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Amyotrophic lateral sclerosis, or motor neuron disease, is an uncommon progressive neurological disorder. Professionals working in the perioperative field may encounter patients with amyotrophic lateral sclerosis only rarely. The relevant published literature on amyotrophic lateral sclerosis is broad in scope, but a contemporary review focused on the perioperative period is absent. This structured narrative review seeks to provide a summary of the contemporary management of patients and then focuses on eliciting if there are perioperative management considerations specific to amyotrophic lateral sclerosis that can be optimised. A comprehensive structured narrative literature review, including grey literature searching, indicated worsening ventilatory failure is of prime concern but that patients may present with a broad range of neurological symptoms, and that cardiovascular and cognitive dysfunction specific to amyotrophic lateral sclerosis may exist and be occult. Exacerbation of neuromuscular weakness during the perioperative period is multifaceted and requires the application of a high standard of the core principles of surgical and anaesthetic management of neuromuscular disease. Standard perioperative approaches require rigorous attention and potential exists for significant alteration. There is a potential high risk of postoperative increased morbidity from neurological decline and mortality from pulmonary complications. A meticulous approach to planning preoperative assessment, shared decision-making, intraoperative and postoperative care is required. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the clinical evolution, structural anomalies associated and neonatal outcomes of fetal neck hyperextension in two cases with prenatal ultrasound diagnosis in two different gestational ages. In 2019, two cases of fetal hyperextension came to our attention. Follow-up information was obtained from hospital medical records and obstetrical care providers. Two woman were investigated in our institution for the presence of fetal abnormalities in the II and III trimester, respectively. In both cases, fetal attitude presented persistent fetal neck hyperextension. One of the two fetuses had a mild ventriculomegaly and suspected for micrognathia. Both had an amniotic fluid increase. One of two had no movement in the lower and upper limbs in ultrasound scans associated with club foot and suspected scoliosis. Both were born by cesarean section with pretty different prognosis: one healthy baby had a retarded psychomotor development and the other one died after 6 months. A precise diagnosis was possible only in one case. The early identification of a fetus with persistent hyperextension of the fetal head should require a detailed ultrasound exam for structural abnormalities and a careful prenatal counseling due to possible postnatal outcome. [ABSTRACT FROM AUTHOR]

Pre-operative respiratory assessment of children with spinal deformity requires an understanding of the deformity, the proposed surgery and most importantly the children themselves. The assessment and the tailoring of investigations will differ according to the age, developmental level and co-morbidities of the child. This review uses a mixture of evidence and case-based practice in order to set out a suggested framework for pre-operative spinal assessment, and suggested recommendations that may be provided to best support children undergoing surgery for spinal deformity. [ABSTRACT FROM AUTHOR]

Epidural analgesia is effective and an accepted treatment for postoperative pain. Urinary retention is a known complication, but its description is mostly in the adult literature. Management of urinary catheter (UC) placement and removal is an important consideration in children receiving epidural analgesia. This is a single-center, retrospective observational study which examined UC management in children undergoing lower extremity orthopedic surgery under general anesthesia with or without epidural analgesia from January 2019–June 2021. Of 239 children included, epidural analgesia was used in 57 (23.8%). They were significantly younger and had more co-morbidities. In total, 75 UCs were placed in the OR, 9 in the ward, and 7 re-inserted. UC placement in the epidural group was more common (93% vs. 17%, p < 0.001) and remained longer (3 days vs. 1 day, p = 0.01). Among children without intra-operative UC, ward placement was more common in the epidural cohort (60% vs. 1.6%, p = 0.007). OR UC placement and ward re-insertion were more common in children with neuromuscular disease (61% vs. 22%, p < 0.001), (17% vs. 3%, p = 0.001), respectively. Based on these findings, we hypothesize that it is justifiable to routinely place a UC intra-operatively in children who undergo hip or lower extremity surgery and are treated with epidural analgesia, and caution is advised before early UC removal in orthopedic children with NMD. [ABSTRACT FROM AUTHOR]

