RARE DISEASE
Becker muscular dystrophy
Becker muscular dystrophy
Becker muscular dystrophy
Synonyms: BMD, Becker dystrophinopathy
Synonyms: BMD, Becker dystrophinopathy
Synonyms: BMD, Becker dystrophinopathy
Drug discovery
9
drugs
With orphan designations
Overview
Becker muscular dystrophy (BMD) is an X-linked recessive disorder caused by mutations in the DMD gene, leading to reduced or abnormal dystrophin production. It presents with progressive proximal muscle weakness, typically emerging in childhood or adolescence, and progresses slower than Duchenne muscular dystrophy. Cardiac involvement (cardiomyopathy, arrhythmias) and respiratory decline are common, often asymptomatic initially. Diagnosis relies on elevated serum CK, genetic testing, and muscle biopsy. Management focuses on multidisciplinary care, including cardiac surveillance, glucocorticoids, and physical therapy to preserve function [1][5][6][16][17].
Burden
Mobility: Loss of ambulation typically occurs in the 30s–50s; wheelchair dependency in ~40% of cases [11][17].
Mortality: Life expectancy often reduced due to heart failure (leading cause) or respiratory complications [13][17].
Healthcare costs: Requires lifelong multidisciplinary care, cardiac devices, and adaptive equipment [6][8][16].
Therapies
Cardioprotection: ACE inhibitors/beta-blockers initiated at early echocardiogram abnormalities [1][6][13].
Symptomatic care: Glucocorticoids (e.g., prednisone) to delay muscle decline, physical therapy, orthotics, and non-invasive ventilation for respiratory support [6][8][11].
Emerging therapies: Myosin inhibitors (e.g., EDG-5506), follistatin gene therapy, and exon-skipping agents in clinical trials [3][18].
Categories: rare cardiac diseases, rare genetic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
553 drug discovery papers about Becker muscular dystrophy, with 5 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
553 drug discovery papers about Becker muscular dystrophy, with 5 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
oligonucleotides
2026-05-20 | Progressive Duchenne/Becker muscular dystrophy, preclinical stage, deletion of exons 45-55 of the DMD gene in the hemizygous state: a clinical case from practice
Background. Duchenne/Becker progressive muscular dystrophy is an X-linked recessive disease caused by mutations in the DMD gene encoding the dystrophin protein. Deletions of exons 45-55 often correspond to the principle of preserving the reading frame, being associated with the Duchenne/Becker muscular dystrophy phenotype. Objective. To present a clinical case of the presymptomatic diagnosis of progressive Duchenne/Becker muscular dystrophy in an early-age patient with deletion of exons 45-55 of the DMD gene, analyze diagnostic markers and justify a strategy for dynamic follow-up. Materials and methods. A retrospective analysis of medical documentation with clinical, laboratory and instrumental methods was performed. In order to form a theoretical base, data was searched and systematized from scientific electronic libraries (CyberLeninka, eLibrary, PubMed, Google Academy) on progressive Duchenne/Becker muscular dystrophy (preclinical phase) and deletion of exons 45-55 of the DMD gene. The review includes literature reviews, scientific publications, and the results of clinical trials on the topic. Conclusion. A clinical case of diagnosis of progressive Duchenne/Becker muscular dystrophy in a 1-year-old male patient with isolated hyperfermentemia (ALT – 120 U/l, AST – 107.1 U/L) and a significant increase in creatine phosphokinase (4817.1 U/L) is described. Conducted: biochemical examination (creatine phosphokinase, lactate dehydrogenase, creatine phosphokinase-MV), instrumental diagnostics, including electrocardiography, ultrasound examination of the heart and abdominal cavity), molecular genetic analysis. The molecular genetic analysis method verified the hemizygous deletion of exons 45-55 of the DMD gene. The diagnosis of progressive Duchenne/Becker muscular dystrophy was established at the preclinical stage, despite the absence of manifest neurological symptoms. The case demonstrates the critical role of determining of creatine phosphokinase as a screening marker and the need for an integrated approach for early diagnosis. The detection of in-frame deletion creates prerequisites for the potential use of exon-skipping therapy.
2026-01-08 | A new dystrophin-deficient rat model mirroring exon skipping in patients with DMD exon 45 deletions.
Pathogenic variants in the dystrophin (DMD) gene cause muscle-wasting disorders ranging from the milder Becker muscular dystrophy (BMD) to the more severe Duchenne muscular dystrophy (DMD). Exon 45 deletion is the most-frequent single-exon deletion in patients diagnosed with DMD. Here, we generated a novel rat model with an exon 45 deletion using CRISPR/Cas9. The DmdΔ45 rat recapitulate key features of DMD, including progressive skeletal muscle degeneration, impaired muscle and cardiac function, and cognitive deficits. Transcriptomics analyses revealed gene expression patterns consistent with dystrophin deficiency. In skeletal muscle, we observed a transition from early stress responses and regeneration to chronic inflammation, fibrosis and metabolic dysfunction. Cardiac profiles similarly progressed from early inflammatory responses to fibrotic remodelling and metabolic impairment. Notably, DmdΔ45 rats displayed a milder phenotype than other DMD rat models. This attenuation is likely due to spontaneous exon skipping, particularly of exon 44, which partially restores the reading frame and increases revertant dystrophin-positive fibres with age. Downregulation of spliceosome-related genes suggests a potential mechanism for this exon skipping. Overall, this model provides valuable insights into phenotypic variability and therapeutic exon-skipping strategies.
2025-11-20 | A Novel Transcriptional Slippage Mechanism Rescues Dystrophin Expression from a DMD Frameshift Variant.
Pathogenic DMD variants usually follow the reading-frame rule: out-of-frame changes cause Duchenne muscular dystrophy, whereas in-frame ones produce Becker muscular dystrophy (BMD). We report a 23-year-old man with BMD-like weakness, calf hypertrophy, elevated creatine kinase, and dilated cardiomyopathy. A novel hemizygous c.2281delG variant converted an A₄GA₅ motif to A₉, predicting a frameshift; however, Western blot showed ~15% full-length dystrophin. cDNA and polymerse chain reaction (PCR)-free direct RNA sequencing demonstrated transcriptional slippage, adding 1 adenine (A₁₀) that restores the reading frame and dystrophin. This RNA-level rescue of an out-of-frame DMD variant explains the mild phenotype and highlights the importance of transcript-level analysis in dystrophinopathies. ANN NEUROL 2026;99:223-230.
2025-11-01 | Genotype-Phenotype Correlation in a Cohort of Egyptian Patients with Dystrophinopathies
Abstract Background Dystrophinopathies are a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD- associated dilated cardiomyopathy (DCM). They are classified according to primary muscle affection, where DMD/ BMD occur when skeletal muscle is affected and DMD - related DCM when heart is primarily affected. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X- linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Objective To describe demographic and clinical data in relation to different genetic mutations and to correlate between phenotypic and genotypic differences in a cohort of Egyptian patients with dystrophinopathies. Methods This Descriptive observational study was conducted in Ain Shams University muscle clinic research committee over 6 months. Our study was conducted upon 109 patients with dystrophinopathies encompassing Duchenne and Becker muscular dystrophies confirmed by Multiplex ligation probe amplification (MLPA) for dystrophin gene. The subjects were randomly chosen from neuromuscular clinic in Ain shams university hospitals. Results In our study, genotype -phenotype correlations were performed showing that most patients with DMD phenotype follow the reading frame rule except for patient with in frame deletion affecting exons 31-41 result still in DMD phenotype. Other exceptions to the reading frame rule was also identified, where two patients with BMD phenotype had out frame deletions of exons 3-7 and exons 46-48. Conclusion Assessing the genotype–phenotype relationship in patients with dystrophinopathies has been supported by data from clinical studies, which might more directly indicate the merits of potential exon-skipping therapies. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments still do not cure the disease only ameliorate the disease severity. Our study revealed that genotype–phenotype correlations of enrolled subjects comply with the reading frame rule in most patients with DMD and BMD phenotype except for some exceptions. In addition to that, we identified cases with specific deletion mutations and nonsense mutations amenable for exon skipping therapies as exon 45 skipping, exon 51 skipping and ataluren therapy respectively.
2025-10-08 | Spectrum of DMD gene mutations in 507 patients: a retrospective genotype-phenotype study using next-generation sequencing.
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, but comprehensive analyses of mutational patterns and clinical correlations remain limited. To characterize the DMD mutational spectrum and its clinical implications in a large Asian cohort. A retrospective genetic analysis of 507 unrelated male DMD/Becker muscular dystrophy patients was conducted at Hunan Children's Hospital (2018-2021). Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) were employed for comprehensive variant detection. Variants were classified per ACMG/AMP guidelines. Exon deletions predominated (64.9%), followed by small mutations (26.0%) and duplications (9.1%). Nonsense mutations were the most frequent small variant (16.0%). Domain analysis revealed mutations clustered in the Central Rod Domain (CRD; exons 45-55). The Carboxy-Terminal Domain (CTD) was associated with the most severe phenotype (earliest loss of ambulation, P < 0.05 vs. Actin-Binding Domain [ABD] or CRD). Exon 53 skipping was applicable in 39.39% of eligible patients. De novo mutations accounted for 7.9% (40/507) of cases. Epilepsy comorbidity occurred in 1.34% (6/448) of DMD patients. This study delineates the DMD mutational landscape in a Chinese cohort, highlighting domain-specific phenotypic severity (CTD > ABD > CRD) and identifying exon 53 as the primary therapeutic target for exon skipping. These findings enhance prognostic precision and guide targeted therapeutic strategies.
proteins
2026-08-31 | Protein intake is associated with adiposity and quality of life in adults with Becker muscular dystrophy.
