Search Results (557)

Background/Objectives: Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder. This retrospective study evaluated the demographic, genetic, and clinical characteristics of children diagnosed with DMD before age three to understand early clinical presentation profiles. Methods: The cohort included 198 boys diagnosed with DMD before three years of age between January 2020 and July 2025. Medical records, serum creatine kinase (CK) levels, language milestones via Denver II criteria, and multi-exon deletion maps were retrospectively evaluated. Results: Regarding the diagnostic entry pathways, the initial clinical trigger that led to medical investigation was incidental hyperCKemia in 91.4% of cases. Regardless of the presentation trigger, a definitive, confirmed diagnosis was established in all 198 cases: 196 patients (99.0%) were securely confirmed via genetic testing (MLPA or sequencing), while 2 patients (1.0%) with negative genetic panels were confirmed via muscle biopsy demonstrating a complete absence of dystrophin expression. Genetic analysis revealed deletions in 77.8% of patients, predominantly multi-exon deletions clustered in the distal hotspot region. Independent ambulation occurred at a median age of 16 months, and 14.6% achieved walking after 18 months. Delayed language development was observed in 29.8% of patients. Conclusions: Our findings indicate that early childhood DMD is characterized not only by early muscle involvement but also by prominent neurodevelopmental features. These findings underscore the value of early CK screening in young boys and support integrating standardized neurodevelopmental surveillance into early DMD care. Full article

Individuals with Duchenne muscular dystrophy (DMD) are prone to nutritional imbalances, and zinc deficiency may contribute to impaired bone health. This study evaluated serum zinc status and the effects of oral supplementation on bone parameters in DMD. In this quasi-experimental before-and-after study, 34 patients were assessed at three time points over eight months. Eligible participants who met the inclusion criteria and agreed to participate received the proposed interventions during routine follow-up at the Neurology outpatient clinic. Anthropometry, dietary intake, bone mineral density (BMD), bone mineral content (BMC), and serum zinc were measured; supplementation (5–15 mg/day) was provided for four months. Baseline zinc deficiency was observed in 36.7% of participants. No significant overall changes were detected. Stratified analyses revealed a modest increase in total body BMD among individuals with adequate baseline BMD (p = 0.02). As this finding emerged from a subgroup analysis, it should be interpreted cautiously, and the potential contribution of physiological growth to the observed change cannot be excluded. In addition, zinc-deficient participants showed a significant rise in serum zinc levels (p = 0.008). These findings suggest that the response to zinc supplementation may vary according to baseline nutritional and skeletal status and underscore the relevance of micronutrient monitoring in individuals with DMD. Trial registration: The trial was also registered in the Brazilian Registry of Clinical Trials under the code RBR-7cfdxm, approved on 14 June 2018. Full article

The DMD gene is best known for its product dystrophin, a large rod-shaped protein that plays a critical role in muscular membrane strength and integrity. Mutations affecting dystrophin lead to Duchenne muscular dystrophy, a fatal X-linked disease characterized by muscular weakness and breakdown. In addition to the full-length dystrophin product that is most often associated with disease, the DMD gene also encodes multiple shorter isoforms of dystrophin with diverse functions. One isoform in particular, Dp71, has been increasingly found to play a wide variety of roles throughout the body. In this narrative review, we consolidate the numerous studies on Dp71 to provide a comprehensive foundation for future work. We outline and summarize the current state of knowledge on the role of Dp71 in the brain, the retina, and skeletal muscles, identifying current knowns and unknowns in the field. We also explore Dp71-based therapies currently being tested in the pre-clinical landscape and identify potential limitations for clinical translation. Full article