Rigid spine syndrome is a rare childhood-onset myopathy characterised by slowly progressive or non-progressive scoliosis, neck and spine contractures, hypotonia, and respiratory insufficiency. Biallelic variants in SELENON account for most cases of rigid spine syndrome, however, the underlying genetic cause in some patients remains unexplained. We used exome and genome sequencing to investigate the genetic basis of rigid spine syndrome in patients without a genetic diagnosis. In five patients from four unrelated families, we identified biallelic variants in HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase). These included six missense variants and one frameshift variant distributed throughout HMGCS1. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some patients; one patient died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles. HMGCS1 encodes a critical enzyme of the mevalonate pathway and has not yet been associated with disease. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy resembling our cohort's presentation. Analyses of recombinant human HMGCS1 protein and four variants (p.S447P, p.Q29L, p.M70T, p.C268S) showed that all mutants maintained their dimerization state. Three of the four mutants exhibited reduced thermal stability, and two mutants showed subtle changes in enzymatic activity compared to the wildtype. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. We demonstrate that the four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays. Additionally, we demonstrate the potential for mevalonic acid supplementation to reduce phenotypic severity in mutant zebrafish. Overall, our analyses suggest that these missense variants in HMGCS1 act through a hypomorphic mechanism. Here, we report an additional component of the mevalonate pathway associated with disease and suggest biallelic variants in HMGCS1 should be considered in patients presenting with an unresolved rigid spine myopathy phenotype. Additionally, we highlight mevalonoic acid supplementation as a potential treatment for patients with HMGCS1-related disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Ptosis and proximal weakness may develop in multiple diseases including oculopharyngeal muscular dystrophy (OPMD) and myasthenia gravis (MG). These two entities can be challenging to differentiate since they may have important clinical and neurophysiological overlap. Systemic lupus erythematosus (SLE), a common autoimmune disease, has been described in association with MG.We present a woman in her 60s with fluctuating bilateral ptosis and proximal muscle weakness. Single fibre electromyography showed increased jitter. Her brother has genetically proven OPMD. The investigation revealed a positive genetic test for OPMD and positive antibodies for acetylcholine receptor. Additionally, she has SLE, treated with hydroxychloroquine for more than 30 years.This case highlights the importance of a thoughtful anamnesis with personal and familial history and raises awareness for the rare coexistence of three pathologies with some common clinical characteristics but different treatments and management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Tuberculosis is a global disease and presents with an array of neurological manifestations. Presentation varies from meningitis, radiculo-myelitis, tuberculoma, brain abscess and other combinations. The association of Guillain-Barre' syndrome (GBS) with tuberculosis has been reported in a few reports. Neurological tuberculosis association with GBS is very rare. We here report an early adolescent patient with tubercular meningitis and tuberculoma who presented with acute areflexic quadriparesis and was subsequently diagnosed as an acute motor sensory axonal neuropathy variant of GBS. The diagnosis was confirmed with clinical examination, nerve conduction studies, positive anti-ganglioside antibody and clinical response to intravenous immunoglobulin. We present a case of an association between tubercular meningitis clinically presenting as encephalopathy and acute flaccid weakness due to GBS., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials., Methods and Analysis: We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a 'living' overview of the ALS clinical trial landscape., Ethics and Dissemination: No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Spinal Muscular Atrophy with Respiratory Distress (SMARD1) is a lethal infantile disease, characterized by the loss of motor neurons leading to muscular atrophy, diaphragmatic paralysis, and weakness in the trunk and limbs. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause a wide spectrum of motor neuron disease. Though mutations in IGHMBP2 are mostly associated with SMARD1, milder alleles cause the axonal neuropathy, Charcot-Marie-Tooth disease type 2S (CMT2S), and some null alleles are potentially a risk factor for sudden infant death syndrome (SIDS). Variant heterogeneity studied using an allelic series can be informative in order to create a broad spectrum of models that better exhibit the human variation. We previously identified the nmd2J mouse model of SMARD1, as well as two milder CMT2S mouse models. Here, we used CRISPR-Cas9 genome editing to create three new, more severe Ighmbp2 mouse models of SMARD1, including a null allele, a deletion of C495 (C495del) and a deletion of L362 (L362del). Phenotypic characterization of the IGHMBP2L362del homozygous mutants and IGHMBP2C495del homozygous mutants respectively show a more severe disease presentation than the previous nmd2J model. The IGHMBP2L362del mutants lack a clear denervation in the diaphragm while the IGHMBP2C495del mutants display a neurogenic diaphragmatic phenotype as observed in SMARD1 patients. Characterization of the Ighmbp2-null model indicated neo-natal lethality (median lifespan = 0.5 days). These novel strains expand the spectrum of SMARD1 models to better reflect the clinical continuum observed in the human patients with various IGHMBP2 recessive mutations., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A boy with nonambulatory Duchenne muscular dystrophy (DMD) tested positive for exon 63 duplication and exhibited intellectual disability, overweight and dyslipidaemia. The patient underwent a comprehensive multidisciplinary approach involving pharmacological and non-pharmacological interventions. Despite challenges, such as socioeconomic constraints and limited access to advanced therapies, the patient received tailored care. The management included prednisone medication, dietary modifications and psychological support. The patient's journey highlighted the complex interplay of medical and psychosocial factors affecting DMD patients in resource-limited settings. Regular monitoring and the involvement of the patient's family in a peer group were arranged to improve overall quality of life. The case underscores the need for accessible and holistic care for DMD patients, addressing both medical and psychosocial challenges., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We present a boy in middle childhood with a medical history of arthrochalasiaEhlers-Danlos syndrome who was diagnosed with scoliosis as a toddler. His treatment began at a regional children's hospital, where initial spine radiographs demonstrated a 43.6° dextroscoliosis curve with the apex at L3. He was initially treated with a Boston brace, and the family was informed that MAGEC (Magnetic Expansion Control) growing rods were likely the definitive treatment due to the high likelihood of progression given the patient's large Cobb angle. However, the decision was made by the family and the Ehlers-Danlos syndrome specialist to proceed with the Wood-Rigo-Cheneau derotational brace., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

