Search Results (566)

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

Growth impairment is a clinical manifestation frequently observed in pediatric patients with cardiomyopathy associated with various inherited disorders, including RASopathies, lysosomal storage diseases, neuromuscular disorders, and metabolic conditions. In this narrative review, we explored the genetic and pathophysiological mechanisms underlying the development of both growth and myocardial impairment in Noonan syndrome (NS)—the most common RASopathy—Duchenne and Becker muscular dystrophies, Pompe disease, mucopolysaccharidoses, and mitochondrial diseases. For each condition, we described the cardiac and growth phenotypes, focusing on epidemiology, clinical implications, and disease-specific therapeutic strategies. In the era of precision medicine, innovative etiologic treatments targeting the underlying molecular mechanisms have emerged. Therefore, elucidating the molecular pathways responsible for growth impairment in pediatric inherited cardiomyopathies remains essential for optimizing multidisciplinary management and improving patient outcomes. Full article

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease (NMD) caused by loss-of-function mutations in the DMD gene. RNA-based therapies, especially antisense oligonucleotides (ASO)-mediated exon skipping and adenosine deaminase acting on RNA (ADAR)-guided RNA editing, have emerged as complementary approaches that modulate pre-mRNA splicing or correct transcripts without altering genomic DNA. Current phosphorodiamidate morpholino oligomer (PMO) drugs targeting exons 51, 53, and 45 provide mutation-class-specific benefit. At the same time, next-generation delivery strategies (e.g., peptide-conjugated PMOs (PPMOs), antibody–oligonucleotide conjugates (AOC), and endosomal-escape vehicles) aim to improve skeletal, cardiac, and diaphragm exposure. In parallel, RNA editing strategies offer a route to correct select nonsense or missense variants at the base level and may, in principle, restore near-native dystrophin expression. Meaningful translation of these modalities requires predictive large-animal models. A genome-edited microminipig (MMP) bearing DMD exon-23 mutations faithfully recapitulates hallmark features of human DMD. That includes early locomotor deficits, elevated serum creatine kinase (CK) and cardiac troponin T, progressive myocardial fibrosis, and a decline in left-ventricular ejection fraction (LVEF), while maintaining a manageable lifespan of approximately 30 months suitable for long-term studies. In particular, the MMP model provides a practical platform for addressing the persistent challenge of efficient therapeutic delivery to the heart and diaphragm through longitudinal dosing, imaging, and biopsy. In this review, we synthesize clinical progress in exon skipping, outline the promise of RNA editing, and integrate recent insights from Duchenne muscular dystrophy model for microminipigs (DMD-MMPs) as an advanced surrogate for preclinical development and translational evaluation. Full article

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by loss-of-function mutations in the dystrophin gene, leading to progressive muscle degeneration, motor decline, respiratory compromise, and cardiomyopathy. Diagnosis typically occurs in early childhood following recognition of motor delays, markedly elevated creatine kinase, and confirmatory genetic testing. Over the past decade, the therapeutic landscape for DMD has expanded substantially, evolving from exclusively supportive care to patient-centric multifaceted treatment paradigms, including corticosteroids, mutation-specific therapies, small molecule disease-modifying approaches, and gene replacement strategies. Despite these advances, no currently available therapy restores full-length dystrophin or completely halts disease progression. This review provides a clinically oriented comprehensive overview of currently Food and Drug Administration (FDA)-approved medications for DMD, with particular emphasis on corticosteroids, exon-skipping therapies, nonsense mutation readthrough agents, recently approved gene therapy, and select ongoing gene therapy trials. We summarize mechanisms of action, clinical efficacy, safety considerations, regulatory status, and highlight the challenges of integrating these therapies into longitudinal care. Through illustrative clinical vignettes, we highlight the real-world complexity of treatment selection, shared decision-making, and longitudinal care planning in contemporary DMD management. Full article

