Search Results (409)

Spinal muscular atrophy 5q (5q SMA) is one of the most prevalent autosomal recessive disorders globally. The underlying cause of 5q SMA is attributed to variants in SMN1. To date, there are no reported cases of gene-based therapy in rare patients with 5q SMA caused by subtle SMN1 variants of unknown clinical significance. We included 10 patients with the clinical manifestations of 5q SMA associated with intragenic variants in combination with a heterozygous SMN1 deletion in this retrospective study. Previously reported pathogenic or likely pathogenic variants were identified (e.g., c.*3+1del, c.815A>G (p.Tyr272Cys), and c.821C>T (p.Thr274Ile)). Variants of unknown clinical significance were also found, including a recurrent, previously unreported variant c.80A>C (p.Gln27Pro). We also report detailed molecular genetic and clinical data on 9 patients with 5q SMA. In addition, we provide results from the cohort of patients with gene-based therapy, consistent with data from patients with a homozygous SMN1 deletion. Full article

Spinal muscular atrophy (SMA) therapies that restore SMN expression improve survival and motor function but often fail to fully stabilize distal motor units or sustain endurance. We propose a hypothesis-driven adjunctive approach, intended to complement SMN-restoring therapies, in which localized nanotube-enabled interfaces acting at or near the distal motor unit and neuromuscular junction enhance neuromuscular transmission reliability in surviving, remodeled motor units. The model predicts a temporal cascade: improved junctional reliability and reduced activity-dependent failure, followed by consistent motor unit output across repeated activation, and ultimately, enhanced endurance and functional reserve. Phenotype-specific responsiveness identifies patients most likely to benefit, specifically those with preserved-but-limited residual motor unit substrate accompanied by measurable neuromuscular junction instability. Drawing on shared mechanisms from ALS, spinal cord injury, and other neuromuscular disorders, we discuss mechanistic, translational, safety, regulatory, and ethical considerations. This framework links objective physiological constructs to functional outcomes, offering a mechanistically grounded path for adjunctive therapy development in SMA and related conditions. Full article

Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood–brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions. Full article

Fetal therapy has evolved into a rapidly advancing field with the potential to alter the natural history of many severe congenital and genetic disorders before irreversible injury occurs. Progress in prenatal imaging, molecular diagnostics, and fetal intervention techniques now enables the earlier identification of disease and, in select settings, targeted prenatal treatment. This review synthesizes the current landscape of fetal therapies, spanning established surgical interventions for structural anomalies and emerging biologic and molecular approaches, including enzyme replacement therapy, stem cell-based strategies, gene therapy, and gene editing. The intrauterine environment provides a distinct therapeutic context, with developmental plasticity, immune immaturity, enhanced tissue accessibility, and relatively permissive central nervous system exposure that together define a time-sensitive window for intervention. Preclinical studies and early clinical experience across both structural anomalies and genetic disorders, including lysosomal storage disorders, osteogenesis imperfecta, and spinal muscular atrophy, support the premise that prenatal treatment can preserve organ development and improve pediatric outcomes. However, translation remains constrained by procedural risks, uncertainty regarding long-term safety and durability, ethical and regulatory complexities, and challenges with equitable access, alongside the need for robust comparative evidence versus early postnatal therapy. As the field advances, multidisciplinary collaboration, rigorous trial design with meaningful developmental endpoints, and ethically grounded implementation frameworks will be essential to guide responsible clinical adoption and maximize benefit for children and families. Full article

Motor neuron diseases (MNDs) encompass a clinically heterogeneous group of neurodegenerative conditions with varying impact on dexterity, mobility, decision making, respiratory and bulbar dysfunction. While consensus best-practice recommendations exist for genetic screening, diagnostic work-up, pharmacological and respiratory management, disease-specific facets of driving safety, assessment approaches and intervention strategies to support patients for safe driving have not been comprehensively reviewed. MNDs have unique, phenotype-specific clinical features, which are distinct form other neuromuscular conditions which necessitate a careful and systematic approach to evaluate driving safety. While MNDs are primarily associated with progressive motor impairment, extrapyramidal, cerebellar, cognitive, behavioural, and respiratory manifestations of the disease also affect driving safety and necessitate comprehensive driving assessments and individualised strategies to enable patients to continue to drive. The majority of existing papers focus on amyotrophic lateral sclerosis, and low-incidence MND phenotypes, such as PLS, SBMA, PPS, are glaringly understudied from a driving safety perspective despite the relatively slower progression of these conditions. Beyond the review of specific aspects of driving in MNDs, the main objective of this review paper is to raise awareness of non-motor aspects of MNDs with regard to driving safety and to explore viable strategies to support patients to maintain their independence. Despite the considerable differences in driving regulations around the globe, there are core, disease-specific aspects of MND which are universal. The careful consideration of these clinical factors, comprehensive domain-by-domain assessments, and the implementation of practical, individualised adaptations may enable patients to continue driving safely, maintain their independence and enhance their quality of life. Full article

Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is an important but under-recognised complication in neuromuscular diseases. In adults, emerging epidemiological data suggests increased VTE occurrence in conditions such as Amyotrophic Lateral Sclerosis, myotonic dystrophy, myasthenia gravis, inflammatory neuropathies, inflammatory myopathies, and POEMS syndrome. This heightened risk reflects not only disease-related immobility but also disorder-specific biological mechanisms, including inflammation, endothelial dysfunction and cardiomyopathy-related stasis. Therapies such as corticosteroids, IVIG-related hyperviscosity, long-term central venous access, perioperative immobility, critical illness, and complex orthopaedic procedures have prothrombotic effects. Despite this multifactorial risk profile, disease-specific guidance for thromboprophylaxis is lacking, and current practice relies heavily on extrapolation from general medical and surgical recommendations rather than data derived from neuromuscular cohorts. In children and adolescents, the VTE burden is less well-characterised, but events have been reported in Duchenne and Becker muscular dystrophy, congenital myopathies, and spinal muscular atrophy particularly with advanced motor impairment, severe cardiomyopathy, ventilatory insufficiency, and prolonged hospitalisation. Beyond venous events, selected neuromuscular disorders also exhibit increased arterial thrombosis risk. Myotonic dystrophy and dystrophinopathies are associated with cardiomyopathy and arrhythmia that predispose to systemic embolism and stroke, while inflammatory myopathies may demonstrate arterial events related to vasculitic or endothelial processes, although overall evidence remains limited. This review summarises available empirical and epidemiological evidence on venous and arterial thrombosis across adult and paediatric neuromuscular disorders, outlines disease-specific mechanistic pathways, examines treatment-related contributors, and highlights key evidence gaps that must be addressed to guide rational and targeted prophylaxis strategies in this complex, heterogeneous population. Full article

Advances in technology have provided a better understanding of the genetic basis of neurodegenerative disorders and their underlying molecular pathophysiology. However, treating these disorders with conventional strategies is a major challenge. The approval of gene targeted therapy for spinal muscular atrophy (SMA) has laid the foundation for developing highly personalized therapies for other neurodegenerative disorders. As intensive research and efforts to advance gene targeted therapies continue, this review provides an overview of viral and non-viral vectors and delivery methods, as well as treatment strategies, including gene addition, replacement, editing, silencing, and splice modulation. Gene targeted approaches and clinical trials for SMA and amyotrophic lateral sclerosis (ALS) have demonstrated success, and additional studies are in progress. The design of efficient clinical trials which facilitate successful translation into clinical practice is of critical importance. Key considerations include the selection of appropriate disease models, understanding the natural history of the disease, and establishing well-defined outcome measures to assess prognosis of the disease and therapeutic efficacy. Finally, the precision of CRISPR-based gene editing offers the potential for one-time corrective therapies for monogenic disorders like SMA and SOD1-ALS. Full article

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder causing progressive muscle weakness. Severe SMA forms are typically observed up to six months postnatally. Disease-modifying therapies provide significant benefits, making newborn screening (NBS) essential for timely diagnosis and treatment initiation. The NBS programme evaluated infants born between April 2023 and October 2024 in the Campania region, Italy. DNA was amplified to detect homozygous deletion of the SMN1 gene by RT-PCR and SMN2 copy number using multiplex ligation-dependent probe amplification. Following treatment, motor functions were assessed using CHOP-INTEND and Bayley III scales. Among 62,801 infants screened for SMA, thirteen (11 females, 2 males) tested positive. The distribution of SMN2 copy numbers was as follows: eight patients had two copies, one patient had three, and four patients had four copies. One year after treatment, motor outcome data were available for four of the eight patients with two SMN2 copies. Among these patients, one achieved the milestones of walking without support, and three were standing with support. At 24 months, three of these patients were walking independently. Pre-symptomatic treatment markedly improves motor function development. This underscores the urgent need for large-scale newborn screening to prevent diagnostic delays and ensure timely, effective therapy. Validated care protocols must be established to facilitate early diagnosis and intervention. Full article

