Becker Muscular Dystrophy Research Articles

Progressive cardiomyopathy with intercalated disc disorganization in a rat model of Becker dystrophy.

Becker muscular dystrophy (BMD) is an X-linked disorder due to in-frame mutations in the DMD gene, leading to a less abundant and truncated dystrophin. BMD is less common and severe than Duchenne muscular dystrophy (DMD) as well as less investigated. To accelerate the search for innovative treatments, we developed a rat model of BMD by deleting the exons 45-47 of the Dmd gene. Here, we report a functional and histopathological evaluation of these rats during their first year of life, compared to DMD and control littermates. BMD rats exhibit moderate damage to locomotor and diaphragmatic muscles but suffer from a progressive cardiomyopathy. Single nuclei RNA-seq analysis of cardiac samples revealed shared transcriptomic abnormalities in BMD and DMD rats and highlighted an altered end-addressing of TMEM65 and Connexin-43 at the intercalated disc, along with electrocardiographic abnormalities. Our study documents the natural history of a translational preclinical model of BMD and reports a cellular mechanism for the cardiac dysfunction in BMD and DMD offering opportunities to further investigate the organization role of dystrophin in intercellular communication.

346P Cognitive profile of children with Duchenne and Becker muscular dystrophies

346P Cognitive profile of children with Duchenne and Becker muscular dystrophies

319P MRI gluteal/thigh muscle fat fraction detects NSAD motor task failures in men with Becker muscular dystrophy

319P MRI gluteal/thigh muscle fat fraction detects NSAD motor task failures in men with Becker muscular dystrophy

320P Clinical characterization of a large single-centre cohort of patients with Becker muscular dystrophy

320P Clinical characterization of a large single-centre cohort of patients with Becker muscular dystrophy

323P Caregiver burden with Duchenne and Becker muscular dystrophy in Japan

323P Caregiver burden with Duchenne and Becker muscular dystrophy in Japan

349P Comparison of short- and long-term proteomic response to the fast skeletal myosin inhibitor, sevasemten (EDG-5506), in Becker muscular dystrophy (BMD)

349P Comparison of short- and long-term proteomic response to the fast skeletal myosin inhibitor, sevasemten (EDG-5506), in Becker muscular dystrophy (BMD)

322P Rasch evaluation of North Star Ambulatory Assessment and North Star Assessment for limb-girdle type muscular dystrophies in Becker muscular dystrophy

322P Rasch evaluation of North Star Ambulatory Assessment and North Star Assessment for limb-girdle type muscular dystrophies in Becker muscular dystrophy

648P MRI demonstrates altered skeletal muscle membrane permeability in Becker muscular dystrophy, representing a potential biomarker for disease activity

648P MRI demonstrates altered skeletal muscle membrane permeability in Becker muscular dystrophy, representing a potential biomarker for disease activity

324P A longitudinal study of creatine kinase, creatinine levels, and appendicular lean mass index in pediatric Becker muscular dystrophy

324P A longitudinal study of creatine kinase, creatinine levels, and appendicular lean mass index in pediatric Becker muscular dystrophy

338P Very late-onset Becker muscular dystrophy caused by a new DMD variant

338P Very late-onset Becker muscular dystrophy caused by a new DMD variant

330P Trends in creatine kinase levels and 10-meter walk-run velocity in pediatric Becker muscular dystrophy treated with glucocorticoid steroids

330P Trends in creatine kinase levels and 10-meter walk-run velocity in pediatric Becker muscular dystrophy treated with glucocorticoid steroids

327P Correlation of biomarkers and timed function tests in pediatric Becker muscular dystrophy

327P Correlation of biomarkers and timed function tests in pediatric Becker muscular dystrophy

351P Sevasemten, a fast myosin inhibitor, in adults with Becker muscular dystrophy results in reduced muscle damage biomarkers and functional stabilization

351P Sevasemten, a fast myosin inhibitor, in adults with Becker muscular dystrophy results in reduced muscle damage biomarkers and functional stabilization

Cardiac MRI in Duchenne and Becker Muscular Dystrophy.

