 943 patients diagnosed with BMD based on a combination of clinical, biochemical and genetic criteria followed by 17 Italian neuromuscular centers. 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 DMD mutations were collected. Disease milestones were analysed in specific DMD mutational groups.

Results
the median age at the last assessment was 26.0 (16.6-41.9) years, with a median age at diagnosis of 7.5 (4.0-14.0) years. In 55% of patients, the diagnosis was prompted by the incidental finding of hyperCKemia. At the last assessment, 13.5% of patients had lost the ability to walk at a median age estimated by Kaplan-Meier analysis of 69 years. Thirty percent of patients exhibited left ventricular impairment and 2.7% respiratory involvement. Ten percent of patients carried out-of-frame mutations, 4% nonsense mutations, and 86% in-frame deletions/duplications. The subset of in-frame deletions was further classified based on the specific mutations. Patients carrying del45-49 compared to del45-47 were associated with an earlier LoA (P=1×10−4), where patients with del45-55 (P=.005), del48 (P=.02), and del48-49 (P=.02) correlated with a later LoA compared to del45-47. del45-55 (P=.002) and del48 (P=.003) were significantly associated with decreased odds of developing a pathological LVEF% compared to del45-47.

Conclusion
Our results contribute to the better understanding of the natural history of BMD and capture precious data in the era of the emerging therapies. The knowledge of the specific DMD mutation may help to define a prognosis in a subset of BMD patients and will serve as a model for the design of future therapies.