Search Results (717)

Background/Objectives: Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder. This retrospective study evaluated the demographic, genetic, and clinical characteristics of children diagnosed with DMD before age three to understand early clinical presentation profiles. Methods: The cohort included 198 boys diagnosed with DMD before three years of age between January 2020 and July 2025. Medical records, serum creatine kinase (CK) levels, language milestones via Denver II criteria, and multi-exon deletion maps were retrospectively evaluated. Results: Regarding the diagnostic entry pathways, the initial clinical trigger that led to medical investigation was incidental hyperCKemia in 91.4% of cases. Regardless of the presentation trigger, a definitive, confirmed diagnosis was established in all 198 cases: 196 patients (99.0%) were securely confirmed via genetic testing (MLPA or sequencing), while 2 patients (1.0%) with negative genetic panels were confirmed via muscle biopsy demonstrating a complete absence of dystrophin expression. Genetic analysis revealed deletions in 77.8% of patients, predominantly multi-exon deletions clustered in the distal hotspot region. Independent ambulation occurred at a median age of 16 months, and 14.6% achieved walking after 18 months. Delayed language development was observed in 29.8% of patients. Conclusions: Our findings indicate that early childhood DMD is characterized not only by early muscle involvement but also by prominent neurodevelopmental features. These findings underscore the value of early CK screening in young boys and support integrating standardized neurodevelopmental surveillance into early DMD care. Full article

Background/Objectives: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder marked by developmental delay, intellectual disability, and progressive movement abnormalities. Variants in RYR1 can cause congenital myopathies, but data on the co-occurrence of variants in populations are limited. The aim of this study was to characterize the clinical and genetic basis of the neurometabolic and neuromuscular abnormalities and to investigate the potential interaction between the identified variants. Methods: Patients with complex, previously undiagnosed clinical presentations underwent neurological evaluation, including brain magnetic resonance imaging, electromyography, biochemical testing, and whole-exome sequencing (WES). Identified variants were analyzed in silico and confirmed by Sanger sequencing in the patient and her parents. Three cases were reviewed, and one of these patients exhibited developmental delay, hypotonia, intellectual disability, and progressive motor dysfunction. Biochemical tests revealed markedly elevated urinary 2-hydroxyglutaric acid levels, consistent with L2HGA. Results: WES identified a homozygous likely pathogenic variant in L2HGDH (c.589_590insGGC, p.Q197insG), confirming the molecular diagnosis of L2HGA. In addition, a heterozygous missense variant in RYR1 (c.7268T>A, p.M2423K), classified as a variant of uncertain significance, was detected and was inherited from her mildly affected father. The L2HGDH variant explains the neurometabolic phenotype of the patient, whereas the RYR1 variant remains of uncertain significance, and its clinical contribution cannot be clearly established. Conclusions: To our knowledge, this case illustrates the co-occurrence of a likely pathogenic L2HGDH variant and a heterozygous RYR1 variant of uncertain significance. The findings expand the mutational spectrum of L2HGA and underscore the value of comprehensive genomic testing in complex neurometabolic and neuromuscular disorders. Full article

Pompe disease (PD) is a rare, autosomal recessive neuromuscular disorder caused by mutations in the gene encoding acid alpha-glucosidase (GAA). The resulting deficiency in GAA, a lysosomal enzyme, leads to the pathological accumulation of glycogen, primarily in cardiac and skeletal muscles. PD presents as a clinical continuum spanning two major phenotypes: infantile-onset Pompe disease (IOPD), the most severe form, typically characterized by onset before 12 months of age, rapid hypertrophic cardiomyopathy, and severe hypotonia; and late-onset Pompe disease (LOPD), which manifests between 12 months of age and adulthood, and is characterized by progressive axial and proximal muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT), available since 2006, has improved survival, particularly in IOPD, but is limited by variable efficacy and limited penetration of the blood–brain barrier, necessitating new approaches. In this comprehensive review, we focus on advances in the understanding and management of PD. First, we explore recent diagnostic advances and the characterization of multisystem involvement in PD. Next, we critically discuss the advantages and limitations of current ERT approaches, and advances achieved with next-generation ERT (avalglucosidase alfa, cipaglucosidase alfa + miglustat). Finally, we summarize cutting-edge, potentially curative strategies, including substrate reduction therapy and novel experimental therapies (e.g., gene therapy) that seek to circumvent the limitations of ERT, provide durable effects, and potentially penetrate the central nervous system. Full article