High levels of pre-existing antibodies are a major challenge for the application of viral vectors since they can severely limit their efficacy. To identify promising candidates among adeno-associated virus (AAV) based vectors for future gene therapies for the treatment of hereditary neuromuscular disorders (NMDs), we investigated the antibody levels in sera from patients with NMDs against 18 AAV types, including 11 AAVs with wild-type capsids, 5 AAVs with peptide-modified capsids and 2 AAVs with shuffled capsids. With regard to the wild-type capsid AAVs, the lowest binding antibody levels were detected against AAV6, AAV5, AAV12 and AAV9, whereas the highest binding antibody levels were detected against AAV10, AAV8, AAV1, and AAV2. The lowest neutralizing antibody levels against wild-type AAVs were detected against AAV12, AAV5, AAV9, AAV7, AAV8 and AAV10, and the highest neutralizing antibody levels were detected against AAV13, AAV2 and AAV3. Interestingly, the influence of peptide modifications or shuffling of AAV capsids on antibody binding and AAV neutralization seemed to depend on the parental AAV. While the sex of the serum donors had no significant impact on binding or neutralizing antibody levels, we observed a trend to higher binding antibodies in older serum donors against some AAV types and a clear positive correlation of neutralizing antibody titers with the age of the serum donors. The disease status on the other hand did not have a meaningful impact on antibody levels, with no changes in AAV neutralization. Our data indicate that several wild-type or peptide-modified AAV may be good candidates for therapeutic application due to low pre-existing antibody levels, and that the age of potential recipients rather than their health status with regard to NMDs has the biggest impact on vector applicability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Wang, Klann, Wiedtke, Sano, Fischer, Schiller, Elfert, Güttsches, Weyen, Grimm, Vorgerd and Bayer.)

Neisseria gonorrhoeae causes a common sexually transmitted infection with manifestations ranging from asymptomatic to urethritis and pelvic inflammatory disease to disseminated infections including septic arthritis. Serious complications may arise in unrecognised or inappropriately treated infections.We report a young, healthy woman who developed fever and joint pain and was diagnosed with an inflammatory arthritis. After starting immune suppressing treatments, she experienced right wrist drop and progressive muscle atrophy, joint contractures and sensory loss. Electrodiagnostic studies showed patchy, mixed neurogenic and myopathic features. Areas of muscle oedema on extremity MRI led to a right brachioradialis biopsy, which showed only nonspecific changes. Other testing, including lumbar puncture and MRI of the brain/spine was noncontributory. Additional history revealed unprotected intercourse with a new partner prior to symptom onset. Urine gonorrhoeae PCR was positive, and right shoulder arthrocentesis confirmed septic arthritis. After intravenous antibiotic treatment with ceftriaxone, she demonstrated slow, incomplete symptomatic improvement., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Tubular aggregates (TA) are skeletal muscle structures that arise from the progressive accumulation of sarcoplasmic reticulum proteins, mainly with aging. Muscle regeneration plays a role in TA formation. TA quantification may aid in the evaluation of muscle aging and genetic muscle degeneration. TA form over time, appears in aging in normal murine muscles. TA reduction in injured conditions may be due to the degeneration-regeneration process in muscles, with loss of damaged muscle fibers and formation of new fibers that do not present protein aggregation. These new regenerated fibers do not improve the function capacity of the aged muscle. Here, we present a methodology for labeling and identifying tubular aggregates in muscle fibers and also the standardization of its quantification., (© 2024. Springer Science+Business Media, LLC.)

Neurological and neuromuscular diseases resulting from familial, sporadic, or de novo mutations have devasting personal, familial, and societal impacts. As the initial product of DNA transcription, RNA transcripts and their associated ribonucleoprotein complexes provide attractive targets for modulation by increasing wild-type or blocking mutant allele expression, thus relieving downstream pathological consequences. Therefore, it is unsurprising that many existing and under-development therapeutics have focused on targeting disease-associated RNA transcripts as a frontline drug strategy for these genetic disorders. This review focuses on the current range of RNA targeting modalities using examples of both dominant and recessive neurological and neuromuscular diseases., (© 2024 Bubenik et al.; Published by Cold Spring Harbor Laboratory Press.)

Background. Limited knowledge is available regarding the impact of oculopharyngeal muscular dystrophy (OPMD) impairments on participation in daily and social activities, which currently hinders occupational therapy practice in this population. Purpose. To describe social participation and explore influencing factors in individuals with OPMD. Methods. Thirty-four individuals were assessed with outcome measures of social participation restrictions, mobility, dysphagia, and fatigue. Spearman correlations and stepwise multiple regression analyses were used. Findings. Results show a negative impact of OPMD on the social participation level, which was more important in participants aged over 60 years. Walking speed was found to be the main factor influencing participation levels for daily and social activities, with faster walking associated with higher participation. Conclusions. This study emphasizes the impact of OPMD impairments and limitations on social participation level. While dysphagia is obviously an important impairment to consider, interventions for mobility limitations should also be considered during clinical follow-up.