Becker Muscular Dystrophy (BMD) is a rare X-linked genetic condition characterised by reduced dystrophin expression, causing progressive skeletal muscle and functional decline, and ultimately poor quality of life (QoL). With no current pharmacological cure, practical easy-to-implement strategies are needed to improve QoL in BMD. Increasing dietary protein intake is beneficial in other clinical populations, exhibiting positive impacts on lean body mass and self-reported pain. While progressive muscle deterioration is a hallmark of BMD, less is known about the interaction between nutritional status, body composition, physical function and QoL in BMD. Therefore, this study aimed to characterise dietary intake and explore relationships between dietary factors and readouts of body composition, muscle size/strength and QoL. Adult males with BMD (n = 20) and age-matched controls (n = 12), completed 2 food diaries ∼6 weeks apart with instructions to state exact quantities, brand names and cooking methods, a battery of physical tests assessing body composition, muscle size, strength, and function, as well as validated questionnaires on perceived physical function, pain/fatigue, QoL, and nutritional knowledge. Adults with BMD reported 29% lower daily energy intake, 25-30% lower carbohydrate and fat intakes, and 21% lower relative protein intake (0.86 vs. 1.08 g/kg/day) than controls (all p < 0.05). Only 10% of the BMD group met the minimum end of The European Society for Clinical Nutrition (ESPEN) recommended protein intake range for disease-related muscle loss (1.2-1.7 g/kg/day). The BMD group exhibited greater fat mass index (FMI) (9.31 kg/m2 vs. 6.30 kg/m2) and 95% of BMD were classified obese or overweight, however no differences in lean mass were observed. Individuals with BMD also exhibited lower tibialis anterior muscle thickness, strength, and physical function, and reported reduced QoL, lower limb function and activities of daily living, along with higher pain and fatigue (67-77%, all p < 0.05). When controlling for age, total energy intake and self-reported physical activity, protein intake (g/kg/day) was negatively associated with fat mass index (r = -0.698, p = 0.017) and positively associated with SF36v2 quality of life (r = 0.503, p = 0.040), whilst BMI was positively associated with pain (r = 0.684, p = 0.002). Our results show adults with BMD report lower overall caloric and relative protein intake than non-dystrophic individuals, with protein intake substantially lower than guidance for other muscle-wasting conditions. Adults with BMD also displayed higher levels of adiposity, reported higher fatigue and pain as well as lower quality of life. The observed positive associations between relative protein intake and QoL, together with the negative associations between relative protein intake and adiposity, support further investigation into the role of protein intake in adults with BMD. Prospective and intervention studies are needed to establish the true nature of these relationships to inform nutritional recommendations for the BMD population.
2026-05-01 | Engineered antibody fusion proteins increase plasma membrane repair to treat muscle diseases
Plasma membrane repair is a highly conserved process that muscle cells use to maintain health under mechanical stress from physiological levels of muscle contraction. Defective sarcolemma repair can cause or exacerbate cardiovascular and muscle diseases, including Duchenne/Becker muscular dystrophy and limb-girdle muscular dystrophies. The tripartite motif family protein 72 (TRIM72), also called mitsugumin 53 (MG53), is essential for membrane repair by facilitating vesicle fusion at injury sites while binding the phospholipid phosphatidylserine (PS). Our laboratory and others have shown that treatment with recombinant TRIM72 protein (rhTRIM72) ameliorates muscle disease pathology in preclinical models. However, the therapeutic potential of rhTRIM72 in muscle diseases was limited by off-target effects on systemic metabolism, poor pharmacokinetics, and manufacturing challenges. To address these issues, we created improved therapeutic proteins by fusing the fragment crystallizable (Fc) domain from the human IgG1 protein to a panel of TRIM72 truncations. We hypothesized that this approach would increase protein serum half-life through endogenous antibody recycling machinery, simplify manufacturing using existing biologic drug purification methods, and decrease off-target effects by truncating TRIM72. Multiple TRIM72/Fc-fusion proteins display effective PS binding activity in biochemical pulldown experiments. Laser confocal microscopy ablation and dye exclusion assays in myoblast cells revealed that TRIM72/Fc-fusion proteins improved plasma membrane repair upon intracellular overexpression or exogenous application. These experiments found that one of the fusion proteins we call MyoSPRY, comprised of the Fc fused to the SPRY domain of TRIM72, could increase membrane repair. Exogenous treatment with MyoSPRY and other Fc-SPRY proteins improved membrane repair in live muscle tissue isolated from a Duchenne muscular dystrophy (DMD) mouse model. Subcutaneous injection experiments show that Fc-fusion proteins exhibit extended half-lives in vivo and protect muscle against acute eccentric contraction injury-induced force decrement in a mouse model of DMD. Together, these results indicate that our novel Fc-fusion proteins address barriers impeding the clinical development of rhTRIM72 and represent a possible therapeutic approach for diseases driven by altered membrane integrity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2025-06-08 | Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS.
Becker muscular dystrophy (BMD) is a rare and heterogeneous form of dystrophinopathy caused by expression of altered dystrophin proteins, as a consequence of in-frame genetic mutations. The majority of the BMD biomarker studies employ targeted approaches and focus on translating findings from Duchenne Muscular Dystrophy (DMD), a more severe disease form with clinical similarities but caused by out-of-frame mutations in the dystrophin gene. Importantly, DMD therapies assume that disease progression can be slowed by promoting the expression of truncated dystrophin comparable to what occurs in BMD patients. In this study, we explore similarities and differences in protein trajectories over time between BMD and DMD serum, and explore proteins related to motor function performance. Serum samples collected from 34 BMD patients, in a prospective longitudinal 3-year study, and 19 DMD patients, were analyzed by using Data Independent Acquisition Tandem Mass Spectrometry (DIA-MS). Subsequent normalization, linear mixed effects model was employed to identify proteins associated with physical tests and dystrophin expression in skeletal muscle. Analysis was also performed to explore the discrepancy between DMD and BMD biomarker abundance trajectories over time. Linear mixed effects models identified 20 proteins with altered longitudinal signatures between DMD and BMD, including creatine kinase M-type (CKM) pyruvate kinase (PKM), fibrinogen gamma chain (FGG), lactate dehydrogenase B (LDHB) and alpha-2-macroglobulin (A2M). Furthermore, several proteins related to innate immune response were associated with motor function in BMD patients. In particular, A2M displayed an altered time-dependent decline in relation to dystrophin expression in the tibialis anterior muscle. Our study revealed differences in the serum proteome between BMD and DMD, which comprises proteins involved in the immune response, extracellular matrix organization and hemostasis but not muscle leakage proteins significantly associated with disease progression in DMD. If further evaluated and validated, these biomarker candidates may offer means to monitor disease progression in BMD patients. A2M is of particular interest due to its association with dystrophin expression in BMD muscle and higher abundance in DMD patients in comparison to BMD. If validated, A2M could be used as a pharmacodynamic biomarker in therapeutic clinical trials aiming to restore dystrophin expression.
2024-04-14 | Long-term clinical follow-up of a family with Becker muscular dystrophy associated with a large deletion in the DMD gene
Duchenne muscular dystrophy is a neuromuscular disease caused by DMD gene mutations that result in an absence of functional dystrophin protein. Patients with Duchenne experience progressive muscle weakness, are typically wheelchair dependent by their early teens, and develop respiratory and cardiac complications that lead to death in their twenties or thirties. Becker muscular dystrophy is also caused by DMD gene mutations, but symptoms are less severe and progression is slower compared with Duchenne. We describe a case study of a patient with Becker muscular dystrophy who was still ambulant at age 61 years and had a milder phenotype than Duchenne, despite 46% of his DMD gene being missing. His affected relatives had similarly mild phenotypes and clinical courses. These data guided the understanding of the criticality of various regions of dystrophin and informed the development of micro-dystrophin constructs to compensate for the absence of functional dystrophin in Duchenne.
2023-10-23 | Growth hormone and testosterone delay vertebral fractures in boys with muscular dystrophy on chronic glucocorticoids
Glucocorticoid use in Duchenne and Becker muscular dystrophy prolongs ambulation but cause significant skeletal toxicity. Our analysis has immediate clinical implications, suggesting that growth hormone and testosterone have a stronger effect prior to first and subsequent vertebral fracture, respectively, relative to bisphosphonates alone in children with dystrophinopathies on chronic glucocorticoids. Glucocorticoids prolong ambulation in boys with Duchenne muscular dystrophy; however, they have significant endocrine side effects. We assessed the impact of growth hormone (GH), testosterone, and/or zoledronic acid (ZA) on vertebral fracture (VF) incidence in patients with dystrophinopathies on chronic glucocorticoids. We conducted a longitudinal retrospective review of 27 males with muscular dystrophy. Accelerated failure time (AFT) models were used to estimate the relative time to VF while on GH, testosterone, and/or ZA compared to ZA alone. Results are reported as failure time ratio, where >1 indicates prolonged time versus <1 indicates shorter time to next VF. The prevalence of growth impairment was 96% (52% utilized GH), pubertal delay was 86% (72% utilized testosterone), and low trauma fractures were 87% (72% utilized ZA). Multivariable analysis of the AFT models showed that participants on either GH or testosterone treatment relative to ZA alone experienced prolonged time to next VF (1.253, P<0.001), with GH being the significant contributor when analyzed independently from testosterone (1.229, P<0.001). Use of ZA with GH or testosterone relative to ZA alone resulted in prolonged time to next VF (1.171, P<0.001), with testosterone being a significant contributor (1.130, P=0.033). GH and testosterone each decreased VF risk in patients independent of or in combination with ZA, respectively.
gene therapies
2026-09-08 | MicroRNA-mRNA Networks in Skeletal Muscle of Tailored Pig Models for Dystrophinopathies.
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked dystrophinopathies caused by mutations in the dystrophin (DMD) gene. A common DMD-causing mutation in humans is exon 52 deletion (DMDΔ52), which disrupts the reading frame and abolishes dystrophin expression. Therapeutic skipping of exon 51 or 53 can restore the reading frame, producing a truncated but functional protein and generating a BMD-like phenotype. Porcine models recapitulating DMDΔ52 (DMD) and DMDΔ51-52 (BMD-like) were used to identify molecular differences and condition-specific miRNA-mRNA networks. Skeletal muscle (triceps brachii) from four DMD, four BMD, and five wild-type (WT) pigs at 3.5 months of age underwent stranded total RNA-seq and small RNA-seq. Differentially expressed mRNAs (|log2FC| ≥ 1, adj. p ≤ 0.05) and miRNAs (adj. p ≤ 0.05) were identified with DESeq2. miRNA-mRNA networks were constructed using RNAhybrid predictions (MFE < -25 kcal/mol, seed pairing) filtered by inverse Pearson correlation. Compared with WT, DMD muscle exhibited 1440 upregulated and 487 downregulated genes, characterized by strong repression of structural, contractile, calcium-handling and metabolic genes (e.g., MYBPC2, MYL3, MYLK2, CACNA2D3, CACNA2D4) and marked upregulation of inflammatory mediators and innate immune receptors (e.g., IL6, IL18, IL1R1, CCR1/2/5, TLR1/2/4/7/9). In contrast, BMD muscle showed partial restoration of these pathways and clustered closer to WT in global expression profiles. Distinct miRNA signatures were observed between DMD and BMD. Differential expression analysis identified 22 upregulated and 12 downregulated miRNAs in DMD versus WT and 36 upregulated and 21 downregulated miRNAs in BMD versus WT. Integration of miRNA and mRNA data yielded extensive regulatory networks (1013 unique pairs for upregulated miRNAs in DMD; 2679 pairs for downregulated miRNAs in BMD). Two condition-specific miRNAs emerged as strong biomarker candidates: ssc-miR-296-3p (upregulated exclusively in DMD, targeting 228 genes enriched in muscle structure and fatty acid metabolism) and ssc-miR-423-5p (elevated specifically in BMD, targeting 67 genes involved in calcium signalling and tissue development). Several dysregulated miRNAs, including miR-199a-5p and miR-199b, overlapped with those reported in human DMD and other muscular dystrophies. Exon 51 skipping in the DMDΔ52 background partially restores key transcriptional programmes in skeletal muscle but does not fully normalize them to WT patterns. The identification of condition-specific miRNAs highlights post-transcriptional regulatory differences between DMD and BMD, positioning them as promising biomarkers and therapeutic targets. These findings underscore the translational value of porcine dystrophinopathy models for mechanistic studies and preclinical evaluation of RNA-targeted interventions.