Congenital Myasthenic Syndrome represents a complex and heterogeneous group of inherited neuromuscular disorders, which result from variants in genes involved in different pathophysiological mechanisms related to the neuromuscular junction. LRP4 (Low-density lipoprotein receptor-related protein 4) represents one of the most important proteins involved in this complex signaling pathway, acting in a complex with agrin and Muscle Skeletal Receptor Tyrosine Kinase (MuSK) proteins. LRP4 became known to most neurologists due to the description of anti-LRP4 antibody-related Myasthenia Gravis. There are, however, different neurological and neuromuscular disorders that result from pathogenic variants in LRP4 gene, especially a rare and potentially treatable Congenital Myasthenic Syndrome. The authors performed a detailed narrative review, including descriptions of the main pathophysiological, clinical, and therapeutic aspects of LRP4-related Congenital Myasthenic Syndromes. Full article

Rare genetic disorders of the central nervous system (CNS) remain some of the most complex and challenging diseases to treat for several reasons. Targeting the CNS, especially the brain, presents one of the greatest obstacles in gene therapy using adeno-associated virus (AAV) vectors. Although various AAVs have been identified for their ability to transduce different cells in the CNS, their effectiveness and efficiency are significantly limited by the presence of neutralising antibodies (NAbs) and restricted cargo capacity. Despite these challenges, our understanding of AAV structure and technological advances continue to enable researchers to develop innovative strategies that have resulted in groundbreaking, FDA-approved therapeutic products now available for Leber congenital amaurosis (LCA) (Luxturna^®), spinal muscular atrophy (SMA) (Zolgensma^®), and the two recent gene therapy products for aromatic L-amino acid decarboxylase (AADC) deficiency, Kebilidi^® and Upstaza^®, which currently hold FDA and EMA approval, respectively. This review aims to highlight recent advances in the field of AAV gene therapy for neurological disorders, identify research gaps, and suggest areas for future investigation to enable potential breakthroughs particularly in neurodegenerative, neurodevelopmental, and neuromuscular disorders. We foresee that more tissue- and cell-specific AAV vectors designed using AI-powered platforms will emerge to precisely and efficiently target specific brain regions, transforming how CNS disorders are treated. Full article

Walking is not merely locomotion but a window into the nervous system, integrating cortical, subcortical, cerebellar, spinal, and peripheral networks into a unified motor behavior. Across neurological diseases—including Parkinson’s disease, atypical parkinsonism, cerebellar ataxias, stroke, multiple sclerosis, neuropathies, neuromuscular disorders, and functional gait syndromes—gait disturbances are among the most disabling clinical features, contributing to falls, loss of independence, institutionalization, and premature mortality. Traditional bedside observation remains indispensable, but it lacks the sensitivity and reproducibility needed to capture subtle, episodic, or prodromal abnormalities. Over the past decade, advances in wearable sensors, marker-based and markerless motion capture, pressure-sensitive walkways, force plates, artificial intelligence, and machine learning have positioned digital mobility outcomes as promising, ecologically valid biomarkers of neurological function. These measures can support differential diagnosis, provide prognostic information on falls and survival, and serve as sensitive endpoints in therapeutic trials. They may also detect early abnormalities, such as increased stride-to-stride variability or prolonged double-support time, before overt clinical deterioration becomes evident. Clinical applications are increasingly evident across disorders, including distinguishing Parkinson’s disease from atypical parkinsonism, quantifying treatment response in normal-pressure hydrocephalus, tracking progression in ataxia and multiple sclerosis, predicting functional decline in motor neuron disease, and guiding rehabilitation after stroke. Integration with neuroimaging, electrophysiology, and molecular biomarkers is beginning to reveal the circuits underlying variability, instability, and freezing, positioning gait as a systems-level marker of neural integrity. Nevertheless, methodological heterogeneity, limited disease-specific validation, insufficient longitudinal data, and lack of consensus on clinically meaningful parameters continue to constrain translation. Cognitive, affective, and environmental influences also remain insufficiently represented in digital frameworks, while equity, accessibility, algorithmic bias, and privacy require careful ethical governance. Reconceptualizing gait as a “sixth vital sign” reframes mobility as a multidimensional biomarker of neural and systemic health. With harmonized protocols, robust validation, multimodal integration, and appropriate ethical frameworks, gait analysis could become a cornerstone of precision neurology. Full article