Newborn screening (NBS) is a well-established public health program that enables early detection and treatment of rare disorders in newborns, preventing severe complications or death. Despite its recognized importance, the scope and implementation of NBS programs vary across Southeastern (SE) and Central Europe. This study aimed to evaluate the current status of NBS in 16 countries of SE and Central Europe and assess progress since the previous survey in 2021. A structured questionnaire was distributed to national experts between April and December 2025, collecting data on program organization, coverage, diseases included, laboratory methods, confirmatory testing, consent practices, and future expansion plans. All countries reported universal screening for congenital hypothyroidism, except Kosovo, where a national NBS is in the process of being established. Expanded NBS using tandem mass spectrometry was available in Austria, Bulgaria, Croatia, Cyprus, Greece, Hungary, North Macedonia, Romania, and Slovenia. Spinal muscular atrophy screening became universal in Austria, Croatia, Hungary, Serbia, and Slovenia. Most countries reported plans for further expansion, with congenital adrenal hyperplasia, severe combined immunodeficiency, spinal muscular atrophy, and cystic fibrosis being the most frequently targeted conditions. Although notable infrastructural progress has been achieved, financial constraints, lack of staff, and organizational barriers remain key challenges. The study’s assessment of program effectiveness was further limited by the absence of region-wide systems for capturing end-to-end performance indicators, such as the age of the infant at treatment initiation or missed cases. Regional collaboration and adoption of best practices are therefore vital to ensure equitable access and continuous advancement of NBS programs. Full article

Background: The aim of this prospective longitudinal observational study was to assess respiratory muscle function after surgical correction of scoliosis in individuals with spinal muscular atrophy (SMA). Material: The study included 20 patients (aged 7–19) with scoliosis in the course of neuromuscular disease, eligible for surgical treatment with diagnosed SMA Type 2 or 3. Methods: Measurements were taken of the maximal inspiratory pressure (MIP) [cmH₂O] and the maximal expiratory pressure (MEP) [cmH₂O] in all patients immediately before surgical correction of scoliosis (measurement I), 7 days after surgery (measurement II) and 3 months after surgery (measurement III). Results: The mean Cobb angle of spinal curvature measured before surgery in the entire group was 102.57 ± 17.96. The mean MEP values in the entire group of patients were 40.48 ± 11.76 cmH₂O before surgery, 36.74 ± 17.17 cmH₂O after 7 days, and 39.17 ± 16.18 cmH₂O 3 months after surgery. The MIP values for the entire group were 64.35 ± 28.40 cmH₂O before surgery, 53.96 ± 28.66 cmH₂O after 7 days, and 67.00 ± 31.27 cmH₂O after 3 months. Conclusions: Surgical correction of spinal curvature creates conditions for maintaining respiratory muscle strength in patients with SMA over a period of several months of observation. As a result of the surgical intervention, respiratory muscle strength did not deteriorate, but even slightly increased. Full article

Screening for spinal muscular atrophy (SMA) was adopted by all US state newborn screening programs between 2018 and 2024; by the end of 2022, 48 states were screening for SMA. We assessed trends in health insurance records of SMA diagnoses to quantify improvements in the timeliness of SMA identification following the adoption of screening. We used nationally representative Medicaid claims data for approximately half of US births covered by public insurance and a convenience sample of employer-sponsored health plans. We analyzed records for birth cohorts with at least 1 full year of follow-up (i.e., through the end of the following calendar year). For 2017 births, 1.3 per 100,000 infants had SMA codes first recorded by 1 month of age; this increased to 6.6 per 100,000 among publicly insured newborns born in 2022. The rollout of SMA newborn screening across US states was also followed by improvements in the timely detection of SMA. The proportion of infants with SMA detected by 1 month increased from 18% in 2017 to 61% in 2021 and is projected to reach 75% in 2022. Growth in timely detection was even greater in the employer-insured sample. Timely diagnosis of SMA can enable the initiation of treatment prior to the irreversible loss of motor function. Full article

It is well established that early diagnosis and subsequent intervention can result in significant benefits in infants with neurodevelopmental disorders such as cerebral palsy (CP). This scoping review aimed to assess the current state of the literature regarding the use of innovative and emerging technologies for early CP screening, diagnosis and phenotyping in pre-ambulatory children. Searches were performed across PubMed, Embase and Cochrane databases; articles were screened by four independent reviewers at the title/abstract and full-text levels. Forty-eight studies met the inclusion criteria. The most frequently used modalities included wearable sensors (e.g., accelerometers, inertial measurement units) and video-based motion analysis. These movement-tracking systems were used to screen for a variety of pediatric-onset neurodevelopmental disorders and have been useful in quantifying spontaneous infant movements, detecting the absence or abnormality of fidgety movement, or identifying atypical motor patterns. Although CP was our primary focus, several studies applied a similar pipeline to autism spectrum disorder (ASD) and spinal muscular atrophy (SMA), underscoring broader relevance for early neurodevelopmental screening, diagnosing and phenotyping. Overall, technology-assisted motor assessment demonstrated promising feasibility and diagnostic potential; however, most studies are limited by small sample sizes, short follow-up durations, and heterogeneous validation methods. Given the benefits of early intervention and the emerging capabilities of wearable and video-based analytics, larger multi-site and longitudinal datasets are needed to support early diagnosis, risk stratification, and functional phenotyping in CP. Full article

