Swallowing dysfunction-dysphagia-is a frequent and debilitating symptom in neuromuscular disorders, leading to malnutrition, cachexia, aspiration pneumonia, and death. Identification of the underlying pathophysiological mechanisms is important for diagnosis and treatment. As standard assessments have limitations, novel imaging techniques are needed. We here studied the utility of real-time MRI and quantitative muscle ultrasound for characterizing dysphagia in two different neuromuscular disorders. This prospective cohort study included 18 patients with inclusion body myositis (IBM, 33% female, age 68.9 ± 7.7 years) and 13 with oculopharyngeal muscular dystrophy (OPMD, 62% female, age 55.9 ± 7.0 years) from two European Neuromuscular research centers (Nijmegen, NL; Göttingen, DE). Swallowing function was studied using real-time MRI (RT-MRI), FEES (flexible endoscopic evaluation of swallowing), and clinical assessments. T1-mapping and quantitative muscle ultrasound (QMUS) were used to analyse tissue properties in swallowing muscles. Outcomes were compared between the two muscle diseases. RT-MRI values were also compared with 22 age- and sex-matched non-myopathic controls. RT-MRI revealed significantly prolonged oral transit times in OPMD vs. controls (difference between means = 581.2 ms, 95% CI 225.9-936.4, p = 0.002). Pharyngeal transit time was significantly prolonged in IBM vs. controls (difference between means = 1132.8 ms, 95% CI 482.2-1783, p = 0.001). A cricopharyngeal bar as a well-established morphological indicator of dysphagia was identified in 80% of patients with IBM compared with 53% in OPMD. Fatty degeneration of the tongue in OPMD significantly correlated between MRI-T1 values and ultrasound echogenicity (Spearman's ρ = -0.52, p = 0.005). ROC revealed excellent discrimination between diseases by combining RT-MRI, T1-mapping and QMUS (AUC = 0.95, 95% CI 0.86-1.00), while FEES and clinical assessments failed to differentiate specific patterns of dysphagia. This study supports the value of novel MRI and ultrasound techniques for clinical use by identifying the pathophysiology and severity of impaired swallowing. Differentiating the phenotypes of dysphagia can aid in the diagnosis and treatment of affected patients. RT-MRI and QMUS may serve as outcome measures for swallowing in clinical trials.

Angiotensin II (AngII) receptor blockers (ARBs) are medications that lower systolic blood pressure (BP) by antagonizing the AngII type 1 receptor (AT1). However, ARBs have documented or suspected therapeutic properties in diseases not caused by high BP including diabetes, muscular dystrophy, chronic obstructive pulmonary diseases (COPD) and Alzheimer's disease. ARBs have multiple pleiotropic properties; 'on-target' AT1-dependent pleiotropy can arise from blocking AngII-AT1 binding in non-BP-regulating cells or via inverse or biased ARB-AT1 agonism. In addition, activation of cells lacking AT1 by ARBs suggests the presence of AT1-independent 'off-target' pleiotropy, whereas supratherapeutic properties in the absence of further BP lowering have also been reported. Herein, to determine how ARB pleiotropy and supratherapeutic properties can be modelled invitro or exvivo, we perform a retrospective analysis of the literature that characterizes their maximal human plasma concentration, Cmax, which is higher and more likely to trigger pleiotropy than their low nanomolar, AT1-blocking concentrations. Our findings suggest that Cmax is variable and heterogeneous between ARBs, with upper range values as high as 13.6 micromolar in the case of valsartan and lower range values as low as 0.4 micromolar for candesartan. We propose that modelling of ARB pleiotropy be conducted at these concentrations, whereas higher concentrations will mimic supratherapeutic applications.

