Motor Neuron Research Articles

Paraneoplastic Syndromes of the Nervous System in Patients Suffering from SCLC. A Review of the Recent Literature

Background. Paraneoplastic Neurological Syndromes (PNS) constitute a heterogeneous cluster of disease manifestations related to various cancers. Small Cell Lung Cancer (SCLC) is strongly related to PNS. This narrative review conducted a survey in the available PubMed literature to highlight the appearance of PNSs in SCLC cases and discuss published research highlights on the subject so that general practitioners can be acquainted with the medical phenomenon present in SCLC patients. Method. A narrative review of the medical literature was conducted as documentary informative research in the PubMed medical database, combined with a survey of the online e-library Google Books. The key words used were: “Paraneoplastic Neurological Syndromes” and “Small Cell Lung Cancer”. Results. Paraneoplastic syndromes are related to the presence of a malignancy and are not secondary to treatment. Paradoxally, both a malignancy and its therapeutic approach may cause a series of PNSs. Paraneoplastic cerebellar degeneration, motor neuron disorders, peripheral neuropathies, hyponatremia, and syndromes such as myasthenic Lambert-Eaton, ectopic Cushing’s, Stiffman, and Opsoclonus-myoclonus syndrome may also appear in SCLC cases. Diagnosis follows specific criteria, and they are caused by tumor-directed antibodies known as onconeural antibodies. Immunosuppressants, intravenous immunoglobulins, plasma exchange, rituximab, cyclophosphamide, azathioprine, and tocilizumab could be considered as treatment agents. Conclusions. Most patients demonstrate poor PNS treatment results with common relapse. The time for beginning treatment of PNS is discussed. A multidisciplinary team is needed for potentially earlier diagnosis and PNS improvement, better prognosis, and increased overall survival and quality of life.

Therapeutic potential of oleanolic acid in modulation of PI3K/Akt/mTOR/STAT-3/GSK-3β signaling pathways and neuroprotection against methylmercury-induced neurodegeneration

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that gradually deteriorates motor neurons, leading to demyelination, muscle weakness, and eventually respiratory failure. The disease involves several pathological processes, such as increased glutamate levels, mitochondrial dysfunction, and persistent neuroinflammation, often exacerbated by environmental toxins like mercury. This study explores the therapeutic potential of Olea europaea active phytoconstituents oleanolic acid (OLA) against ALS by targeting the overactivated PI3K/Akt/mTOR/STAT-3/GSK-3β signalling pathways. Methods involved in-silico studies, in vitro and in vivo experiments in which varying doses of methylmercury 5 mg/kg, p.o. and OLA (100 and 200 mg/kg, i.p.) were administered to rats for 42 days. Behavioural assessments, gross morphological, histopathological, and neurochemical parameters were measured in cerebrospinal fluid (CSF), blood plasma, and brain homogenates (cerebral cortex, hippocampus, striatum, midbrain, cerebellum) along with complete blood count (CBC) analysis. Results revealed OLA's significant neuroprotective properties. OLA effectively modulated targeted pathways, reducing pro-inflammatory cytokines, restoring normal levels of myelin basic protein (MBP) and neurofilament light chain (NEFL), and reducing histopathological changes. Gross pathological studies indicated less tissue damage, while CBC analysis showed improved hematology parameters. Additionally, the combination of OLA and edaravone (10 mg/kg, i.p.) demonstrated enhanced efficacy, improving motor functions and extending survival in ALS model rats. In conclusion, OLA exhibits significant therapeutic potential for ALS, acting as a potent modulator of key pathological signaling pathways. The findings suggest the feasibility of integrating OLA into existing treatment regimens, potentially improving clinical outcomes for ALS patients. However, further research must validate these findings in human clinical trials.