Cardiovascular magnetic resonance imaging (CMRI) is the noninvasive technique of choice for early detection of cardiac involvement in Duchenne and Becker muscular dystrophy (DMD and BMD, respectively), but is seldom used in routine clinical practice in the Indian context. We sought to determine the prevalence of CMRI abnormalities in patients with DMD and BMD and to compare the CMRI parameters with the phenotypic and genotypic characteristics. A prospective, observational study was conducted on patients genetically diagnosed with DMD and BMD who could complete CMRI between March 2020 and March 2022. Abnormal CMRI was the presence of any late gadolinium enhancement (LGE) that signifies myocardial fibrosis (LGE positivity), regional wall motion abnormality, or reduced left ventricular ejection fraction (LVEF <55%). A total of 46 patients were included: 38 patients with DMD and eight with BMD. Cardiac abnormality was seen in 23 (50%) patients. LGE was more common than impaired LVEF in DMD (16, 42.1%), while impaired LVEF was more common in BMD (5, 62.5%). LGE was most frequently found in lateral wall (18/19) followed by inferior (6/19), septal (5/19), anterior (2/19), and apex (1/19). Among the various clinicodemographic parameters, only age (r = 0.495, P = 0.002) and disease duration (r = 0.407, P = 0.011) were found to significantly correlate with LGE in patients with DMD. No association was found between the various CMRI parameters and the genotype. The current study highlights the differences in myocardial fibrosis and LV dysfunction between DMD and BMD, along with other CMRI parameters. Notably, a genotype-CMRI correlation was not found in the current cohort, which needs to be further explored.

The cryptic complex rearrangements involving the DMD gene: etiologic clues about phenotypical differences revealed by optical genome mapping

BackgroundDeletion or duplication in the DMD gene is one of the most common causes of Duchenne and Becker muscular dystrophy (DMD/BMD). However, the pathogenicity of complex rearrangements involving DMD, especially segmental duplications with unknown breakpoints, is not well understood. This study aimed to evaluate the structure, pattern, and potential impact of rearrangements involving DMD duplication.MethodsTwo families with DMD segmental duplications exhibiting phenotypical differences were recruited. Optical genome mapping (OGM) was used to explore the cryptic pattern of the rearrangements. Breakpoints were validated using long-range polymerase chain reaction combined with next-generation sequencing and Sanger sequencing.ResultsA multi-copy duplication involving exons 64–79 of DMD was identified in Family A without obvious clinical symptoms. Family B exhibited typical DMD neuromuscular manifestations and presented a duplication involving exons 10–13 of DMD. The rearrangement in Family A involved complex in-cis tandem repeats shown by OGM but retained a complete copy (reading frame) of DMD inferred from breakpoint validation. A reversed insertion with a segmental repeat was identified in Family B by OGM, which was predicted to disrupt the normal structure and reading frame of DMD after confirming the breakpoints.ConclusionsValidating breakpoint and rearrangement pattern is crucial for the functional annotation and pathogenic classification of genomic structural variations. OGM provides valuable insights into etiological analysis of DMD/BMD and enhances our understanding for cryptic effects of complex rearrangements.

