Journal of neuromuscular diseases最新文献

Homozygous KY variants have been described to cause congenital myopathy, myofibrillar myopathy type 7, and hereditary spastic paraplegia. We report the findings in two families harboring the homozygous missense NM_178554.4:c.727T > C p.(Cys243Arg) and splice site NM_178554.4:c.710 + 1G > A KY variants leading to early-onset myopathy with equinovarus deformity, lateral tongue atrophy, kyphoscoliosis, and contractures. Myopathological examination showed a myopathic pattern in conjunction with fibers containing eosinophilic sarcoplasmic inclusions positive for kyphoscoliosis peptidase and filamin-C but not desmin, myofibrillar degeneration, and focal mitochondrial loss. Kyphoscoliosis peptidase protein expression levels were markedly reduced, and in silico analysis of the predicted protein variants suggested impairment of the kyphoscoliosis peptidase catalytic triad.

We evaluated the safety and effectiveness of onasemnogene abeparvovec (OA) for 34 patients with spinal muscular atrophy (SMA) and tracheostomies enrolled in the RESTORE registry. Most patients (76.5%) received other SMA treatments before and/or after OA. Safety findings were consistent with OA's established profile. There were four fatalities, three caused by respiratory events unrelated to OA, one of unknown cause. Overall, patients exhibited positive motor outcomes, even in cases where the need for tracheostomy emerged after treatment. These real-world data support OA treatment for patients with SMA and tracheostomies and can inform future access, treatment, and care decisions.Trial registration: Clinicaltrials.gov NCT identifier NCT04174157, registration date September 12, 2019.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease resulting from biallelic pathogenic variants of the survival motor neuron 1 (SMN1) gene that leads to motor neuron degeneration, progressive muscle atrophy, and weakness. In its most severe form and without timely initiation of treatment, SMA can be fatal or lead to a requirement for permanent ventilation by 2 years of age. Approved treatments for SMA target an increase in SMN protein production. These include nusinersen and risdiplam, which modify splicing of the SMN2 pre-mRNA, and onasemnogene abeparvovec, a viral-mediated gene therapy. In 2020, an expert panel provided recommendations and practical considerations regarding onasemnogene abeparvovec administration. As more countries have approved onasemnogene abeparvovec and new data have emerged from clinical trials and real-world use, a similar expert panel provides updated recommendations along with additional guidance. Specific recommendations are centered around family preparation prior to and immediately following dosing to minimize risk of infectious illness, timing of anti-adeno-associated virus serotype 9 antibody titer testing for those patients with exclusionary titers, modifying immunization schedules, avoiding potential complications with long-term corticosteroid administration, safety monitoring, considerations for combination therapy, implementing newborn screening, and emphasizing the need for ongoing multidisciplinary care and adherence to standard-of-care guidelines.

Background: Quantitative muscle MRI is one of the most promising biomarkers to detect subclinical disease progression in patients with neuromuscular disorders, including Duchenne muscular dystrophy (DMD). However, its clinical application has been limited partly due to the time-intensive process of manual segmentation.

Objective: We present a simple and fast automated approach to obtain quantitative measurement of thigh muscle fat fraction and investigate its reliability in patients with DMD.

Methods: Clinical and radiological baseline and 6-month follow-up data of 41 ambulant patients with DMD were analysed retrospectively. Axial 2-point Dixon MR images of all thigh muscles were used to quantify mean fat fraction, while clinical outcomes were measured by the Motor Function Measure (MFM) and its D1 domain. Data obtained by automated segmentation were compared to manual segmentation and correlated with clinical outcomes. Results were also used to compare the statistical power when using automated or manual segmentation.

Results: A mean increase of 3.55% in thigh muscle fat fraction at 6-month follow-up could be detected by both methods without any significant difference between them (p=0.437). The automated muscle segmentation method demonstrated a strong correlation with manually segmented data (Pearson's ρ = 0.97). Additionally, there was no statistically significant difference between the automated and manual segmentation methods in their association with clinical progression, as measured by the total MFM score and its D1 domain (p = 0.235 and p = 0.425, respectively).