Effect of Trailokya Vijya Vati in Various Disease – A Review

Introduction: One of the strongest traditional medicines is Trailokya Vijaya Vati, which contains vijaya as one of its main constituents. “Trailokya Vijaya Vati” means “victory over the outer three worlds” in literal translation. According to Ayurveda, the medication is considered a “Aashukari” or drug that offers immediate comfort since it directly affects motor neurons, or “Vaat-Vaahini Naadi.” Because of this, it offers prompt relief from conditions involving different kinds of pain. Materials and Methods: Information on trailokya vijya vati in various disease was gathered from the Laghutrayi, the Brihattrayi and its commentaries, and other Ayurvedic and modern texts. Results: The binary preparation known as Trailokya Vijaya Vati, which combines Vijaya sativa with Bambusa arundianaceae, was initially documented in Rasa Vigyana, a modern Ayurvedic Alchemy and Pharmaceutics treatise. Discussion: Apasmara (seizure disorders), Rajahkashtajanya Shoola (dysmenorrhea and related symptoms), Rajayakshma (tuberculosis and similar wasting diseases), Atisara (diarrhea, colitis, IBS, IBDs, etc.), and Shoola (acute and chronic pains emerging from varied pathologies and origins) are just a few of the plethora of health conditions for which this potent formulation is renowned for producing amazing therapeutic effects. Conclusion: Trailokya Vijaya Vati improves general health and well-being by balancing the three doshas (Pitta, Kapha, and Vata) in the body The main constituents in Trailokya Vijaya Vati, a traditional medicine, are Bambusa arundinacea and Vijaya. The Ayurvedic text Rasa Vigyana describes this powerful formulation, which has been shown to have therapeutic effects for a variety of health conditions, such as anxiety, insomnia, seizures, psychological and psychosomatic disorders, dysmenorrhea, diarrhea, tuberculosis, and acute and chronic pain. The medication helps to manage seizures and has a relaxing impact on the brain.[1] Trailokya Vijaya Vati is also effective in relieving neuropathic pain. One kind of persistent pain that results from harm to the nerve system is called neuropathic pain. Trailokya Vijaya Vati’s natural components have the potential to lessen inflammation and ease neuropathic pain. Chemotherapy adverse effects can be effectively mitigated using Trailokya Vijaya Vati. Abdominal pain and renal colic

Dyke-Davidoff-Masson Syndrome in a Tanzanian patient: a case report

BackgroundDyke-Davidoff-Masson Syndrome (DDMS) is a rare neurological disorder resulting from an insult to the developing brain in utero or during early life which is characterized by refractory seizures and a wide variety of deficits. Due to its rarity, the condition is often overlooked although a detailed history and imaging can help distinguish it from other similar conditions and provide early diagnosis.Case presentationA 30-year-old African female presented with a history of recurrent seizures and intellectual disability. She was born via vaginal delivery, and her post-natal history was unremarkable. Her developmental milestones were normal until the age of three, when she was hospitalized for two weeks due to a febrile illness accompanied by generalized seizures, from which she fully recovered. On cognitive assessment, she scored 14 out of 60 on the Ravens Standard Progressive Matrices (RSPM), indicating an intellectual disability. Neurological examination revealed constructional apraxia, an upper motor neuron lesion (UMNL) affecting the facial nerve, and left-sided spastic paresis. Additionally, a slow, sinuous writhing movement involving all the fingers of her left hand was observed. A computed tomography (CT) scan of her head confirmed a diagnosis of Dyke-Davidoff-Masson syndrome (DDMS). The scan showed significant volume loss in the right cerebral hemisphere, gross dilation of the right lateral ventricle with ex-vacuo dilatation, right calvarial thickening, and hyperpneumatization of the right frontal sinus. She was managed conservatively with anticonvulsants, which effectively controlled her seizures.ConclusionIn the setting of recurrent seizures, intellectual disability, hemiparesis, or facial asymmetry, a clinician should have a high index of suspicion for DDMS. Late diagnosis is often related to intractable seizures to anticonvulsants, necessitating hemispherectomy, which is not a readily available option in limited resource settings.