A - 45 Duchenne and Becker Muscular Dystrophy: Sibling Case Studies

Abstract Objective Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular condition primarily affecting males. Progressive proximal muscle wasting and weakness is seen and a shortened life span can occur due to cardiac involvement. Becker Muscular Dystrophy (BMD) is a milder form of DMD. Non-progressive cognitive impairment (e.g., lower IQ) in DMD has been well established, while the cognitive profile in BMD is less known. DMD/BMD are caused by mutations in the dystrophin protein. Research suggests that mutations downstream of exon 63 in the DMD gene are associated with poorer cognitive outcomes compared to upstream 1–30. Our cases explore the association between genetic/medical factors upon cognitive and behavioral outcomes, and neuropsychological similarities/differences between DMD and BMD. Method The current sibling case studies include one BMD set (mutations at exon 45–49) and two DMD sets (exon 61–74, and 13, respectively). They are part of a larger IRB-approved research dataset. Notably in DMD set two, the siblings have different biological fathers. Results The BMD siblings have comparable neuropsychological profiles (e.g., below average IQ, academic challenges, attention/executive problems). In DMD set one, one sibling has average intelligence with no academic challenges, while the other sibling has a low average IQ with challenges in math and spelling. In DMD set two, one sibling has intact cognitive functioning, while the other sibling performs well below average across neurocognitive domains. Conclusions Our results indicate variabilities in DMD/BMD, highlighting the contributing role of established factors (e.g., mutation location) and additional non-DMD influences (e.g., genetic contributions from biological father) to understand neuropsychological profiles.

Muscular dystrophy patients show low exercise‐induced blood flow in muscles with normal strength

AbstractObjectiveNeuromuscular evaluation increasingly employs muscle ultrasonography to determine muscle thickness, mean grayscale echointensity, and visual semiquantitative echotexture attenuation. However, these measures provide low sensitivity for detection of mild muscle abnormality. Exercise‐induced intramuscular blood flow is a physiologic phenomenon, which may be impaired in mildly affected muscles, particularly in dystrophinopathies, and may indicate functional muscle ischemia. We aimed to determine if muscle blood flow is reduced in patients with neuromuscular disorders and preserved muscle strength, and if it correlates with echointensity and digital echotexture measurements.MethodsPeak exercise‐induced blood flow, echointensity, and echotexture were quantified in the elbow flexor muscles of 15 adult patients with Becker muscular dystrophy (BMD) and 13 patients with other muscular dystrophies (OMD). These were compared to 17 patients with Charcot–Marie–Tooth type 1 (CMT1) neuropathy and 21 healthy adults from a previous study.ResultsMuscle blood flow was reduced in all patient groups compared to controls, most prominently in BMD patients (p &lt; 0.0001). Echointensity was similarly increased in all patient groups (p &lt; 0.05), while echotexture was reduced only in muscular dystrophy patients (p ≤ 0.002). In BMD, blood flow correlated with echotexture (Pearson r = 0.6098, p = 0.0158) and strength (Spearman r = 0.5471; p = 0.0370). In patients with normal muscle strength, reduced muscle blood flow was evident in all patient groups (p &lt; 0.001), echotexture was reduced in BMD and OMD (p &lt; 0.01), and echointensity was increased in CMT (p &lt; 0.05).InterpretationMuscle blood flow is a sensitive measure to detect abnormality, even in muscles with normal strength. Increased echointensity may indicate a neurogenic disorder when strength is preserved, while low echotexture suggests a dystrophic disease.

The Dutch Dystrophinopathy Database: A National Registry with Standardized Patient and Clinician Reported Real-World Data.

Duchenne and Becker muscular dystrophy lack curative treatments. Registers can facilitate therapy development, serving as a platform to study epidemiology, assess clinical trial feasibility, identify eligible candidates, collect real-world data, perform post-market surveillance, and collaborate in (inter)national data-driven initiatives. In addressing these facets, it's crucial to gather high-quality, interchangeable, and reusable data from a representative population. We introduce the Dutch Dystrophinopathy Database (DDD), a national registry for patients with DMD or BMD, and females with pathogenic DMD variants, outlining its design, governance, and use. The design of DDD is based on a system-independent information model that ensures interoperable and reusable data adhering to international standards. To maximize enrollment, patients can provide consent online and participation is allowed on different levels with contact details and clinical diagnosis as minimal requirement. Participants can opt-in for yearly online questionnaires on disease milestones and medication and to have clinical data stored from visits to one of the national reference centers. Governance involves a general board, advisory board and database management. On November 1, 2023, 742 participants were enrolled. Self-reported data were provided by 291 Duchenne, 122 Becker and 38 female participants. 96% of the participants visiting reference centers consented to store clinical data. Eligible patients were informed about clinical studies through DDD, and multiple data requests have been approved to use coded clinical data for quality control, epidemiology and natural history studies. The Dutch Dystrophinopathy Database captures long-term patient and high-quality standardized clinician reported healthcare data, supporting trial readiness, post-marketing surveillance, and effective data use using a multicenter design that is scalable to other neuromuscular disorders.