Spinal muscular atrophy (SMA) is a recessive developmental disorder caused by the genetic loss or mutation of the gene SMN1 (survival of motor neuron 1). SMA is characterized by neuromuscular symptoms and muscle weakness. Several years ago, SMA treatment underwent a radical transformation, with the approval of 3 different SMN-dependent disease-modifying therapies. This includes 2 SMN2 splicing therapies - risdiplam and nusinersen. One main challenge for type II SMA patients treated with these drugs is ongoing muscle fatigue, limited mobility, and other skeletal problems. To date, few molecular studies have been conducted on SMA patient-derived tissues after treatment, limiting our understanding of what targets remain unchanged after the spinal cord-targeted therapies are applied. Therefore, we collected paravertebral muscle from 8 type II patients undergoing spinal surgery for scoliosis and 7 controls. We used RNA-seq to characterize their transcriptional profiles and correlate these molecular changes with muscle histology. Despite the limited cohort size and heterogeneity, we observed a consistent loss of oxidative phosphorylation (OXPHOS) machinery of the mitochondria, a decrease in mitochondrial DNA copy number, and a correlation between signals of cellular stress, denervation, and increased fibrosis. This work provides new putative targets for combination therapies for type II SMA.

Palliative care is important for many patients who require noninvasive ventilation. The particular needs of patients with neuromuscular disease and chronic obstructive pulmonary disease are explored. Advance care planning is explored with tips for undertaking this important communication task. Brief comments regarding symptom burden, weaning, voluntary assisted dying, and self-care are included., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Initiation of home non-invasive ventilation (NIV) requires careful consideration of the patient's condition, motivation, expectations, wishes, and social circumstances. The decision to start NIV depends on a combination of factors including patient symptoms and objective evidence of nocturnal hypoventilation. A solid understanding of the underlying pathophysiology is key to a systematic and well-balanced clinical approach to titrating NIV. The location where NIV is initiated is not the most relevant issue, provided that it is a comfortable, safe environment in which adequate monitoring can be assured. The majority of patients prefer their own home for treatment initiation., Competing Interests: Disclosure During the preparation of this work the authors did not use any AI and AI-assisted technologies in the writing process, except from endnote to order the references., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Telemonitoring in non-invasive ventilation is constantly evolving to enable follow-up of adults and children. Depending on the device and manufacturer, different ventilator variables are displayed on web-based platforms. However, high-granularity measurement is not always available remotely, which precludes breath-by-breath waveforms and precise monitoring of nocturnal gas exchange. Therefore, telemonitoring is mainly useful for monitoring utilization of the device, leaks, and respiratory events. Coordinated relationships between patients, homecare providers, and hospital teams are necessary to transform available data into diagnosis and actions. Telemonitoring is time and cost-consuming. The balance between cost, workload, and clinical benefit should be further evaluated., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD) are neuromuscular disorders that affect muscular function. The most common causes of morbidity and mortality are respiratory complications, including restrictive lung disease, ineffective cough, and sleep-disordered breathing. The paradigm of care is changing as new disease-modifying therapies are altering disease trajectory, outcomes, expectations, as well as patient and caregiver experiences. This article provides an overview on therapeutic advances for SMA and DMD in the last 10 years, with a focus on the effects of disease-modifying therapies on respiratory function., Competing Interests: Disclosure Dr R. Amin is a committee member of the American College of Chest Physicians and a pediatrics committee member of the American Thoracic Society. R. Amin holds research grants from Canadian Institutes of Health Research, Canada, Cure SMA Canada, Canada, Muscular Dystrophy Canada, Canada, VHA Home Healthcare, Canada, Boehringer-Ingelheim, Germany, Medigas, Canada, ProResp, Canada, Baxter Corporation Endowment Fund for Home Care, United States, and Ontario Ministry of Health and Long-Term Care, Canada. Dr L. Xiao is a committee member of the American College of Chest Physicians. Dr. Xiao holds research grants from Muscular Dystrophy Canada, Baxter Corporation Endowment Fund for Home Care, International Pediatric Sleep Association, United States, and the Sleep Research Society Foundation, United States., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Undiagnosed chronic hypercapnic respiratory failure may be encountered during the evaluation of sleep-related breathing disorders at the sleep clinic. This article reviews the mechanism of chronic hypercapnic respiratory failure and the systematic approach to the assessment of specific sleep disorders associated with nocturnal hypoventilation encountered in clinical practice., Competing Interests: Disclosure The authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Typically, patients with progressive neuromuscular disorders (NMDs) develop acute respiratory failure (ARF), are intubated, and when failing spontaneous breathing trials (SBTs) undergo a tracheotomy and receive tracheostomy mechanical ventilation (TMV). However, increasing numbers of patients use nasal noninvasive ventilation (NIV), initially for sleep and this is extended to continuous dependence (CNVS). This can be used as a strategy to assist in successful extubation . We retrospectively reviewed 19 centers offering CNVS and mechanical insufflation-exsufflation (MI-E) as an alternative to TMV. Methods: Centers with publications or presentations concerning CNVS outcomes data were pooled for amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy type 1 (SMA1). Progression to CNVS dependence without hospitalization, duration of dependence, and extubations and decannulations to CNVS were recorded. Prolongation of life was defined by duration of CNVS dependence without ventilator free breathing ability (VFBA). Results: There were 1623 part time (

Paediatric neuromuscular diseases are under-recognised and under-diagnosed in Africa, especially those of genetic origin. This may be attributable to various factors, inclusive of socioeconomic barriers, high burden of communicable and non-communicable diseases, resource constraints, lack of expertise in specialised fields and paucity of genetic testing facilities and biobanks in the African population, making access to and interpretation of results more challenging. As new treatments become available that are effective for specific sub-phenotypes, it is even more important to confirm a genetic diagnosis for affected children to be eligible for drug trials and potential treatments. This perspective article aims to create awareness of the major neuromuscular diseases clinically diagnosed in the South African paediatric populations, as well as the current challenges and possible solutions. With this in mind, we introduce a multi-centred research platform (ICGNMD), which aims to address the limited knowledge on NMD aetiology and to improve genetic diagnostic capacities in South African and other African populations.