In skeletal muscle, there are two main progenitor populations crucial for growth, maintenance, and repair: satellite cells (SCs) and interstitial cells, of which fibro-adipogenic progenitor cells (FAPs) are the best characterized fraction. However, data on how specific diseases or physiological conditions affect the biological properties of FAPs are limited. In this review we analyze data obtained with FAPs purified from skeletal muscle tissue from Duchenne muscular dystrophy (both human patients and mdx mice models), hindlimb functional unloading (rats), and type 2 diabetes (T2DM, human patients). Here we discuss how disuse/disease affect FAP’s properties: the adaptive metabolic remodeling; the alterations in adipogenic differentiation in vitro; the possible role of particular subpopulations of FAPs in disease development; the role of FAPs in cell-to-cell interactions during skeletal muscle degeneration and regeneration. Current research has outlined how different physiological and pathological conditions alter FAPs’ behavior, highlighting FAPs as a potential target for clinical protocols aimed at treating or mitigating skeletal muscle disorders. Future studies should clarify how FAPs govern cell-to-cell interactions during skeletal muscle degeneration and regeneration, offering critical insights for therapies targeting diverse neuromuscular diseases. Full article

RNA-based therapeutics are reshaping the treatment landscape for skeletal muscle disorders by enabling modulation of RNA processing or direct correction of disease-causing alleles. In Duchenne muscular dystrophy (DMD), four antisense oligonucleotides—eteplirsen, golodirsen, viltolarsen, and casimersen—have received FDA approval; these phosphorodiamidate morpholino oligomers (PMOs) induce exon skipping to restore the reading frame and enable expression of internally truncated dystrophin. Beyond splice switching, RNA therapeutics include RNase H-active gapmers and steric-blocking antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) that mediate post-transcriptional gene silencing, and RNA-guided gene-modifying technologies such as CRISPR systems that can reframe or repair endogenous alleles. Despite major progress in DMD, broader clinical impact remains constrained by inefficient delivery to skeletal and especially cardiac muscle, the need for repeat administration for most modalities, and safety considerations that limit dose escalation and durability. Next-generation approaches aim to overcome these barriers through peptide- or antibody-conjugated oligonucleotides that enhance cellular uptake and tissue distribution, alternative chemistries with improved stability and potency, and viral or non-viral platforms for durable splice modulation. In parallel, CRISPR-based strategies—including base and prime editing—offer the prospect of one-time correction, while raising important questions regarding delivery, immunogenicity, editing specificity, and long-term safety. This review synthesizes recent advances in antisense and gene-modifying strategies for skeletal muscle and highlights practical priorities for translation, including improved muscle/heart delivery, controllable safety mechanisms, scalable manufacturing, and standardized biomarker-to-clinical outcome relationships. Full article

Background/Objectives: Duchenne muscular dystrophy (DMD) is a rare progressive neuromuscular disorder associated with increasing care demands. Despite the critical role of caregivers, their physical activity (PA) levels and health-related quality of life (HRQoL) have not been sufficiently investigated. This study aimed to compare PA levels and HRQoL between caregivers of children with DMD and caregivers of typically developing children. Methods: This cross-sectional observational study included 44 individuals: caregivers of children with DMD (n = 22) and caregivers of typically developing children (n = 22). The 36-Item Short-Form Health Survey (SF-36) was used for assessing HRQoL and the International Physical Activity Questionnaire—Short Form (IPAQ-SF) for determining PA levels. Results: IPAQ-SF-derived metabolic equivalent of task (MET) values and PA levels were similar between the groups (DMD caregivers: 1744.63 ± 1163.22, controls: 1945.09 ± 1042.12; p > 0.05). Caregivers of children with DMD demonstrated significantly poorer scores in several SF-36 domains, including vitality, social functioning, role limitations due to physical problems, bodily pain, and mental health (p < 0.05), with the largest difference observed in role limitations due to emotional problems (DMD caregivers: 45.27 ± 28.33, controls: 84.83 ± 24.63; p < 0.05). Physical functioning and general health perception scores were comparable (p > 0.05). Conclusions: Caregivers of children with DMD experience substantial impairments in multiple HRQoL domains, particularly those related to psychosocial well-being and pain, despite comparable PA levels and physical functioning. These findings suggest that reduced HRQoL is not directly explained by PA alone and highlight the need for multidisciplinary interventions targeting psychological health, pain management, and social well-being. Full article

