Journal of neuromuscular diseases最新文献

Myasthenia Gravis (MG) is a chronic autoimmune neuromuscular condition that significantly impacts patients' lives. Whilst psychosocial challenges are increasingly recognised as important in understanding the lived experience of patients, insight into these experiences during periods of clinical stability remains underexplored. This qualitative study explores the psychological and social aspects of living with MG through thematic analysis of semi-structured interviews with eight adults from a specialist MG care clinic in London, all considered clinically stable for at least three months. Data were derived from participants initially interviewed about their day-to-day experience of physical symptoms to inform development of a symptom monitoring tool. As psychosocial themes emerged strongly but remained unanalysed, this paper presents a secondary analysis focusing on psychosocial themes. Three overarching themes emerged: (1) coping with adaptation - including the burden of planning, struggles to accept diagnosis, therapeutic challenges and fear of the future; (2) social and identity disruption - involving changes in self-image, social withdrawal, and occupational challenges; and (3) emotional and psychological impact - highlighting negative emotions and cognitive fatigue. Uncertainty emerged as a meta-theme underpinning all other themes, reflecting, driving, and being created by MG's fluctuating symptoms. Findings suggest that psychological and social challenges underscored by uncertainty persist independently of symptom stability, highlighting the importance of uncertainty-focused interventions and integrated psychosocial support in MG care.

Purpose: Skeletal muscle constitutes 30-40% of total body mass and is now considered an endocrine organ, given its secretion of a variety proteins, metabolites, and cytokines. We have previously shown that the absence of dystrophin in skeletal muscle contributes to lethal systemic stress pathology in the mdx mouse model of Duchenne muscular dystrophy through a mechanism that remains to be identified. Here we searched for secreted protein signaling factors, or myokines, released from dystrophin-deficient skeletal muscle that influence the organism-wide integrated stress response. We performed skeletal muscle extracellular fluid extraction and discovery proteomics for wild-type, mdx, and transgenic mdx mice rescued by expression of a dystrophin construct, all analyzed under basal conditions and following brief scruff restraint stress that causes inactivity in mdx mice.

Major findings: Our analysis demonstrated that skeletal muscle dystrophinopathy is associated with increased expression of numerous proteins in both intact mdx skeletal muscle and extracellular fluid compared to healthy mice. Brief scruff restraint revealed protein candidates with differential abundance in mdx extracellular fluid. Specifically, altered follistatin-like 1 protein and adiponectin secretion in response to scruff stress was shown to be dependent on skeletal muscle dystrophinopathy. The diverse signaling roles of follistatin-like 1 in the cardiovascular, musculoskeletal, and nervous system implicate it as a particularly intriguing myokine candidate regulating the mdx stress response.

Conclusions: Our current study informs on the skeletal muscle secretory profile in mdx following a stressful stimulus and provides new leads to elucidate the mechanism by which mdx skeletal muscle orchestrates inter-organ stress signaling.

The Neuromuscular Disease Network for Canada aims to accelerate research and improve care for individuals living with neuromuscular disorders by connecting basic scientists, clinicians, and trainees nationwide. As part of this mission, the network held its second Basic Research Summer School (May 7-8, 2025, York University, Toronto), integrating patient and caregiver perspectives with advanced scientific sessions and full-day methodological workshops. The program emphasized experimental rigor, reproducibility, and collaboration across research pillars, while launching the Basic Science Trainee Committee and Canada's first national, publicly accessible database of standard operating procedures for muscle research. This trainee-led, reproducibility-focused model of Summer School provides a transferable framework for building standardized preclinical capacity across international neuromuscular disorders research networks.

The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gne^lox/lox gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreER^T2/Rosa-CreER^T2Gne^lox/lox mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreER^T2/+Gne^lox/lox mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gne^lox/lox mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.

Introduction: Temperature-induced aggravation of weakness is a well-known characteristic of demyelinating and motor neuron disorders. We investigated prevalence, frequency, and severity of symptoms during heat and cold exposure in patients with 5q-spinal muscular atrophy (SMA).

Methods: We conducted a longitudinal cohort study systematically assessing temperature-induced symptoms by means of a standardized questionnaire at baseline and after one year in adolescents and adults with SMA types 1-4 and age-matched healthy and disease controls. All patients were treatment-naïve for SMN-augmenting therapies at baseline.