A Drosophila computational brain model reveals sensorimotor processing

The recent assembly of the adult Drosophila melanogaster central brain connectome, containing more than 125,000 neurons and 50 million synaptic connections, provides a template for examining sensory processing throughout the brain1,2. Here we create a leaky integrate-and-fire computational model of the entire Drosophila brain, on the basis of neural connectivity and neurotransmitter identity3, to study circuit properties of feeding and grooming behaviours. We show that activation of sugar-sensing or water-sensing gustatory neurons in the computational model accurately predicts neurons that respond to tastes and are required for feeding initiation4. In addition, using the model to activate neurons in the feeding region of the Drosophila brain predicts those that elicit motor neuron firing5—a testable hypothesis that we validate by optogenetic activation and behavioural studies. Activating different classes of gustatory neurons in the model makes accurate predictions of how several taste modalities interact, providing circuit-level insight into aversive and appetitive taste processing. Additionally, we applied this model to mechanosensory circuits and found that computational activation of mechanosensory neurons predicts activation of a small set of neurons comprising the antennal grooming circuit, and accurately describes the circuit response upon activation of different mechanosensory subtypes6–10. Our results demonstrate that modelling brain circuits using only synapse-level connectivity and predicted neurotransmitter identity generates experimentally testable hypotheses and can describe complete sensorimotor transformations.

TDP-43 Amyloid Fibril Formation via Phase Separation-Related and -Unrelated Pathways.

Intrinsically disordered regions (IDRs) in proteins can undergo liquid-liquid phase separation (LLPS) for functional assembly, but this increases the chance of forming disease-associated amyloid fibrils. Not all amyloid fibrils form through LLPS however, and the importance of LLPS relative to other pathways in fibril formation remains unclear. We investigated this question in TDP-43, a motor neuron disease and dementia-causing protein that undergoes LLPS, using thioflavin T (ThT) fluorescence, NMR, transmission electron microscopy (TEM), and wide-angle X-ray scattering (WAXS) experiments. Using a fluorescence probe modified from ThT strategically designed for targeting protein assembly rather than β-sheets and supported by TEM images, we propose that the biphasic ThT signals observed under LLPS-favoring conditions are due to the presence of amorphous aggregates. These aggregates represent an intermediate state that diverges from the direct pathway to β-sheet-dominant fibrils. Under non-LLPS conditions in contrast (at low pH or at physiological conditions in a construct with key LLPS residues removed), the protein forms a hydrogel. Real-time WAXS data, ThT signals, and TEM images collectively demonstrate that the gelation process circumvents LLPS and yet still results in the formation of fibril-like structural networks. We suggest that the IDR of TDP-43 forms disease-causing amyloid fibrils regardless of the formation pathway. Our findings shed light on why both LLPS-promoting and LLPS-inhibiting mutants are found in TDP-43-related diseases.

Is Intraoperative Muscle Motor Evoked Potential Variability due to Fluctuating Lower Motor Neuron Background Excitability?

This pilot study tests the contribution of fluctuating lower motor neuron excitability to motor evoked potential (MEP) variability. In six pediatric patients with idiopathic scoliosis and normal neurologic examination, cascades of 30 intraoperative H-reflexes (HRs) and MEPs were evoked in the soleus muscle using constant-current stimulators and recorded through surface electrodes with a 20-second interstimulus interval. First, HRs were obtained with an intensity capable of evoking the maximum response. Subsequently, MEPs were obtained with double trains and an intensity of 700 to 900 mA. Coefficients of variation (CVs) of amplitude and area under the curve from HRs and MEPs were compared using a paired two-tailed Student t test. Coefficients of correlation between the mean CVs of HR and MEP parameters were also assessed. Pooling the results from the six patients, the mean CV of amplitude from the MEP (24.6 ± 3) was significantly higher than that from the HR (3.5 ± 4.4) (P = 0.000091). The mean CV of the MEP area under the curve (21.8 ± 4.8) was also statistically significantly higher than that from the HR area under the curve (3.4 ± 4.5) (P = 0.00091). The coefficients of correlation of the mean CV of the HR amplitude and area under the curve compared with the corresponding values of the MEP were low (r = 0.29) and very low (r = 0.03), respectively. Our results suggest that fluctuations in lower motor neuron excitability may be less important than previously thought to explain the magnitude of MEP variability. The efficacy of corticospinal volleys to recruit a larger and more stable lower motor neuron population would be critical to obtain reproducible MEPs.

A human-specific progenitor sub-domain extends neurogenesis and increases motor neuron production.

