Natural history of Becker muscular dystrophy: <i>DMD</i> gene mutations predict clinical severity

Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease attributable to mutations in DMD, 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. 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 centres. Patients' demographics, main signs and symptoms at BMD onset, neuropsychiatric comorbidities, age at loss of ambulation, cardiac left ventricular ejection fraction, pulmonary forced vital capacity and DMD mutations were collected. Disease milestones were analysed in specific DMD mutational groups. 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 hyperCKaemia. 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 per cent of patients exhibited left ventricular impairment and 2.7% respiratory involvement. Ten per cent of patients carried out-of-frame mutations, 4% nonsense mutations and 86% in-frame deletions/duplications. The subset of in-frame deletions was classified further based on the specific mutations. Patients carrying del45-49 compared with del45-47 were associated with an earlier loss of ambulation (P = 1 × 10-4), whereas patients with del45-55 (P = 0.005), del48 (P = 0.02) and del48-49 (P = 0.02) were correlated with a later loss of ambulation compared with del45-47. Both del45-55 (P = 0.002) and del48 (P = 0.003) were significantly associated with decreased odds of developing a pathological left ventricular ejection fraction compared with del45-47. Our results contribute to a better understanding of the natural history of BMD and capture precious data in the era of emerging therapies. The knowledge of the specific DMD mutation might help to define a prognosis in a subset of BMD patients and will serve as a model for the design of future therapies.

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Journal
Brain
Published
2024-11-05
DOI
https://doi.org/10.1093/brain/awae358
Citations
12
Primary Topic
Muscle Physiology and Disorders
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article
Field-Weighted Citation Impact
2.81

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article

Natural history of Becker muscular dystrophy: DMD gene mutations predict clinical severity

Giulia Ricci, Gemma Marinella, Riccardo Masson, Giovanni Colacicco et al.
12 citations
Brain
Muscle Physiology and Disorders
2.81
article

Natural history of Becker muscular dystrophy: DMD gene mutations predict clinical severity

Giulia Ricci, Gemma Marinella, Riccardo Masson, Giovanni Colacicco, Daniele Sabbatini, Adele D’Amico, Giuliana Capece, Gabriele Siciliano, Stefano Carlo Previtali, Anna Ardissone, Valeria Sansone, F. Fortunato, Francesca Magri, Chiara Panicucci, Enrica Rolle, Tiziana Mongini, Serenella Servidei, Alessandro Pini, Federica Ricci, Pietro Riguzzi, Vincenzo Nigro, G Gadaleta, Domenico Gorgoglione, Sonia Messina, Eugenio Maria Mercuri, Alessandra Ferlini, Stefano Parravicini, Alberto Lerario, Roberta Battini, Monica Traverso, Marika Pane, Luca Bello, Alberto A. Zambon, Matteo Villa, Guido Urbano, Alessandra Di Bari, Daniele Velardo, Annamaria Gallone, Angela Lucia Berardinelli, Isabella Moroni, Andrea Barp, Lorenzo Maggi, Francesca Salmin, Melania Giannotta, Maria Grazia D’Angelo, Cosimo Allegra, Emilio Albamonte, Luisa Politano, Michela Catteruccia, Alfredo Petrosino, Fabio Bruschi, Roberta Nicotra, Francesca Torri, Concetta Palermo, Maria Sframeli, Alice Gardani, Cristina Sancricca, Claudio Bruno, Sara Vianello, Martina Penzo, Elena Pegoraro, Esther Picillo, Marta Briganti
article en
12 citations

Abstract

Becker muscular dystrophy (BMD) is an X-linked neuromuscular disease attributable to mutations in DMD, 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. 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 centres. Patients' demographics, main signs and symptoms at BMD onset, neuropsychiatric comorbidities, age at loss of ambulation, cardiac left ventricular ejection fraction, pulmonary forced vital capacity and DMD mutations were collected. Disease milestones were analysed in specific DMD mutational groups. 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 hyperCKaemia. 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 per cent of patients exhibited left ventricular impairment and 2.7% respiratory involvement. Ten per cent of patients carried out-of-frame mutations, 4% nonsense mutations and 86% in-frame deletions/duplications. The subset of in-frame deletions was classified further based on the specific mutations. Patients carrying del45-49 compared with del45-47 were associated with an earlier loss of ambulation (P = 1 × 10-4), whereas patients with del45-55 (P = 0.005), del48 (P = 0.02) and del48-49 (P = 0.02) were correlated with a later loss of ambulation compared with del45-47. Both del45-55 (P = 0.002) and del48 (P = 0.003) were significantly associated with decreased odds of developing a pathological left ventricular ejection fraction compared with del45-47. Our results contribute to a better understanding of the natural history of BMD and capture precious data in the era of emerging therapies. The knowledge of the specific DMD mutation might help to define a prognosis in a subset of BMD patients and will serve as a model for the design of future therapies.

BrainVol. 148(5)
Università Cattolica del Sacro Cuore (IT), University of Pisa (IT), University of Messina (IT), University of Padua (IT), University of Milan (IT), University of Campania "Luigi Vanvitelli" (IT), University of Ferrara (IT), University of Pavia (IT), Fondazione Roma (IT), Istituto Giannina Gaslini (IT), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT), Urology Foundation (GB), Centro Clinico Nemo (IT), Istituto delle Scienze Neurologiche di Bologna (IT), Bambino Gesù Children's Hospital (IT), University of Campania "Luigi Vanvitelli" (IT), Fondazione Stella Maris (IT), IRCCS Ospedale San Raffaele (IT), IRCCS Eugenio Medea (IT), Telethon Institute Of Genetics And Medicine (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), University of Turin (IT), University of Genoa (IT)
Ministero della Salute
Good health and well-being
Openalex Percentile: Top 9%
Muscle Physiology and Disorders
2.81
DOIOpen Access PDFOpenAlex
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