Respiratory muscle paralysis is known as a very common complication of Guillain–Barré syndrome (GBS). However, most research has focused on its later stages rather than its earlier stages, including the prognosis of patients with this condition, or factors that act as early predictors of risk. Therefore, our study aimed to identify early predictors of respiratory muscle paralysis in patients with GBS and determine the short-term prognosis of such patients. We recruited 455 GBS patients (age ≥ 18) who had been hospitalized in the First Affiliated Hospital of Harbin Medical University between 2016 and 2021, retrospectively. We recorded clinical and laboratory data and used linear and logistic regression analysis to investigate the relationship between early clinical, examination results, and subsequent respiratory muscle paralysis. Among the 455 patients, 129 were assigned to a respiratory muscle paralysis group and 326 were assigned to a non-respiratory muscle paralysis group. Compared with the non-affected group, the time from onset to admission was shorter (p = 0.0003), and the Medical Research Council (MRC) score at admission and discharge was smaller in the affected group (p < 0.0001). Compared with the non-affected group, the affected group had higher Hughes and Erasmus GBS Respiratory Insufficiency Score (EGRIS) scores at admission and longer hospital stays (p < 0.0001). Patients in the affected group were more likely to have bulbar palsy and lung infections (p < 0.0001). To conclude, bulbar palsy, a higher EGRIS score and Hughes score at admission, a lower MRC score, and a shorter time between onset and admission, are all predictive risk factors for respiratory muscle paralysis in patients with GBS. An increase in any of these factors increases the risk of muscle paralysis. Patients with respiratory muscle paralysis have a poorer short-term prognosis than those without respiratory muscle paralysis. Therefore, we should attempt to identify patients with one or more of these characteristics in the early stages of admission, provide ventilation management, and administer IMV treatment if necessary.

Mitochondrial fission and fusion are required for maintaining functional mitochondria. The mitofusins (MFN1 and MFN2) are known for their roles in mediating mitochondrial fusion. Recently, MFN2 has been implicated in other important cellular functions, such as mitophagy, mitochondrial motility, and coordinating endoplasmic reticulum-mitochondria communication. In humans, over 100 MFN2 mutations are associated with a form of inherited peripheral neuropathy, Charcot–Marie–Tooth disease type 2A (CMT2A). Here we describe an ENU-induced mutant mouse line with a recessive neuromuscular phenotype. Behavioral screening showed progressive weight loss and rapid deterioration of motor function beginning at 8 weeks. Mapping and sequencing revealed a missense mutation in exon 18 of Mfn2 (T1928C; Leu643Pro), within the transmembrane domain. Compared to wild-type and heterozygous littermates, Mfn2L643P/L643P mice exhibited diminished rotarod performance and decreases in activity in the open field test, muscular endurance, mean mitochondrial diameter, sensory tests, mitochondrial DNA content, and MFN2 protein levels. However, tests of peripheral nerve physiology and histology were largely normal. Mutant leg bones had reduced cortical bone thickness and bone area fraction. Together, our data indicate that Mfn2L643P causes a recessive motor phenotype with mild bone and mitochondrial defects in mice. Lack of apparent nerve pathology notwithstanding, this is the first reported mouse model with a mutation in the transmembrane domain of the protein, which may be valuable for researchers studying MFN2 biology.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival of motor neuron 1 (SMN1) gene, which leads to a reduced level in the SMN protein within cells. Patients with SMA suffer from a loss of alpha motor neurons in the spinal cord leading to skeletal muscle atrophy in addition to deficits in other tissues and organs. Patients with severe forms of the disease require ventilator assistance and typically succumb to the disease due to respiratory failure. Onasemnogene abeparvovec is an adeno-associated virus (AAV)-based gene therapeutic that has been approved for infants and young children with SMA, and it is delivered through intravenous administration using a dose based on the weight of the patient. While excellent outcomes have been observed in treated patients, the greater viral dose necessary to treat older children and adults raises legitimate safety concerns. Recently, onasemnogene abeparvovec use was investigated in older children through a fixed dose and intrathecal administration, a route that provides a more direct delivery to affected cells in the spinal cord and central nervous system. The promising results observed in the STRONG trial may support approval of onasemnogene abeparvovec for a greater proportion of patients with SMA.

Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to < 16 years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD. Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014. [ABSTRACT FROM AUTHOR]

Objectives: Spinal muscular atrophy with lower extremity predominance 1 (SMALED1) and Charcot-Marie-Tooth diseasetype 2O (CMT2O) are two kinds of hereditary neuromuscular diseases caused by DYNC1H1 mutations. In this study, we reported two patients with SMALED1 caused by DYNC1H1 mutations. The genotype-phenotype correlations were further analyzed by systematically reviewing previous relevant publications. Materials and Methods: Two patients' with SMALED1 and their parents' clinical data were collected, and detailed clinical examinations were performed. WES was then applied, which was confirmed by Sanger sequencing. PubMed, Web of Science, CNKI, and Wanfang Data were searched, and all publications that met the inclusion criteria were carefully screened. Any individual patient without a detailed description of clinical phenotypes was excluded. Results: The two patients manifested delayed motor milestones and muscle wasting of both lower extremities. The diagnosis was further confirmed as SMALED1. Genetic testing revealed heterozygous DYNC1H1 mutations c.1792C>T and c.790C>G; the latter is a novel dominant mutation. Genotype-phenotype analysis of DYNC1H1 variants and neuromuscular diseases revealed that mutations in the DYN1 region of DYNC1H1 protein were associated with a more severe phenotype, more complicated symptoms, and more CNS involvement than the DHC_N1 region. Conclusion: Our study potentially expanded the knowledge of the phenotypic and genetic spectrum of neuromuscular diseases caused by DYNC1H1 mutations. The genotype-phenotype correlation may reflect the pathogenesis underlying the dyneinopathy caused by DYNC1H1 mutations. [ABSTRACT FROM AUTHOR]

Pompe disease is a rare autosomal recessive disorder caused by the deficiency of acid α-glycosidase resulting in accumulation of glycogen in the lysosomes. The late-onset form of the disease (LOPD) causes primarily progressive muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT) introduced in 2006, showed mild improvement or stabilization of the symptoms although long-term data are limited. Aim of the study was to describe the progression of body composition and walking ability in LOPD patients receiving ERT consistently for 9 years. Lean body mass, bone mineral density, body fat and 6 min walking distance were assessed in three male and three female LOPD patients (height 165.8 ± 11.2 cm, age 42.3 ± 11.8yrs, body mass 71.1 ± 20.8 kg, at study entry), every three years, for 9 years since ERT initiation (T0, T3, T6, T9). Total body and upper extremities' lean mass remained unchanged (p < 0.05), but it was decreased for the lower extremities (T3:13.06 ± 3.848 kg vs. T9:11.63 ± 3.49 kg, p < 0.05). Lean body mass was not significantly different after 9 years of ERT compared to before the ERT initiation (T0 to T9). Bone mineral density remained unchanged. Percent body fat increased (T0:39.1 ± 10.3%, vs. T9:43.1 ± 10.4%, p < 0.05). Six minute walking distance tended to increase after 3 years of ERT and decreased gradually thereafter, with no difference between T0-T9. Lean mass of the lower extremities adjusted for body weight was significantly correlated with 6 min walking distance (r = 0.712, p < 0.05). The current data show that enzyme replacement therapy may preserve lean body mass, bone mineral density and walking capacity in LOPD patients. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy is a rare, neurodegenerative disorder caused by biallelic deletions in the survival motor neuron (SMN1) gene. Onasemnogene abeparvovec is a one-time, intravenous gene replacement therapy designed to deliver the SMN1 transgene. Although available in many geographies, it is not approved globally. The Global Managed Access Program (GMAP) expanded treatment access to patients in countries where treatment was not approved. Previous onasemnogene abeparvovec clinical trials included patients with body weight <8.5 kg. Through GMAP, children weighing ≥8.5 kg received onasemnogene abeparvovec. We describe safety data for heavier patients in GMAP.Methods: GMAP records were reviewed to identify patients weighing ≥8.5 kg at onasemnogene abeparvovec dosing. To obtain corresponding adverse event (AE) data, the Novartis ARGUS safety database was searched using patient identification numbers and birth dates/dosing dates for any reported AE for GMAP patients.Results: As of September 2, 2021, 102 patients weighing ≥8.5 kg at time of dosing were identified. Fifty-four (53%) had one or more reported AEs. Three patients were reported to be deceased. All three deaths were assessed to be secondary to acute respiratory events. Most (62%) AEs were non-serious. The most frequently reported AEs included increases in hepatic laboratory values, decreased platelets and thrombocytopenia, pyrexia, vomiting, and decreased appetite.Conclusions: Safety findings for patients weighing ≥8.5 kg administered onasemnogene abeparvovec through GMAP were consistent with those described in clinical trials and included hepatotoxicity, thrombotic microangiopathy, and thrombocytopenia. [ABSTRACT FROM AUTHOR]

Individuals with neuromuscular and chest wall disorders experience respiratory muscle weakness, reduced lung volume and increases in respiratory elastance and resistance which lead to increase in work of breathing, impaired gas exchange and respiratory pump failure. Recently developed methods to assess respiratory muscle weakness, mechanics and movement supplement traditionally employed spirometry and methods to evaluate gas exchange. These include recording postural change in vital capacity, respiratory pressures (mouth and sniff), electromyography and ultrasound evaluation of diaphragmatic thickness and excursions. In this review, we highlight key aspects of the pathophysiology of these conditions as they impact the patient and describe measures to evaluate respiratory dysfunction. We discuss potential areas of physiologic investigation in the evaluation of respiratory aspects of these disorders. [ABSTRACT FROM AUTHOR]

