Journal of neuromuscular diseases最新文献

Background: Losmapimod is an orally administered small molecule and selective p38α/β mitogen-activated protein kinase (MAPK) inhibitor able to reduce aberrant expression of DUX4 in vitro and thereby potentially slowing disease progression in patients with facioscapulohumeral muscular dystrophy (FSHD).

Objective: This global, randomized, placebo-controlled, double-blind phase 3 study in patients with FSHD1 and FSHD2 examined the efficacy and safety of losmapimod over a 48-week treatment period compared to placebo (NCT05397470, EUDRACT 2022-000389-16).

Methods: The primary endpoint was change in quantification of reachable workspace (RWS) expressed as relative surface area (RSA). Other endpoints included measures of muscle composition (fat content and lean muscle) using magnetic resonance imaging (MRI), muscle strength using quantitative dynamometry, and quality of life measures.

Results: 130 participants received losmapimod and 130 participants received placebo, with 252 participants completing the 48-week treatment period. There were no statistically significant differences between groups in change in RSA and all secondary efficacy endpoints from baseline to Week 48. Losmapimod treatment was well-tolerated, and most adverse events were mild.

Conclusions: Losmapimod was generally well tolerated with a favorable safety profile at a dose of 15 mg twice daily. Although none of the efficacy endpoints were met, study design and data from the study may inform future studies of FSHD therapies.

Background: Prodromal symptoms of sporadic amyotrophic lateral sclerosis (SALS) including muscle cramps were reported; however, their detailed characteristics have not been sufficiently studied.

Objectives: To clarify the detailed profiles of prodromal symptoms in SALS.

Methods: Patients with SALS (n = 47) and healthy controls (n = 25) were enrolled. A questionnaire-based survey was conducted to investigate symptoms before and after disease onset, including sensory, autonomic, sleep, cognitive disturbances, and frequent muscle cramps. Frequent muscle cramps were defined as those occurring at least twice per month in the lower limbs, or at least once per month in the upper limbs or trunk. We evaluated the relationship between surveyed symptoms and clinical characteristics.

Results: Prodromal frequent muscle cramps were observed in 29.8% of SALS patients, most frequently in the lower limbs. With disease progression, the sites with cramps increased, and the frequency of cramps during awakening also increased. The SALS patients with prodromal cramps had greater lean mass than those without (p = 0.023). Multivariate analysis showed that the presence of cramps after disease onset was associated with a slower longitudinal decline in the ALSFRS-R score (p = 0.048). Upper limb-onset SALS patients experienced cramps more frequently before onset than bulbar-onset patients did (p = 0.033).

Conclusions: Frequent muscle cramps often precede muscle weakness during the prodromal phase of limb-onset SALS. The frequency of cramps increased with disease progression. Prodromal cramps were associated with lean mass, whereas cramps after disease onset were associated with a slower rate of disease progression.

Adults with myotonic dystrophy type 1 who require non-invasive ventilation (NIV) often have difficulty with adherence. Few risk factors for non-adherence have been identified, and these are mostly unmodifiable. As part of a quality assurance initiative, we sought to identify psychosocial barriers to NIV adherence to improve supports around isolation and mental health. We found that substance use was associated with non-adherence to NIV in our cohort. Cognitive impairment, the receipt of provincial income support, presence of a psychiatric condition, living alone, and marital status were not associated with NIV adherence. Interventions that limit the impact of substance use may improve NIV in this population.

The evolving landscape of generalised myasthenia gravis (gMG) treatment with new targeted immunotherapy options presents challenges for neurologists and potentially leads to therapeutic inertia (TI), the failure to initiate or intensify treatment when therapeutic goals are not met. This study aimed to assess neurologists' therapeutic decision-making process in gMG and its influencing factors. A cross-sectional, web-based study was conducted, involving 149 neurologists (mean age [standard deviation]: 39.0 [9.4] years; 54.4% male; median MG experience [interquartile range]: 7 [3-15] years). Participants responded to 8 simulated case scenarios, 7 of which assessed TI. Overall, 79.9% of neurologists (n = 119/149) exhibited TI in at least 2 of the 7 scenarios. Multivariate analysis revealed that lower organisational support (odd ratio [OR] = 0.308, 95%CI:0.109-0.870, p = 0.0262) and greater reluctance to adopt new treatments (OR = 0.015, 95%CI:0.001-0.739, p = 0.0347) were significant predictors of TI. Understanding these factors is crucial for optimising gMG treatment decisions, underscoring the importance of updated guidelines and continued professional education.