Conclusions: The presented automated segmentation technique is a fast and reliable tool for assessing disease progression, particularly in the early stages of DMD. It is one of the few studies validated using manual segmentation, and with further refinement, it has the potential to become a good surrogate marker for disease progression in various neuromuscular disorders.

Background: The advent of three effective disease modifying therapies for SMA has highlighted the need to understand the epidemiology of spinal muscular atrophy (SMA) and its disability impact.

Objective: We aimed to establish the nationwide incidence and prevalence of SMA in Aotearoa-New Zealand, and to estimate the patients' disability and the impact of this on health resource utilisation.

Methods: We used multiple sources to identify patients with SMA and verified the diagnosis, disabilities and resources utilisation by review of the individual patient notes and genetic results. The four year incidence period was from 1st July 2015 to 30th June 2019. Prevalence date was 1st March 2019. Of note, this time period pre-dated access to disease modifying therapy in New Zealand. Census data for 2018 was used for denominators. Descriptive statistics and capture-recapture were used to analyse the data. For context, we reviewed international SMA epidemiology.

Results: The incidence per 100,000 live births was 8.0 (95% confidence interval (CI): 4.8-12.5). The standardised prevalence rate of SMA on 1st March 2019 was 1.78 per 100,000 (95% CI: 1.24, 2.33). Prevalence was significantly lower amongst Māori at 0.34 (95% CI: 0.08, 1.13; p = 0.006). Substantial decline from best motor milestone performance was seen; seven patients with SMA1 died without access to disease modifying therapy. 74% of the total cohort used wheelchairs. 23% required respiratory support. 62% had scoliosis, of whom 61% had had surgery. Surviving SMA1 patients had very high health service utilisation.

Conclusions: Incidence and prevalence figures match closely with international studies. This is the first record of low SMA rates in Māori. While the largest burden of disease falls on patients with SMA1 and 2 there is still substantial use of health resources among SMA3 and SMA4 patients.

BackgroundThe application of recombinant adeno associated virus (rAAV) in gene therapy is accepted as an effective strategy for the treatment of monogenic diseases. However, eligibility for such therapies is contingent upon the absence or minimal presence of antibodies against adeno-associated virus (AAV) capsid protein. While the passive transfer of maternal immunoglobulins in utero is well established, the potential impact of maternal antibodies transferred via breastfeeding remains less explored.ObjectiveThis study aims to quantify and compare the levels of anti-AAV9 and anti-AAVrh74 immunoglobulin G (IgG) and M (IgM) in both plasma and human milk from a group of healthy lactating mothers.MethodsIn this cross-sectional study, we analyzed plasma and human milk samples from healthy lactating mothers. We used an enzyme linked immunosorbent assay (ELISA) to determine the levels of circulating IgG and IgM antibodies against AAV9 and AAVrh74 capsids and compared their concentrations in the paired samples.ResultsThirty-one paired plasma and human milk samples were analyzed. The median age at participation was 34 years (range: 25-43), median duration of breastfeeding at the time of sample collection was 7.5 months (range:0.7-33), and median body mass index was 23 Kg/m² (range: 19.7-35.4). Median anti-AAV9 IgG in plasma and human milk, were 183 U/mL (range: 29-7214) and 1 U/mL (range: 1-33), respectively. Median anti-AAVrh74 IgG, in plasma and human milk were 138 U/mL (range: 23-8725) and 1 U/mL (range: 1-27), respectively. The differences in anti-AAV9 and anti-AAVrh74 IgG levels between plasma and human milk were statistically significant (p < 0.0001). Additionally, a strong correlation (r: 0.97, p: < 0.0001) was observed between anti-AAV9 and anti-AAVrh74 IgG levels in plasma.ConclusionsThe levels of anti-AAV9 and anti-AAVrh74 antibodies in human milk are remarkably lower than those in plasma. Consequently, breastfeeding should not be restricted for term infants who are potential candidates for AAV-related gene therapy products.

