Search Results (762)

Pediatric-onset neuromuscular diseases (NMDs) represent a clinically and genetically heterogeneous group of rare disorders, often posing significant diagnostic challenges due to overlapping phenotypes. Next-generation sequencing (NGS), particularly whole-exome sequencing (WES), has transformed the diagnostic landscape; however, its clinical utility varies across phenotypic subgroups. We conducted a combined retrospective–prospective cohort study that included 100 pediatric patients with suspected neuromuscular disorders evaluated at a tertiary referral center between 2015 and 2025. Patients were stratified into seven clinically defined diagnostic categories prior to genetic testing. NGS-based diagnostics (primarily WES) were performed following initial clinical and targeted evaluations. Diagnostic yield and predictors of a positive genetic result were analyzed using univariate and multivariable statistical approaches. A molecular diagnosis was established in 71% of patients, including 64% with pathogenic/likely pathogenic variants and 7% with clinically consistent variants of uncertain significance. Diagnostic yield varied significantly across disease categories (p < 0.001), reaching near-complete rates in well-defined phenotypes such as congenital myasthenic syndromes, neuropathies, and metabolic myopathies, while markedly lower yield was observed in unclassified cases (38.2%). Multivariable logistic regression identified disease group as the only independent predictor of diagnostic success (B = −0.436, p = 0.001). Frequently implicated genes included DMD, RYR1, and LAMA2, reflecting a predominance of structural and excitation–contraction coupling defects. NGS demonstrates high diagnostic utility in pediatric neuromuscular disorders, particularly when applied in a phenotype-driven framework. Diagnostic performance is strongly influenced by the degree of clinical definition prior to testing, highlighting the continued importance of expert phenotyping in the genomic era. Full article

Background/Objectives: The Individualized Neuromuscular Quality-of-Life Questionnaire (INQoL) is a widely used measure of quality of life in patients with various neuromuscular diseases. This study aimed to adapt and test the validity and reliability of this measure in Hungarian patients with neuromuscular disease. Methods: According to the widely accepted method of validation, we first translated the original INQoL version into Hungarian, and then a native English speaker translated it back into English to test its validity. Following a pretest procedure, the INQoL was administered to 80 patients with various muscular diseases and 30 age-matched controls. The internal consistency and test–retest reliability were assessed. Concurrent validity was measured using the 36-item Short Form Survey (SF-36) questionnaire. Results: For all INQoL subscales, Cronbach’s alpha was above 0.7, demonstrating the reliability of the subscales. The highest Cronbach alpha value was for the Weakness subscale (0.983) and the lowest for the Treatment subscale (0.794). The intraclass correlation coefficient test values ranged from 0.810 (Treatment) to 0.988 (Pain), indicating excellent test–retest reliability. There was a strong correlation between the SF-36 Physical Function and multiple INQoL subscales, including Weakness (r = 0.754, p < 0.001), Fatigue (r = 0.704, p < 0.001), Activities (r = 0.744) p < 0.001, Independence (r = 0.791 p < 0.001), Body Image (r = 0.714 p < 0.001), and overall Quality of Life (r = 0.742 p < 0.001). Conclusions: Our findings indicate that the Hungarian-language adaptation of the questionnaire possesses adequate reliability and construct validity for assessing the quality of life in patients with muscular disorders. Full article

Background/Objective: Playing-related musculoskeletal disorders are highly prevalent among bowed string musicians and may impair performance and career longevity. This study aimed to evaluate the effects of motor control-based interventions on pain, functional outcomes, range of motion, and neuromuscular parameters in musicians playing bowed string instruments. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines. PubMed, Scopus, Web of Science Core Collection, and Cochrane CENTRAL were searched from inception to October 2025, and the search was updated before resubmission to identify any newly published eligible studies. Eligibility screening, full-text assessment, data extraction, and risk-of-bias assessment were independently verified by a second reviewer. Risk of bias was assessed according to study design using RoB 2 for the randomized controlled trial and ROBINS-I for non-randomized interventional studies. Results: Four interventional studies met the inclusion criteria. Three studies reported improvements in pain-related outcomes or PRMD severity, and three reported improvements in functional outcomes. One study demonstrated improved cervical range of motion, whereas one study reported altered shoulder girdle muscle activation patterns with reduced playing comfort. Overall, the certainty of the available evidence was limited by small sample sizes, non-randomized designs, and risk of bias. Conclusions: Limited evidence suggests that motor control-based interventions may be associated with improvements in pain and playing-related function in bowed string musicians; however, the evidence base remains small and methodologically heterogeneous, and conclusions should be interpreted with caution. Full article