2026-06-05 | Gene editing restores full-length dystrophin and affects iron homeostasis in hiPSC-derived cardiomyocytes from Becker Muscular Dystrophy patients.
Becker Muscular Dystrophy (BMD) is caused by in-frame mutations in the DMD gene, leading to the production of internally truncated but partially functional dystrophin. Although cardiac involvement is a major contributor to disease burden in BMD, the cellular mechanisms driving cardiomyopathy remain incompletely understood. While emerging evidence suggests that iron imbalance may contribute to oxidative stress and mitochondrial dysfunction in muscular dystrophies, its role in BMD-associated cardiomyopathy has not been defined. Building on our previous findings of dysregulated iron homeostasis in dystrophin-deficient cardiomyocytes from Duchenne muscular dystrophy (DMD), we investigated whether similar alterations are present in BMD using patient-specific and genome-corrected hiPSC-CM models. HiPSC lines derived from two BMD patients and their CRISPR/Cas9-corrected isogenic controls displayed normal karyotype, pluripotency, and efficient differentiation into cardiomyocytes (hiPSC-CMs). BMD hiPSC-CMs showed elevated ROS levels and decreased cytoplasmic and mitochondrial labile iron pools, accompanied by reduced expression of mitoNEET (CISD1), a regulator of mitochondrial iron handling. We also detected changes in the expression of genes involved in iron storage (FTH1), uptake (TFRC), and export (SLC40A1), suggesting a dysregulation of iron trafficking. Importantly, correction of DMD mutation by CRISPR/Cas9 gene editing reversed the effects observed in BMD cardiomyocytes. These results extend our previous observations in DMD to BMD cardiomyocytes and suggest that full-length dystrophin is essential for maintaining cardiac iron homeostasis.
2026-05-21 | Natural history of cardiac involvement in women carrying pathogenic DMD gene variants: a 7-year longitudinal study.
Cardiac involvement is increasingly recognized in women carrying pathogenic variants in the dystrophin (DMD) gene, both Duchenne and Becker-associated, but the long-term natural history of cardiac structure, function, and conduction abnormalities in this group is not well understood. We conducted a prospective 7-year follow-up study to investigate the evolution of ventricular function, myocardial fibrosis, and arrhythmias. 34 women with confirmed pathogenic DMD gene variants (19 predicted to cause Duchenne muscular dystrophy and 15 Becker muscular dystrophy) underwent assessments after a mean of 7 years. Evaluations included cardiac magnetic resonance imaging with late gadolinium enhancement, 24-h Holter monitoring, 12-lead electrocardiography (ECG), cardiac biomarkers, and clinical examinations. At the group level, left ventricular ejection fraction (LVEF) remained stable over follow-up (p = 0.403). Six women had a ≥ 5% change in LVEF: three improved with treatment, and three declined by 5-8%. Fibrosis was present in 9 women at both baseline and follow-up; 3 showed visual progression, and no new cases were identified. Although the median ventricular premature contractions per hour (VPC/h) increased from 0.23/h to 6.38/h (p < 0.001), this increase is likely not clinically meaningful as age-related increases in ventricular ectopy are also seen in healthy populations, and high-burden arrhythmias-according to prespecified thresholds-remained uncommon. ECG parameters remained stable (PR, QRS, and QTc unchanged), with no new bundle-branch blocks or high-grade atrioventricular block detected. No association was observed between LVEF, VPC/h, and supraventricular premature contraction per hour over the 7-year follow-up period. Over 7 years, women carrying pathogenic DMD gene variants have very little or no progression of cardiac findings (LVEF, fibrosis, and arrhythmias). Given these findings, frequent routine rhythm monitoring is not indicated. Follow-up should be risk-stratified: closer for women with symptoms, baseline high-burden ectopy, reduced LVEF, or pre-existing fibrosis; others can be reviewed at extended intervals.
2026-04-26 | Neurocognitive and autism spectrum profiles associated with dystrophin isoform disruption in childhood dystrophinopathies: insights from a Brazilian cohort.
To examine the association between dystrophin isoform disruption and cognitive and behavioral outcomes, including autism spectrum disorder (ASD), in a large cohort of boys with Duchenne muscular dystrophy (DMD) and related dystrophinopathies. In this retrospective cohort study (2014-2025), 161 boys with genetically confirmed dystrophinopathy (145 DMD, 14 Becker muscular dystrophy, and 2 intermediate muscular dystrophy) were classified according to predicted involvement of the brain-expressed dystrophin isoforms Dp427, Dp140, and Dp71. Cognitive function was assessed using standardized intelligence measures (WISC-IV or WASI), complemented by comprehensive neuropsychological evaluation. ASD was diagnosed according to DSM-5 criteria and confirmed through multidisciplinary assessment. Intellectual disability (ID) was identified in 63 of 161 patients (39.1%), including 47 (29.1%) with mild and 16 (10.0%) with moderate ID. ASD was diagnosed in 16 patients (10%), and in 81% of cases ASD identification preceded or coincided with the diagnosis of dystrophinopathy. An isoform-dependent gradient was observed: patients with mutations restricted to exons 1-44 (Dp427-only) showed the highest frequency of normal cognition, whereas those with mutations affecting Dp140 or Dp71 exhibited progressively higher rates of ID and ASD. Cognitive impairment and ASD are frequent non-muscular manifestations of childhood dystrophinopathies and correlate closely with disruption of brain-expressed dystrophin isoforms, particularly Dp140 and Dp71. Integrating genetic and neuropsychological assessment into routine clinical care is essential for early recognition and timely intervention.
2026-04-08 | Thrombosis in Neuromuscular Medicine: Current Evidence, Unmet Needs, and Future Directions
Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is an important but under-recognised complication in neuromuscular diseases. In adults, emerging epidemiological data suggests increased VTE occurrence in conditions such as Amyotrophic Lateral Sclerosis, myotonic dystrophy, myasthenia gravis, inflammatory neuropathies, inflammatory myopathies, and POEMS syndrome. This heightened risk reflects not only disease-related immobility but also disorder-specific biological mechanisms, including inflammation, endothelial dysfunction and cardiomyopathy-related stasis. Therapies such as corticosteroids, IVIG-related hyperviscosity, long-term central venous access, perioperative immobility, critical illness, and complex orthopaedic procedures have prothrombotic effects. Despite this multifactorial risk profile, disease-specific guidance for thromboprophylaxis is lacking, and current practice relies heavily on extrapolation from general medical and surgical recommendations rather than data derived from neuromuscular cohorts. In children and adolescents, the VTE burden is less well-characterised, but events have been reported in Duchenne and Becker muscular dystrophy, congenital myopathies, and spinal muscular atrophy particularly with advanced motor impairment, severe cardiomyopathy, ventilatory insufficiency, and prolonged hospitalisation. Beyond venous events, selected neuromuscular disorders also exhibit increased arterial thrombosis risk. Myotonic dystrophy and dystrophinopathies are associated with cardiomyopathy and arrhythmia that predispose to systemic embolism and stroke, while inflammatory myopathies may demonstrate arterial events related to vasculitic or endothelial processes, although overall evidence remains limited. This review summarises available empirical and epidemiological evidence on venous and arterial thrombosis across adult and paediatric neuromuscular disorders, outlines disease-specific mechanistic pathways, examines treatment-related contributors, and highlights key evidence gaps that must be addressed to guide rational and targeted prophylaxis strategies in this complex, heterogeneous population.
small molecules
2026-08-04 | Volatile-Free Total Intravenous Anesthesia for Major Gynecologic Surgery in a Manifesting Female Carrier of Becker Muscular Dystrophy: A Case Report
Becker muscular dystrophy (BMD) is a rare X-linked dystrophinopathy caused by dystrophin gene (DMD gene) variants, resulting in reduced or dysfunctional dystrophin. Despite a milder course than Duchenne muscular dystrophy, patients face significant perioperative risk from skeletal muscle degeneration, respiratory weakness, cardiomyopathy, and conduction abnormalities. Succinylcholine and volatile anesthetics have been associated with life-threatening hyperkalemia, rhabdomyolysis, and malignant hyperthermia-like reactions in dystrophinopathies. Clinically manifest BMD in females is exceptionally rare due to skewed X-inactivation, and perioperative data in this population remain scarce. We report a 39-year-old woman with genetically confirmed, clinically manifested BMD who underwent elective left salpingo-oophorectomy with surgical staging for a large adnexal mass. She had severe proximal weakness and was non-ambulatory but had no respiratory, swallowing, or aspiration symptoms. Multidisciplinary preoperative evaluation (neurology, cardiology, hepatology, anesthesiology, gynecologic oncology, intensive care) confirmed preserved cardiac function (ejection fraction >70%), normal conduction, no respiratory compromise evidenced by normal pulmonary function tests, and adequate hepatic reserve. A trigger-free anesthetic strategy was used: the workstation was prepared to eliminate residual volatile agents, and total intravenous anesthesia was maintained with propofol, dexmedetomidine, and midazolam, avoiding succinylcholine and volatile agents. Reduced-dose atracurium provided neuromuscular blockade, and multimodal opioid-sparing analgesia included bilateral rectus sheath blocks and non-opioid analgesics. Surgery was uneventful, with no hemodynamic instability, arrhythmias, hyperkalemia, or rhabdomyolysis. The patient was extubated in the operating room after full neuromuscular recovery, then electively admitted to the ICU for observation given the risk of delayed respiratory compromise. Her postoperative course was uncomplicated, with stable cardiorespiratory function and effective analgesia. Histopathology confirmed an adult granulosa cell tumor of the ovary. This case suggests that major gynecologic surgery can be safely performed in clinically manifest female BMD patients through multidisciplinary planning, trigger-free total intravenous anesthesia, careful neuromuscular blockade, opioid-sparing analgesia, and planned ICU surveillance, offering valuable guidance for this rare, high-risk population.