Neurogenesis lasts ~10 times longer in developing humans compared to mice, resulting in a >1,000-fold increase in the number of neurons in the CNS. To identify molecular and cellular mechanisms contributing to this difference, we studied human and mouse motor neurogenesis using a stem cell differentiation system that recapitulates species-specific scales of development. Comparison of human and mouse single-cell gene expression data identified human-specific progenitors characterized by coexpression of NKX2-2 and OLIG2 that give rise to spinal motor neurons. Unlike classical OLIG2+ motor neuron progenitors that give rise to two motor neurons each, OLIG2+/NKX2-2+ ventral motor neuron progenitors remain cycling longer, yielding ~5 times more motor neurons that are biased toward later-born, FOXP1-expressing subtypes. Knockout of NKX2-2 converts ventral motor neuron progenitors into classical motor neuron progenitors. Such new progenitors may contribute to the increased production of human motor neurons required for the generation of larger, more complex nervous systems.

A variant of the Hspa8 synaptic chaperone modifies disease in a SOD1G86R mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a relatively common and invariably fatal, paralyzing motor neuron disease for which there are few treatment options. ALS is frequently associated with ubiquitin-positive motor neuronal aggregates, a pathology suggestive of perturbed proteostasis. Indeed, cellular chaperones, which are involved in protein trafficking and degradation often underlie familial ALS. Spinal muscular atrophy (SMA) is a second, common paralytic condition resulting from motor neuron loss and muscle atrophy. While SMA is now effectively treated, mechanisms underlying motor neuron degeneration in the disease remain far from clear. To address mechanistic questions about SMA, we recently identified a genetic modifier of the disease. The factor, a G470R variant in the constitutively expressed cellular chaperone, Hspa8, arrested motor neuron loss, prevented the abnormal accumulation of neurofilament aggregates at nerve terminals and suppressed disease. Hspa8 is best known for its role in autophagy. Amongst its many clients is the ALS-associated superoxide dismutase 1 (SOD1) protein. Given its suppression of the SMA phenotype, we tested potential disease-mitigating effects of Hspa8G470R in a mutant SOD1 mouse model of ALS. Unexpectedly, disease in mutant SOD1 mice expressing the G470R variant was aggravated. Motor performance of the mice deteriorated, muscle atrophy worsened, and lifespan shrunk even further. Paradoxically, SOD1 protein in spinal cord tissue of the mice was dramatically reduced. Our results suggest that Hspa8 modulates the ALS phenotype. However, rather than mitigating disease, the G470R variant exacerbates it.

Unraveling Axonal Transcriptional Landscapes: Insights from iPSC-Derived Cortical Neurons and Implications for Motor Neuron Degeneration.

Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment specific analysis. In this study, we employ a robust RNA-sequencing (RNA-seq) approach, using microfluidic devices, to generate high-quality axonal transcriptomes from iPSC-derived cortical neurons (CNs). We achieve high specificity of axonal fractions, ensuring sample purity without contamination. Comparative analysis revealed a unique and specific transcriptional landscape in axonal compartments, characterized by diverse transcript types, including protein-coding mRNAs, RNAs encoding ribosomal proteins (RPs), mitochondrial-encoded RNAs, and long non-coding RNAs (lncRNAs). Previous works have reported the existence of transcription factors (TFs) in the axon. Here, we detect a set of TFs specific to the axon and indicative of their active participation in transcriptional regulation. To investigate transcripts and pathways essential for central motor neuron (MN) degeneration and maintenance we analyzed KIF1C-knockout (KO) CNs, modeling hereditary spastic paraplegia (HSP), a disorder associated with prominent length-dependent degeneration of central MN axons. We found that several key factors crucial for survival and health were absent in KIF1C-KO axons, highlighting a possible role of these also in other neurodegenerative diseases. Taken together, this study underscores the utility of microfluidic devices in studying compartment-specific transcriptomics in human neuronal models and reveals complex molecular dynamics of axonal biology. The impact of KIF1C on the axonal transcriptome not only deepens our understanding of MN diseases but also presents a promising avenue for exploration of compartment specific disease mechanisms.