Duchenne muscular dystrophy (DMD) remains a major challenge in genetic medicine due to the difficulty of achieving durable, body-wide restoration of dystrophin in post-mitotic muscle tissues. Although current therapies—including exon skipping and micro-dystrophin gene replacement—have demonstrated clinical feasibility, their benefits are limited by incomplete efficacy, mutation specificity, and the need for repeated or high-dose interventions. These limitations highlight the need for strategies capable of directly and permanently correcting the underlying genetic defect. Recent advances in genome editing have positioned CRISPR-based technologies as promising candidates for this objective. Rather than functioning as a single approach, gene-editing platforms encompass a spectrum of strategies—including exon deletion, exon reframing, base editing, and prime editing—each with distinct advantages depending on the mutational context. In particular, the emergence of precision editing tools has enabled controlled nucleotide-level modifications, expanding the range of correctable mutations while reducing reliance on double-strand DNA breaks. In this review, we adopt a comparative and translational perspective to evaluate gene-editing strategies for DMD. We examine how different approaches align with specific mutation types, summarize key findings from preclinical studies, and analyze the major barriers to clinical implementation, including delivery efficiency, immune responses, editing durability, and genomic safety. We further discuss emerging innovations in editing technologies and delivery systems that aim to address these limitations. Collectively, this work reframes gene editing as a decision-oriented and application-driven therapeutic framework. Continued integration of advances in genome engineering, delivery platforms, and muscle biology will be essential to translate these technologies into safe, effective, and durable treatments capable of altering the clinical trajectory of DMD. Full article

Duchenne muscular dystrophy (DMD) is a fatal rare disease caused by dystrophin deficiency, with no effective clinical treatments available to date. Using mdx mice as a model, this study investigated the therapeutic efficacy and interaction of mini utrophin (a truncated utrophin) and Yes-associated protein (YAP) delivered via recombinant adeno-associated virus (rAAV). Results showed that mini utrophin was efficiently expressed in mdx mouse skeletal muscle, significantly increased phosphorylated YAP (p-YAP) levels, restored the expression of dystrophin–glycoprotein complex (DGC) components (α/γ-sarcoglycans), reduced serum creatine kinase (CK) leakage, alleviated pathological damages such as central nucleation and inflammatory infiltration, and comprehensively improved grip strength, treadmill endurance, and pole climbing ability in mice. However, the co-overexpression of YAP completely antagonized these therapeutic effects, resulting in no improvement in pathological phenotypes or motor function of mdx mice. This study confirms that mini utrophin can effectively reverse DMD-related phenotypes, while excessive YAP activation abrogates its therapeutic efficacy, suggesting that precise regulation of YAP activity is required in DMD treatment and providing experimental basis for optimizing gene therapy strategies. Full article

Background/Objectives: Duchenne muscular dystrophy (DMD) is a fatal, progressive neuromuscular disorder caused by mutations in the dystrophin gene, leading to the absence of functional dystrophin protein. As the largest gene in the human genome, the DMD locus is highly susceptible to mutations, contributing to a prevalence of approximately 1 in 3800–6300 live male births worldwide. This review aims to provide a comprehensive and critical synthesis of current and emerging therapeutic strategies for DMD. Methods: We conducted a narrative review of the literature, integrating findings from clinical trials, regulatory approvals, and preclinical studies. We categorized therapeutic approaches into mutation-agnostic and mutation-specific strategies, with emphasis on the mechanism of action, clinical progress, and translational limitations. Results: Current standards of care, including corticosteroids and supportive interventions, remain foundational in disease management. Mutation-specific approaches such as exon skipping and adeno-associated virus (AAV)-mediated gene replacement can restore dystrophin expression, although clinical benefit remains variable and is influenced by factors such as mutation type, delivery efficiency, and durability. Emerging genome editing strategies offer the potential for permanent correction but face significant challenges related to delivery, safety, and scalability. Emerging mutation-agnostic therapies targeting inflammation, fibrosis, and membrane instability provide broader applicability but do not directly address the underlying genetic defect. Across modalities, key limitations include modest functional outcomes, safety concerns, and variability in clinical trial endpoints. Conclusions: The DMD therapeutic landscape is rapidly evolving, and future progress will likely depend on optimizing delivery platforms, improving durability, and integrating combination strategies to address the multifaceted nature of disease progression. Full article