2026-07-01 | Human Disposition, Metabolism, and Excretion of Sevasemten (EDG‐5506), a Selective Modulator of Fast Myosin in Healthy Volunteers
Abstract Sevasemten (EDG‐5506) is a novel, orally bioavailable, investigational small molecule designed to selectively modulate type II fast skeletal myosin with the goal of protecting dystrophic muscle from contraction‐induced injury. Sevasemten is in clinical development for the treatment of Becker and Duchenne muscular dystrophy. In the current Phase 1 study (NCT05730842), eight participants were dosed with a 20 mg single oral suspension dose of sevasemten containing approximately 500 µCi [ 14 C] sevasemten. Blood and urine samples were collected to evaluate the pharmacokinetics (PK), oral absorption, metabolism, and excretion (AME) of sevasemten and its metabolites. A second cohort of seven participants received a single 20 mg oral dose of sevasemten, followed 2 h later by a single dose of [ 14 C] sevasemten administered as a single intravenous (IV) bolus with approximately 1 µCi [ 14 C] sevasemten to determine absolute bioavailability. Sevasemten was excreted primarily in urine (52.1%) subsequent to CYP3A‐mediated metabolism, and 8.89% was eliminated in the feces, for a total of 61.0% recovered over 840 h post‐dose. Most of the recoverable radioactivity was excreted by 576 h (24 days). However, sevasemten total radioactivity in plasma and whole blood was characterized by a very slow elimination phase of 16.1–20.6 days; total recovery of radioactivity was not achieved. Sevasemten was well tolerated, with no serious adverse events or adverse events leading to study discontinuation. Sevasemten has favorable PK properties for once daily administration and continues to be investigated for the treatment of Becker and Duchenne muscular dystrophies.
2026-06-17 | Effects of sevasemten (EDG-5506) on safety, biomarkers, and functional measures in adults with Becker muscular dystrophy: results of a phase 1b, open-label study.
Sevasemten (EDG-5506) is an orally administered, investigational small molecule that selectively modulates fast muscle fibre contraction by inhibiting fast myosin ATPase. In animal models of Duchenne and Becker muscular dystrophy (DMD and BMD, respectively), sevasemten reduced the muscle contraction injury that leads to inflammation, fibrosis and muscle loss without affecting function. The aim of this study was to evaluate the long-term safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics of sevasemten in adult participants with BMD who had already experienced a decline in function and would be anticipated to continue to decline based on natural history. This open-label, dose escalation, phase 1 b study (NCT05160415) was conducted at a single site and enrolled ambulatory adults with BMD aged 18-55 years; the study is completed. Eligible participants received 10 mg of sevasemten once daily (QD) for 8 weeks, followed by 15 mg QD for 4 months, 20 mg QD for 9 months, and 10 mg QD for 9 months. The primary objective was to assess the safety and tolerability of sevasemten in adults with BMD; endpoints included adverse events (AEs), PK, change from baseline in circulating biomarkers of muscle injury, as well as physical function measures. The study enrolled 12 adults with BMD. Sevasemten was well tolerated; all AEs were mild or moderate in severity and there were no serious AEs or AEs leading to discontinuation. Treatment with sevasemten was associated with reductions in circulating biomarkers of muscle injury that were evident within 4 weeks and sustained for up to 24 months. Physical function, as assessed by North Star Ambulatory Assessment (NSAA), was stable over 24 months. Sevasemten treatment for up to 24 months in adults with BMD was well tolerated and associated with durable reductions in muscle injury biomarkers, consistent with preclinical studies and near maximal with the 10 mg dose, as well as functional stabilisation. Further clinical development is ongoing. Edgewise Therapeutics, Inc.
2026-05-22 | Heart failure guideline-directed medical therapy in young adults with dystrophin-related cardiomyopathy: the HOPE-MD registry.
Duchenne (DMD) and Becker (BMD) muscular dystrophies often progress to dilated cardiomyopathy and heart failure with reduced ejection fraction (HFrEF), a major cause of death in affected patients. Although guideline-directed medical therapy (GDMT) improves HFrEF outcomes, its real-world use in dystrophinopathies is poorly defined. We assessed GDMT utilization and optimization in the study population. HOPE-MD is a European, multicentre, retrospective registry including adults with genetically confirmed DMD or BMD and left ventricular ejection fraction (LVEF) ≤40%. GDMT was defined as concurrent use of a renin-angiotensin system inhibitor (RASi), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter-2 inhibitor (SGLT2i). Doses were categorized as target (≥100%), intermediate (50-99%), or low (<50%). Among 274 patients (age, 28 years; LVEF, 35%; DMD, 80%), 44 (16%) received GDMT at baseline, with only one quarter at ≥50% of the target dose. Underutilization was greatest for MRAs (n=140, 51%) and SGLT2i (n=60, 22%), whereas RASi (n=246, 90%) and beta-blockers (n=235, 86%) were frequently prescribed. After 24 months (n=141), 40% received GDMT, and 22% received ≥50% of the target dose, primarily through MRA and SGLT2i initiation/uptitration. Contraindications accounted for only a small proportion of undertreatment. At a median follow-up of 2.2 (1.7-2.6) years, optimized GDMT was not associated with a statistically significant difference in the rates of death or HF hospitalization compared with low-dose or no GDMT (adjusted HR 0.70, 95% CI 0.28-1.74). GDMT use and dose escalation were suboptimal in European patients with DMD/BMD and HFrEF.
2026-01-09 | Muscle involvement in women carrying pathogenic DMD gene variants: A 6.5-year follow-up study.
Women carrying pathogenic DMD gene variants can develop muscle affection, such as muscle weakness and fat replacement. The long-term progression of the muscle involvement is unknown. This study investigates the 6.5-year changes in muscle function and -fat fraction in women carrying pathogenic DMD gene variants to enhance understanding of disease progression and its natural history. Muscle structure and -function were investigated at baseline and after 6.5 years in 34 women carrying pathogenic DMD gene variants (19 predicted to confer Duchenne Muscular Dystrophy (DMD), 15 Becker Muscular Dystrophy (BMD)). After a clinical evaluation, muscle fat fraction was assessed using Dixon MRI, muscle strength with isokinetic dynamometry, and muscle biomarkers with blood samples for creatine kinase and myoglobin. Muscle fat fraction in the lower back, thigh, and calf increased significantly over 6.5 years. The average increases were generally less than 2%, but some carriers with significant baseline abnormalities experienced a more substantial increase in fat fraction, reaching as high as 31%. Although overall disease progression did not differ significantly between DMD and BMD carriers, all women who showed rapid progression were DMD carriers. Small but significant changes occurred in muscle strength and biomarkers. The progression of muscle involvement in women carrying pathogenic DMD gene variants is generally slow. However, those with severe baseline abnormalities on MRI-often associated with a lower age of symptom onset-experience a more rapid progression of muscle fat fraction, suggesting that baseline MRI findings could help predict future disease progression in this population.
other
2026-08-11 | Mexico’s First Heart Transplant in a Patient with Becker Muscular Dystrophy Reveals an Overlooked Cause of Idiopathic Dilated Cardiomyopathy
Background: Pathogenic variants in the DMD gene are a frequently overlooked cause of dilated cardiomyopathy (DCM) in idiopathic cases, especially when skeletal myopathy is mild or seemingly absent. Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy are at opposite ends of this clinical spectrum but result from pathogenic variants in the same gene. Cardiomyopathy is a major cause of premature death in muscular dystrophies. Case presentation: We describe a 37-year-old man who underwent orthotopic heart transplantation for presumed idiopathic DCM with refractory heart failure. He had a six-year history of progressive proximal weakness, pseudohypertrophy of the calf, a positive Gowers sign, and markedly elevated creatine kinase (6638 IU/L). Multiplex ligation-dependent probe amplification (MLPA) revealed an in-frame deletion of exons 45–47 of DMD [c. (6438+1_6439-1)_(6912+1_6913-1) del; NM_004006.2], confirming BMD. Immunofluorescence showed reduced and patchy dystrophin expression. Conclusions: To our knowledge, this is the first documented heart transplant in a patient with BMD in Mexico. This case demonstrates the value of considering muscular dystrophy in the differential diagnosis of apparently idiopathic dilated cardiomyopathy (DCM), a step that opens the door to accurate diagnosis, carrier screening, and genetic counseling, and supports the view that heart transplantation is a viable option in carefully selected patients with muscular dystrophy cardiomyopathy.
2023-02-04 | Challenges and Future Prospects of Targeting Myostatin/Activin A Signaling to Treat Diseases of Muscle Loss and Metabolic Dysfunction
Abstract Over the past 25 years, considerable progress has been made in terms of elucidating the regulatory and signaling mechanisms underlying the control of skeletal muscle mass by myostatin and other secreted proteins belonging to the transforming growth factor-β superfamily. Preclinical studies demonstrating the potential benefits of targeting the activities of these ligands have fueled the development of numerous biologics capable of perturbing this signaling pathway and increasing muscle mass and function. These biologics have been tested in numerous clinical trials for a wide range of indications characterized by muscle loss and excess adiposity. Here, we review the results of these trials and discuss some of the challenges and future prospects for targeting this signaling pathway to treat muscle and metabolic diseases. Myostatin inhibitors may improve metabolic outcomes by increasing muscle mass, and metabolic disorders may be attractive potential indications for these molecules.
2023-01-27 | Activated Oncostatin M signaling drives cancer-associated skeletal muscle wasting
Summary Progressive weakness and muscle loss are associated with multiple chronic conditions including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy, however, available anti-cytokine therapies failed to prevent muscle wasting in cancer patients. We previously reported that muscle-specific deletion of the Oncostatin M (OSM) receptor (OSMR) preserved muscle mass and function in tumor-bearing mice. Here, we show that OSM is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes utilizing the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing revealed the induction of various muscle atrophy-related genes, including Atrogin1 . OSM overexpression in mice caused muscle wasting while the neutralization of circulating OSM protected from tumor-driven loss of muscle mass and function. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.
2022-04-04 | Effect of Denosumab on Bone Health in Adult Patients with Duchenne/Becker Muscular Dystrophy: A Report of 2 Cases.
Duchenne/Becker muscular dystrophy (DMD/BeMD) is caused by a loss of dystrophin leading to muscular weakness. Glucocorticoids are used to delay loss of muscle strength but frequently result in osteoporosis and fractures. Bisphosphonates are the drug of choice, and there are limited data on the efficacy of denosumab. We describe 2 patients who were treated with denosumab and had stable to improved bone density with no side effects. Denosumab can be considered for the treatment of osteoporosis in adults with DMD/BeMD, especially when the response to bisphosphonates is not satisfactory.
2020-08-31 | Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?