Results: We included 103 patients with SMA types 1-4 (median age 39 years, range 13-67 years), 25 healthy controls and 46 disease controls. Eighty-four (82%) patients with SMA and 24 (52%) disease controls were non-ambulatory. Ninety patients with SMA (87%) reported cold-induced symptoms, primarily as aggravation of weakness (85%, n = 88), i.e., cold paresis. Cold paresis was more prevalent in non-ambulatory patients with SMA (94% vs. 47%) and associated with lower Revised Upper Limb Module (RULM) scores in these patients. Healthy controls did not report cold-induced symptoms, in contrast to the 30 (65%) disease controls who did experience cold paresis. Cold paresis was more prevalent in non-ambulatory patients with SMA compared to disease controls. The prevalence of cold paresis was unchanged after one year of disease-modifying treatment.

Conclusions: Cold paresis is commonly experienced by patients with SMA, particularly those with more severe weakness based on SMA type, ambulatory status, and RULM score. Better understanding of the underlying mechanisms of cold paresis might lead to new symptomatic treatment to preserve motor functionality.Trial registration information: NL72562.041.20 (registered at www.toetsingonline.nl; 26-03-2020).

BackgroundThis study aimed to investigate sleep quality, restless legs syndrome (RLS), and excessive daytime sleepiness in adults with spinal muscular atrophy (SMA) and their relationships with motor function, quality of life (QoL), fatigue, and depression.MethodsWe included 43 adults with SMA (31 non-ambulatory; 11 using non-invasive ventilation) and 43 age- and sex-matched healthy controls (HC). Subjective sleep quality and daytime sleepiness were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS). RLS was diagnosed using the International RLS Study Group diagnostic criteria. Revised Upper Limb Module (RULM), Hammersmith Functional Motor Scale Expanded (HFMSE) and respiratory function, as well as, 36-Item Short Form Health Survey (SF-36), Beck Depression Inventory (BDI) and Fatigue Severity Scale (FSS) were recorded.ResultsSMA patients had significantly worse scores in sleep efficiency domain of the PSQI (0.7 ± 1.0 vs. 0.3 ± 0.6, p = 0.04) as well as in global PSQI score compared to HC (5.5 ± 3.5 vs. 4.0 ± 2.6, p = 0.029). Patients classified as poor sleepers (PSQI > 5) had a higher body mass index (BMI), greater BDI, and ESS scores. No association between global PSQI score and HFMSE or RULM score was observed. Patients classified as poor sleepers had lower total SF-36 score in comparison to good sleepers (53.2 ± 15.4 vs. 69.6 ± 12.3, p < 0.001). RLS was present in five SMA patients (11.6%).ConclusionPoor sleep quality is common in adults with SMA. It contributes to a lower QoL and should be addressed as a part of the standard of care in adults with SMA.

Patient-oriented research is increasingly recognized as an important methodology in health sciences. Benefits of patient engagement include aligning research priorities to those living with health conditions, developing better recruitment strategies and protocols, and integrating findings more meaningfully. However, for research teams to work well with patient-partners, training for all stakeholders is needed. While training exists, none consider the uniqueness of the neuromuscular disease experience. To address this gap, our team of researchers, clinicians, and patient-partners collaborated to increase the capacity for patient-engagement in neuromuscular disease research. Our methods included: 1) conducting a landscape of available resources, and 2) using adult education principles and a backwards design process to develop unique training modules. The result is an online platform with three modules focusing on the neuromuscular disease context, addressing the inclusion, diversity, equity, and accessibility needs of those with neuromuscular diseases, and building teamwork skills. Early evaluation of the first two modules indicates high satisfaction and knowledge gain. Through this process, we have learned about the barriers of patient-oriented research, how to support the required system culture shift, and how to plan for long-term sustainability.

Background: Health plan policies managing neuromuscular disease (NMD) therapies may impose burdensome requirements on patients and providers. While prior research has explored payer restrictions for rare NMD treatments, limited evidence exists on policies specifically governing therapy initiation and reauthorization.

