Journal of neuromuscular diseases最新文献

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.

Background: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder frequently associated with central nervous system (CNS) involvement, especially in congenital and childhood-onset forms. However, behavioral alterations in preclinical models have so far been only partially characterized, underscoring the need for more comprehensive analyses to support the development of targeted therapeutic approaches.

Objective: This study aimed to provide a comprehensive behavioral characterization of DMSXL mice, a transgenic model carrying large CTG repeat expansions in the human DMPK gene, to identify robust and translational CNS-relevant phenotypes for preclinical studies.

Methods: Using both longitudinal and cross-sectional designs, we assessed a wide range of behavioral domains including motor function, emotional reactivity, cognition, and social interaction over time in DMSXL mice. The study was conducted in two independent laboratories with complementary expertise in DM1 pathophysiology and behavioral phenotyping.

Results: DMSXL mice displayed a consistent pattern of behavioral alterations reflecting CNS dysfunction. These alterations included dysregulation of emotional responses such as altered anxiety-like behavior and impaired risk evaluation, subtle deficits in object recognition and spatial memory, and reduced sociability and social discrimination. Sensorimotor gating and goal-directed behaviors were also affected, while working memory and general locomotion during open field exploration were largely preserved.

Conclusions: This study defines a constellation of behavioral impairments in DMSXL mice that mirror CNS symptoms in DM1 patients and establishes a set of sensitive, age-dependent endpoints suitable for CNS-targeted therapeutic evaluation. The behavioral framework presented here offers valuable guidance for the design of future preclinical trials in DM1.

Background: Myotonic Dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder. Gastrointestinal (GI) symptoms significantly impact quality of life, but remain under-assessed. Currently, no DM1 specific GI questionnaire is available. The Gastrointestinal Symptoms Rating Scale (GSRS) is widely used but lacks validation with modern clinimetric methods.

Objectives: To evaluate the GSRS using Rasch analysis in DM1 patients and develop a disease-specific, interval-level GI symptom measure.

Methods: Rasch analysis evaluated item fit, threshold ordering, differential item functioning (DIF), local dependency, and unidimensionality. Model fit was evaluated using chi-square statistics, item and person fit residuals, and the Person Separation Index (PSI).

Results: Four hundred and three DM1 patients (206 women, mean age 48.3 years) completed the GSRS questionnaire. The GSRS initial data did not meet Rasch model expectations. Three items (hard stools, heartburn, diarrhea) were removed and the item nausea was split by age category. The item constipation had misfit exceeding the Bonferroni threshold, but was retained due to its clinical relevance. The final model did not fulfill Rasch requirements (item fit residuals: -0.23, SD 1.29; person fit residuals: mean -0.27, SD 1.15; item-trait Chi-square: p-value < 0.001; degrees of freedom: 60). Acceptable person separation index (0.76) was obtained.

Conclusion: This study highlights the challenges of measuring GI symptoms in DM1. Although this research is an important first step, more research is needed for developing a questionnaire that reflects the patient experience whilst simultaneously considering measurement accuracy.

Background and objective: Women carrying pathogenic DMD gene variants can develop muscle affection, such as muscle weakness and fat replacement. The long-term progression of the muscle involvement is unknown. This study investigates the 6.5-year changes in muscle function and -fat fraction in women carrying pathogenic DMD gene variants to enhance understanding of disease progression and its natural history.

Methods: Muscle structure and -function were investigated at baseline and after 6.5 years in 34 women carrying pathogenic DMD gene variants (19 predicted to confer Duchenne Muscular Dystrophy (DMD), 15 Becker Muscular Dystrophy (BMD)). After a clinical evaluation, muscle fat fraction was assessed using Dixon MRI, muscle strength with isokinetic dynamometry, and muscle biomarkers with blood samples for creatine kinase and myoglobin.

Results: Muscle fat fraction in the lower back, thigh, and calf increased significantly over 6.5 years. The average increases were generally less than 2%, but some carriers with significant baseline abnormalities experienced a more substantial increase in fat fraction, reaching as high as 31%. Although overall disease progression did not differ significantly between DMD and BMD carriers, all women who showed rapid progression were DMD carriers. Small but significant changes occurred in muscle strength and biomarkers.