Exposure to an environmentally representative mixture of polybrominated diphenyl ethers (PBDEs) alters zebrafish neuromuscular development

Polybrominated diphenyl ethers (PBDEs) are a prevalent group of brominated flame retardants (BFRs) added to several products such as electronics, plastics, and textiles to reduce their flammability. They are reported as endocrine disruptors and neurodevelopmental toxicants that can accumulate in human and wildlife tissues, thus making their ability to leach out of products into the environment a great cause for concern. In this study, zebrafish (Danio rerio) embryos and larvae were exposed to a wide concentration range (1.5, 15, 150 and 300 pM) of a PBDE mixture from one to six days post-fertilization (dpf). Hatching rates, mortality and general morphology were assessed during the exposure period. A delay in hatching was observed at the two highest PBDEs concentrations and mortality rate increased at 6 dpf. By 4 dpf, larvae exposed to 150 pM and 300 pM PBDEs developed an upcurved phenotype. Analysis of motor behavior at 6 dpf revealed that PBDE exposure acutely reduced locomotion. To further analyze these motor deficits, we assessed the neural network density and motor neuron and neuromuscular junctions (NMJ) development by immunostaining and imaging. Acetylated α-tubulin staining revealed a significant loss of neurons in a dose-dependent manner. Synaptic vesicle protein 2 (SV2) and ⍺-bungarotoxin (⍺-BTX) staining revealed a similar pattern, with a significant loss of SV2 and nicotinic acetylcholine receptors, thus preventing the colocalization of presynaptic neurons with postsynaptic neurons. Consistent with these results, the presence of cleaved caspase-3 and acridine orange positive cells showed increased cell death in zebrafish larvae exposed to PBDEs. Our results suggest that exposure to PBDEs leads to deficits in the zebrafish neuromuscular system through neuron death, inducing morphological and motor deficiencies throughout their development. They provide valuable insight into the neurotoxic effects of PBDEs, further highlighting the relevance of the zebrafish model in toxicological studies.

A reassessment of spinal cord pathology in severe infantile spinal muscular atrophy: Reassessment of spinal cord pathology.

Spinal muscular atrophy (SMA) is a life-limiting paediatric motor neuron disease characterised by lower motor neuron loss, skeletal muscle atrophy and respiratory failure, if untreated. Revolutionary treatments now extend patient survival. However, a limited understanding of the foundational neuropathology challenges the evaluation of therapeutic success. As opportunities to study treatment-naïve tissue decrease, we have characterised spinal cord pathology in severe infantile SMA using gold-standard techniques, providing a baseline to measure treatment success and therapeutic limitations. Detailed histological analysis, stereology and transmission electron microscopy were applied to post-mortem spinal cord from severe infantile SMA patients to estimate neuron number at the end of life; characterise the morphology of ventral horn, lateral horn and Clarke's column neuron populations; assess cross-sectional spinal cord area; and observe myelinated white matter tracts in the clinically relevant thoracic spinal cord. Ventral horn neuron loss was substantial in all patients, even the youngest cases. The remaining ventral horn neurons were small with abnormal, occasionally chromatolytic morphology, indicating cellular damage. In addition to ventral horn pathology, Clarke's column sensory-associated neurons displayed morphological features of cellular injury, in contrast to the preserved sympathetic lateral horn neurons. Cellular changes were associated with aberrant development of grey and white matter structures that affected the overall dimensions of the spinal cord. We provide robust quantification of the neuronal deficit found at the end of life in SMA spinal cord. We question long-accepted dogmas of SMA pathogenesis and shed new light on SMA neuropathology out with the ventral horn, which must be considered in future therapeutic design.

Neuroplastic alterations in common synaptic inputs and synergistic motor unit clusters controlling the vastii muscles of individuals with ACL reconstruction.