Objectives: To examine initial and reauthorization coverage policies for therapies targeting five NMDs-Duchenne muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, generalized myasthenia gravis, and Lambert-Eaton myasthenic syndrome-across all U.S. state Medicaid programs and leading commercial health plans.

Methods: We constructed a database of coverage decisions issued by 50 states and DC Medicaid programs and 35 major commercial insurers, including both fee-for-service and managed care organizations. We analyzed (1) policy availability and coverage frequency, (2) initial coverage requirements (e.g., subgroup restrictions, step therapy, prescriber type), (3) reauthorization criteria, and (4) approval durations.

Results: Of 1204 potential decisions, 908 (75%) had publicly available policies. Of these, 558 (46%) included reauthorization criteria. Among covered therapies, 96% imposed restrictions beyond FDA label indications. Requirements varied by payer type, NMD, and therapy. Average approval durations were 6 months for initial coverage and 10 months for reauthorization.

Conclusions: Many plans lacked publicly accessible policies, and most covered therapies were subject to restrictive requirements. These barriers-such as step therapy, narrow prescriber criteria, and short approval periods-may delay treatment and disrupt care continuity. Findings underscore the need for greater transparency and reform in prior authorization and pharmacy benefit design to support timely access to NMD therapies.

Background: Understanding treatment patterns in myasthenia gravis (MG) is crucial for clinical practice. However, longitudinal data are limited.

Objective: This study aimed to provide an overview of treatment patterns in different subgroups throughout the disease course.

Methods: All adult patients with acetylcholine receptor (AChR), muscle-specific kinase (MuSK), or seronegative MG enrolled in the Dutch-Belgian myasthenia registry were included. AChR-MG patients were classified into early-onset (EOMG) (≤50 years) and late-onset (LOMG) (>50 years) MG. Mixed-effects regression was used to compare differences between the different subgroups.

Results: A total of 506 patients were included (147 AChR EOMG, 265 AChR LOMG, 26 MuSK, and 94 seronegative MG patients). Data were available within a year of diagnosis for 84 patients. Most patients initially started treatment with pyridostigmine (93%; 78/84), followed by corticosteroids (52%; 44/84) and azathioprine or mycophenolate mofetil (30%; 25/84). After ten years, the use of pyridostigmine (65%; 54/83) and corticosteroid use (36%; 30/83) declined, whereas the use of azathioprine and mycophenolate mofetil increased (55%; 46/83). Seronegative patients received fewer treatments than AChR MG patients, independent of functional status and disease duration (OR 0.38, 95% CI 0.17-0.84, p = 0.018), and were less likely to use corticosteroids (OR 0.15, 95% CI [0.05-0.41], p < 0.001). Patients with LOMG reported more frequently immunosuppressive use compared to patients with EOMG (OR 4.69, 95% CI 1.16-19.02, p = 0.031).

Conclusions: This analysis offers valuable insights into treatment patterns in different subgroups of patients with MG. A substantial proportion of patients continues to rely on corticosteroids, suggesting an ongoing need for alternative treatment options.

Duchenne muscular dystrophy (DMD) is a muscle wasting disease where patients lose muscle tissue and function. The disease is caused by pathogenic variants that abolish the production of functional dystrophin protein. There are many therapeutic approaches in clinical development for DMD patients, but so far showing clinical benefit in trials has proven challenging. On May 6, 2025, the World Duchenne Organization convened a multistakeholder drug development round table meeting to discuss pertinent aspects of drug development in the DMD field: trial design, the impact of variable doses and regimen of glucocorticoids on disease trajectory, gene therapy and the use of real world evidence. Herein the most important discussion points, realizations and recommendations are summarized. As current therapeutic approaches for DMD patients aim to slow down disease progression, measuring benefit will likely be challenging. The trial design should consider the mechanism of action of the therapeutic approach, the expected therapeutic effect, and the exposure to glucocorticoids could be considered as a stratification factor (regimen and when glucocorticoids were initiated). For gene therapy there are many uncertainties yet, and in hindsight trials were not all properly designed. Looking forward, additional data needs to be collected to assess the therapeutic effect and its longevity. Finally, real world data can only be used if it has sufficient quantity and quality. This will require global alignment and collaboration.