Delandistrogene moxeparvovec is a recombinant adeno-associated virus rhesus isolate serotype 74 vector-based gene therapy that addresses the absence of functional dystrophin in Duchenne muscular dystrophy (DMD). EMBARK is a phase 3, two-part, crossover, randomized, placebo-controlled trial assessing the safety and efficacy of delandistrogene moxeparvovec (single intravenous dose 1.33 × 1014vector genomes/kg) in ambulatory male patients with DMD aged 4 to < 8years; N = 125. One-year results demonstrated the manageable safety of delandistrogene moxeparvovec, consistent with previous clinical trials. The primary endpoint (change from baseline in North Star Ambulatory Assessment [NSAA] total score at 52weeks compared with placebo) did not meet statistical significance. However, key secondary endpoints, comprising timed function tests, suggested slowing or stabilization of disease progression with delandistrogene moxeparvovec, which could become increasingly evident over longer periods of time. We report 2-year follow-up of safety and functional outcomes in patients receiving delandistrogene moxeparvovec in EMBARK part1. As a result of the crossover study design, 2-year functional outcomes of patients receiving delandistrogene moxeparvovec in part1 of EMBARK were compared, by pre-specified analysis, with a matched propensity score-weighted external control (EC). At 2years, EMBARK patients showed statistically significant benefit versus the EC cohort in functional outcomes prognostic for delaying loss of ambulation (NSAA, Time to Rise, 10-m Walk/Run), demonstrating sustained stabilization or slowing of disease progression. Delandistrogene moxeparvovec micro-dystrophin expression and sarcolemmal localization were maintained over 64weeks. No new safety signals were observed between week52 and week104. Between baseline and week104, there were no treatment-related deaths, study discontinuations due to adverse events, or clinically significant complement-mediated adverse events. At 2years, stabilization or slowing of DMD disease progression was observed in ambulatory male patients with DMD aged 4 to < 8years receiving delandistrogene moxeparvovec versus a matched EC cohort. Safety was consistent with EMBARK 1-year data and manageable with appropriate monitoring. GOV: NCT05096221.

Clinical and Genetic Characterization of CAPN3-Related Limb-Girdle Muscular Dystrophies in an Egyptian Cohort.

Heterogeneous expression of the laminin-binding O-mannosyl glycan on α-dystroglycan in pancreatic cancer cell line MIA PaCa-2 and the correlation with cell properties.

cPLA2 in musculoskeletal and autoimmune diseases: Molecular mechanisms and therapeutic insights.

Does Motor Function Differ According to the Site of Mutation in Duchenne Muscular Dystrophy?

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that affects dystrophin production, characterized by progressive neuromuscular dysfunction, often accompanied by osteoporosis. We prospectively evaluate the effects of bisphosphonates on bone micro-architecture reflected by trabecular bone score (TBS) of patients with DMD. A total of 72 male children or adolescents with DMD were included, with a mean age of 9.5 ± 1.8 years. They were divided into bisphosphonate treatment groups and control group based on areal bone mineral density (aBMD) and history of fragility fractures. Patients in bisphosphonate treatment groups randomly received intravenous infusion of 5 mg zoledronic acid (ZOL) annually or oral 70 mg alendronate weekly for three years. All patients took calcium 600 mg plus 125 IU vitamin D daily and calcitriol 0.25 μg every other day. TBS at the lumbar spine (LS) and aBMD at the LS, femoral neck (FN) and total hip (TH) were measured annually by dual-energy X-ray absorptiometry. Serum levels of β-isomerized carboxy-telopeptide of type I collagen and alkaline phosphatase were measured annually during the follow-up. A total of 25 (86.2%), 26 (92.9%) and 13 (86.7%) patients in the ZOL, alendronate and control groups completed the study. After 3 years, TBS Z-score increased from baseline by 1.13 (p < 0.01), 0.68 (p < 0.01) and 0.26 (p > 0.05) in the ZOL, alendronate and control groups, respectively. The mean increase in TBS Z-score from baseline was significantly greater in both bisphosphonate treatment groups compared to the control group (p < 0.05). No significant difference was found between the ZOL and alendronate groups. LS, FN and TH aBMD increased by 35.8%, 23.7% and 34.5% in the ZOL group (all p < 0.01 vs. baseline and control group) and by 21.5%, 29.3% and 25.0% in the alendronate group (all p < 0.05 vs. baseline and control group). LS and FN aBMD Z-scores increased by 1.56 and 1.63 in the ZOL group (all p < 0.01 vs. baseline), by 1.32 and 1.48 in the alendronate group (all p < 0.05 vs. baseline). Bisphosphonates demonstrated a favourable safety profile during the study period. This relatively long-term study confirms that zoledronic acid and alendronate are beneficial to improve micro-architecture reflected by TBS and aBMD of children or adolescents with DMD.