This cross-sectional study aims to elucidate the neural mechanisms underlying the control of knee extension forces in individuals with anterior cruciate ligament reconstruction (ACLR). Eleven soccer players with ACLR and nine control players performed unilateral isometric knee extensions at 10% and 30% of their maximum voluntary force (MVF). Simultaneous recordings of high-density surface electromyography (HDEMG) and force output were conducted for each lower limb, and HDEMG data from the vastus lateralis (VL) and vastus medialis (VM) muscles were decomposed into individual motor unit spike trains. Force steadiness was estimated using the coefficient of variation of force. An intramuscular coherence analysis was adopted to estimate the common synaptic input (CSI) converging to each muscle. A factor analysis was applied to investigate the neural strategies underlying the control of synergistic motor neuron clusters, referred to as motor unit modes. Force steadiness was similar between lower limbs. However, motor neurons innervating the VL on the reconstructed side received a lower proportion of CSI at low-frequency bandwidths (<5 Hz) compared with the unaffected lower limbs (P < 0.01). Furthermore, the reconstructed side demonstrated a higher proportion of motor units associated with the neural input common to the synergistic muscle, as compared with the unaffected lower limbs (P < 0.01). These findings indicate that the VL muscle of reconstructed lower limbs contribute marginally to force steadiness and that a plastic rearrangement in synergistic clusters of motor units involved in the control of knee extension forces is evident following ACLR.NEW & NOTEWORTHY Chronic quadriceps dysfunction is common after anterior cruciate ligament reconstruction (ACLR). We investigated voluntary force control strategies by estimating common inputs to motor neurons innervating the vastii muscles. Our results showed attenuated common inputs to the vastus lateralis and plastic rearrangements in functional clusters of motor neurons modulating knee extension forces in the reconstructed limb. These findings suggest neuroplastic adjustments following ACLR that may occur to fine-tune the control of quadriceps forces.

Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.

Altered RNA metabolism and misregulation of transactive response DNA-binding protein of 43kDa (TDP-43), an essential RNA-binding protein (RBP), define amyotrophic lateral sclerosis (ALS). Intermediate-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with increased risk for ALS, but the underlying biological mechanisms remain unknown. Here, we studied the spatiotemporal dynamics and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (rat) primary cortical neurons and mouse motor neuron axons invivo. We report that Ataxin-2 polyQ expansions aberrantly sequester TDP-43 within RNP condensates and disrupt both its motility along the axon and liquid-like properties. We provide evidence that Ataxin-2 governs motility and translation of neuronal RNP condensates and that Ataxin-2 polyQ expansions fundamentally perturb spatial localization of mRNA and suppress local translation. Overall, our results support a model in which Ataxin-2 polyQ expansions disrupt stability, localization, and/or translation of critical axonal and cytoskeletal mRNAs, particularly important for motor neuron integrity.

686P Identification and characterization of actionable deep intron 8 IGHMBP2 hotspot pathogenic variants through motor neuron RNAseq and whole genome

686P Identification and characterization of actionable deep intron 8 IGHMBP2 hotspot pathogenic variants through motor neuron RNAseq and whole genome

A rare case of tetanus with early manifestation of apnea but without trismus

BackgroundTetanus is a life-threatening disease caused by tetanus neurotoxin (TeNT) produced by Clostridium tetani. Early symptoms of tetanus are trismus and muscle stiffness, both caused by spasticity. TeNT mainly exerts its effect by impairment of inhibitory neurons in the spine and brainstem, resulting in the hyperactivity of motor neurons, which causes spasticity and muscle spasms. Apnea is not a symptom that is predicted to occur in the early stages. Case ReportWe present a rare case of severe tetanus with an early manifestation of apnea but without trismus. We believe that apnea was caused by spasms of the intercostal muscles and its early manifestation was due to a high load of TeNT, considering that the speed of disease progression is related to disease severity. We hypothesize that the absence of trismus was also due to a high load of TeNT, exerting toxic effect at the neuromuscular junction and causing flaccid paralysis of the massetersWhy Should an Emergency Physician Be Aware of This?:Since there is no diagnostic laboratory test for tetanus, emergency physicians must be well aware of symptoms that may or may not appear in tetanus. Tetanus should be considered as a differential diagnosis for patients arriving at the emergency department with apnea as an early symptom. The absence of trismus should not rule out the possibility of tetanus.

Onasemnogene abeparvovec gene therapy for spinal muscular atrophy: A cohort study from the United Arab Emirates.

