Muscle & Nerve最新文献

Introduction/aims: Survival Motor Neuron 1 (SMN1)-related spinal muscular atrophy (SMA) is characterized by α-motor neuron degeneration, with sensory function assumed to be clinically preserved. However, recent studies in severely affected patients and animal models have challenged this view. Therefore, we assessed the maximum sensory nerve action potential (SNAP) amplitude of the median nerve in patients with SMA and examined its changes during treatment with SMN-splicing modifying therapies.

Methods: We longitudinally assessed median nerve maximum SNAPs in 103 genetically confirmed patients with SMA (types 1c-4, aged ≥ 12 years) before and approximately 1 year after treatment with nusinersen or risdiplam. For comparison, we included 53 age- and sex-matched healthy controls, using identical settings. We also compared data with reference values from a previously published cohort.

Results: Maximum SNAPs were abnormal in 6 patients with SMA (6%), which was comparable to controls (8%), even when corrected for age. In patients younger than 50 years, abnormal maximum SNAPs were more prevalent in patients with SMA types 1 and 2. Maximum SNAPs were higher in SMA compared with controls. Maximum SNAPs showed an age-related decline in most cohorts, but the decline was steeper in patients with SMA type 1c. There was no difference in SNAPs after 1 year of treatment.

Discussion: Our findings suggest the preserved sensory integrity of the median nerve in the majority of patients with SMA (94%), even in longstanding disease. The resilience of sensory neurons of the median nerve, and whether this extends to other peripheral nerves, warrants further investigation.

Trial registration: The study was approved by the local medical ethics committee (no. 20-143) and registered in the Dutch registry for clinical studies and trials (www.toetsingonline.nl-NL72562.041.20, March 26, 2020).

Introduction: We assessed whether muscle fibers in myostatin knockout (MSTN-/-) mice are just larger or also exhibit morphological, metabolic, and functional differences from MSTN+/+ mice.

Methods: We compared single fiber contractile properties and histological fiber properties in muscles from MSTN-/- and MSTN+/+ mice.

Results: Even though in permeabilized muscle fibers from the extensor digitorum longus and soleus muscle maximal force was higher (p < 0.001) there were no significant differences in specific power (power per unit volume), specific tension (force per cross-sectional area), maximal shortening velocity, or curvature of the force-velocity relationship between MSTN-/- and MSTN+/+ mice. In histological sections of the soleus muscle, fibers were larger (p < 0.001), but the succinate dehydrogenase staining intensity and capillary density did not differ significantly between MSTN-/- and MSTN+/+ mice, which was explicable by the larger number of capillaries around a fiber (p < 0.001). A model showed no significant differences in soleus muscle oxygenation.

Discussion: The larger force-generating capacity of fibers from MSTN-/- mice is explicable by the larger fiber cross-sectional area. The data indicate that muscle fibers from MSTN-/- mice are quantitatively, but not qualitatively different from muscle fibers from MSTN+/+ mice. Myostatin inhibition may help increase muscle mass in conditions accompanied by muscle weakness without a detrimental impact on muscle quality, but systemic side effects need to be considered.

Introduction/aims: Desminopathies are a group of rare human myopathies and cardiomyopathies caused by pathogenic variants of the desmin gene. Here, we analyzed the effects of the R349P mutant desmin on the proteomic profiles of individual fiber types of murine skeletal muscle.

Methods: Soleus and tibialis anterior muscles from hetero- and homozygous R349P desmin knock-in mice and wild-type siblings were used to collect fiber type-specific material by laser microdissection to determine their proteomic profiles.

Results: Aberrant proteomic profiles were observed in all four fiber types of homozygous mice. Type I and IIa fibers from homozygous muscle showed an increased abundance of 15 fibrotic proteins, for example, collagens I, IV, and VI, and associated proteins. Filamin-C, xin actin-binding repeat-containing proteins 1 and 2, and Kelch-like protein 41 were more abundant in homozygous fibers. A high number of proteins associated with the mitochondrial complexes had markedly lower amounts in all types of homozygous and type IIb heterozygous fibers, whereby 20 proteins of complex I, 6 proteins of complex III, 7 proteins of complex IV, and 4 proteins of complex V were found to be decreased in homozygous mice in at least one fiber type. This reduction included all mtDNA-encoded proteins of complexes I and V, as well as ADP/ATP translocase 1 and 2.

Discussion: Our proteomic findings highlight a more severe myodegenerative process in fibers derived from homozygous R349P desmin knock-in mice. R349P desmin altered the abundance of proteins of the sarcomeric and extrasarcomeric cytoskeleton, extracellular matrix, and mitochondrial energy metabolism.

Introduction/aims: While dystrophinopathies are primarily characterized by progressive muscle weakness with onset during childhood, dystrophin also plays a role in brain development. This study aimed to characterize how neurodevelopmental and psychiatric disorders are currently identified and managed in clinical care of those with Becker and Duchenne muscular dystrophy (BDMD).

Methods: Parent Project Muscular Dystrophy (PPMD) disseminated surveys to caregivers and health care providers (HCPs) in the United States to assess the frequency and management of neurodevelopmental and psychiatric disorders of those with dystrophinopathy.