Background: Assessment of pain is not routine, standardized, or well-understood in individuals with Duchenne muscular dystrophy (DMD), even though pain is a common problem reported by more than half of the patients with DMD. Previous studies in this area included multiple neuromuscular diseases with highly variable phenotypes. Therefore, our aim was to specifically focus on DMD and evaluate the comprehensive pain characteristics according to the disease stages, from ambulatory to late non-ambulatory.Methods: This cross-sectional study was conducted in an out-patient pediatric rehabilitation clinic including 148 male participants with confirmed DMD (14.5 ± 5.3 years of age). Face-to-face interviews were conducted using a structured questionnaire concerning the pain frequency, duration, intensity, location, aggravating/relieving factors, pain interference (Brief Pain Inventory), pain phenotype (PainDETECT Questionnaire), and functional ability (DMD Functional Ability Self-Assessment Tool). Pain characteristics were analyzed according to the clinical stage: ambulatory (Amb), early non-ambulatory (ENA), and late non-ambulatory (LNA).Results: Of the 148 participants who completed the assessment, 66 (44.6%) reported pain during the previous 4 weeks. There were no differences in the pain duration or intensity among the three groups. Pain location (Amb: calf, ENA: knee, LNA: lumbosacral region), aggravating factor (Amb: ambulation, ENA: transfer, LNA: sitting), and relieving factor (Amb: rest and massage, ENA and LNA: positional change) differed according to the clinical stage. Individuals in the LNA stage reported an increase in the frequency of pain and number of pain sites. The effect of pain on mood was also found to be greater in the LNA group than in the other clinical stages.Conclusion: There is a change in the pain characteristics, including the location, aggravating/relieving factors, pain frequency, and pain interference, with the progress of the disease in patients with DMD. Thus, clinicians could more efficiently and critically assess and manage the patients' pain based on these findings. [ABSTRACT FROM AUTHOR]

Objectives: To determine the impact of genetic muscle disorders and identify the sociodemographic, illness, and symptom factors influencing quality of life. Methods: Adults (aged 16–90 years) with a confirmed clinical or molecular diagnosis of a genetic muscle disorder identified as part of a nationwide prevalence study were invited to complete an assessment of the impact of their condition. Quality of life was measured using the World Health Organization Quality of Life questionnaire. Impact was measured via the prevalence of symptoms and comparisons of quality of life against New Zealand norms. Multivariate regression models were used to identify the most significant predictors of quality of life domains. Results: 490/596 participants completed the assessment (82.2% consent rate). Quality of life was lower than the general population on physical (t = 9.37 p < 0.0001, d = 0.54) social (t = 2.27 p = 0.02, d = 0.13) and environmental domains (t = 2.28 p = 0.02, d = 0.13), although effect sizes were small. No difference was found on the psychological domain (t = − 1.17 p = 0.24, d = 0.07). Multivariate regression models (predicting 42%–64% of the variance) revealed personal factors (younger age, being in employment and in a relationship), symptoms (lower pain, fatigue, and sleep difficulties), physical health (no need for ventilation support, fewer activity limitations and no comorbidities), and psychosocial factors (lower depression, anxiety, behavioural dyscontrol and higher self-efficacy, satisfaction with health care and social support) contributed to improved quality of life. Conclusions: A range of factors influence the quality of life in adults diagnosed with a genetic muscle disorder and some may serve as targets for multi-faceted intervention. [ABSTRACT FROM AUTHOR]

Background & Objective: We present 11-year data of patients with neuromuscular disease (NMD) that were treated in the pediatric intensive care unit of a tertiary children's hospital. Methods: The data of all cases followed-up in the pediatric intensive care unit (PICU) were retrospectively analyzed. Patients were evaluated in terms of age, gender, diagnosis, PRISM, neuroanatomical localization, hospitalization time-age, cause of admission to pediatric intensive care unit, clinical course, complications and clinical discharge status. Results: A NMD was detected in 43 of the 1,411 patients admitted within the study period and accounted for approximately 3% of pediatric intensive care unit admissions. NMD consisted of genetic (n= 35, 74.8%), acquired (n=6, 13.8%) and metabolic (n=2, 4.6%) causes. The diagnoses included spinal muscular atrophy type 1 (n=12, 27.9%), Duchenne and Becker muscular dystrophy (n=7, 16.2%), congenital myopathy (n=6, 13.9%), congenital muscular dystrophy (n=5, 11.6%), Guillain-Barre syndrome and its variants (n=2, 4.6%), spinal muscular atrophy associated with respiratory distress type 1 (n=2, 2.3%), critical illness neuropathy (n=2, 4.6%), acute flaccid myelitis (n=2, 4.6%), congenital myasthenic syndrome (n=1, 2.3%), peripheral neuropathy associated with disorder of riboflavin transporter (n=1, 2.3%), juvenile amyotrophic lateral sclerosis (n=1, 2.3%), stress-induced childhood-onset neurodegeneration with ataxia and variable seizures (n=1, 2.3%), and metabolic myopathy (n=1, 2.3%). Respiratory complications (n=31, 72%) were the most common reasons of admission to the pediatric intensive care unit. Seven (16.2%) patients have the NMD diagnosis confirmed during their first admission in PICU. These included both genetic cause of NMDs (n=4) and acquired NMDs (n=3). Mortality rate was 6.9% (n=3). Forty-three patients diagnosed with NMD had 75 times PICU admissions. The disease with the highest rate of re-admission to the PICU was SMA type 1, and the most common reason for re-admission was respiratory reasons. Conclusion: Accurate diagnosis of NMD and knowledge of causes of admission to PICU is crucial for increasing awareness, sensitivity and effectiveness when treating these diseases. [ABSTRACT FROM AUTHOR]

Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9-mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases. [ABSTRACT FROM AUTHOR]

Background/Aims Patients with muscular dystrophy usually have impaired lung function and respiratory muscle strength, leading to pneumonia and respiratory failure, which are significant causes of morbidity and mortality. Inspiratory muscle training might be a safe adjunct treatment to increase the strength and endurance of weakened respiratory muscles. The researchers have developed a new protocol for inspiratory muscle training and evaluated its effect on inspiratory muscle strength and coughing capacity. Methods A total of 12 participants diagnosed with muscle dystrophy and decreased maximal inspiratory pressure (<60 cmH2O) participated in this prospective study. Training was individually tailored, starting with low resistance levels and progressing according to tolerance and symptoms. The primary outcome measure was maximal inspiratory pressure. Secondary outcomes were maximal expiratory pressure, peak cough flow and the feasibility of the intervention. Results There were two participants who did not complete the study, and three were lost to follow-up; therefore, only seven patients finished the intervention. In these patients, the authors found a statistically significant improvement in the maximal inspiratory pressure (P=0.018) and peak cough flow (P=0.046) after 3 months of training. There was also an improvement in the maximal expiratory pressure, although this was not statistically significant (P=0.176). Median compliance to training was 99% (94.5–100). Conclusions This intervention led to statistically significant improvements in inspiratory muscles strength and coughing capacity in patients with muscular dystrophy. The results were significantly positive and contribute to the evidence in support of this underused, yet possibly beneficial, treatment, although larger randomised controlled trials are required to verify this. [ABSTRACT FROM AUTHOR]

Purpose: The hypoxic challenge test (HCT) is used to evaluate safety for air travel in individuals with respiratory disease by breathing in 15% oxygen for 20 min. Our aim was to determine if a prolonged HCT, lasting 120 min, identified more individuals with neuromuscular disease at potential risk than the standard HCT lasting 20 min. Methods: This was a cross-sectional study. All of the clinical testing took place at SickKids, Toronto, Canada. Patients were included in the study if they had a diagnosis of NMD, greater than 6 years of age, resting oxygen saturation ≥ 94%, and partial pressure of carbon dioxide (pCO2) ≤ 45 mmHg. Notable exclusion criteria were left ventricular ejection fraction < 30%, presence of a tracheostomy, and use of non-invasive ventilation for more than 12 h daily. Participants underwent a standard HCT as well as the prolonged HCT on the same day. Results: Twenty-three patients consented to the study. One patient was withdrawn because he was unable to follow the study procedures. The 22 study participants had a mean age of 14.9 years (standard deviation (SD) of 5 years). Seventeen (77%) participants were male. Two participants were withdrawn on the day of testing due to hypercapnia. Twenty participants completed the standard and prolonged HCTs. None of the participants had a positive standard or prolonged HCT. Conclusion: Our results suggest that performing a standard or prolonged HCT may, in fact, not be of clinical utility in individuals with less severe NMD. [ABSTRACT FROM AUTHOR]

Background: Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies; it is also currently under review for the US Food and Drug Administration (FDA) qualification. Summary: Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development.

ABSTRACT BACKGROUND: Postpoliomyelitis syndrome is a clinical condition that can affect poliomyelitis survivors. OBJECTIVE: Our aim was to evaluate knowledge of poliomyelitis and postpoliomyelitis syndrome among Brazilian healthcare professionals. DESIGN AND SETTING: Cross-sectional study conducted at a Brazilian public higher education institution located in the state of Goiás. METHODS: The participants (n = 578) were Brazilian physicians, physical therapists, nurses, nutritionists and psychologists. A self-administered questionnaire (30 questions) was designed to probe knowledge about poliomyelitis and postpoliomyelitis syndrome. From the questionnaire, we created a structured test to objectively evaluate the knowledge of these professionals. The test was composed of 20 questions and was scored over a range from 0 (totally ill-informed) to 20 (totally well-informed). RESULTS: In general, the physicians, physical therapists and nurses demonstrated better understanding of poliomyelitis and postpoliomyelitis syndrome. The healthcare professionals who had received previous information about poliomyelitis and postpoliomyelitis syndrome had significantly higher scores than those who had never received information (P < 0.001). On average, this difference was approximately 28.6%. CONCLUSIONS: The findings from the present study indicate that there is a critical need for improvement of knowledge about postpoliomyelitis syndrome among Brazilian healthcare professionals. The services provided by these professionals may therefore become compromised. Furthermore, public healthcare initiatives should be implemented to improve knowledge among healthcare professionals.