Skeletal muscle is vital for movement and metabolism, and its dysfunction underpins disorders like muscular dystrophy and sarcopenia, severely impacting life quality. In these diseases, various cell death pathways are pivotal, driving core pathological features such as fiber loss and chronic inflammation. This study reviews the central role of cell death in skeletal muscle diseases, and analyzes its roles and mechanisms in genetic muscle disorders such as Duchenne muscular dystrophy (DMD), glycogen storage diseases (GSD), mitochondrial myopathies, as well as acquired muscle disorders such as idiopathic inflammatory myopathy, sarcopenia, rhabdomyolysis, and myasthenia gravis (MG). We also explore the potential of cell death-related molecules as biomarkers and discuss emerging therapeutic strategies that target these pathways, aiming to provide new insights for diagnosis and treatment. Full article

Duchenne muscular dystrophy (DMD) is a fatal X-linked neuromuscular disorder caused by mutations in the dystrophin gene. Prime editing is a versatile genome editing technology capable of introducing precise nucleotide changes without generating double-strand DNA breaks, making it a promising approach for correcting pathogenic point mutations. In this study, we applied prime editing to modify mdx-4cv and mdx-5cv mutation-equivalent sites in mouse C2C12 myoblasts in vitro. Initial editing efficiencies were unexpectedly low and were associated with the presence of a 5′-TTCT-3′ motif within engineered prime editing guide RNAs (epegRNAs). epegRNA designs containing this motif exhibited reduced prime editing efficiency, whereas silent substitution eliminating the motif significantly improved editing outcomes, indicating that specific sequence features within epegRNAs can influence editing performance. Rational redesign of epegRNAs to remove this motif substantially enhanced editing efficiency, achieving up to 20% modification at the 4cv target site using an NGG PAM and 21% editing at the 5cv locus using an NGAG PAM. These findings highlight an important sequence-dependent constraint in epegRNA design and provide practical guidance for optimizing prime editing strategies targeting Dmd mutations in vitro. Full article

Background: Cardiomyopathy is a major cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). We evaluated whether N-terminal pro–brain natriuretic peptide (NT-proBNP) identifies severe systolic dysfunction and assessed its diagnostic performance. Methods: Male patients with genetically confirmed DMD and established cardiomyopathy were included if NT-proBNP measurement and echocardiographic ejection fraction (EF) were available within one month. Severe systolic dysfunction was defined as EF < 40%. Clinical, cardiac, and respiratory variables were analysed. ROC analysis with bootstrap validation and exploratory logistic regressions was performed. Results: NT-proBNP levels were significantly higher in patients with EF < 40% (median 843 vs. 81 pg/mL). A cut-off >200 pg/mL identified severe systolic dysfunction with 90.5% sensitivity and 90.9% specificity (AUC 0.96, 95% CI 0.88–1.00). During 24 months of follow-up, five deaths occurred. NT-proBNP showed moderate discrimination for mortality (AUC 0.79) and was associated with mortality in exploratory analysis. Conclusions: NT-proBNP was associated with severe systolic dysfunction in Duchenne cardiomyopathy and may complement imaging. Prospective validation is warranted. Full article