Myostatin, also known as growth differentiation factor 8 (GDF8), is a transforming growth factor-β (TGF-β) family member that functions to limit skeletal muscle growth. Accordingly, loss-of-function mutations in myostatin result in a dramatic increase in muscle mass in humans and various animals, while its overexpression leads to severe muscle atrophy. Myostatin also exerts a significant effect on bone metabolism, as demonstrated by enhanced bone mineral density and bone regeneration in myostatin null mice. The identification of myostatin as a negative regulator of muscle and bone mass has sparked an enormous interest in developing myostatin inhibitors as therapeutic agents for treating a variety of clinical conditions associated with musculoskeletal disorders. As a result, various myostatin-targeting strategies involving antibodies, myostatin propeptides, soluble receptors, and endogenous antagonists have been generated, and many of them have progressed to clinical trials. Importantly, most myostatin inhibitors also repress the activities of other closely related TGF-β family members including GDF11, activins, and bone morphogenetic proteins (BMPs), increasing the potential for unwanted side effects, such as vascular side effects through inhibition of BMP 9/10 and bone weakness induced by follistatin through antagonizing several TGF-β family members. Therefore, a careful distinction between targets that may enhance the efficacy of an agent and those that may cause adverse effects is required with the improvement of the target specificity. In this review, we discuss the current understanding of the endogenous function of myostatin, and provide an overview of clinical trial outcomes from different myostatin inhibitors.
oligonucleotides
2026-05-20 | Progressive Duchenne/Becker muscular dystrophy, preclinical stage, deletion of exons 45-55 of the DMD gene in the hemizygous state: a clinical case from practice
Background. Duchenne/Becker progressive muscular dystrophy is an X-linked recessive disease caused by mutations in the DMD gene encoding the dystrophin protein. Deletions of exons 45-55 often correspond to the principle of preserving the reading frame, being associated with the Duchenne/Becker muscular dystrophy phenotype. Objective. To present a clinical case of the presymptomatic diagnosis of progressive Duchenne/Becker muscular dystrophy in an early-age patient with deletion of exons 45-55 of the DMD gene, analyze diagnostic markers and justify a strategy for dynamic follow-up. Materials and methods. A retrospective analysis of medical documentation with clinical, laboratory and instrumental methods was performed. In order to form a theoretical base, data was searched and systematized from scientific electronic libraries (CyberLeninka, eLibrary, PubMed, Google Academy) on progressive Duchenne/Becker muscular dystrophy (preclinical phase) and deletion of exons 45-55 of the DMD gene. The review includes literature reviews, scientific publications, and the results of clinical trials on the topic. Conclusion. A clinical case of diagnosis of progressive Duchenne/Becker muscular dystrophy in a 1-year-old male patient with isolated hyperfermentemia (ALT – 120 U/l, AST – 107.1 U/L) and a significant increase in creatine phosphokinase (4817.1 U/L) is described. Conducted: biochemical examination (creatine phosphokinase, lactate dehydrogenase, creatine phosphokinase-MV), instrumental diagnostics, including electrocardiography, ultrasound examination of the heart and abdominal cavity), molecular genetic analysis. The molecular genetic analysis method verified the hemizygous deletion of exons 45-55 of the DMD gene. The diagnosis of progressive Duchenne/Becker muscular dystrophy was established at the preclinical stage, despite the absence of manifest neurological symptoms. The case demonstrates the critical role of determining of creatine phosphokinase as a screening marker and the need for an integrated approach for early diagnosis. The detection of in-frame deletion creates prerequisites for the potential use of exon-skipping therapy.
2026-01-08 | A new dystrophin-deficient rat model mirroring exon skipping in patients with DMD exon 45 deletions.
Pathogenic variants in the dystrophin (DMD) gene cause muscle-wasting disorders ranging from the milder Becker muscular dystrophy (BMD) to the more severe Duchenne muscular dystrophy (DMD). Exon 45 deletion is the most-frequent single-exon deletion in patients diagnosed with DMD. Here, we generated a novel rat model with an exon 45 deletion using CRISPR/Cas9. The DmdΔ45 rat recapitulate key features of DMD, including progressive skeletal muscle degeneration, impaired muscle and cardiac function, and cognitive deficits. Transcriptomics analyses revealed gene expression patterns consistent with dystrophin deficiency. In skeletal muscle, we observed a transition from early stress responses and regeneration to chronic inflammation, fibrosis and metabolic dysfunction. Cardiac profiles similarly progressed from early inflammatory responses to fibrotic remodelling and metabolic impairment. Notably, DmdΔ45 rats displayed a milder phenotype than other DMD rat models. This attenuation is likely due to spontaneous exon skipping, particularly of exon 44, which partially restores the reading frame and increases revertant dystrophin-positive fibres with age. Downregulation of spliceosome-related genes suggests a potential mechanism for this exon skipping. Overall, this model provides valuable insights into phenotypic variability and therapeutic exon-skipping strategies.
2025-11-20 | A Novel Transcriptional Slippage Mechanism Rescues Dystrophin Expression from a DMD Frameshift Variant.
Pathogenic DMD variants usually follow the reading-frame rule: out-of-frame changes cause Duchenne muscular dystrophy, whereas in-frame ones produce Becker muscular dystrophy (BMD). We report a 23-year-old man with BMD-like weakness, calf hypertrophy, elevated creatine kinase, and dilated cardiomyopathy. A novel hemizygous c.2281delG variant converted an A₄GA₅ motif to A₉, predicting a frameshift; however, Western blot showed ~15% full-length dystrophin. cDNA and polymerse chain reaction (PCR)-free direct RNA sequencing demonstrated transcriptional slippage, adding 1 adenine (A₁₀) that restores the reading frame and dystrophin. This RNA-level rescue of an out-of-frame DMD variant explains the mild phenotype and highlights the importance of transcript-level analysis in dystrophinopathies. ANN NEUROL 2026;99:223-230.
2025-11-01 | Genotype-Phenotype Correlation in a Cohort of Egyptian Patients with Dystrophinopathies
Abstract Background Dystrophinopathies are a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD- associated dilated cardiomyopathy (DCM). They are classified according to primary muscle affection, where DMD/ BMD occur when skeletal muscle is affected and DMD - related DCM when heart is primarily affected. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X- linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Objective To describe demographic and clinical data in relation to different genetic mutations and to correlate between phenotypic and genotypic differences in a cohort of Egyptian patients with dystrophinopathies. Methods This Descriptive observational study was conducted in Ain Shams University muscle clinic research committee over 6 months. Our study was conducted upon 109 patients with dystrophinopathies encompassing Duchenne and Becker muscular dystrophies confirmed by Multiplex ligation probe amplification (MLPA) for dystrophin gene. The subjects were randomly chosen from neuromuscular clinic in Ain shams university hospitals. Results In our study, genotype -phenotype correlations were performed showing that most patients with DMD phenotype follow the reading frame rule except for patient with in frame deletion affecting exons 31-41 result still in DMD phenotype. Other exceptions to the reading frame rule was also identified, where two patients with BMD phenotype had out frame deletions of exons 3-7 and exons 46-48. Conclusion Assessing the genotype–phenotype relationship in patients with dystrophinopathies has been supported by data from clinical studies, which might more directly indicate the merits of potential exon-skipping therapies. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments still do not cure the disease only ameliorate the disease severity. Our study revealed that genotype–phenotype correlations of enrolled subjects comply with the reading frame rule in most patients with DMD and BMD phenotype except for some exceptions. In addition to that, we identified cases with specific deletion mutations and nonsense mutations amenable for exon skipping therapies as exon 45 skipping, exon 51 skipping and ataluren therapy respectively.
2025-10-08 | Spectrum of DMD gene mutations in 507 patients: a retrospective genotype-phenotype study using next-generation sequencing.
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, but comprehensive analyses of mutational patterns and clinical correlations remain limited. To characterize the DMD mutational spectrum and its clinical implications in a large Asian cohort. A retrospective genetic analysis of 507 unrelated male DMD/Becker muscular dystrophy patients was conducted at Hunan Children's Hospital (2018-2021). Multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) were employed for comprehensive variant detection. Variants were classified per ACMG/AMP guidelines. Exon deletions predominated (64.9%), followed by small mutations (26.0%) and duplications (9.1%). Nonsense mutations were the most frequent small variant (16.0%). Domain analysis revealed mutations clustered in the Central Rod Domain (CRD; exons 45-55). The Carboxy-Terminal Domain (CTD) was associated with the most severe phenotype (earliest loss of ambulation, P < 0.05 vs. Actin-Binding Domain [ABD] or CRD). Exon 53 skipping was applicable in 39.39% of eligible patients. De novo mutations accounted for 7.9% (40/507) of cases. Epilepsy comorbidity occurred in 1.34% (6/448) of DMD patients. This study delineates the DMD mutational landscape in a Chinese cohort, highlighting domain-specific phenotypic severity (CTD > ABD > CRD) and identifying exon 53 as the primary therapeutic target for exon skipping. These findings enhance prognostic precision and guide targeted therapeutic strategies.
proteins
2026-08-31 | Protein intake is associated with adiposity and quality of life in adults with Becker muscular dystrophy.
Becker Muscular Dystrophy (BMD) is a rare X-linked genetic condition characterised by reduced dystrophin expression, causing progressive skeletal muscle and functional decline, and ultimately poor quality of life (QoL). With no current pharmacological cure, practical easy-to-implement strategies are needed to improve QoL in BMD. Increasing dietary protein intake is beneficial in other clinical populations, exhibiting positive impacts on lean body mass and self-reported pain. While progressive muscle deterioration is a hallmark of BMD, less is known about the interaction between nutritional status, body composition, physical function and QoL in BMD. Therefore, this study aimed to characterise dietary intake and explore relationships between dietary factors and readouts of body composition, muscle size/strength and QoL. Adult males with BMD (n = 20) and age-matched controls (n = 12), completed 2 food diaries ∼6 weeks apart with instructions to state exact quantities, brand names and cooking methods, a battery of physical tests assessing body composition, muscle size, strength, and function, as well as validated questionnaires on perceived physical function, pain/fatigue, QoL, and nutritional knowledge. Adults with BMD reported 29% lower daily energy intake, 25-30% lower carbohydrate and fat intakes, and 21% lower relative protein intake (0.86 vs. 1.08 g/kg/day) than controls (all p < 0.05). Only 10% of the BMD group met the minimum end of The European Society for Clinical Nutrition (ESPEN) recommended protein intake range for disease-related muscle loss (1.2-1.7 g/kg/day). The BMD group exhibited greater fat mass index (FMI) (9.31 kg/m2 vs. 6.30 kg/m2) and 95% of BMD were classified obese or overweight, however no differences in lean mass were observed. Individuals with BMD also exhibited lower tibialis anterior muscle thickness, strength, and physical function, and reported reduced QoL, lower limb function and activities of daily living, along with higher pain and fatigue (67-77%, all p < 0.05). When controlling for age, total energy intake and self-reported physical activity, protein intake (g/kg/day) was negatively associated with fat mass index (r = -0.698, p = 0.017) and positively associated with SF36v2 quality of life (r = 0.503, p = 0.040), whilst BMI was positively associated with pain (r = 0.684, p = 0.002). Our results show adults with BMD report lower overall caloric and relative protein intake than non-dystrophic individuals, with protein intake substantially lower than guidance for other muscle-wasting conditions. Adults with BMD also displayed higher levels of adiposity, reported higher fatigue and pain as well as lower quality of life. The observed positive associations between relative protein intake and QoL, together with the negative associations between relative protein intake and adiposity, support further investigation into the role of protein intake in adults with BMD. Prospective and intervention studies are needed to establish the true nature of these relationships to inform nutritional recommendations for the BMD population.