Duchenne muscular dystrophy, caused by mutations in the DMD gene encoding dystrophin, is a severe progressive muscle-wasting disorder characterized by impaired muscle regeneration. We reveal the alternative splicing of transcription factor E2-alpha (encoding transcription factors E12 and E47) plays a pivotal role in myogenic progression. E47 is highly expressed in proliferating myoblasts and promotes proliferation, whereas E12 is upregulated during differentiation and drives myogenic commitment. Mechanistically, we identify the nuclear splicing factor polypyrimidine tract binding protein 1 as a key regulator of transcription factor E2-alpha mutually exclusive alternative splicing. Polypyrimidine tract binding protein 1 levels decline during normal myoblast differentiation, facilitating the switch from E47 to E12. However, in Duchenne muscular dystrophy patients and mdx mice, polypyrimidine tract binding protein 1 remains aberrantly elevated, resulting in dysregulated E47/E12 ratios (increased E47 and decreased E12), which disrupts myogenic differentiation and impairs muscle regeneration. Therapeutically, polypyrimidine tract binding protein 1 knockdown restores myoblast differentiation, enhances muscle repair, and improves muscle function in mdx mice. Furthermore, we demonstrate that dergrasyn, a deubiquitinase inhibitor, induces polypyrimidine tract binding protein 1 degradation, restores myogenic differentiation, and ameliorates dystrophic pathology. Our findings identify polypyrimidine tract binding protein 1 as a potential therapeutic target for Duchenne muscular dystrophy and highlight modulation of transcription factor E2-alpha splicing as a promising strategy to restore muscle regeneration.

Exon skipping antisense oligonucleotides (AONs) have been extensively studied as a promising method of treating Duchenne muscular dystrophy (DMD), yet the clinical efficacy of the conditionally approved AONs still remains low. Using phosphorothioated locked nucleic acid/2'-fluoro-RNA AONs, we aimed to increase AON efficiency by employing skeletal muscle-targeting conjugate molecules, cholesterol, and docosanoic acid to improve the biodistribution of the therapeutic. While conjugate molecules were able to induce high levels of skipping in an in vitro model, invivo studies in the hDMDdel52/mdx mouse model caused adverse symptomatic and systemic immune reactions, up to and including death, with little to no appreciable increase in exon skipping. Our study cautions against using these AON conjugates in an animal model due to severe toxicity.

Population-Based Investigation of DMD Genotype and Neurodevelopmental Concerns in Duchenne Muscular Dystrophy.

ConspectusTranscytosis, traditionally regarded as biological, constitutes an intrinsic and powerful pathway for macromolecule transport across endothelial and epithelial barriers. The emerging concept of Enhanced Transcytosis and Retention (ETR) is distinct from passive extravasation or tissue leakiness. It recasts nanocarrier delivery as an orchestrated chain of interfacial equilibria in which encoded surface chemistry directs receptor recognition, active barrier crossing, and subsequent accumulation within target tissues. Here, we delineate the chemical framework underpinning ETR-mediated delivery, emphasizing that the chemical identity of a nanocarrier, i.e., its surface functional groups, coordination motifs, hydration shell, reactive ligands, surface free energy, and biocorona, dictates a hierarchical sequence of interactions. To enable ETR access, we propose a triadic interaction model among the nanocarrier, an endogenous or engineered protein-based material, and a specific cellular receptor. This architecture represents a fundamental shift from conventional two-entity protein-adsorption frameworks, converting inherently stochastic protein deposition into a chemically programmable, design-driven active transport process. At the inner interface (between nanocarrier and protein material), surface functional groups, roughness, and topology determine the composition, orientation, and reactivity of a given biomolecule, such as endogenous or engineered proteins. At the outer interface (protein-cell receptor), these nanocarrier-protein complexes engage cell receptors through amino acid sequence-specific molecular recognition, topological complementarity, hydrogen-bond cooperativity, and electrostatic complementarity that collectively trigger ETR active access. Such an ETR framework, first exemplified in solid tumors (e.g., pancreatic cancer and triple negative breast cancer), now extends to diverse pathological contexts including the blood-brain barrier and dystrophic muscle. By viewing ETR drug delivery through a chemical lens, this manuscript integrates structure-reactivity principles with biological transport, providing a molecularly actionable framework for otherwise inaccessible tissues. Noteworthy, artificial intelligence (AI) guided protein engineering, using strategies such as point mutagenesis and noncanonical amino-acid substitution, will enable the creation of highly optimized and artificial ligands that assemble ETR-activating units with molecular-level precision.