Duchenne muscular dystrophy (DMD) causes progressive skeletal, respiratory and cardiac muscle weakness in affected males. Most DMD patients develop scoliosis following loss of ambulation. This narrative review describes recommendations for the management of scoliosis in DMD patients using a review of the current literature evidence and a consensus review by the DMD Care UK Spinal Surgery Working Group. Advances in medical treatments have improved life expectancy for DMD patients. Spinal bracing is not effective in preventing the deterioration of scoliosis. Seating and wheelchair adaptations can provide postural support. The multidisciplinary assessment of patients with DMD requiring treatment for scoliosis is reviewed, with particular focus on bone, cardiac and respiratory health. The indications, surgical techniques, and type of spinal instrumentation for surgical management for progressively severe scoliosis with or without pelvic obliquity are discussed. Anaesthetic techniques, intraoperative neuromonitoring, perioperative care, and postoperative management in the ICU are discussed for the optimal management of DMD patients undergoing surgery to correct spinal deformity. Finally, regional and holistic functional assessments, patient satisfaction and long-term health, quality of life, and life expectancy for DMD patients undergoing treatment for spinal deformity are reviewed. Full article

Muscle biopsy has long been regarded as the cornerstone for diagnosing pediatric muscular disorders; however, it is invasive and may be limited by sampling error and inconclusive histopathological findings. This study aimed to evaluate whether whole-exome sequencing (WES) can effectively replace muscle biopsy as a first-line diagnostic approach in children with suspected neuromuscular disorders. Between January 2018 and December 2025, we prospectively enrolled 47 pediatric patients presenting with clinical features suggestive of muscular disorders at a tertiary medical center in Taiwan. The cohort included patients with suspected muscular dystrophies (n = 21), congenital myopathies (n = 23), and multiplex ligation-dependent probe amplification (MLPA)-negative Duchenne muscular dystrophy (DMD; n = 3). All patients underwent WES as the initial diagnostic test without prior muscle biopsy. Trio-based analysis using parental samples was performed in 29.8% of cases. Variant interpretation followed the American College of Medical Genetics and Genomics (ACMG) guidelines. WES identified a definitive molecular diagnosis in 72.3% of patients (34/47). Diagnostic yields varied by subgroup: 100% (3/3) in MLPA-negative DMD, 71.4% (15/21) in muscular dystrophies, and 69.6% (16/23) in congenital myopathies. Pathogenic or likely pathogenic variants were detected in 31 distinct genes, including COL6A1 and COL6A3, which are associated with Ullrich congenital muscular dystrophy. Notably, 58.8% of diagnosed patients (20/34) received molecular diagnoses that differed from their initial clinical impression, encompassing conditions such as ZSWIM6-associated neurodevelopmental disorders, GJB2-related hearing loss, OCRL-associated Lowe syndrome, and various metabolic or syndromic disorders. In all three MLPA-negative DMD cases, WES identified point mutations amenable to mutation-specific therapies. No patient required a muscle biopsy for diagnostic confirmation during the study period. First-tier WES demonstrates high diagnostic utility in pediatric muscular disorders while avoiding invasive muscle biopsy. The high rate of diagnostic reclassification underscores the substantial phenotypic overlap between primary neuromuscular diseases and other neurological or systemic conditions. These findings support the early implementation of genetic testing to enable accurate diagnosis and timely initiation of targeted therapies. Full article

Background: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by the absence of functional dystrophin, leading to progressive muscle degeneration, inflammation, and alterations in the central nervous system. The sustained inflammatory response in DMD increases glial activation and the release of tumor necrosis factor alpha (TNF-α), which contributes to muscle fiber damage. Here, we investigated the anti-inflammatory and neuroprotective effects of Etanercept, a TNF-α receptor-blocking therapeutic, on the spinal cord of MDX mice, a widely used model of DMD. Methods: Adult male MDX and control C57BL/10 mice received vehicle or Etanercept (3, 6, or 12 mg/Kg, intraperitoneally (i.p.)) every 72 h for two weeks, along with daily gait assessment. At the end of treatment, flow cytometry and immunolabeling analyses were performed in the lumbar spinal cord. Results: Etanercept at 12 mg/Kg reduced astrogliosis and microglial activation; restored synaptic markers, including synaptophysin, glutamic acid decarboxylase 65 (GAD-65), and vesicular glutamate transporter 1 (VGLUT-1); and decreased pro-inflammatory cytokines. The treatment reduced GFAP+/TNF-α+ astrocytes and significantly downregulated Th1 lymphocyte polarization in treated MDX mice. These cellular effects were accompanied by improvements in locomotor function. Conclusions: Together, our findings indicate that TNF-α blockade by Etanercept exerts neuroprotective and anti-inflammatory actions in the spinal cord of dystrophic mice, providing new insights into the impact of TNF-α signaling on neuroinflammatory processes in DMD. Full article