Single-Nucleus RNA Sequencing Unravels Early Mechanisms of Human Becker Muscular Dystrophy.

The transcriptional heterogeneity at a single-nucleus level in human Becker muscular dystrophy (BMD) dystrophic muscle has not been explored. Here, we aimed to understand the transcriptional heterogeneity associated with myonuclei, as well as other mononucleated cell types that underly BMD pathogenesis by performing single-nucleus RNA sequencing. We profiled single-nucleus transcriptional profiles of skeletal muscle samples from 7 BMD patients and 3 normal controls. A total of 17,216 nuclei (12,879 from BMD patients and 4,337 from controls) were classified into 13 known cell types, including 9 myogenic lineages and 4 non-myogenic lineages, and 1 unclassified nuclear type according to their cell identities. Among them, type IIx myonuclei were the first to degenerate in response to dystrophin reduction. Differential expression analysis revealed that the fibro-adipogenic progenitors (FAPs) population had the largest transcriptional changes among all cell types. Sub-clustering analysis identified a significantly compositional increase in the activated FAPs (aFAPs) subpopulation in BMD muscles. Pseudotime analysis, regulon inference, and deconvolution analysis of bulk RNA-sequencing data derived from 29 BMD patients revealed that the aFAPs subpopulation, a distinctive and previously unrecognized mononuclear subtype, was profibrogenic and expanded in BMD patients. Muscle quantitative real-time polymerase chain reaction and immunofluorescence analysis confirmed that the mRNA and protein levels of the aFAPs markers including LUM, DCN, and COL1A1 in BMD patients were significantly higher than those in controls, respectively. Our results provide insights into the transcriptional diversity of human BMD muscle at a single-nucleus resolution and new potential targets for anti-fibrosis therapies in BMD. ANN NEUROL 2024.

Social and emotional alterations in mice lacking the short dystrophin-gene product, Dp71

BackgroundThe Duchenne and Becker muscular dystrophies (DMD, BMD) are neuromuscular disorders commonly associated with diverse cognitive and behavioral comorbidities. Genotype–phenotype studies suggest that severity and risk of central defects in DMD patients increase with cumulative loss of different dystrophins produced in CNS from independent promoters of the DMD gene. Mutations affecting all dystrophins are nevertheless rare and therefore the clinical evidence on the contribution of the shortest Dp71 isoform to cognitive and behavioral dysfunctions is limited. In this study, we evaluated social, emotional and locomotor functions, and fear-related learning in the Dp71-null mouse model specifically lacking this short dystrophin. ResultsWe demonstrate the presence of abnormal social behavior and ultrasonic vocalization in Dp71-null mice, accompanied by slight changes in exploratory activity and anxiety-related behaviors, in the absence of myopathy and alterations of learning and memory of aversive cue-outcome associations.ConclusionsThese results support the hypothesis that distal DMD gene mutations affecting Dp71 may contribute to the emergence of social and emotional problems that may relate to the autistic traits and executive dysfunctions reported in DMD. The present alterations in Dp71-null mice may possibly add to the subtle social behavior problems previously associated with the loss of the Dp427 dystrophin, in line with the current hypothesis that risk and severity of behavioral problems in patients increase with cumulative loss of several brain dystrophin isoforms.