Severe Combined Immunodeficiency (SCID), Spinal Muscular Atrophy (SMA), and X-Linked Agammaglobulinemia (XLA) are rare but life-threatening genetic disorders in infants that can lead to severe infections, progressive neuromuscular degeneration, or severe immune dysfunction associated with significant morbidity and mortality if not diagnosed early. Advances in newborn screening (NBS) technologies have enabled pre-symptomatic detection of these conditions, allowing early initiation of life-saving interventions such as hematopoietic stem cell transplantation, gene therapy, and immunoglobulin replacement therapy. However, the absence of a standardized national clinical pathway linking screening, confirmatory testing, and specialist referral in Malaysia continues to contribute to delayed diagnosis and suboptimal patient outcomes. This review examines and synthesizes current evidence on the clinical pathways for early diagnosis and management of SCID, SMA, and XLA, with particular emphasis on diagnostic workflows, screening technologies, and healthcare system challenges within the Malaysian context. The review examines disease epidemiology, consequences of delayed diagnosis, and the role of expanded NBS under the Screening for Health, Intervention, Nurturing of Every Child (SHINE) program in improving early diagnosis and management. In addition, the paper outlines the current NBS landscape, the use of multiplex real-time polymerase chain reaction (PCR) assays for simultaneous detection of T-cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and survival motor neuron 1 (SMN1) gene deletion of exon 7 from dried blood spot (DBS) samples. A structured diagnostic framework incorporating screening interpretation, confirmatory testing, and urgency-based referral pathways is also proposed. By addressing current operational barriers and coordinating laboratory referral systems, expanding NBS programs could significantly improve early diagnosis and long-term outcomes for infants affected by SCID, SMA, and XLA in Malaysia. Full article

Fatigue and muscle wasting are common clinical manifestations of inherited and acquired neuromuscular disorders, including peripheral neuropathies, neuromuscular junction disorders, and myopathies. These conditions encompass a wide disease spectrum with variable prognoses, making accurate diagnosis essential for appropriate management. Congenital myasthenic syndromes (CMSs) are rare, inherited disorders characterized by impaired neuromuscular transmission. Although symptoms often begin in infancy or early childhood, later onset during adolescence or adulthood is increasingly recognized. Clinical phenotypes vary according to the underlying molecular defect, but fatigable weakness predominantly affecting axial and proximal limb muscles is a hallmark feature. We report an adolescent male who developed progressive proximal muscle weakness and wasting over several years, resulting in significant functional impairment. Initial evaluation suggested limb–girdle muscular dystrophy. However, comprehensive investigations, including whole-exome sequencing, identified a heterozygous CHRNB1 mutation consistent with postsynaptic CMS. Targeted pharmacological therapy led to clinical improvement. This case highlights the importance of considering CMS in patients presenting with limb–girdle weakness and underscores the value of genetic testing in establishing an accurate diagnosis and guiding treatment. Full article

Wilson–Turner syndrome (WTS) is an X-linked developmental disorder associated with variants in the LAS1L gene, which plays a role in ribosome biogenesis. We report a 6-year-and-5-month-old boy presenting with growth retardation, early developmental delay, and mild scoliosis. Exome sequencing analysis identified a novel hemizygous LAS1L frameshift variant, c.2082dup (p.Leu697ProfsTer59), inherited from his asymptomatic mother that was absent from population databases. Functional analysis in HEK-293T cells suggested reduced protein expression with a partial loss of function effect, while structural modeling indicated potential alteration of the C-terminal region. The patient lacked classical WTS features, including craniofacial dysmorphism, truncal obesity, hypogonadism, and neuromuscular involvement. This case expands the phenotypic spectrum of LAS1L-related disorders and highlights the consideration of LAS1L variants in children with unexplained growth failure, scoliosis, or developmental delay, even in the absence of classical WTS features. Full article