Discussion: The progression of muscle involvement in women carrying pathogenic DMD gene variants is generally slow. However, those with severe baseline abnormalities on MRI-often associated with a lower age of symptom onset-experience a more rapid progression of muscle fat fraction, suggesting that baseline MRI findings could help predict future disease progression in this population.

Background: Neuromuscular diseases (NMD) cause progressive muscle weakness, significantly impairing functional abilities. Light powered assistive devices hold strong promises for improving mobility and independence in NMD. The current work investigated the efficacy and biomechanical effects of the MyoSuit that provides assistance during functional tasks, by supporting hips and knees.

Methods: Seventeen adults with NMD studied during a 2-min walk test, a 10-meter walk test, and a 30-s sit-to-stand test with and without using the MyoSuit. Muscle activation, joint kinematics, and spatio-temporal gait parameters were recorded.

Results: Knee extensor and hip extensor strength were 22.8 ± 42.9% and 71.2 ± 58.2% of predicted force, respectively. 2MWT was 76.3 ± 25.1% of predicted distance. Walking and sit-to-stand performances were reduced. Significantly, cadence, and stride length decreased, while step duration increased. Muscle activation showed decreased rectus femoris and altered timing in gluteus maximus and gastrocnemius medialis. The range of motion of hip abduction-adduction increased, and hip flexion-extension decreased during gait. Major contributors to reduced gait performance as identified using a LASSO were longer double support and step duration, and lower stride length, foot strike angle and variability in lateral step and hip adduction.

Conclusion: The MyoSuit was not associated with improvements in functional performance in NMD. The use of the device was associated with kinematic alterations and the assistance provided alleviated recruitment of the rectus femoris. The proposed approach is promising but further tailoring of the device is required to address specific needs of individuals with severe muscle weakness.

IntroductionMyasthenia gravis (MG) is a rare, debilitating autoimmune disease associated with pathogenic immunoglobulin G autoantibodies directed against components of the neuromuscular junction. The autoimmune nature of the disease and long-term immunosuppressive treatment may increase susceptibility to infections and malignancies, but studies investigating the association between MG and infections or malignancies remain scarce.MethodsWe conducted a retrospective, observational study using Optum's deidentified Market Clarity Data (Market Clarity) to evaluate the incidence rate (IR) of infections and malignancies in US-based patients with MG in a real-world setting. Adults with ≥2 diagnosis claims of MG were identified over a 2-year period (2016-2019) and propensity score (PS) matched with controls from the general population without MG. Patients with malignancies in the 1-year look-back period were excluded.ResultsPatients with MG (N = 5002) were compared with the PS-matched general population (N = 20,008). The IR of serious infections (primary outcome) was higher in the MG cohort compared with the general population (52.81 vs 31.46 per 1000 person-years [PY], respectively). IRs of opportunistic infections (87.48 vs 57.01 per 1000 PY) and infection-related death (3.98 vs 1.94 per 1000 PY) were also higher in the MG cohort compared with the general population. The overall rate of malignancy was higher in the MG cohort compared with the general population (73.55 vs 50.01 per 1000 PY, respectively).ConclusionsIn this analysis, patients with MG were more susceptible to serious infections, infection-related death, and malignancies.

In the era of disease-modifying therapy (DMT), almost all patients with spinal muscular atrophy (SMA) type I treated after onset, but before 6 months of age, develop early-onset, rapidly progressive scoliosis by 2 years of age, despite improvements in their motor function. Seven symptomatic patients with SMA type I who were treated before the age of 6 months were included in this retrospective observational study. Scoliosis had developed in all patients by 27 months of age. Among them, the patients who could stand with support or independently (standing patients; n = 3) tended to present with more progressive scoliosis than the sitters (n = 4). All standing patients demonstrated thoracic hyperkyphosis before or at the time of their scoliosis diagnosis. Despite receiving DMT, these patients continued to show residual key manifestations of SMA type I. Chronic difficulty maintaining posture due to trunk muscle weakness in the lying, sitting, or standing position was considered to be the main contributor to the development and progression of the scoliosis. The development and progression of such scoliosis, which begins in infancy, may be related to inappropriate postural management, which is not currently recognized as such by clinicians, caregivers, or guardians. In this population, it is important to closely monitor patients for such scoliosis from soon after the diagnosis of SMA. As this type of scoliosis progresses rapidly during the early developmental stage, when surgery is not possible, it is necessary to establish a proactive non-surgical management strategy for it.