Background: Prior SMA mortality studies have shown excess mortality in people with SMA, but the literature lacks data on disparities in SMA-related mortality. This study examined disparities in SMA-related mortality in the United States in the post-treatment era (2018–2023). Methods: This was a population-based study using the CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database. The International Classification of Disease (ICD), 10th Revision, Clinical Modification codes, G12.0, G12.1, G12.8, and G12.9, were used to identify SMA. The data were stratified by biological sex, race/ethnicity (Non-Hispanic/NH White, NH Black, Hispanic, Asian) and Census regions (West, Northeast, Midwest, South). The analysis was conducted by calculating rate ratios (RR) of age-adjusted mortality rate (AAMR). Results: There were 821 (45.8% female) SMA-related deaths across the study period. Males were associated with higher AAMR than females (RR = 1.189, 95% CI: 1.035 to 1.366). The SMA-AAMR for NH White individuals was the highest compared to Hispanic individuals (RR = 1.808, 95% CI: 1.420 to 2.300), followed by NH Black and Asian individuals. The West carried the highest AAMR compared to the Northeast (RR = 1.581, 95% CI: 1.263 to 1.978), followed by the Midwest and the South. The age at death distribution showed a bimodal pattern, as follows: 5–14 years and 65–74 years. The infant age group (<1 year) was associated with the highest AAMR compared to all other age groups. Conclusion: Our findings showed that SMA-related mortality was highest in infants, NH White individuals, the West, and males. These data may assist future efforts to reduce the burden of SMA. Full article

Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by bi-allelic deletions or pathogenic SMN1 variants. Early diagnosis through neonatal screening is essential for timely therapeutic intervention, significantly improving clinical outcomes. In August 2022, a pilot neonatal screening program for SMA was launched in Romania, aiming to assess feasibility and impact. Objectives are to present the preliminary results of the ongoing SMA neonatal screening pilot program in Romania, evaluating its effectiveness in early detection and referral for treatment. The program started in August 2022 with four maternity hospitals and has progressively expanded to 28 maternity hospitals nationwide. Dried blood spot samples from newborns were analyzed for SMN1 gene deletions using real-time PCR. Positive results were confirmed through genetic testing, and affected infants, along with their families, were referred for further medical evaluation and early therapeutic intervention. Approximately 60,000 newborns have been screened since the program’s inception, and 12 newborns tested positive for SMN1 deletions, resulting in an estimated incidence rate of 1 in 5125 live births. All confirmed cases were promptly referred for specialized care, with early access to disease-modifying therapies. The program has faced challenges in logistics, parental awareness, and equitable access to treatment, but its expansion from 4 to 28 maternities demonstrates increasing feasibility, suitability, and acceptance. Conclusions: The Romanian pilot neonatal screening program for SMA has successfully identified affected infants early, proving its feasibility and clinical impact. The ongoing expansion suggests a strong foundation for a future national program, which could significantly improve early SMA diagnosis and patient outcomes in Romania. Full article

Nonsense mutations, responsible for ~11% of gene lesions causing human monogenic diseases, introduce premature termination codons (PTCs) that lead to truncated proteins and nonsense-mediated mRNA decay (NMD). In the central nervous system (CNS), these mutations drive severe, progressive neurological conditions such as spinal muscular atrophy, Rett syndrome, and Duchenne muscular dystrophy. Readthrough therapies—strategies to override PTCs and restore full-length protein expression—have evolved from early aminoglycosides to modern precision tools including suppressor tRNAs, RNA editing, and CRISPR-based platforms. Yet clinical translation remains hampered by inefficient CNS delivery, variable efficacy, and the absence of personalized stratification. In this review, we propose a translational framework—the 4 Ds of Readthrough Therapy—to systematically address these barriers. The framework dissects the pipeline into Detection (precision patient identification and biomarker profiling), Delivery (engineered vectors for CNS targeting), Decoding (context-aware molecular correction), and Durability (long-term safety and efficacy). By integrating advances in machine learning, nanocarriers, base editing, and adaptive trial designs, this roadmap provides a structured strategy to bridge the translational gap. We advocate that a synergistic, modality-tailored approach will transform nonsense suppression from palliative care to durable, precision-based cures for once-untreatable neurological disorders. Full article