Background/Objectives: Recombinant adeno-associated virus (AAV) vectors have revolutionized gene therapy for monogenic diseases such as Duchenne muscular dystrophy (DMD). However, high systemic doses required for muscle transduction cause a spectrum of toxicities ranging from transient hepatic inflammation to fatal multi-organ failure leading to death. These adverse events have reshaped the risk–benefit considerations for gene therapy in DMD. Methods: We conducted a narrative review describing complications associated with AAV-mediated gene therapies in the DMD field. PubMed and Clinicaltrials databases were used to search for peer-reviewed manuscripts published between 1987 and 2025. Publicly available abstracts and press releases were also used to describe AAV-mediated adverse events that have been discovered. Priority was given to large prospective cohorts, meta-analyses, and high-impact publications. Results: We outlined the mechanistic basis of AAV toxicity—spanning innate and adaptive immune activation, vector–host interactions, transgene overexpression, and host vulnerability—and discussed their therapeutic implications for DMD. We also highlighted ongoing strategies for vector re-design, immune modulation, patient selection, and regulatory adaptation, aiming to improve efficacy with safety in the next generation of muscular dystrophy gene therapies. Conclusions: Patient safety remains the number one priority in the AAV-mediated gene therapies field. Achieving long-term benefits requires continued optimization of existing vectors, implementation of strict criteria for patient selection, and regulation of immune responses, with close collaboration and transparent dialog among scientists, clinicians, and regulatory agencies, informed by both successful cases as well as tragic deaths reported in the fields of neuromuscular diseases. Full article

Background/Objectives: Cardiomyopathy (CM) is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD) patients. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, is implicated in various cardiovascular diseases. However, the role of ferroptosis in DMD-CM remains unexplored. Methods: Here, we used dystrophin and utrophin double-knockout (mdx:utr^−/−) mice as a model that exhibits cardiac pathological phenotypes similar to those seen in DMD patients to investigate the potential role of ferroptosis. Results: We observed an increased level of iron deposition and lipid peroxidation in the hearts of mdx:utr^−/− mice. Live/Dead viability assays revealed that mdx:utr^−/− cardiomyocytes exhibited greater susceptibility to ferroptosis than WT cardiomyocytes both at baseline and upon exposure to ferroptosis inducers. We also used mdx:utr^−/− mice with a heterozygous sarcolipin (SLN) knockout background (sln^+/−) to investigate the effect of SLN reduction on ferroptosis susceptibility in DMD-CM. Notably, ferroptosis was significantly suppressed in cardiomyocytes from mdx:utr^−/−:sln^+/− mice (p < 0.01). Western blot analysis confirmed the upregulation of transferrin receptor 1 (TfR1) and 15-lipoxygenase-1 (15LOX1), along with the downregulation of heme oxygenase-1 (HMOX-1) and ferroptosis suppressor protein 1 (FSP1) in mdx:utr^−/− hearts, while glutathione peroxidase 4 (GPX4) levels remained unchanged. A similar pattern of alterations in ferroptosis-related biomarkers was observed in human heart samples from DMD patients compared to healthy controls. Conclusions: Our results provide direct evidence that ferroptosis contributes to the pathology of DMD-CM and suggest that reducing SLN expression and inhibiting ferroptosis may represent potential therapeutic strategies for this condition. Full article