Background: 5q spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder characterized by progressive muscle weakness. Nusinersen, the first disease-modifying therapy for SMA, has demonstrated efficacy in both clinical trials and real-world studies. However, the precise timing of therapeutic onset following Nusinersen administration remains unclear. Methods: This retrospective study analyzed clinical data from patients with genetically confirmed 5q SMA who received Nusinersen treatment for at least six months at Peking University First Hospital. Motor function was assessed using standardized scales prior to each dose. Results: In total, 74 patients were screened, of whom 62 were enrolled, including 14 with type 1, 29 with type 2, and 19 with type 3 SMA. Thirty-two patients completed motor function assessments. After six months of treatment, 62.5% achieved a primary clinically meaningful response (an increase of ≥4 points in CHOP-INTEND or ≥3 points in HFMSE). Seven patients (21.9%) attained or regained motor milestones. Median improvements were 6 points in CHOP-INTEND (p = 0.001), 4 points in HFMSE (p = 0.003), and 1.5 points in RULM (p = 0.045). Further analysis indicated that the available median time to treatment response was approximately 2 months. In patients with severe scoliosis or prior spinal surgery, ultrasound-guided lumbar puncture demonstrated a high success rate (94.9%). Regarding safety, intrathecal injection-related adverse events occurred in eight patients (12.9%), and no adverse events led to treatment discontinuation. Conclusions: During the loading phase, Nusinersen provides clinical benefit for the majority of patients, with a median time to therapeutic response for monitoring of approximately 2 months. Ultrasound-guided intrathecal administration is the preferred approach for individuals with complicated spinal conditions. These findings may help guide clinical expectations for physicians, patients, and caregivers. Full article

Temporomandibular disorder (TMD) and bruxism affect a significant portion of the adult population, yet why patients with comparable occlusal findings respond so differently to identical interventions remains unexplained by both structural and biopsychosocial frameworks. Traditional occlusal paradigms identified the importance of structural relationships but could not account for clinical variability. Biopsychosocial models advanced understanding of central regulation but lack the physiological specificity needed to connect regulatory state to functional jaw behavior. This paper proposes the Functional Occlusion Regulated Model (FORM), a hierarchical framework integrating central regulatory state, masticatory performance, and structure into a coherent model of jaw function, and identifies its clinical and research implications. Narrative synthesis of the peer-reviewed literature across masticatory physiology, autonomic neuroscience, pain neuroscience, and clinical dentistry was conducted; seventy-two references are cited. Converging evidence supports a three-tier hierarchy in which autonomic and neuromuscular regulatory state is proposed to shape masticatory performance, which influences how structural occlusal conditions are expressed and clinically experienced. FORM generates four testable predictions distinguishing it from existing models, and a preliminary clinical observation documents symptom resolution through regulatory intervention alone without occlusal modification, representing an early published dental observation of this connection. FORM provides a physiologically grounded framework for understanding treatment response variability and proposes central regulatory state as a potentially important upstream influence on functional jaw outcomes. Full article

Background/Objectives: Presynaptic terminals (PTs) in the neuromuscular junction (NMJ) are essential regulators of skeletal muscle function and are responsible for the translation of electrical impulses from motor neurons into muscle contraction. The present exploratory study aimed to compare PT adaptations in spinalis muscle samples from the concave and convex regions of the spine in three cases of advanced scoliosis, which exhibited marked asymmetry in muscle development. Methods: Spinalis muscle sample pairs were retrieved after surgical procedures and subjected to immunofluorescence (IF)-based spatial analysis of PTs, histological assessment of muscle fibers, and expression analyses of inflammatory and neurotrophic proteins. Results: IF images revealed distinct differences in PT parameters between spinalis samples obtained from the corresponding concave and convex sides of spinal deformities. Advanced statistical models revealed a consistent tendency for concave spinalis muscles to develop lower PT numbers, along with decreased expression of relevant components, neurofilament M, and synaptic vesicle glycoprotein 2. Moreover, these impairments were accompanied by increased expression levels of IFN alpha, which has been previously implicated in NMJ disorders, neuropathies, and myopathies. Conclusions: In the concave regions of spinal deformities, continuously compressed spinalis muscles may be particularly susceptible to PT alteration and denervation. However, comprehensive multicenter validation studies are required to better define the relationships among PT alterations, IFN alpha expression, and muscle tissue compression. Full article