Background: Overactive bladder (OAB) is a common functional disorder in paediatric populations and is associated with significant psychological burden and impaired quality of life. Although oxybutynin is widely used as first-line pharmacological therapy, a substantial proportion of children exhibit incomplete symptom control or limited tolerability. Emerging evidence suggests that targeting metabolic dysfunction, oxidative stress, and neuromuscular excitability may provide additional therapeutic benefit. This retrospective observational study evaluated the clinical impact of an adjunctive nutraceutical formulation containing myo-inositol, microlipodispersed magnesium, folic acid, and vitamin C (LEVIGON™ PRO, Sanitpharma; Milan, Italy) in children with OAB receiving oxybutynin. Methods: Medical records of children diagnosed with OAB were retrospectively reviewed. After applying inclusion and exclusion criteria, 120 patients aged 5–15 years were included and allocated to two groups based on documented treatment: oxybutynin plus LEVIGON™ PRO (Group A, n = 60) or oxybutynin alone (Group B, n = 60). The primary outcome was complete daytime urinary continence at Day 112. Secondary outcomes included weekly incontinence episodes, voiding frequency, bladder wall thickness, uroflowmetry parameters, and Patient Perception of Bladder Condition (PPBC) scores. An exploratory subgroup analysis was performed in 34 children with impaired fasting glucose (ifg), assessing fasting glucose, insulin, and homa-ir. results: by day 112, complete daytime continence was achieved in 61.7% of patients in group a and 48.3% in group b (absolute risk difference 13.4%; nnt ≈ 7.5; p = 0.14). across secondary endpoints, the combination therapy group showed significantly greater longitudinal improvements (group × time interaction, p < 0.05), including reductions in weekly incontinence episodes, voiding frequency, post-void residual volume, and ppbc scores, as well as increases in mean voided volume, qmax, and reductions in bladder wall thickness. in the ifg subgroup, greater reductions in fasting glucose, fasting insulin, and homa-ir were observed in group a compared with group b (p < 0.01). Both treatments were well tolerated, with no serious adverse events reported. conclusions: adjunctive nutraceutical therapy combined with oxybutynin was associated with greater improvements in several clinically relevant secondary outcomes in children with OAB, with a favourable tolerability profile. Although the primary endpoint did not reach statistical significance, the overall pattern of findings may suggest a possible additive benefit; however, these findings may be influenced by residual confounding inherent to the retrospective observational design. Therefore, the results should be considered hypothesis generating and require confirmation in prospective randomized controlled trials. Full article

Emery–Dreifuss muscular dystrophy (EDMD) is a rare inherited neuromuscular disorder within the spectrum of nuclear envelope diseases, classically characterized by early musculo-tendinous contractures, slowly progressive myopathy, and cardiac involvement dominated by conduction disease and arrhythmias, with variable evolution toward cardiomyopathy and heart failure. This narrative review provides a comprehensive and clinically actionable synthesis of cardiovascular manifestations across EDMD genotypes and phenotypes, outlining pragmatic diagnostic and therapeutic pathways for real-world care. A targeted literature search was performed in PubMed, Embase, and Web of Science, focusing on studies addressing cardiovascular involvement in EDMD. Relevant original studies, case series, registries, guideline documents, and high-quality reviews were selected and synthesized narratively, with particular emphasis on diagnostic strategies, risk stratification, and management approaches. Cardiac involvement in EDMD encompasses a broad and heterogeneous spectrum, including atrial disease and conduction disturbances, ventricular arrhythmias, dilated cardiomyopathy, thromboembolic complications, and sudden cardiac death. Phenotypic expression varies according to the underlying genetic substrate, with distinct atrial- and ventricular-dominant trajectories. Early recognition and structured cardiovascular surveillance are essential to guide timely intervention, including anticoagulation, device therapy, and heart failure management. Despite growing awareness, significant gaps remain in risk prediction and standardized management strategies. EDMD represents a paradigmatic model of cardiomyopathy characterized by prominent electrical instability and systemic involvement. A structured, genotype- and phenotype-informed approach centered on early surveillance, proactive arrhythmia and thromboembolic risk management and timely device therapy may improve clinical decision-making in real-world settings. Future perspectives include the integration of precision medicine and the development of gene- and pathway-targeted therapies, with the potential to shift from symptomatic management toward disease-modifying strategies. Full article

