Journal of neuromuscular diseases最新文献

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.

Congenital disorders are a significant contributor to neonatal intensive care unit (NICU) admissions and neonatal mortality, adding to substantial healthcare costs and emotional burden for families. The introduction of rapid next-generation sequencing (NGS), also known as massively parallel sequencing (MPS), in the NICU has advanced neonatal care by enabling rapid and precise diagnoses. This review explores various NGS technologies utilized in the NICU, their clinical utility, and their role in newborn screening (NBS). It also highlights several challenges hindering its widespread adoption. Addressing these barriers will require a combined effort from all the different stakeholders to ensure fair and responsible integration of NGS into neonatal care.

Objective: This scoping review aims to explore and map the most frequently reported limitations in activities of daily living (ADLs) among individuals with spinal muscular atrophy (SMA), with the goal of informing clinical assessment and multidisciplinary care strategies.

Methods: The review followed the Joanna Briggs Institute (JBI) methodology for scoping reviews and adhered to the PRISMA-ScR reporting guidelines. A comprehensive search was conducted across PubMed, Scopus, Web of Science, and Embase up to December 2024. Eligible studies included qualitative, quantitative, and mixed-methods designs that reported ADL limitations in individuals with any SMA subtype. Data were extracted and descriptively synthesized, with additional input from a multidisciplinary rehabilitation team to provide practical clinical recommendations.

Results: Sixteen studies were included, encompassing a wide range of methodologies and SMA types. The most frequently reported ADL limitations included mobility (e.g., walking, transferring, climbing stairs) and self-care tasks (e.g., dressing, toileting, feeding). Upper limb function and instrumental ADLs, such as cooking, writing, and technology use, were less frequently assessed but emerged as important in maintaining autonomy, particularly in adults. Recent studies post-gene therapy demonstrates a broader focus on daily functioning and patient-reported outcomes. A multidisciplinary framework outlining domain-specific interventions and professional roles was developed based on the extracted data.

Conclusions: While mobility remains central to SMA-related disability, this review highlights the substantial burden of self-care and upper limb limitations. Findings support a shift toward more comprehensive, patient-centered assessment and rehabilitation approaches in SMA care.

BackgroundSince the approval of onasemnogen abeparvovec (OA) for gene addition therapy in children with spinal muscular atrophy (SMA), there has been a considerable increase of evidence regarding its effectiveness and safety. Consequently, the previous recommendations needed to be revised.ObjectiveThe primary objective was to develop an evidence- and expert-based best practice protocol ensuring optimal patient safety and comprehensive support for affected families. The harmonization of treatment algorithms is expected to facilitate the collection of standardized real-world data, laying the foundation for future evidence-based adjustments.MethodsA modified, two-part Delphi process was selected as a standardized methodology. Experts specializing in SMA from all 31 neuromuscular treatment centers within Germany, Austria and Switzerland, and patient advocacy groups participated in an industry-independent Delphi panel. Existing evidence concerning effectiveness, safety, and guidelines of OA was analyzed in a systematic literature followed by development of consensus statements regarding its effectiveness.ResultsStrong consensus was reached regarding the following statements on effectiveness: (1) OA gene addition therapy for SMA demonstrates a clear advantage compared to the natural progression of the disease. (2) Superiority of any of the three approved disease-modifying therapies has not been proven. (3) Earlier initiation of therapy with fewer symptoms and shorter disease duration leads to better outcomes. (4) There is no clinical evidence supporting the superiority of combining two treatments over monotherapy.Conclusions: The systematic literature analysis constitutes the basis for the subsequent part 2, which involves the generation of expert-based recommendations for the surveillance of SMA gene addition therapy.

