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.

Becker muscular dystrophy (BMD) is due to Duchenne muscular dystrophy gene variants allowing partial expression of dystrophin. A detailed description of disease trajectories in different genetic subgroups, and the identification of factors predicting progressive vs stable disease, are indispensable for designing and interpreting current and future clinical trials. We recruited male participants with a molecularly confirmed diagnosis of BMD at our Institution, and followed them up with an observational longitudinal design with functional evaluations, including North Star Ambulatory Assessment (NSAA), 6-minute walk test, and timed function tests. We recruited 107 participants. Time-to-event analyses of age at loss of ambulation estimated that only 25% of individuals with BMD lose ambulation by age 60 years. Functional measures, over a follow-up of a mean ± SD of 6.4 ± 3.5 evaluations per participant, and a time of 6.1 ± 3.6 years, showed a poor performance in the common deletions del 45–47 and del 45–48, and preserved muscle function with del 48 and deletions ending on exon 51. In the overall cohort, all measures declined significantly over time, but this decrease was more evident in genetic groups with more marked weakness, and in participants with baseline values of NSAA of 32/34 or lower. These data refine genotype-phenotype correlations in BMD; quantify the decline in several practical and reliable motor outcome measures, which can be directly applied to power calculations for clinical trials; and point to useful inclusion/exclusion criteria for trials. Long-term outcomes will serve as a comparator for “real-world” efficacy data of upcoming therapeutics.

Ryanodine receptor 1-related myopathies (RYR1-RM) are caused by RYR1 gene variants and comprise a wide spectrum of histopathological manifestations. Here, we focus on patients carrying RYR1 variants and muscle histopathology consistent with central core disease (CCD) or multi-minicore disease (MmD). RNA-sequencing analyses of skeletal muscle biopsies obtained from both CCD and MmD patients and from healthy controls were performed to better understand the molecular pathways activated by RYR1 variants. Our analyses revealed that, beyond the well-established role of RYR1 in calcium homeostasis, broader cellular pathways are implicated. In CCD, differentially expressed genes were enriched for pathways related to oxidative stress response, SMAD signalling, and apoptosis, consistent with the role of intracellular calcium dysregulation in promoting mitochondrial dysfunction and cell death. In contrast, MmD patients exhibited enrichment of pathways related to immune activation. This was corroborated by the upregulation of GTPase-regulating genes and the down-regulation of transcriptional repressors such as ZFP36 and ATN1. When considering all RYR1-RM patients collectively, Wnt signalling, immune-related pathways, and oxidative phosphorylation emerged as shared enriched pathways, indicating possible convergent mechanisms across histopathological phenotypes. Our study suggests that complex gene regulation driven by RYR1 variants may be a unifying feature in CCD and MmD, offering new insight into potential therapeutic targets.