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. Full article

The dystrophin gene encodes multiple dystrophin isoforms with tissue-specific functions, including several shorter isoforms expressed in the central nervous system and retina. While Duchenne muscular dystrophy (DMD) has historically been characterized as a primary myopathy resulting from loss of the full-length dystrophin Dp427, increasing clinical evidence indicates that dysfunction of shorter dystrophin isoforms contributes to significant extramuscular pathology, including retinal disease. In particular, loss of the Dp71 isoform has been implicated in retinal inflammation, blood–retinal barrier breakdown, and pathological angiogenesis. In this study, we investigated whether low-level residual expression of Dp71 is sufficient to mitigate retinal inflammation in the mdx3Cv mouse model, which displays reduced—but not absent—expression of multiple dystrophin isoforms. Western blot analysis revealed that mdx3Cv retinas express approximately 4% of wild-type Dp71 protein levels. Despite this marked reduction, mdx3Cv mice did not exhibit the inflammatory phenotype previously observed in Dp71-null mice. Retinal VEGF protein levels and VEGF receptor (FLT-1 and KDR) mRNA expression were preserved, while VEGF mRNA levels were modestly reduced. Furthermore, expression of inflammatory markers ICAM-1 and ALOX5AP, leukocyte adhesion to retinal vasculature, Aquaporin-4 expression, and BRB permeability to albumin were all comparable to wild-type littermates. Together, these findings demonstrate that minimal residual expression of Dp71 is sufficient to preserve retinal vascular homeostasis and prevent inflammatory and permeability defects in the mdx3Cv retina. These results further suggest that partial dystrophin restoration—at levels achievable with current exon-skipping or gene-based therapies—may be adequate to prevent or attenuate retinal pathology in DMD, providing a realistic and clinically relevant therapeutic target. Full article

Background: Duchenne muscular dystrophy (DMD) is a rare, disabling, and life-threatening X-linked recessive disorder caused by mutations in the dystrophin gene. The current standard of care is treatment with corticosteroids, which aim to decrease inflammation-induced muscle damage and delay disease progression. Here, we aim to describe clinical, genetic, and diagnostic characteristics and evaluate current management practices of DMD patients in the Kingdom of Saudi Arabia (KSA). Methods: This was an ambispective (prospective and retrospective) observational multicenter study evaluating characteristics of patients aged 1–14 years with genetically confirmed DMD in the KSA. The variables of interest were demographics, genetic mutations, clinical characteristics, and initial management. The relationship between the age at diagnosis, initial management plan (standard of care), and age at initiation of treatment on disease outcomes was also evaluated. Results: A total of 226 patients (181 in the retrospective part and 45 in the prospective part) were enrolled. The most common type of genetic mutation was large deletions (134 patients, 59.3%). The median age of first symptom was 2.7 years (IQR: 2.0–4.6 years) and the median age at diagnosis was 7.0 years (IQR: 4.8–8.5 years). Among these patients, the most common initial symptoms were difficulty in walking (87.7%) and waddling gait (41%). The initial management plan for DMD patients involved medication (75.6%) and physical therapy (71.0%). The most frequently prescribed initial medications were vitamin D (82%) and corticosteroids (62.3%). In total, 6/226 patients (2.6%) received ataluren; they all had identified nonsense mutations. The median age of corticosteroid initiation was 7.1 years (IQR: 5.7–8.7). The median age at loss of ambulation (LoA) was 9.8 years (IQR: 8.0–11.4 years) in the non-treated patients; it was 10.1 years (IQR: 9.3–11.2 years) in the steroid-only group and 10.8 years (10.8, 10.8) in the combined ataluren and steroid treatment group. Discussion: Age of diagnosis and age of treatment initiation is relatively late in the KSA. However, early diagnosis and early treatment onset is associated with better clinical outcomes, mainly a delay in LoA. Therefore, there is an urgent need for raising awareness and enhancing early screening in the KSA. Full article