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The role of muscle biopsy in the investigation of neuromuscular disease remains firmly established but has evolved. Expertise in diagnostic myopathology remains relevant and supports clinical practice. Neuromuscular disease is rare; thus clinicopathological correlation, or better, collaboration is important. The process starts in the clinic with the identification of patients for whom muscle biopsy will be beneficial for diagnosis and management in a multidisciplinary neuromuscular care setting. In this review article, we describe the current use of muscle biopsy in our adult practice and discuss several carefully selected real cases [e.g., asymmetric hand weakness, dysphagia and proximal weakness, subacute weakness with raised creatine kinase (CK), non-specific presentation], where biopsy and collaboration have been instrumental in achieving the correct diagnosis for the patient. We discuss areas of diagnostic difficulty, such as fairly common starting scenarios leading to unusual entities, atypical presentations of common diseases and novel pathological findings. We will focus on the idiopathic inflammatory myopathies (IIMs), the most common indication for adult muscle biopsies in many diagnostic settings, whereby the use of an integrated clinical-serological-pathological classification is now firmly established. We will also explore the evolving role for and continuing need of muscle biopsy in the genomic era, particularly with assessing the potential pathogenicity of reported genetic variants of uncertain significance (VUS). We describe a pragmatic approach to detecting the more common disorders, which also enables us to distinguish 'the horses from the zebras' and manage diagnostic uncertainty., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Establishing a molecular diagnosis remains challenging in half of individuals with childhood-onset neuromuscular diseases (NMDs) despite exome sequencing. This study evaluates the diagnostic utility of combining genomic approaches in undiagnosed NMD patients. We performed deep phenotyping of 58 individuals with unsolved childhood-onset NMDs that have previously undergone inconclusive exome studies. Genomic approaches included trio genome sequencing and RNASeq. Genetic diagnoses were reached in 23 out of 58 individuals (40%). Twenty-one individuals carried causal single nucleotide variants (SNVs) or small insertions and deletions, while 2 carried pathogenic structural variants (SVs). Genomic sequencing identified pathogenic variants in coding regions or at the splice site in 17 out of 21 resolved cases, while RNA sequencing was additionally required for the diagnosis of 4 cases. Reasons for previous diagnostic failures included low coverage in exonic regions harboring the second pathogenic variant and involvement of genes that were not yet linked to human diseases at the time of the first NGS analysis. In summary, our systematic genetic analysis, integrating deep phenotyping, trio genome sequencing and RNASeq, proved effective in diagnosing unsolved childhood-onset NMDs. This approach holds promise for similar cohorts, offering potential improvements in diagnostic rates and clinical management of individuals with NMDs., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: Data were collected and analyzed following the ethics guidelines of Hospital Sant Joan de Déu (PIC 98-20). The family provided written informed consent for the study., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Introduction/aims: Neuromuscular ultrasound (NMUS) is gaining prominence as a valuable tool for diagnosing neuromuscular disorders at the point of care. Neuromuscular disorder diagnostic criteria guidelines have begun incorporating NMUS findings. As interest grows, fellowship programs must consider incorporating training into their curricula. This study evaluated the current state of NMUS training, potential barriers, and interest in training across Canadian neuromuscular fellowship programs., Methods: A 23-question online survey was developed and distributed via email to all 10 neuromuscular fellowship program directors across Canada., Results: Seven (70%) programs responded to the survey. There was general agreement among programs on the value of NMUS, however, only one (14.3%) program reported they would consider recent graduates to be competent in NMUS. Critical barriers to incorporation of NMUS training included lack of a formalized curriculum, faculty expertise and time, and equipment. Two (28.6%) programs reported that accessibility of equipment and one (14.3%) that faculty expertise was not a barrier to NMUS training. Two (28.6%) programs have local NMUS training options available to fellows (in only one program is NMUS training mandatory). All programs expressed interest in additional training opportunities, and three (43%) programs reported taking steps toward incorporating NMUS training into their curricula., Discussion: NMUS training is in its infancy in Canada, with several common barriers identified across programs. There is universal interest in further NMUS training opportunities for fellows, highlighting the importance of a common approach to addressing the educational gap to support development of formalized NMUS training mechanisms in Canada., (© 2025 Wiley Periodicals LLC.)

In Japan, there are no nationwide guidelines for presymptomatic testing for hereditary neuromuscular diseases. Although each institution has been dealing with this situation by using their own procedures to date, it is necessary to develop a standardized guidelines based on the Japanese medical system, because the development of disease-modifying therapies has progressed, and we are entering an era in which early diagnosis and early treatment are necessary. The guidelines presented here were devised by the Committee on Medical Genetics of the Japan Neurological Society. During their development, Delphi surveys were conducted among individuals with extensive experience in presymptomatic testing throughout Japan, with 42 experts participating in all three surveys, and a consensus-building process was undertaken. Finally, the guidelines consist of 45 recommendations for performing presymptomatic testing for adult-onset inherited neurological and muscular diseases.

This cross-sectional study aimed to describe electrodiagnostic (Edx) findings of neuromuscular disorders (NMD) associated with COVID-19 infection. Patients with history of COVID-19 infection and neuromuscular symptoms were included. After documenting the demographics, detailed examination and nerve conduction studies / electromyography (NCS / EMG) were performed. Descriptive statistics were determined. Polyneuropathy was the most common electrophysiological diagnosis (n = 22, 40%) and amongst these, Guillian Barre Syndrome (GBS) was the most common (n = 13, 23.6%). Patients with history of invasive ventilation had 2.5 times the risk of developing myopathic disorder [OR 2.5, 95% CI 0.6 - 9.9] and 2.6 times the risk of developing neuropathic disorder than those who did not require invasive ventilation [OR 2.6, 95% CI 0.8-8.5]. Polyneuropathy is the most common NMD associated with COVID-19 infection. Patients with history of invasive ventilation after COVID-19 are susceptible to develop neuropathic disorders. Further studies are needed to establish the causality of this correlation. Key Words: Polyneuropathy, Myopathy, Moneuritis multiplex, Facial nerve palsy, Critical illness polyneuropathy / myopathy, Neuromuscular junction disorders, Guillian barre syndrome.