BackgroundDuchenne muscular dystrophy (DMD) is a severe muscle disease with an unmet therapeutic need. Despite ongoing research efforts, only a few medicines have achieved marketing authorisation in the EU to date. We present a regulatory science overview summarising the insights obtained from the evaluation by the Paediatric Committee (PDCO) of the European Medicines Agency (EMA) of paediatric investigation plans (PIPs) for this condition, with the primary objective of providing recommendations for future developments.MethodsWe reviewed the PIPs approved by the PDCO and related regulatory procedures analysimg the available information in our own databases completing it with a search in the EU Clinical Trials Register (EudraCT) and Clinical Trials Information System (CTIS) databases to provide context.ResultsBetween January 2005 and December 2024, 16 PIPs were agreed. By 2024, 1 PIP has been completed, the remaining ones are ongoing. So far, 3 medicines for the treatment of DMD have received a positive opinion by EMA's Committee for Medicinal Products for Human Use (CHMP). Main characteristics and critical factors contributing to successful developments are outlined.ConclusionsThis study presents the first in-depth evaluation of PIPs approved within the EU for DMD offering insights into potential strategic approaches for clinical development of investigational medicinal products. It highlights the accumulated experience of regulators and stakeholders, particularly regarding pivotal trials that establish clinical efficacy in key patient subgroups. Furthermore, it underscores the emerging value of innovative methodologies - such as extrapolation of efficacy and integration of real-world evidence - while acknowledging persistent challenges related to data quality.

Pathogenic variants in the MYH2 gene are associated with congenital myopathy. We report 13 unrelated patients and a systematic review of published cases through 30 October 2024, supplemented by HGMD Pro (2024.2) and LOVD (https://www.lovd.nl/) databases. In the case series, most patients (n = 11/13, 84.6%) exhibited clinical symptoms from early childhood to middle adulthood. The mean age of onset was 22.8 years (vs 7.73 years in literature review), likely because of absence of birth contractures, described in early reports. External ophthalmoparesis, though not a defining feature, should raise suspicion of MYH2-related myopathy in patients with a CPEO-like presentation and limb-girdle weakness. Notably, two patients presented with postural tremor of the upper limbs as their first symptom. Although rimmed vacuoles were a characteristic feature in initial reports of MYH2-related myopathy, they were absent in our case series. The most informative stain was ATPase, detecting the lack or reduction of type 2A fibres. Electron microscopy revealed additional features, such as the presence of cores associated with rods in one patient and pathological subsarcolemmal mitochondrial accumulations in 2 patients. Fifteen novel variants were identified amongst the 13 patients of this study, expanding the current genetic landscape for MYH2-related muscle diseases. The phenotypic and histological diversity observed can not be fully accounted for by genetic factors alone, suggesting the presence of additional contributing factors. This wide variability may lead to under-recognition of this disease, thus the importance of clinicians' awareness on the topic.

BackgroundHereditary spastic paraplegia (HSP) is a heterogenous group of rare genetic disorders characterized by progressive corticospinal and dorsal spinal cord axonal degeneration manifesting as muscle weakness and spasticity of the lower extremities. Over 98% of solved HSP cases are caused by pathogenic variants in the nuclear DNA.CaseWe report a family carrying the m.9035T > C [p.(Leu170Pro)] pathogenic variant in the mitochondrial MT-ATP6 gene in the setting of maternally inherited, late-onset HSP. The proband (age 67 years) presented with classical, late-onset, pure HSP. Her affected daughter (age 39 years) developed late-onset, complex HSP, with asymmetrical axonal sensorimotor polyneuropathy. Her second daughter (age 46 years) carried the same pathogenic variant with high heteroplasmy but was clinically unaffected at last assessment, suggesting age-dependent or incomplete penetrance.Summary of literatureThe substitution of a leucine for a proline affects a highly conserved transmembrane helix of the subunit "a" at a key functional domain in the mitochondrial ATP synthase complex. The m.9035T > C variant has been reported in several families presenting with common phenotypic presentations of ATP6-related disorders such as maternally inherited Leigh syndrome (MILS) and the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP). HSP is a rare presentation in ATP6-related disorders; mitochondrial ATP6-induced HSP has previously been published in only one family carrying a homoplasmic m.9176T > C [p.(Leu217Pro)] variant.ConclusionThis report highlights the role of MT-ATP6 pathogenic variants in complex and pure HSP and raises the relevance of genetic testing of MT-ATP6 in undiagnosed cases of sporadic or maternally inherited HSP.

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.