Background: There is a considerable challenge in managing non-dystrophic myotonias (NDM), due to the lack of gold-standard outcome measures to assess NDM burden on activities of daily living and quality of life from the patient's perspective.

Objective: In this study, we aim to develop and validate a specific NDM patient-reported outcome (PRO) questionnaire.

Methods: The Active-NDM questionnaire was developed through a modified 2-round Delphi procedure integrating feedback from stakeholders and a systematic literature review, with input from 11 national clinical experts. The questionnaire was validated in a pilot study of 10 patients with NDM. Both clinical experts and patients assessed questions for pertinence/relevance and clarity. We excluded questions that were not considered pertinent/relevant, and reformulated any judged to be poorly formulated, by >80% of the experts/patients. We also excluded questions with <80% reproducibility during the pilot study.

Results: Based on feedback from experts and findings of the systematic literature review, we identified 130 questions, of which 100 were unduplicated. During the Delphi process, we removed 66 questions due to lack of pertinence and/or relevance. In the pilot study, patients with NDM evaluated the resulting 34-questions for pertinence, clarity, and reproducibility. Subsequently we removed 9 questions that did not achieve the required level of reproducibility.

Conclusion: We developed the Active-NDM questionnaire, composed by 25 questions, figuring as a new NDM-specific measure to determine the impact of the disease on patients' activities of daily living and quality of life. Active-NDM could be a valuable tool in the management of patients with NDM. These findings should be interpreted as preliminary. Larger-scale validation studies are warranted to confirm the tool's psychometric properties and generalizability.

Clinicaltrials: gov identifier: NCT06136416.

Background: Clinical Outcome Assessments (COAs) are essential for monitoring progression and treatment response in neuromuscular diseases. However, substantial variability exists in training, confidence, and implementation of COAs among clinical evaluators working with individuals with Spinal Muscular Atrophy (SMA). This study aimed to identify and address these gaps within the Canadian clinical context through a phased educational initiative guided by the Rare Knowledge Mining Methodological Framework (RKMMF).

Methods: A qualitative, phased design was used. A needs assessment with 71 physiotherapists and occupational therapists via focus groups identified inconsistent access to SMA-specific training and challenges in applying standardized assessments. Based on these findings, expert faculty co-developed and delivered bilingual workshops incorporating real-world evaluation videos, simulation-based learning, and multidisciplinary case discussions. Pre- and post-workshop surveys, based on an adapted Kirkpatrick Model, measured changes in familiarity, preparedness, and clinical confidence. Data were analyzed using thematic content analysis and descriptive statistics.

Results: Seventy-nine evaluators from Canada participated. Pre-workshop data revealed major gaps in familiarity with SMA-specific COAs. Post-workshop surveys indicated a 75% average increase in self-reported preparedness, with the greatest gains in the Adapted Test of Neuromuscular Disorders 3.0. Four key themes emerged: limited training and support networks; the critical role of multidisciplinary collaboration; constraints of current COAs due to ceiling and floor effects; and the value of integrating patient-reported outcomes in clinical practice.

Conclusion: Peer-led, evidence-informed workshops significantly improved clinical preparedness in SMA assessment. These findings support the need for ongoing training strategies and demonstrate the RKMMF as a scalable approach for capacity-building in rare disease care.

This meeting report summarizes the presentations and discussions held at the summit on 'Challenges in Gene Therapy' hosted by the Muscular Dystrophy Association (MDA) in 2024. Topics broadly cover in vitro and in vivo models for understanding of gene therapy related immune responses, strategies to improve safety and efficacy of next-generation gene therapies, and clinical site readiness for gene therapy and post-treatment monitoring. This year's summit also marked the launch of MDA's gene therapy support network - a national resource for patients and clinicians in the MDA care center network aimed at providing sites with the information and resources needed to deliver genetic medicines within our neuromuscular community. A series of recommendations around 8 topic areas including predicting immune responses, long-term follow up of treated individuals, and ethical considerations was derived from content presented at the meeting.