LAMA2 Triple Variant in a Mexican Child with Congenital Muscular Dystrophy.

Abstract Background and Objectives Muscle‐Eye‐Brain disease (MEB) is a dystroglycanopathy that belongs to the congenital muscular dystrophies. Central nervous system manifestations include congenital brain abnormalities, neurodevelopmental delay, and epilepsy, making it a rare but important cause of developmental and epileptic encephalopathy. This systematic review aims to explore all current literature data regarding clinical and electroencephalographic features of MEB cases with epilepsy. Materials and Methods We conducted a literature review of previously published cases of patients with MEB and epilepsy in the PubMed and Scopus databases in the English language, focusing on seizure semiology and electroencephalographic features. Results We included 52 studies with 80 patients. The clinical spectrum of patients with MEB is broad, including hypotonia at birth, ocular symptoms, delay of motor milestones, and intellectual disability. Serum creatine kinase levels are significantly elevated (median value 1600 IU/L). POMGnT1 mutation is, by far, the most common mutation in MEB patients, reported in 38.8% of cases, followed by GMPPB (10%), FKTN, POMT2, or DPM2 mutations (less than 10%, respectively). Epilepsy is a common feature, with onset usually in the first 6 months of life. Absences are the most common seizure type (58.8% of patients), followed by generalized tonic–clonic (33.8%) and focal seizures (21.3%). Patients present with drug‐resistant epilepsy in approximately one fourth of cases (21.3%). Electroencephalogram (EEG) shows focal or multifocal discharges in approximately half of the cases, with a predominance over frontal or temporal regions. Slow and disorganized EEG background activity is commonly observed in 92.9% of cases. Conclusion Epilepsy is a common feature in MEB patients; its age of onset is usually in the first months of life, and it is often drug‐resistant. It can manifest with all seizure types, with absences being the most common type. EEG shows focal or multifocal discharges with a slow and disorganized EEG background. The POMGnT1 mutation is the most common in MEB patients with epilepsy. A clear understanding of the electroclinical patterns in MEB patients can contribute to improved diagnostic precision and management.

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.

Mutations in the SNUPN gene, which encodes snurportin-1, a nuclear import adaptor for U1 small nuclear ribonucleoproteins (snRNP), have recently been implicated in limb-girdle muscular dystrophy, attributed to disrupted pre-messenger RNA splicing in skeletal muscle. U1 small nuclear ribonucleoproteins play a vital role in pre-messenger RNA splicing, a process essential for transcript fidelity and the regulation of gene expression across tissues. However, the impact of SNUPN mutations on the CNS remains unclear. We identified pathogenic variants in the SNUPN gene in two families with spinocerebellar atrophy. One patient exhibited mild changes in skeletal muscle, while the other did not. To elucidate the pathogenic mechanisms, nuclear transport of the mutated snurpotin-1, and its interaction with importin beta were analysed in vitro. Then, we generated a knock-in mouse carrying the patients' variants and assessed its motor function and cerebellar morphology in vivo. Furthermore, we analysed U1 snRNP localization and RNA splicing in cerebellar Purkinje cells by both RNA- and single-cell RNA sequencing. Mutated snurportin-1 displayed impaired nuclear transport and reduced binding to importin beta. The knock-in mouse mimicking the compound heterozygous variants exhibited cerebellar ataxia, cerebellar atrophy and dendritic abnormalities in Purkinje cells. Abnormal RNA splicing and reduced expression were observed in many genes related to neuronal development and synaptic organization in Purkinje cells, leading to an immature cytoskeleton and reduced secretion of sonic hedgehog. The defects in Purkinje cells caused secondary abnormalities in granule cell migration and interneuron development. Our findings suggest that snurportin-1 plays a critical role in cerebellar development through U1 snRNP-mediated RNA processing and that its dysfunction may contribute to spinocerebellar ataxia. These results expand the clinical spectrum of SNUPN-related disorders beyond skeletal muscle and highlight splicing dysregulation as a potential mechanism underlying cerebellar atrophy.