Background/Objectives: Radial extracorporeal shock wave therapy (rESWT) is used to treat neuromuscular disorders such as spasticity, but the mechanisms by which rESWT modulates muscle tone remain incompletely understood. One proposed mechanism involves mechanical perturbation of the neuromuscular junction (NMJ), particularly destabilization of acetylcholine receptor (AChR) clusters in the postsynaptic membrane. Because rapsyn knockout mice are not viable, Caenorhabditis elegans (C. elegans) provides an alternative model for studying neuromuscular signaling, expressing the rapsyn homolog RPY-1, a postsynaptic scaffolding protein involved in AChR organization at the NMJ. This study examined whether loss of RPY-1 alters locomotor responses of C. elegans to radial extracorporeal shock wave (rESW) exposure. Methods: Wild-type worms and rpy-1 knockout worms (rpy-1-KOs) were exposed to defined numbers of rESWs. Locomotor behavior was quantified using automated tracking of parameters describing speed, trajectory and body-wave dynamics. Behavioral responses were analyzed both as absolute values and relative to genotype-specific baseline values. Results: rESW exposure produced pronounced alterations in locomotor behavior across all parameters analyzed. Absolute values revealed baseline differences between genotypes. After normalization to genotype-specific baseline values, wild-type worms and rpy-1-KOs responded similarly to moderate exposure levels. At higher exposure levels, genotype-dependent differences became more apparent. Locomotor impairment was most pronounced immediately after exposure but improved during the subsequent recovery period of three hours. Conclusions: rESWs induced strong but largely reversible locomotor alterations in C. elegans during the first hours after exposure. Loss of the rapsyn homolog RPY-1 modified these responses, particularly at higher exposure levels. These findings indicate that RPY-1 influences behavioral responses to rESW exposure, while direct effects on NMJ structure or AChR organization cannot be determined from the present data. 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

X-linked dystrophin-deficient muscular dystrophy (DD-MD) is an uncommon neuromuscular disorder in cats. We described an adult male cat with chronic tongue protrusion, dysphagia, muscle hypertrophy, and a history of rhabdomyolysis associated with anesthesia. Clinical pathology revealed markedly increased CK activity, muscle histopathology demonstrated a dystrophic phenotype, and an absence of dystrophin protein was confirmed by immunofluorescent staining. Whole genome sequencing identified two potential disease-causing variants, including a new missense variant in the DMD gene (c.2207T>C; p.Gln736Arg), which was considered causative of the clinical phenotype. A second variant in the CLIC2 gene was also detected but was considered unlikely to cause myopathic signs. The clinical course remained stable over 1.5 years with supportive management and dietary modification, and no further episodes of rhabdomyolysis occurred. This case expands the known spectrum of feline DMD variants and highlights the value of genetic testing combined with muscle histopathology for diagnosing chronic presentations of MD. Avoidance of inhalant anesthetics may be important in managing affected cats due to the risk of acute muscle injury. Full article