BackgroundSpinal muscular atrophy (SMA) is caused by loss-of-function of the survival motor neuron 1 (SMN1) gene and deficiency of the ubiquitously expressed SMN protein. Genetic therapies can partially rescue motor units and improve prognosis of SMA, but effects of SMN shortage in other tissues has not been studied in detail.MethodsWe longitudinally assessed renal function in a cohort of patients with SMA before and after the start of genetic therapies.ResultsWe enrolled 263 patients with SMA types 1c-4. Median age was 33 years (IQR: 22-49). Fifty (19%) patients had serum cystatin C based eGFR rates <90 ml/min/1.73m², indicating increased risk of developing chronic kidney failure, 9 (3.5%) patients had eGFR compatible with chronic kidney failure (eGFR <60 ml/min/1.73m²) and 2 patients showed end-stage renal failure based on eGFR <15 ml/min/1.73m². Symptoms of tubular dysfunction (abnormal low serum potassium levels (<3.8 mmol/L) and proteinuria) were present in 134 (51.7%) and 53 patients (22%), respectively. Forty-two (16%) patients had a history of kidney stones or nephrocalcinosis. Treatment with nusinersen or risdiplam resulted in reduction of the number of patients with hypokalaemia, but not of those with proteinuria. Cystatin C eGFR continued to decline during treatment.ConclusionsPatients with SMA are at risk of impaired renal clearance, which does not improve after treatment with SMN2-splicing modifying therapies. Tubular function may improve partially following the start of treatment. These data indicate that SMN protein deficiency affects kidneys and that this will probably cause health problems in later life.

BackgroundMyotonic Dystrophy Type 1 (DM1), the most common genetic neuromuscular disorder in adults, poses significant challenges for drug development due to its multisystem nature and high clinical variability in symptoms and disease progression. With a growing number of therapies entering clinical trials, this study addresses the urgent need for biomarkers that can serve as surrogate endpoints.MethodsWe profiled 437 serum samples from adult DM1 patients collected at two timepoints of the OPTIMISTIC trial using bottom-up mass spectrometry with data-independent acquisition. Associations between protein expression, the disease-causing CTG-repeat and 25 clinical outcome measures were studied using linear mixed-effect models. All key study findings were validated in an independent cohort of 69 DM1 patients and 10 healthy controls.ResultsOf the 259 identified proteins, 161 showed significant associations with the CTG-repeat length (FDR < 5%). Hypogammaglobulinemia was confirmed and shown to be worse in severely affected patients. A strong proteomic signature was associated with clinical measures of functional capacity, with the 6-Minute Walk Test showing the strongest signal (70 associations, FDR < 5%). These novel associations reveal a compelling link between chronic inflammation and reduced functional capacity. A machine learning algorithm identified a minimal set of 13 proteins robustly reflecting both the underlying genetic defect and functional capacity.ConclusionsDM1 induces a broad disease fingerprint in the serum proteome, predominantly affecting proteins of the immune system. A carefully selected panel of proteins showed the greatest potential to meet the statistical criteria required for surrogate endpoints in clinical trials.

Spinal muscular atrophy (SMA) comprises a spectrum of clinical severities, yet the pathomechanisms of late-onset forms (Type III) remain insufficiently understood. While severe early-onset SMA has been extensively investigated using existing models, their translational relevance to adult disease is limited. Here, we recommend the 4-copy SMN2 mouse (FVB.Cg-Smn1tm1Hung Tg(SMN2)2Hung/J) as the most appropriate model for late-onset SMA. This model exhibits delayed onset, progressive motor dysfunction, and extended survival, enabling the study of chronic neurodegenerative processes, including astrocyte-mediated motor neuron pathology. Its prolonged therapeutic window makes the model suitable for mechanistic and translational investigations of late-onset SMA.