Proteomics-guided exome re-analysis identifies bi-allelic variants in the nuclear envelope LEMD2 gene, expanding its phenotypic spectrum. Created in BioRender. Pauper, M. (2026) https://BioRender.com/xamvo92.

Response to the Letter Regarding "If Becker Muscular Dystrophy Initially Manifests with Heart Disease and Rhabdomyolysis, Neurological Work-up is Imperative".

A multidisciplinary care approach is fundamental in neuromuscular diseases due to their complex characteristics, requiring a timely diagnosis and optimization of the management plan. Diagnostic yield has greatly improved in the last years, due either to powerful genetic-molecular techniques or increased attention of physicians to red flags that can indicate a neuromuscular disorder for prompting a specialist evaluation. The improvement of standards of care and the availability of effective disease-modifying treatments such as enzymatic replacement therapies, RNA-based and also gene therapy, but also steroid therapy for Duchenne muscular dystrophy, have expanded life expectancy of patients, also improving their quality of life, although at the same time leading to new and more complex phenotypes. It also means that, for diseases with infantile onset, greater number of patients reach adulthood, this making it necessary to establish a “transition” process from pediatric to adult care centers for structured management plans and to mitigate the risk to be lost. We have now developed in Tuscany a program for transition involving two pediatric reference centers for rare and neuromuscular disorders (IRCCS Meyer, Florence and IRCCS Stella Maris, Calambrone, Pisa) and the adult reference center for neuromuscular disorder of Pisa, University Hospital, Ospedale Santa Chiara, ERN-NMD affiliated). This program, started in 2023, includes combined and integrated evaluation of adolescent-juvenile patients from childhood neuropsychiatrists and pediatricians and adult neurologists who, in exchanging their expertise, accompany affected people in this comprehensive journey for ensuring suitable standards of care. In total, 70 neuromuscular patients transitioned from the pediatric centers to the adult center, among them 11 affected by Duchenne muscular dystrophy and 30 by Becker muscular dystrophy, for which clinical and investigation data have been extensively collected for better understanding of disease natural history and responses to interventions and treatment.

Nesprin-2 and its paralog Nesprin-1 are subunits of LINC complexes that are essential for brain development. To position the nucleus for neuronal migration, Nesprin-2 interacts with the motors kinesin-1 and dynein, which are recruited by the adapter Bicaudal D2 (BicD2), but the molecular details of these interactions are elusive. Here, structural models of minimal Nesprin-2/BicD2 complexes with 1:2 and 2:2 stoichiometry were predicted using AlphaFold and experimentally validated by mutagenesis, binding assays, and single-molecule biophysical studies. The core of the binding site is formed by spectrin repeats of Nesprin-2, which form an α-helical bundle with BicD2 that is structurally distinct from the Rab6/BicD2 and Nup358/BicD2 complexes. Such structural differences could fine-tune the motility of associated dynein and kinesin-1 motors for these transport pathways. Furthermore, the Nesprin-2 fragment interacts with full-length BicD2 and activates dynein/dynactin/BicD2 complexes for processive motility, suggesting that no additional components are required to reconstitute this transport pathway. Interestingly, either one or two Nesprin-2 molecules can bind to a BicD2 dimer and activate BicD2/dynein/dynactin complexes for processive motion, resulting in similar speed and run lengths. The BicD2/dynein binding site is spatially close but does not overlap with the kinesin-1 recruitment site, thus both motors may interact with Nesprin-2 simultaneously. Several mutations of Nesprin-1 and 2 that cause Emery-Dreifuss muscular dystrophy are found in the motor-recruiting domain and may alter interactions with kinesin-1 and BicD2/dynein, consistent with the abnormally positioned nuclei found in patients with this disease.