Pompe disease (PD) is a neuromuscular autosomal recessive disorder caused by mutation in the GAA gene, which encodes acid α-glucosidase (GAA), an enzyme responsible for hydrolyzing glycogen to glucose. Deficiency of this enzyme leads to pathological accumulation of glycogen in almost all tissues of the body, with the most pronounced effects in cardiac and skeletal muscle, as well as in the central nervous system. Two major clinical forms of PD are recognized: infantile-onset PD, characterized by almost complete absence of GAA activity and severe cardiomyopathy and neurological abnormalities, and late-onset PD, which primarily presents with impairment of respiratory and motor function. Since 2006, enzyme replacement therapy with recombinant GAA has been used to treat PD, improving survival and quality of life. However, this approach has several limitations: the need for lifelong infusions, the risk of immune responses, and the inability of the enzyme to cross the blood–brain barrier, which is particularly critical for infantile-onset PD. Consequently, alternative strategies are being developed, including gene therapy using adeno-associated virus vectors for GAA delivery to target tissues; these approaches are currently in phase I/II clinical trials. Transplantation of genetically modified hematopoietic stem cells also represents a promising therapeutic strategy, offering a single-intervention treatment with long-lasting effects. This review discusses the molecular mechanisms of PD, current and emerging disease models, and therapeutic approaches, which together open prospects for the development of potentially one-time curative treatments, despite persistent challenges such as immunogenicity and the need for long-term efficacy monitoring. Full article

Abnormal gait associated with neuromuscular and musculoskeletal disorders represents a growing clinical burden, particularly in aging populations. This study presents a modular, low-cost Smart Rehabilitation Walker (SRW) that integrates multimodal sensing and real-time haptic feedback to enable simultaneous gait monitoring and corrective intervention in both clinical and home environments. The system combines force-sensing resistors for bilateral load symmetry assessment, inertial measurement units for fall detection, and surface electromyography (sEMG) for neuromuscular activity monitoring within a closed-loop assistive feedback architecture. A 15-day pilot study involving ten individuals with rheumatoid arthritis and clinically observed neurological gait abnormalities demonstrated measurable improvements in gait biomechanics. The Force Symmetry Index (FSI), calculated using the Robinson symmetry metric, decreased from an average of 0.9691 to 0.2019, corresponding to a 79.26% average reduction in inter-limb load asymmetry. Concurrently, sEMG measurements showed a substantial increase in neuromuscular activation (ΔEMG = 4.28), with statistical analysis confirming a significant improvement across participants (paired t-test: t(9) = 13.58, p < 0.001). To model rehabilitation trajectories, a nonlinear predictive framework based on Gaussian Process Regression achieved high predictive accuracy (R² ≈ 0.9, with a mean RMSE of 0.0385), while providing uncertainty-aware trend estimation. Validation using an independent amyotrophic lateral sclerosis gait dataset further demonstrated the transferability of the analytical pipeline. These results highlight the potential of sensor-enabled assistive walkers as scalable platforms for quantitative gait rehabilitation, adaptive feedback, and long-term mobility monitoring. Full article

Myasthenia gravis (MG) is a rare autoimmune disorder characterized by muscle weakness and fatigue, caused by autoantibodies produced by B-cells that target proteins in the postsynaptic membrane of the neuromuscular junction. Clinical manifestations are heterogeneous and may include diplopia, ptosis, dysarthria, dysphagia, and limb muscle weakness, with severity ranging from mild symptoms to life-threatening myasthenic crisis. Despite advances in diagnostic approaches and the availability of immunomodulatory and biological therapies, there remains a need for an improved understanding of the disease mechanisms and biomarker development in MG. Blood-derived exosomes are small extracellular vesicles that carry proteins, lipids, nucleic acids, and glycoconjugates, and are involved in intercellular communication and the transfer of biological material between cells. Circulating exosomes may reflect aspects of cellular and immune status and have been proposed as a minimally invasive source of biomarkers in various diseases. In this review, we summarize current evidence on the potential role of exosomes in MG, with a focus on their involvement in disease-associated processes and their possible utility as biomarkers, as well as directions for future research. 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