Background/Objectives: Arthrochalasia Ehlers–Danlos syndrome (aEDS) is a rare connective tissue disorder characterized by severe joint hypermobility, congenital hip dislocation, skin hyperextensibility, and muscle hypotonia. It is typically caused by heterozygous splice-site variants in COL1A1 or COL1A2, leading to exon 6 skipping. Autosomal recessive forms are extremely rare and have been reported predominantly in families from Saudi Arabia carrying the homozygous COL1A1 missense variant c.2050G>A, p.(Glu684Lys), with clinical presentations ranging from severe to mild. Methods: Clinical and molecular genetic evaluation of the patient was performed. Whole-exome sequencing was carried out, followed by confirmatory Sanger sequencing in the proband and both parents. Results: A 10-month-old boy presented with severe congenital hypotonia, bilateral hip dislocation, generalized joint hypermobility, skin hyperextensibility and craniofacial dysmorphism. A homozygous likely pathogenic variant NM_000088.4:c.2050G>A, p.(Glu684Lys) was identified in exon 31 of COL1A1; both healthy parents were confirmed to be heterozygous carriers of this variant. To our knowledge this is the first reported case in the Russian population and one of the few cases described worldwide of an autosomal recessive arthrochalasia-like EDS phenotype. Conclusions: This case further refines the phenotypic characterization associated with the recurrent homozygous COL1A1 p.(Glu684Lys) variant, demonstrating an arthrochalasia-like EDS phenotype of intermediate severity between the severe neonatal form with respiratory distress and recurrent fractures and the classical EDS. It further highlights the importance of considering collagenopathies in the differential diagnosis of congenital hypotonia, particularly in cases initially suggestive of neuromuscular disorders. Full article

Arthrogryposis multiplex congenita (AMC) is a diverse group of conditions characterized by multiple joint contractures. Although individually rare, these disorders are estimated to affect 1 in 3000–5000 live births. Their common pathophysiological mechanism is fetal akinesia, a sustained reduction of fetal movement that may arise from intrinsic disturbances—such as central nervous system malformations, motor neuronopathies, neuropathies, neuromuscular junction defects, congenital myopathies, muscular dystrophies, or metabolic diseases—or from extrinsic factors including uterine constraint, maternal illness, infections, or toxic exposures. Reduced fetal motion leads to relatively uniform clinical manifestations, known as the fetal akinesia deformation sequence (FADS), which is characterized by craniofacial anomalies, pulmonary hypoplasia, growth restriction, and contractures. Currently, AMC is classified by clinical features, such as distal arthrogryposis or lethal congenital contracture syndromes. However, advances in molecular genetics have shown wide variability among conditions classified into the same category. Prognosis is widely variable, ranging from lethal perinatal forms to non-progressive mild conditions. This review discusses AMC etiologies from a topographic standpoint, considering the different levels of the motor system involved, by combining current clinical, genetic, and pathophysiological information. Full article

Physical energy-based therapies are non-invasive adjunctive interventions that deliver mechanical, electromagnetic, light, or radiofrequency/thermal energy to tissues with the aim of reducing symptoms and improving tolerance of active rehabilitation. Osteoarthritis (OA) is a heterogeneous whole-joint disorder in which cartilage degeneration, subchondral bone remodeling, synovitis, peri-articular tissue dysfunction, neuromuscular impairment, and pain sensitization may interact to produce pain, stiffness, and activity restriction. As conservative therapy for OA, education, progressive therapeutic exercise, weight management when indicated, and self-management remain the core of care. Nevertheless, some patients cannot fully participate in exercise because of pain, fear of movement, load intolerance, comorbidity, or limited access to supervised rehabilitation. This narrative review synthesizes evidence published mainly between 2016 and 2026 for extracorporeal shock wave therapy (ESWT), photobiomodulation/low-level laser therapy (PBMT/LLLT), pulsed electromagnetic field therapy (PEMF), transfer energy capacitive and resistive/capacitive–resistive electric transfer (TECAR/CRET) therapy, body weight support and aquatic unloading strategies, and mechanosonic vibration therapies. The available literature suggests that ESWT and PBMT/LLLT may provide short- to mid-term pain and function benefits in selected patients with knee OA when parameters are aligned with evidence-supported dosing windows. PEMF and vibration therapies show promising but less consistent effects because protocols, devices, sham conditions, and populations vary. TECAR/CRET and unloading approaches are best interpreted as enabling tools that may reduce guarding, improve walking tolerance, or increase the quality of therapeutic exercise, rather than stand-alone disease-modifying treatments. Current national and society guidelines consistently prioritize exercise, education, and weight management; most of the modalities reviewed here are absent from guidelines or are supported only indirectly, which justifies cautious wording and individualized use. A practical application model is, therefore, time-limited and goal-oriented: identify the barrier to rehabilitation, select a modality with a plausible mechanism and published protocol, monitor pain and functional response, and discontinue the modality if it does not improve participation in active care. Full article