Muscle degeneration is the hallmark of muscular dystrophies—genetically heterogeneous disorders traditionally approached through the lens of molecular pathogenesis or symptomatic management in isolation. Here, we present a deliberately interdisciplinary synthesis that bridges molecular genetics, clinical phenotyping, and evidence-based orthopedic decision-making to address a significant critical gap: the lack of genotype-informed, function-oriented frameworks for musculoskeletal complications. We re-evaluate disease entities—not only by their molecular etiology (e.g., DMD, LMNA, DUX4 dysregulation), but through the prism of orthopedic manifestations as diagnostic gateways and therapeutic milestones. For instance, early rigid spine in LMNA-related dystrophy is not merely a sign of contracture, but a red flag demanding cardiac risk stratification before surgical planning, in alignment with current consensus. Similarly, scoliosis management in Duchenne muscular dystrophy is discussed through quantitative decision thresholds (Cobb angle ≥ 20–30°, FVC ≥ 30–35%) derived from long-term outcome studies, rather than general clinical recommendations. Critically, we confront challenges posed by disease-modifying therapies: patients now survive into their 30s and 40s, yet develop novel, therapy-exacerbated orthopedic phenotypes (e.g., steroid-induced osteoporosis, atypical spinal rigidity). Therefore, we argue that precision orthopedics—tailored surveillance, genotype-stratified intervention timing (e.g., D4Z4 repeat-guided monitoring in FSHD, and realistic functional goal-setting (e.g., scapular arthrodesis for overhead function)—should become the gold standard of care. For example, desminopathies may show marked phenotypic variability even within the same mutation. Our review thus serves not only as a molecular overview, but as a practical roadmap for neurologists, geneticists, orthopedic surgeons, and rehabilitation specialists seeking to translate genomic insights into durable functional outcomes. Full article

Nonsense mutations, responsible for ~11% of gene lesions causing human monogenic diseases, introduce premature termination codons (PTCs) that lead to truncated proteins and nonsense-mediated mRNA decay (NMD). In the central nervous system (CNS), these mutations drive severe, progressive neurological conditions such as spinal muscular atrophy, Rett syndrome, and Duchenne muscular dystrophy. Readthrough therapies—strategies to override PTCs and restore full-length protein expression—have evolved from early aminoglycosides to modern precision tools including suppressor tRNAs, RNA editing, and CRISPR-based platforms. Yet clinical translation remains hampered by inefficient CNS delivery, variable efficacy, and the absence of personalized stratification. In this review, we propose a translational framework—the 4 Ds of Readthrough Therapy—to systematically address these barriers. The framework dissects the pipeline into Detection (precision patient identification and biomarker profiling), Delivery (engineered vectors for CNS targeting), Decoding (context-aware molecular correction), and Durability (long-term safety and efficacy). By integrating advances in machine learning, nanocarriers, base editing, and adaptive trial designs, this roadmap provides a structured strategy to bridge the translational gap. We advocate that a synergistic, modality-tailored approach will transform nonsense suppression from palliative care to durable, precision-based cures for once-untreatable neurological disorders. Full article

Skeletal muscle injury triggers inflammatory response, of which the accumulation of intramuscular monocytes/macrophages is a prominent feature. Macrophages in injured muscle comprise both blood monocytes-derived infiltrating macrophages, which are recruited through CCR2 signaling, and pre-existing muscle resident macrophages, which are established during embryogenesis and maintained until adulthood through self-renewal proliferation. During regenerative acute muscle injury, infiltrating monocytes/macrophages are heterogeneously activated in a temporal dynamic, responding to the changing microenvironment in injured muscle and contributing to the complete injury repair. Injury-associated monocytes/macrophages recede with the completion of muscle injury repair. In contrast, injury-associated monocytes/macrophages persist in dystrophic muscle of Duchenne muscular dystrophy (DMD), likely accounting for persistent inflammation and progressive fibrosis of DMD muscle. We review here the current knowledge on monocyte/macrophage infiltration and activation in both acutely injured skeletal muscle and dystrophic muscle with subsequent discussion of the potential therapeutic implication in treating muscular dystrophy. Full article