The continued evolution of genomic technologies over the past few decades has revolutionized the field of neurogenetics, offering profound insights into the genetic underpinnings of neurological disorders. Identification of causal genes for numerous monogenic neurological conditions has informed key aspects of disease mechanisms and facilitated research into critical proteins and molecular pathways, laying the groundwork for therapeutic interventions. However, the question remains: has this transformative trend reached its zenith? In this review, we suggest that despite significant strides in genome sequencing and advanced computational analyses, there is still ample room for methodological refinement. We anticipate further major genetic breakthroughs corresponding with the increased use of long-read genomes, variant calling software, AI tools, and data aggregation databases. Genetic progress has historically been driven by technological advancements from the commercial sector, which are developed in response to academic research needs, creating a continuous cycle of innovation and discovery. This review explores the potential of genomic technologies to address the challenges of neurogenetic disorders. By outlining both established and modern resources, we aim to emphasize the importance of genetic technologies as we enter an era poised for discoveries.

The TNNC2 gene is crucial for skeletal muscle function, and pathogenic variants have been linked to congenital myopathies characterized by hypotonia, muscle weakness, and respiratory insufficiency. To date, TNNC2-related myopathies have been associated only with autosomal dominant missense variants. We report here the first family case of a recessive form of myopathy related to TNNC2. We identified the homozygous splice variant TNNC2(NM_003279.3):c.314 + 1G > C p.(?) in two siblings with a severe clinical presentation, resulting in one neonatal death and one medical termination of pregnancy. This variant induces a splicing defect that leads to a complete loss of the TNNC2 physiological transcript. This case expands the spectrum of TNNC2 variants with a late-onset fetal loss. To the best of our knowledge, this is the first case reporting a recessive form of severe neonatal hypotonia due to TNNC2 variant.

Mitochondrial diseases, characterized by disruptions in cellular energy production, manifest diverse clinical phenotypes despite a shared molecular aetiology. Of note is the frequent involvement of the brain in these pathologies. Given the inherent challenges associated with accessing human tissue and the limitations of mouse models, especially concerning mitochondrial DNA (mtDNA), in vitro modelling is crucial in elucidating brain-related manifestations of mitochondrial diseases.In this review we recapitulate the current available in vitro models used to study neuronal cell types and advance our understanding of mitochondrial brain disease. This inquiry is especially pertinent considering the scarcity of suitable animal models, necessitating reliance on in vitro models to elucidate underlying molecular mechanisms. We found fifty papers modelling neuronal mechanisms of mitochondrial diseases in-vitro. While there was an even split between nuclear and mtDNA mutations, MELAS was the most commonly modelled syndrome. The emerging technologies in the stem cell field have revolutionized our approach to investigate cellular specificity in mitochondrial diseases, and we found a clear shift from neuroblastoma cell lines to iPSC-derived models. Interestingly, most of these studies reported impaired neuronal differentiation in mutant cells independent of the syndrome being modelled. The generation of appropriate in vitro models and subsequent mechanistic insights will be central for the development of novel therapeutic avenues in the mitochondrial field.

BackgroundThe new treatment paradigm in Spinal Muscular Atrophy (SMA) has introduced novel phenotypes, changes in trajectories and clinical questions not fully addressed in clinical trials. To explore these challenges, several international initiatives have emerged. CuidAME was created as a nationwide clinical network in Spain designed to standardise SMA care, facilitate knowledge sharing, and capture data in a longitudinal comprehensive registry.ObjectiveEvaluating the usefulness of the CuidAME project to capture data in a real-world setting.MethodsThis multicentric cohort study includes individuals with SMA followed at participating hospitals. Clinical examinations and multidisciplinary assessments were performed during routine clinical visits. We present a cross-sectional analysis of the registry population.ResultsAs of February 2025, 543 participants from 25 hospitals were recruited: 12 were presymptomatic, 125 (23%) had SMA type 1, 208 (35%) type 2, 194 (38%) type 3, and 4 (<1%) type 4. Among the cohort, 91% (n = 495) had received at least one disease-modifier treatment, with 17 discontinuations. The registry included 5092 motor assessments, 1565 performed before treatment initiation.ConclusionsCuidAME is an academic, longitudinal, real-world data collection project that demonstrated a fast and effective model for implementation facilitating the standardization of clinical practices and outcome measures across Spain. By aligning with core dataset used in other registries and establishing multidisciplinary working groups, the initiative will contribute to sharing knowledge to advance SMA care and improve patient outcomes.