Spinal muscular atrophy (SMA) manifests with progressive motor neuron degeneration, leading to muscle weakness. Onasemnogene abeparvovec is a US Food and Drug Administration-approved gene replacement therapy for SMA. This study aimed to present short-term data of children in the United Arab Emirates (UAE) treated with onasemnogene abeparvovec, particularly in the context of children requiring invasive ventilatory support via tracheostomy. A retrospective analysis was performed on 60 children who received onasemnogene abeparvovec. All these children received corticosteroids. They were followed up for up to 3 months. Motor function assessments were performed before and after the gene therapy. Comprehensive clinical evaluations, including pulmonary functions, were performed at baseline and the 3-month mark. Forty-three percent were male, and the mean age at the time of infusion was 29.6 months (SD ± 17.2). The mean weight was 10.1 kg (SD 2.6). All children demonstrated marked improvements in motor function within 3 months of gene therapy administration. No adverse effects attributable to corticosteroid therapy were observed. Positive clinical outcomes, including increased ventilator-free intervals, reduced antibiotic dependency, and fewer hospital admissions, were reported among children with invasive ventilation via tracheostomy. This study demonstrates the favorable tolerability and promising responses to onasemnogene abeparvovec in invasively ventilated pediatric patients. Early improvements in motor function, as observed within 3 months post-treatment, suggest its potential as a viable therapeutic option for this vulnerable patient population.

Dtx2 Deficiency Induces Ependymo-Radial Glial Cell Proliferation and Improves Spinal Cord Motor Function Recovery.

Traumatic injury to the spinal cord can lead to significant, permanent disability. Mammalian spinal cords are not capable of regeneration; in contrast, adult zebrafish are capable of such regeneration, fully recovering motor function. Understanding the mechanisms underlying zebrafish neuroregeneration may provide useful information regarding endogenous regenerative potential and aid in the development of therapeutic strategies in humans. DELTEX proteins (DTXs) regulate a variety of cellular processes. However, their role in neural regeneration has not been described. We found that zebrafish dtx2, encoding Deltex E3 ubiquitin ligase 2, is expressed in ependymo-radial glial cells in the adult spinal cord. After spinal cord injury, the heterozygous dtx2 mutant fish motor function recovered quicker than that of the wild-type controls. The mutant fish displayed increased ependymo-radial glial cell proliferation and augmented motor neuron formation. Moreover, her gene expression, downstream of Notch signaling, increased in Dtx2 mutants. Notch signaling inactivation by dominant-negative Rbpj abolished the increased ependymo-radial glia proliferation caused by Dtx2 deficiency. These results indicate that ependymo-radial glial proliferation is induced by Dtx2 deficiency by activating Notch-Rbpj signaling to improve spinal cord regeneration and motor function recovery.

124P Hidden in plain sight: genome reanalysis to identify an intragenic novel variant in the SMN locus in a patient with an undiagnosed lower motor neuron disease

124P Hidden in plain sight: genome reanalysis to identify an intragenic novel variant in the SMN locus in a patient with an undiagnosed lower motor neuron disease

Clinical characterization and founder effect analysis in Chinese amyotrophic lateral sclerosis patients with SOD1 common variants

Objective In the Asian population, SOD1 variants are the most common cause of amyotrophic lateral sclerosis (ALS). To date, more than 200 variants have been reported in SOD1. This study aimed to summarize the genotype–phenotype correlation and determine whether the patients carrying common variants derive from a common ancestor. Methods A total of 103 sporadic ALS (SALS) and 11 familial ALS (FALS) probands were included and variants were screened by whole exome sequencing. Functional analyses were performed on fibroblasts derived from patients with SOD1 p.V48A and control. Haplotype analysis was performed in the probands with p.H47R or p.V48A and their familial members. Results A total of 25 SOD1 variants were identified in 44 probands, in which p.H47R, p.V48A and p.C112Y variants were the most common variants. 94.3% and 60% of patients with p.H47R or p.V48A had lower limb onset with predominant lower motor neurons (LMNs) involvement. Patients with p.H47R had a slow progression and prolonged survival time, while patients with p.V48A exhibited a duration of 2–5 years. Patients with p.C112Y variant showed remarkable phenotypic variation in age at onset and disease course. SOD1V48A fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast. Haplotype analysis showed that seven families had two different haplotypes. p.H47R and p.V48A variants did not originate from a common founder. Conclusions Our study expanded the understanding of the genotype–phenotype correlation of ALS with SOD1 variants and revealed that the common p.H47R or p.V48A variant did not have a founder effect.