2026-05-01 | Engineered antibody fusion proteins increase plasma membrane repair to treat muscle diseases
Plasma membrane repair is a highly conserved process that muscle cells use to maintain health under mechanical stress from physiological levels of muscle contraction. Defective sarcolemma repair can cause or exacerbate cardiovascular and muscle diseases, including Duchenne/Becker muscular dystrophy and limb-girdle muscular dystrophies. The tripartite motif family protein 72 (TRIM72), also called mitsugumin 53 (MG53), is essential for membrane repair by facilitating vesicle fusion at injury sites while binding the phospholipid phosphatidylserine (PS). Our laboratory and others have shown that treatment with recombinant TRIM72 protein (rhTRIM72) ameliorates muscle disease pathology in preclinical models. However, the therapeutic potential of rhTRIM72 in muscle diseases was limited by off-target effects on systemic metabolism, poor pharmacokinetics, and manufacturing challenges. To address these issues, we created improved therapeutic proteins by fusing the fragment crystallizable (Fc) domain from the human IgG1 protein to a panel of TRIM72 truncations. We hypothesized that this approach would increase protein serum half-life through endogenous antibody recycling machinery, simplify manufacturing using existing biologic drug purification methods, and decrease off-target effects by truncating TRIM72. Multiple TRIM72/Fc-fusion proteins display effective PS binding activity in biochemical pulldown experiments. Laser confocal microscopy ablation and dye exclusion assays in myoblast cells revealed that TRIM72/Fc-fusion proteins improved plasma membrane repair upon intracellular overexpression or exogenous application. These experiments found that one of the fusion proteins we call MyoSPRY, comprised of the Fc fused to the SPRY domain of TRIM72, could increase membrane repair. Exogenous treatment with MyoSPRY and other Fc-SPRY proteins improved membrane repair in live muscle tissue isolated from a Duchenne muscular dystrophy (DMD) mouse model. Subcutaneous injection experiments show that Fc-fusion proteins exhibit extended half-lives in vivo and protect muscle against acute eccentric contraction injury-induced force decrement in a mouse model of DMD. Together, these results indicate that our novel Fc-fusion proteins address barriers impeding the clinical development of rhTRIM72 and represent a possible therapeutic approach for diseases driven by altered membrane integrity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2025-06-08 | Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS.
Becker muscular dystrophy (BMD) is a rare and heterogeneous form of dystrophinopathy caused by expression of altered dystrophin proteins, as a consequence of in-frame genetic mutations. The majority of the BMD biomarker studies employ targeted approaches and focus on translating findings from Duchenne Muscular Dystrophy (DMD), a more severe disease form with clinical similarities but caused by out-of-frame mutations in the dystrophin gene. Importantly, DMD therapies assume that disease progression can be slowed by promoting the expression of truncated dystrophin comparable to what occurs in BMD patients. In this study, we explore similarities and differences in protein trajectories over time between BMD and DMD serum, and explore proteins related to motor function performance. Serum samples collected from 34 BMD patients, in a prospective longitudinal 3-year study, and 19 DMD patients, were analyzed by using Data Independent Acquisition Tandem Mass Spectrometry (DIA-MS). Subsequent normalization, linear mixed effects model was employed to identify proteins associated with physical tests and dystrophin expression in skeletal muscle. Analysis was also performed to explore the discrepancy between DMD and BMD biomarker abundance trajectories over time. Linear mixed effects models identified 20 proteins with altered longitudinal signatures between DMD and BMD, including creatine kinase M-type (CKM) pyruvate kinase (PKM), fibrinogen gamma chain (FGG), lactate dehydrogenase B (LDHB) and alpha-2-macroglobulin (A2M). Furthermore, several proteins related to innate immune response were associated with motor function in BMD patients. In particular, A2M displayed an altered time-dependent decline in relation to dystrophin expression in the tibialis anterior muscle. Our study revealed differences in the serum proteome between BMD and DMD, which comprises proteins involved in the immune response, extracellular matrix organization and hemostasis but not muscle leakage proteins significantly associated with disease progression in DMD. If further evaluated and validated, these biomarker candidates may offer means to monitor disease progression in BMD patients. A2M is of particular interest due to its association with dystrophin expression in BMD muscle and higher abundance in DMD patients in comparison to BMD. If validated, A2M could be used as a pharmacodynamic biomarker in therapeutic clinical trials aiming to restore dystrophin expression.
2024-04-14 | Long-term clinical follow-up of a family with Becker muscular dystrophy associated with a large deletion in the DMD gene
Duchenne muscular dystrophy is a neuromuscular disease caused by DMD gene mutations that result in an absence of functional dystrophin protein. Patients with Duchenne experience progressive muscle weakness, are typically wheelchair dependent by their early teens, and develop respiratory and cardiac complications that lead to death in their twenties or thirties. Becker muscular dystrophy is also caused by DMD gene mutations, but symptoms are less severe and progression is slower compared with Duchenne. We describe a case study of a patient with Becker muscular dystrophy who was still ambulant at age 61 years and had a milder phenotype than Duchenne, despite 46% of his DMD gene being missing. His affected relatives had similarly mild phenotypes and clinical courses. These data guided the understanding of the criticality of various regions of dystrophin and informed the development of micro-dystrophin constructs to compensate for the absence of functional dystrophin in Duchenne.
2023-10-23 | Growth hormone and testosterone delay vertebral fractures in boys with muscular dystrophy on chronic glucocorticoids
Glucocorticoid use in Duchenne and Becker muscular dystrophy prolongs ambulation but cause significant skeletal toxicity. Our analysis has immediate clinical implications, suggesting that growth hormone and testosterone have a stronger effect prior to first and subsequent vertebral fracture, respectively, relative to bisphosphonates alone in children with dystrophinopathies on chronic glucocorticoids. Glucocorticoids prolong ambulation in boys with Duchenne muscular dystrophy; however, they have significant endocrine side effects. We assessed the impact of growth hormone (GH), testosterone, and/or zoledronic acid (ZA) on vertebral fracture (VF) incidence in patients with dystrophinopathies on chronic glucocorticoids. We conducted a longitudinal retrospective review of 27 males with muscular dystrophy. Accelerated failure time (AFT) models were used to estimate the relative time to VF while on GH, testosterone, and/or ZA compared to ZA alone. Results are reported as failure time ratio, where >1 indicates prolonged time versus <1 indicates shorter time to next VF. The prevalence of growth impairment was 96% (52% utilized GH), pubertal delay was 86% (72% utilized testosterone), and low trauma fractures were 87% (72% utilized ZA). Multivariable analysis of the AFT models showed that participants on either GH or testosterone treatment relative to ZA alone experienced prolonged time to next VF (1.253, P<0.001), with GH being the significant contributor when analyzed independently from testosterone (1.229, P<0.001). Use of ZA with GH or testosterone relative to ZA alone resulted in prolonged time to next VF (1.171, P<0.001), with testosterone being a significant contributor (1.130, P=0.033). GH and testosterone each decreased VF risk in patients independent of or in combination with ZA, respectively.
gene therapies
2026-09-08 | MicroRNA-mRNA Networks in Skeletal Muscle of Tailored Pig Models for Dystrophinopathies.
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked dystrophinopathies caused by mutations in the dystrophin (DMD) gene. A common DMD-causing mutation in humans is exon 52 deletion (DMDΔ52), which disrupts the reading frame and abolishes dystrophin expression. Therapeutic skipping of exon 51 or 53 can restore the reading frame, producing a truncated but functional protein and generating a BMD-like phenotype. Porcine models recapitulating DMDΔ52 (DMD) and DMDΔ51-52 (BMD-like) were used to identify molecular differences and condition-specific miRNA-mRNA networks. Skeletal muscle (triceps brachii) from four DMD, four BMD, and five wild-type (WT) pigs at 3.5 months of age underwent stranded total RNA-seq and small RNA-seq. Differentially expressed mRNAs (|log2FC| ≥ 1, adj. p ≤ 0.05) and miRNAs (adj. p ≤ 0.05) were identified with DESeq2. miRNA-mRNA networks were constructed using RNAhybrid predictions (MFE < -25 kcal/mol, seed pairing) filtered by inverse Pearson correlation. Compared with WT, DMD muscle exhibited 1440 upregulated and 487 downregulated genes, characterized by strong repression of structural, contractile, calcium-handling and metabolic genes (e.g., MYBPC2, MYL3, MYLK2, CACNA2D3, CACNA2D4) and marked upregulation of inflammatory mediators and innate immune receptors (e.g., IL6, IL18, IL1R1, CCR1/2/5, TLR1/2/4/7/9). In contrast, BMD muscle showed partial restoration of these pathways and clustered closer to WT in global expression profiles. Distinct miRNA signatures were observed between DMD and BMD. Differential expression analysis identified 22 upregulated and 12 downregulated miRNAs in DMD versus WT and 36 upregulated and 21 downregulated miRNAs in BMD versus WT. Integration of miRNA and mRNA data yielded extensive regulatory networks (1013 unique pairs for upregulated miRNAs in DMD; 2679 pairs for downregulated miRNAs in BMD). Two condition-specific miRNAs emerged as strong biomarker candidates: ssc-miR-296-3p (upregulated exclusively in DMD, targeting 228 genes enriched in muscle structure and fatty acid metabolism) and ssc-miR-423-5p (elevated specifically in BMD, targeting 67 genes involved in calcium signalling and tissue development). Several dysregulated miRNAs, including miR-199a-5p and miR-199b, overlapped with those reported in human DMD and other muscular dystrophies. Exon 51 skipping in the DMDΔ52 background partially restores key transcriptional programmes in skeletal muscle but does not fully normalize them to WT patterns. The identification of condition-specific miRNAs highlights post-transcriptional regulatory differences between DMD and BMD, positioning them as promising biomarkers and therapeutic targets. These findings underscore the translational value of porcine dystrophinopathy models for mechanistic studies and preclinical evaluation of RNA-targeted interventions.
2026-06-05 | Gene editing restores full-length dystrophin and affects iron homeostasis in hiPSC-derived cardiomyocytes from Becker Muscular Dystrophy patients.
Becker Muscular Dystrophy (BMD) is caused by in-frame mutations in the DMD gene, leading to the production of internally truncated but partially functional dystrophin. Although cardiac involvement is a major contributor to disease burden in BMD, the cellular mechanisms driving cardiomyopathy remain incompletely understood. While emerging evidence suggests that iron imbalance may contribute to oxidative stress and mitochondrial dysfunction in muscular dystrophies, its role in BMD-associated cardiomyopathy has not been defined. Building on our previous findings of dysregulated iron homeostasis in dystrophin-deficient cardiomyocytes from Duchenne muscular dystrophy (DMD), we investigated whether similar alterations are present in BMD using patient-specific and genome-corrected hiPSC-CM models. HiPSC lines derived from two BMD patients and their CRISPR/Cas9-corrected isogenic controls displayed normal karyotype, pluripotency, and efficient differentiation into cardiomyocytes (hiPSC-CMs). BMD hiPSC-CMs showed elevated ROS levels and decreased cytoplasmic and mitochondrial labile iron pools, accompanied by reduced expression of mitoNEET (CISD1), a regulator of mitochondrial iron handling. We also detected changes in the expression of genes involved in iron storage (FTH1), uptake (TFRC), and export (SLC40A1), suggesting a dysregulation of iron trafficking. Importantly, correction of DMD mutation by CRISPR/Cas9 gene editing reversed the effects observed in BMD cardiomyocytes. These results extend our previous observations in DMD to BMD cardiomyocytes and suggest that full-length dystrophin is essential for maintaining cardiac iron homeostasis.