Background: Although Duchenne muscular dystrophy (DMD) is primarily characterized as a skeletal muscle-wasting disorder, the resulting pathophysiological changes extend to multiple non-muscle tissues and organ systems. Among these, renal and urinary tract dysfunctions have been reported, albeit in relatively few studies, as potential complications in DMD patients, sometimes occurring from an early age. Importantly, as life expectancy improves, the incidence of renal impairment is also expected to increase. This narrative review summarizes the available evidence on kidney involvement in DMD and discusses the associated biomarkers of renal dysfunction within the context of multisystem disease progression. Methods: The review draws on data from both human and animal studies and analyzes published evidence to explore kidney involvement in DMD, with a focus on clinical manifestations, biomarkers of renal dysfunction, and potential pathogenic mechanisms. Results: Available data indicate a close association between cardiac and renal dysfunction, particularly in patients with advanced-stage DMD. The review explores potential underlying mechanisms of renal impairment, including intrinsic dystrophin deficiency in the kidney, secondary effects of cardiovascular complications, and the nephrotoxic impact of drug therapies, highlighting renal function as an active determinant of clinical risk. Conclusions: While cardiac function monitoring is already a cornerstone of multidisciplinary care for this multisystem disease, systematic assessment of renal function should also be implemented, with implications for clinical management and drug safety. Moreover, the risk of drug-induced nephrotoxicity warrants attention in both clinical management and the development of novel therapeutic strategies for DMD. Full article

Muscle regeneration following injury reveals a striking paradox: the same phenomenon, fiber branching, can serve as both a beneficial adaptation in healthy muscle and a pathological hallmark in disease. In healthy muscle, branched fibers emerge as an adaptive response to extreme mechanical loading, redistributing stress, enhancing hypertrophy, and protecting against injury. Conversely, in conditions such as Duchenne Muscular Dystrophy, excessive and complex branching contributes to mechanical weakness, increased susceptibility to damage, and progressive functional decline. This review explores the dichotomy of fiber branching in muscle physiology, synthesizing current research on its molecular and cellular mechanisms. By understanding the paradoxical nature of fiber branching, we aim to uncover new perspectives for therapeutic strategies that balance its adaptive and pathological roles to improve outcomes for muscle diseases. Full article

Background: Duchenne muscular dystrophy (DMD) results from pathogenic variants in the DMD gene, one of the most significant and most mutation-prone genes in the human genome. Although global mutation registries are well developed, genetic data from Central Asian populations remain extremely limited, leaving essential gaps in regional epidemiology and in the understanding of genotype–phenotype patterns. Methods: We conducted a retrospective analysis of patients with genetically confirmed dystrophinopathy in Kazakhstan. Variants were identified using multiplex ligation-dependent probe amplification (MLPA) for exon-level copy number alterations and next-generation sequencing (NGS) with Sanger confirmation for sequence-level changes. All variants were classified under ACMG guidelines. Statistical modelling incorporated mutation-class grouping, exon-hotspot mapping, reading-frame status, CPK stratification, chi-squared association testing, Spearman correlations, Kaplan–Meier ambulation survival curves, and multivariable logistic and Cox regression. Results: multi-exon deletions were the predominant mutation class, with a marked concentration within the canonical hotspot spanning exons 44–55. Recurrent deletions affecting exons 46–50 and 45–50 appeared in several unrelated patients. NGS confirmed severe protein-truncating variants, including p. Lys1049* and p. Ser861Ilefs*7. Phenotypic severity followed a consistent hierarchy: hotspot-associated deletions and early truncating variants showed the earliest loss of ambulation, whereas splice-site variants and duplications demonstrated the mildest courses. CPK levels correlated with the extent of genomic involvement, though extreme elevations did not consistently predict early functional decline. Regression models identified hotspot localization and out-of-frame effect as independent predictors of ambulation loss. Conclusions: This study provides the first statistically modelled characterisation of DMD gene mutations in Kazakhstan. While the mutational landscape largely mirrors global patterns, notable variability in clinical severity suggests the presence of population-specific modifiers. Integrating comprehensive molecular diagnostics with statistical-genetics approaches enhances prognostic accuracy and supports the development of mutation-targeted therapeutic strategies in Central Asia. Full article