Skeletal muscle differentiation is tightly regulated by membrane potential dynamics and voltage-dependent ion channel activity. Potassium (K⁺) and calcium (Ca²⁺) currents cooperate to orchestrate the transition of myoblasts into fusion-competent myotubes, and alterations in this process are associated with dystrophic phenotypes. Here, we investigated the electrophysiological remodeling accompanying C2C12 myogenesis and the modulatory effects of the polyphenol resveratrol (RES) on calcium voltage-gated channel subunit alpha 1 S (CACNA1S, Cav1.1, L-type) currents. Whole-cell patch-clamp recordings were performed in proliferating and differentiating C2C12 cells to characterize the temporal expression of K⁺ currents and voltage-dependent Ca²⁺ channels (VDCCs). During differentiation, three electrophysiological subpopulations were identified according to K⁺ current profiles: SK4+/EAG−/Kir−, SK4−/EAG+/Kir−, and SK4−/EAG+/Kir+. This sequence paralleled a progressive membrane hyperpolarization from −20 mV to −70 mV, consistent with the physiological maturation of myogenic cells. In C2C12 myocytes, nimodipine-sensitive L-type currents were the only Ca²⁺ conductance observed. Their activation threshold (~−30 mV) and half-activation voltage (V/2 ≈ −12 mV) indicated the co-expression of embryonic and adult Cav1.1 isoforms. Exposure to RES (30 µM, 48 h) produced a depolarizing shift in activation (ΔV/2 ≈ +9 mV) and a reduction in current amplitude across all voltages, consistent with a transition toward the adult splice variant of Cav1.1. These findings suggest that RES promotes electrophysiological maturation of skeletal muscle cells by modulating calcium channel expression and gating behavior. Given its known ability to correct splicing abnormalities in CACNA1S and related genes, resveratrol emerges as a promising pharmacological agent for restoring calcium homeostasis in neuromuscular disorders such as myotonic dystrophy type 1 (DM1). Full article

Sarcopenia is a progressive and multifactorial muscle disorder associated with diminished strength, reduced functional capacity, and increased risk of adverse health outcomes including frailty, falls, and mortality. Despite its clinical burden, the molecular pathogenesis of sarcopenia remains poorly understood, which hinders the development of precise therapeutic strategies. This review examines emerging evidence linking anabolic resistance, mitochondrial dysfunction, neuromuscular instability, and chronic inflammation to impaired regeneration and disrupted proteostasis. While nutritional interventions such as high-quality protein, leucine metabolites, and vitamin D supplementation preserve lean mass, they fail to consistently restore function independently. Although exercise remains the cornerstone therapy, its benefits are often constrained in patients with multimorbidity or reduced mobility. Given the biological heterogeneity of sarcopenia, there is a need to shift from generic supportive care to stratified, mechanism-based therapy. Emerging omics technologies including transcriptomic, proteomic, and metabolic profiling offer a promising avenue to define molecular endotypes. This will guide the development of precision-based management strategies. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multisystemic disorder characterized by severe, persistent fatigue not alleviated by rest and worsened by minimal exertion, often accompanied by post-exertional malaise (PEM), unrefreshing sleep, cognitive dysfunction, and autonomic disturbances. Despite decades of research, its pathophysiology remains incompletely understood, and skeletal muscle involvement has only recently gained attention. This review aims to provide a historical and pathophysiological synthesis of ME/CFS, emphasizing the pivotal role of skeletal muscle in the onset and persistence of symptoms, and to integrate molecular, cellular, and pathophysiological evidence into a coherent explanatory framework. This is a narrative review of published literature (1990–2025) with critical integration of clinical, biochemical, and experimental data on oxidative stress, mitochondrial dysfunction, Excitation–Contraction (E-C coupling) dysregulation, and muscle secretome alterations in ME/CFS also in relation to post-viral syndromes (e.g., Long COVID). Evidence consistently points to mitochondrial oxidative stress, redox imbalance, impaired Ca²⁺ handling, and altered signaling pathways in skeletal muscle of patients with ME/CFS. Historical milestones show an evolution from psychogenic interpretations toward recognition of ME/CFS as a biological disorder with neuromuscular and metabolic underpinnings. ME/CFS can be interpreted as a skeletal muscle–metabolic disorder characterized by oxidative distress, mitochondrial dysfunction, and impaired energy regulation, leading to the clinical picture of exercise intolerance and post-exertional malaise. Integrating basic and clinical research through a translational approach provides the foundation for new diagnostic tools, targeted therapies, and biomarkers. Full article