2026-05-21 | Natural history of cardiac involvement in women carrying pathogenic DMD gene variants: a 7-year longitudinal study.
Cardiac involvement is increasingly recognized in women carrying pathogenic variants in the dystrophin (DMD) gene, both Duchenne and Becker-associated, but the long-term natural history of cardiac structure, function, and conduction abnormalities in this group is not well understood. We conducted a prospective 7-year follow-up study to investigate the evolution of ventricular function, myocardial fibrosis, and arrhythmias. 34 women with confirmed pathogenic DMD gene variants (19 predicted to cause Duchenne muscular dystrophy and 15 Becker muscular dystrophy) underwent assessments after a mean of 7 years. Evaluations included cardiac magnetic resonance imaging with late gadolinium enhancement, 24-h Holter monitoring, 12-lead electrocardiography (ECG), cardiac biomarkers, and clinical examinations. At the group level, left ventricular ejection fraction (LVEF) remained stable over follow-up (p = 0.403). Six women had a ≥ 5% change in LVEF: three improved with treatment, and three declined by 5-8%. Fibrosis was present in 9 women at both baseline and follow-up; 3 showed visual progression, and no new cases were identified. Although the median ventricular premature contractions per hour (VPC/h) increased from 0.23/h to 6.38/h (p < 0.001), this increase is likely not clinically meaningful as age-related increases in ventricular ectopy are also seen in healthy populations, and high-burden arrhythmias-according to prespecified thresholds-remained uncommon. ECG parameters remained stable (PR, QRS, and QTc unchanged), with no new bundle-branch blocks or high-grade atrioventricular block detected. No association was observed between LVEF, VPC/h, and supraventricular premature contraction per hour over the 7-year follow-up period. Over 7 years, women carrying pathogenic DMD gene variants have very little or no progression of cardiac findings (LVEF, fibrosis, and arrhythmias). Given these findings, frequent routine rhythm monitoring is not indicated. Follow-up should be risk-stratified: closer for women with symptoms, baseline high-burden ectopy, reduced LVEF, or pre-existing fibrosis; others can be reviewed at extended intervals.
2026-04-26 | Neurocognitive and autism spectrum profiles associated with dystrophin isoform disruption in childhood dystrophinopathies: insights from a Brazilian cohort.
To examine the association between dystrophin isoform disruption and cognitive and behavioral outcomes, including autism spectrum disorder (ASD), in a large cohort of boys with Duchenne muscular dystrophy (DMD) and related dystrophinopathies. In this retrospective cohort study (2014-2025), 161 boys with genetically confirmed dystrophinopathy (145 DMD, 14 Becker muscular dystrophy, and 2 intermediate muscular dystrophy) were classified according to predicted involvement of the brain-expressed dystrophin isoforms Dp427, Dp140, and Dp71. Cognitive function was assessed using standardized intelligence measures (WISC-IV or WASI), complemented by comprehensive neuropsychological evaluation. ASD was diagnosed according to DSM-5 criteria and confirmed through multidisciplinary assessment. Intellectual disability (ID) was identified in 63 of 161 patients (39.1%), including 47 (29.1%) with mild and 16 (10.0%) with moderate ID. ASD was diagnosed in 16 patients (10%), and in 81% of cases ASD identification preceded or coincided with the diagnosis of dystrophinopathy. An isoform-dependent gradient was observed: patients with mutations restricted to exons 1-44 (Dp427-only) showed the highest frequency of normal cognition, whereas those with mutations affecting Dp140 or Dp71 exhibited progressively higher rates of ID and ASD. Cognitive impairment and ASD are frequent non-muscular manifestations of childhood dystrophinopathies and correlate closely with disruption of brain-expressed dystrophin isoforms, particularly Dp140 and Dp71. Integrating genetic and neuropsychological assessment into routine clinical care is essential for early recognition and timely intervention.
2026-04-08 | Thrombosis in Neuromuscular Medicine: Current Evidence, Unmet Needs, and Future Directions
Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is an important but under-recognised complication in neuromuscular diseases. In adults, emerging epidemiological data suggests increased VTE occurrence in conditions such as Amyotrophic Lateral Sclerosis, myotonic dystrophy, myasthenia gravis, inflammatory neuropathies, inflammatory myopathies, and POEMS syndrome. This heightened risk reflects not only disease-related immobility but also disorder-specific biological mechanisms, including inflammation, endothelial dysfunction and cardiomyopathy-related stasis. Therapies such as corticosteroids, IVIG-related hyperviscosity, long-term central venous access, perioperative immobility, critical illness, and complex orthopaedic procedures have prothrombotic effects. Despite this multifactorial risk profile, disease-specific guidance for thromboprophylaxis is lacking, and current practice relies heavily on extrapolation from general medical and surgical recommendations rather than data derived from neuromuscular cohorts. In children and adolescents, the VTE burden is less well-characterised, but events have been reported in Duchenne and Becker muscular dystrophy, congenital myopathies, and spinal muscular atrophy particularly with advanced motor impairment, severe cardiomyopathy, ventilatory insufficiency, and prolonged hospitalisation. Beyond venous events, selected neuromuscular disorders also exhibit increased arterial thrombosis risk. Myotonic dystrophy and dystrophinopathies are associated with cardiomyopathy and arrhythmia that predispose to systemic embolism and stroke, while inflammatory myopathies may demonstrate arterial events related to vasculitic or endothelial processes, although overall evidence remains limited. This review summarises available empirical and epidemiological evidence on venous and arterial thrombosis across adult and paediatric neuromuscular disorders, outlines disease-specific mechanistic pathways, examines treatment-related contributors, and highlights key evidence gaps that must be addressed to guide rational and targeted prophylaxis strategies in this complex, heterogeneous population.
small molecules
2026-08-04 | Volatile-Free Total Intravenous Anesthesia for Major Gynecologic Surgery in a Manifesting Female Carrier of Becker Muscular Dystrophy: A Case Report
Becker muscular dystrophy (BMD) is a rare X-linked dystrophinopathy caused by dystrophin gene (DMD gene) variants, resulting in reduced or dysfunctional dystrophin. Despite a milder course than Duchenne muscular dystrophy, patients face significant perioperative risk from skeletal muscle degeneration, respiratory weakness, cardiomyopathy, and conduction abnormalities. Succinylcholine and volatile anesthetics have been associated with life-threatening hyperkalemia, rhabdomyolysis, and malignant hyperthermia-like reactions in dystrophinopathies. Clinically manifest BMD in females is exceptionally rare due to skewed X-inactivation, and perioperative data in this population remain scarce. We report a 39-year-old woman with genetically confirmed, clinically manifested BMD who underwent elective left salpingo-oophorectomy with surgical staging for a large adnexal mass. She had severe proximal weakness and was non-ambulatory but had no respiratory, swallowing, or aspiration symptoms. Multidisciplinary preoperative evaluation (neurology, cardiology, hepatology, anesthesiology, gynecologic oncology, intensive care) confirmed preserved cardiac function (ejection fraction >70%), normal conduction, no respiratory compromise evidenced by normal pulmonary function tests, and adequate hepatic reserve. A trigger-free anesthetic strategy was used: the workstation was prepared to eliminate residual volatile agents, and total intravenous anesthesia was maintained with propofol, dexmedetomidine, and midazolam, avoiding succinylcholine and volatile agents. Reduced-dose atracurium provided neuromuscular blockade, and multimodal opioid-sparing analgesia included bilateral rectus sheath blocks and non-opioid analgesics. Surgery was uneventful, with no hemodynamic instability, arrhythmias, hyperkalemia, or rhabdomyolysis. The patient was extubated in the operating room after full neuromuscular recovery, then electively admitted to the ICU for observation given the risk of delayed respiratory compromise. Her postoperative course was uncomplicated, with stable cardiorespiratory function and effective analgesia. Histopathology confirmed an adult granulosa cell tumor of the ovary. This case suggests that major gynecologic surgery can be safely performed in clinically manifest female BMD patients through multidisciplinary planning, trigger-free total intravenous anesthesia, careful neuromuscular blockade, opioid-sparing analgesia, and planned ICU surveillance, offering valuable guidance for this rare, high-risk population.
2026-07-01 | Human Disposition, Metabolism, and Excretion of Sevasemten (EDG‐5506), a Selective Modulator of Fast Myosin in Healthy Volunteers
Abstract Sevasemten (EDG‐5506) is a novel, orally bioavailable, investigational small molecule designed to selectively modulate type II fast skeletal myosin with the goal of protecting dystrophic muscle from contraction‐induced injury. Sevasemten is in clinical development for the treatment of Becker and Duchenne muscular dystrophy. In the current Phase 1 study (NCT05730842), eight participants were dosed with a 20 mg single oral suspension dose of sevasemten containing approximately 500 µCi [ 14 C] sevasemten. Blood and urine samples were collected to evaluate the pharmacokinetics (PK), oral absorption, metabolism, and excretion (AME) of sevasemten and its metabolites. A second cohort of seven participants received a single 20 mg oral dose of sevasemten, followed 2 h later by a single dose of [ 14 C] sevasemten administered as a single intravenous (IV) bolus with approximately 1 µCi [ 14 C] sevasemten to determine absolute bioavailability. Sevasemten was excreted primarily in urine (52.1%) subsequent to CYP3A‐mediated metabolism, and 8.89% was eliminated in the feces, for a total of 61.0% recovered over 840 h post‐dose. Most of the recoverable radioactivity was excreted by 576 h (24 days). However, sevasemten total radioactivity in plasma and whole blood was characterized by a very slow elimination phase of 16.1–20.6 days; total recovery of radioactivity was not achieved. Sevasemten was well tolerated, with no serious adverse events or adverse events leading to study discontinuation. Sevasemten has favorable PK properties for once daily administration and continues to be investigated for the treatment of Becker and Duchenne muscular dystrophies.
2026-06-17 | Effects of sevasemten (EDG-5506) on safety, biomarkers, and functional measures in adults with Becker muscular dystrophy: results of a phase 1b, open-label study.