Results: 320 caregivers (C) and 74 HCPs responded to surveys. Caregivers indicated higher rates of neurodevelopmental and psychiatric disorders than HCPs, including anxiety (50.5% C, n = 112; 17.8% HCP, n = 19), attention-deficit hyperactivity disorder (ADHD) (32.0% C, n = 73; 15.9% HCP, n = 17), obsessive-compulsive disorder (OCD) (25.9% C, n = 57; 11.2% HCP, n = 12), depression (21.6% C, n = 48; 18.7% HCP, n = 20), and autism spectrum disorder (ASD) (21.0% C, n = 47; 10.3% HCP, n = 11). Results also indicated gaps in the assessment and care of these conditions, including lack of routine screening, reduced access to psychologists and psychiatrists, and lack of clarity amongst HCPs about who should manage neurodevelopmental and psychiatric concerns in those with dystrophinopathy.

Discussion: Closing the identified gaps in assessment, perception, and care will require increased awareness of neurodevelopmental and psychiatric conditions in dystrophinopathy and screening tools to facilitate early identification of these conditions during routine clinical care.

Introduction/aims: Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy. We aimed to compare clinical outcomes in patients with antibodies against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) treated on immunotherapy regimens with and without maintenance intravenous immunoglobulin (IVIG). The secondary aim was to assess outcomes in a subset that received IVIG monotherapy.

Methods: This was a retrospective longitudinal cohort study. Multivariate logistic regression was used to analyze the association between IVIG and the probability of reaching normal creatine kinase (CK) and normal/near-normal proximal muscle strength at 3- and 6-month follow-ups. In patients treated with IVIG monotherapy, changes in CK and strength were analyzed using Wilcoxon signed rank tests.

Results: Patients treated with IVIG (n = 40) had higher odds of CK normalization at 6 months (OR 9.44, 95% CI 1.19-74.89, p = 0.03) although not at 3 months (p = 0.08) compared to patients not treated with IVIG (n = 13). Increased odds of normal/near-normal proximal muscle strength was not observed at 3 months (p = 0.14) or 6 months (p = 0.35). Subgroup analysis of patients on IVIG monotherapy (n = 15) showed a median CK reduction of 84.5% at 3 months (p < 0.001) and 95.7% at 6 months (p < 0.001). CK normalized in 40% by 6 months. Proximal muscle strength improved at 3 months (p = 0.003) and 6 months (p = 0.008). 76.9% had normal/near-normal proximal strength by 6 months.

Discussion: Patients treated with immunotherapy regimens that included IVIG were more likely to reach normal CK at 6 months. Maintenance IVIG monotherapy also induced marked improvements in CK and strength. IVIG monotherapy can be an effective first-line treatment for HMGCR IMNM.

Introduction/aims: The rising use of disease-modifying therapy is progressively impacting the health-related quality of life (HRQoL) of patients with spinal muscular atrophy (SMA) in their daily lives. This study aimed to evaluate the changes in HRQoL and independence in children with later-onset SMA receiving longitudinal treatment with nusinersen.

Methods: Forty-nine pediatric patients with later-onset SMA (symptom onset after 6 months of age) and their caregivers were enrolled. The HRQoL of patients evaluated by the proxy-reported Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM) and the independence level determined by the SMA Independence Scale-Upper Limb Module (SMAIS-ULM) were assessed. Caregiver HRQoL was assessed using the Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM). Motor function was recorded using the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM), with subsequent analysis of the correlation between motor function, HRQoL, and independence scores.

Results: A significant difference was observed across all domains of the proxy-reported PedsQL NMM and in the independence assessment over the 18-month follow-up period (p < 0.001). A positive correlation was identified between RULM and total PedsQL NMM scores (Pearson-r = 0.539, p < 0.001), as well as SMAIS-ULM scores (Spearman-rho = 0.507, p < 0.001). Scores in all modules of the PedsQL FIM improved over time (p < 0.001).

Discussion: This study demonstrates the longitudinal effects of nusinersen treatment on multifaceted aspects of SMA patients, as captured by patient-reported outcome measures (PROMs). The inclusion of PROMs should be considered as part of the SMA multidisciplinary assessment.

Introduction/aims: Primary hypokalemic periodic paralysis (HypoPP) can present with periodic paralysis and/or permanent muscle weakness. Permanent weakness is accompanied by fat replacement of the muscle. It is unknown whether the permanent muscle weakness is solely due to fat replacement or if other factors affect the ability of the remaining muscle fibers to contract. We aimed to investigate muscle fat replacement and contractility in persons with HypoPP-causing variants in CACNA1S and to compare the results to healthy controls.

Methods: In this cross-sectional study, we used T1-weighted and 2-point Dixon magnetic resonance imaging (MRI) to assess fat replacement of the muscle and stationary dynamometry to assess muscle strength. Contractility was determined by maximal muscle contraction divided by the contractile cross-sectional muscle area.

Results: We included 45 persons with HypoPP-causing variants in CACNA1S and data from 37 healthy controls. We found that fat fraction was increased in ankle dorsiflexors and knee extensors and flexors, and further found that muscle strength was decreased in knee extensors and flexors in persons with HypoPP-causing variants in CACNA1S compared to healthy controls. Additionally, we found decreased contractility of thigh muscles in persons with HypoPP-causing variants in CACNA1S compared to healthy controls.

Discussion: The decreased contractility could relate to skeletal muscle voltage-gated calcium channel dysfunction, subclinical attacks of paralysis, and/or changed muscle architecture, but this needs further investigation.