Sevasemten (EDG-5506) is an orally administered, investigational small molecule that selectively modulates fast muscle fibre contraction by inhibiting fast myosin ATPase. In animal models of Duchenne and Becker muscular dystrophy (DMD and BMD, respectively), sevasemten reduced the muscle contraction injury that leads to inflammation, fibrosis and muscle loss without affecting function. The aim of this study was to evaluate the long-term safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics of sevasemten in adult participants with BMD who had already experienced a decline in function and would be anticipated to continue to decline based on natural history. This open-label, dose escalation, phase 1 b study (NCT05160415) was conducted at a single site and enrolled ambulatory adults with BMD aged 18-55 years; the study is completed. Eligible participants received 10 mg of sevasemten once daily (QD) for 8 weeks, followed by 15 mg QD for 4 months, 20 mg QD for 9 months, and 10 mg QD for 9 months. The primary objective was to assess the safety and tolerability of sevasemten in adults with BMD; endpoints included adverse events (AEs), PK, change from baseline in circulating biomarkers of muscle injury, as well as physical function measures. The study enrolled 12 adults with BMD. Sevasemten was well tolerated; all AEs were mild or moderate in severity and there were no serious AEs or AEs leading to discontinuation. Treatment with sevasemten was associated with reductions in circulating biomarkers of muscle injury that were evident within 4 weeks and sustained for up to 24 months. Physical function, as assessed by North Star Ambulatory Assessment (NSAA), was stable over 24 months. Sevasemten treatment for up to 24 months in adults with BMD was well tolerated and associated with durable reductions in muscle injury biomarkers, consistent with preclinical studies and near maximal with the 10 mg dose, as well as functional stabilisation. Further clinical development is ongoing. Edgewise Therapeutics, Inc.
2026-05-22 | Heart failure guideline-directed medical therapy in young adults with dystrophin-related cardiomyopathy: the HOPE-MD registry.
Duchenne (DMD) and Becker (BMD) muscular dystrophies often progress to dilated cardiomyopathy and heart failure with reduced ejection fraction (HFrEF), a major cause of death in affected patients. Although guideline-directed medical therapy (GDMT) improves HFrEF outcomes, its real-world use in dystrophinopathies is poorly defined. We assessed GDMT utilization and optimization in the study population. HOPE-MD is a European, multicentre, retrospective registry including adults with genetically confirmed DMD or BMD and left ventricular ejection fraction (LVEF) ≤40%. GDMT was defined as concurrent use of a renin-angiotensin system inhibitor (RASi), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter-2 inhibitor (SGLT2i). Doses were categorized as target (≥100%), intermediate (50-99%), or low (<50%). Among 274 patients (age, 28 years; LVEF, 35%; DMD, 80%), 44 (16%) received GDMT at baseline, with only one quarter at ≥50% of the target dose. Underutilization was greatest for MRAs (n=140, 51%) and SGLT2i (n=60, 22%), whereas RASi (n=246, 90%) and beta-blockers (n=235, 86%) were frequently prescribed. After 24 months (n=141), 40% received GDMT, and 22% received ≥50% of the target dose, primarily through MRA and SGLT2i initiation/uptitration. Contraindications accounted for only a small proportion of undertreatment. At a median follow-up of 2.2 (1.7-2.6) years, optimized GDMT was not associated with a statistically significant difference in the rates of death or HF hospitalization compared with low-dose or no GDMT (adjusted HR 0.70, 95% CI 0.28-1.74). GDMT use and dose escalation were suboptimal in European patients with DMD/BMD and HFrEF.
2026-01-09 | Muscle involvement in women carrying pathogenic DMD gene variants: A 6.5-year follow-up study.
Women carrying pathogenic DMD gene variants can develop muscle affection, such as muscle weakness and fat replacement. The long-term progression of the muscle involvement is unknown. This study investigates the 6.5-year changes in muscle function and -fat fraction in women carrying pathogenic DMD gene variants to enhance understanding of disease progression and its natural history. Muscle structure and -function were investigated at baseline and after 6.5 years in 34 women carrying pathogenic DMD gene variants (19 predicted to confer Duchenne Muscular Dystrophy (DMD), 15 Becker Muscular Dystrophy (BMD)). After a clinical evaluation, muscle fat fraction was assessed using Dixon MRI, muscle strength with isokinetic dynamometry, and muscle biomarkers with blood samples for creatine kinase and myoglobin. Muscle fat fraction in the lower back, thigh, and calf increased significantly over 6.5 years. The average increases were generally less than 2%, but some carriers with significant baseline abnormalities experienced a more substantial increase in fat fraction, reaching as high as 31%. Although overall disease progression did not differ significantly between DMD and BMD carriers, all women who showed rapid progression were DMD carriers. Small but significant changes occurred in muscle strength and biomarkers. The progression of muscle involvement in women carrying pathogenic DMD gene variants is generally slow. However, those with severe baseline abnormalities on MRI-often associated with a lower age of symptom onset-experience a more rapid progression of muscle fat fraction, suggesting that baseline MRI findings could help predict future disease progression in this population.
other
2026-08-11 | Mexico’s First Heart Transplant in a Patient with Becker Muscular Dystrophy Reveals an Overlooked Cause of Idiopathic Dilated Cardiomyopathy
Background: Pathogenic variants in the DMD gene are a frequently overlooked cause of dilated cardiomyopathy (DCM) in idiopathic cases, especially when skeletal myopathy is mild or seemingly absent. Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy are at opposite ends of this clinical spectrum but result from pathogenic variants in the same gene. Cardiomyopathy is a major cause of premature death in muscular dystrophies. Case presentation: We describe a 37-year-old man who underwent orthotopic heart transplantation for presumed idiopathic DCM with refractory heart failure. He had a six-year history of progressive proximal weakness, pseudohypertrophy of the calf, a positive Gowers sign, and markedly elevated creatine kinase (6638 IU/L). Multiplex ligation-dependent probe amplification (MLPA) revealed an in-frame deletion of exons 45–47 of DMD [c. (6438+1_6439-1)_(6912+1_6913-1) del; NM_004006.2], confirming BMD. Immunofluorescence showed reduced and patchy dystrophin expression. Conclusions: To our knowledge, this is the first documented heart transplant in a patient with BMD in Mexico. This case demonstrates the value of considering muscular dystrophy in the differential diagnosis of apparently idiopathic dilated cardiomyopathy (DCM), a step that opens the door to accurate diagnosis, carrier screening, and genetic counseling, and supports the view that heart transplantation is a viable option in carefully selected patients with muscular dystrophy cardiomyopathy.
2023-02-04 | Challenges and Future Prospects of Targeting Myostatin/Activin A Signaling to Treat Diseases of Muscle Loss and Metabolic Dysfunction
Abstract Over the past 25 years, considerable progress has been made in terms of elucidating the regulatory and signaling mechanisms underlying the control of skeletal muscle mass by myostatin and other secreted proteins belonging to the transforming growth factor-β superfamily. Preclinical studies demonstrating the potential benefits of targeting the activities of these ligands have fueled the development of numerous biologics capable of perturbing this signaling pathway and increasing muscle mass and function. These biologics have been tested in numerous clinical trials for a wide range of indications characterized by muscle loss and excess adiposity. Here, we review the results of these trials and discuss some of the challenges and future prospects for targeting this signaling pathway to treat muscle and metabolic diseases. Myostatin inhibitors may improve metabolic outcomes by increasing muscle mass, and metabolic disorders may be attractive potential indications for these molecules.
2023-01-27 | Activated Oncostatin M signaling drives cancer-associated skeletal muscle wasting
Summary Progressive weakness and muscle loss are associated with multiple chronic conditions including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy, however, available anti-cytokine therapies failed to prevent muscle wasting in cancer patients. We previously reported that muscle-specific deletion of the Oncostatin M (OSM) receptor (OSMR) preserved muscle mass and function in tumor-bearing mice. Here, we show that OSM is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes utilizing the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing revealed the induction of various muscle atrophy-related genes, including Atrogin1 . OSM overexpression in mice caused muscle wasting while the neutralization of circulating OSM protected from tumor-driven loss of muscle mass and function. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.
2022-04-04 | Effect of Denosumab on Bone Health in Adult Patients with Duchenne/Becker Muscular Dystrophy: A Report of 2 Cases.
Duchenne/Becker muscular dystrophy (DMD/BeMD) is caused by a loss of dystrophin leading to muscular weakness. Glucocorticoids are used to delay loss of muscle strength but frequently result in osteoporosis and fractures. Bisphosphonates are the drug of choice, and there are limited data on the efficacy of denosumab. We describe 2 patients who were treated with denosumab and had stable to improved bone density with no side effects. Denosumab can be considered for the treatment of osteoporosis in adults with DMD/BeMD, especially when the response to bisphosphonates is not satisfactory.
2020-08-31 | Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders?
Myostatin, also known as growth differentiation factor 8 (GDF8), is a transforming growth factor-β (TGF-β) family member that functions to limit skeletal muscle growth. Accordingly, loss-of-function mutations in myostatin result in a dramatic increase in muscle mass in humans and various animals, while its overexpression leads to severe muscle atrophy. Myostatin also exerts a significant effect on bone metabolism, as demonstrated by enhanced bone mineral density and bone regeneration in myostatin null mice. The identification of myostatin as a negative regulator of muscle and bone mass has sparked an enormous interest in developing myostatin inhibitors as therapeutic agents for treating a variety of clinical conditions associated with musculoskeletal disorders. As a result, various myostatin-targeting strategies involving antibodies, myostatin propeptides, soluble receptors, and endogenous antagonists have been generated, and many of them have progressed to clinical trials. Importantly, most myostatin inhibitors also repress the activities of other closely related TGF-β family members including GDF11, activins, and bone morphogenetic proteins (BMPs), increasing the potential for unwanted side effects, such as vascular side effects through inhibition of BMP 9/10 and bone weakness induced by follistatin through antagonizing several TGF-β family members. Therefore, a careful distinction between targets that may enhance the efficacy of an agent and those that may cause adverse effects is required with the improvement of the target specificity. In this review, we discuss the current understanding of the endogenous function of myostatin, and provide an overview of clinical trial outcomes from different myostatin inhibitors.
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Drug Discovery Landscape
9 orphan drug designations for Becker muscular dystrophy.
9 orphan drug designations for Becker muscular dystrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
human allogeneic cardiosphere-derived cells | cell therapies | FDA | Capricor, Inc. | |
Induced pluripotent stem cells-derived myogenic progenitor cells | cell therapies | EMA | — | Biopatents IP Consultancy |
human induced pluripotent stem cell derived myogenic progenitor cells | cell therapies | FDA | — | IPS HEART |
Sevasemten | small molecules | EMA | Les Laboratoires Servier | |
vamorolone | small molecules | FDA | ReveraGen BioPharma Inc. | |
Dexepicatechin | small molecules | EMA | MWB Consulting | |
Givinostat | small molecules | EMA | Italfarmaco S.p.A. | |
adeno-associated virus transgene of follistatin | gene therapies | FDA | Milo Biotechnology | |
Ataluren [Translarna] | small molecules | EMA | PTC Therapeutics International Limited |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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