Aim: We report the epidemiology, treatment and outcomes of acute flaccid myelitis (AFM), including the first two cases of enterovirus (EV) D68 myelitis, in Singapore., Methods: Retrospective observational study from a paediatric hospital in Singapore, from January 2012 to December 2022. Clinical, laboratory, neuroimaging and outcome data were analysed., Results: Eight patients were identified (all male). Median age at presentation was 3 (interquartile range (IQR) 2.2-10.0) years. Seven (87.5%) patients were clustered in two time periods (July 2018-January 2019 and April-August 2022). Presenting features were a preceding febrile respiratory illness (n = 6) or hand-foot-and-mouth disease (n = 2), upper limb weakness (n = 5, 62.5%) and neurogenic bladder (3, 37.5%), while the spinal cord lesions were predominantly in the cervical region (7, 87.5%). Five (62.5%) and six (75.0%) patients had elevated cerebrospinal fluid (CSF) white cells (median 7.5/mm 3 (IQR 2.8-40.3)) and protein (median 0.6 g/L (IQR 0.4-0.7)), respectively. CSF was negative for pathogens. Two (50%) of four patients with EV detected in respiratory/rectal swabs had EVD68 (2022 cluster). All received intravenous methylprednisolone, six (75%) had additional intravenous immunoglobulin and either plasma exchange therapy (n = 1) or intravenous tocilizumab (n = 1). Median modified Rankin Scale (mRS) at acute illness was 4 (IQR grades 3-5), with an improvement (median 2 (IQR 1.8-2.3) mRS grades) on follow-up (median duration 3.7 (IQR 1.4-4.1) years). One patient (12.5%) had a full recovery and seven (87.5%) have moderate disability (mRS 2-3)., Conclusion: Disability risk in AFM is high despite aggressive immunotherapy. We report the first two confirmed cases of EV D68 AFM in Singapore and Southeast Asia., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: The diagnosis of intensive care unit (ICU)-acquired weakness (ICUAW) and critical illness neuromyopathy (CINM) is frequently hampered in the clinical routine. We evaluated a novel panel of blood-based inflammatory, neuromuscular, and neurovascular biomarkers as an alternative diagnostic approach for ICUAW and CINM., Methods: Patients admitted to the ICU with a Sequential Organ Failure Assessment score of ≥ 8 on 3 consecutive days within the first 5 days as well as healthy controls were enrolled. The Medical Research Council Sum Score (MRCSS) was calculated, and motor and sensory electroneurography (ENG) for assessment of peripheral nerve function were performed at days 3 and 10. ICUAW was defined by an MRCSS < 48 and CINM by pathological ENG alterations, both at day 10. Blood samples were taken at days 3, 10, and 17 for quantitative analysis of 18 different biomarkers (white blood cell count, C-reactive protein, procalcitonin, C-terminal agrin filament, fatty-acid-binding protein 3, growth and differentiation factor 15, syndecan 1, troponin I, interferon-γ, tumor necrosis factor-α, interleukin-1α [IL-1α], IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, and monocyte chemoattractant protein 1). Results of the biomarker analysis were categorized according to the ICUAW and CINM status. Clinical outcome was assessed after 3 months., Results: Between October 2016 and December 2018, 38 critically ill patients, grouped into ICUAW (18 with and 20 without) and CINM (18 with and 17 without), as well as ten healthy volunteers were included. Biomarkers were significantly elevated in critically ill patients compared to healthy controls and correlated with disease severity and 3-month outcome parameters. However, none of the biomarkers enabled discrimination of patients with and without neuromuscular impairment, irrespective of applied classification., Conclusions: Blood-based biomarkers are generally elevated in ICU patients but do not identify patients with ICUAW or CINM., Trial Registration: ClinicalTrials.gov identifier: NCT02706314., Competing Interests: Conflicts of Interest: UW has received speaker honoraria and travel grants from Bristol-Myers Squibb, Boehringer Ingelheim Pharma, Daiichi-Sankyo, Ipsen Pharma, Merz Pharmaceuticals, and Pfizer Pharma and an unrestricted research grant from Merz Pharmaceuticals independent from this study. He serves as joint editor-in-chief of the European Journal of Ultrasound (Thieme, Stuttgart, Germany). JE received financial support for attending study meetings from B. Braun Melsungen AG independent from this study. FK, FL, D-CF, AR, KP, LD, RP, and RB have nothing to declare. Ethical Approval/Informed Consent: The study was performed in accordance with the Declaration of Helsinki and was approved by the local ethics committee of the University of Rostock (ethics identifier AS 2016–0016). Written informed consent for participation was given by volunteers, patients, or a legal representative before enrollment. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02706314., (© 2024. The Author(s).)

Background: Neuromuscular diseases (NMDs) and mitochondriopathies are rare and heterogeneous disorders. Diagnosis is often difficult and delayed, partly due to the lack of reliable biomarkers. Chitotriosidase (CHIT1) as a candidate marker for lysosomal storage diseases is elevated in Niemann pick disease type C as a prototype of this group of diseases. Most recently, a relevant role of the lysosomal pathway in mitochondriopathies has been discussed, but markers of lysosomal involvement have not been investigated. Therefore, the aim of this study was to evaluate CHIT1 concentrations in a broad spectrum of NMDs and mitochondriopathies., Methods: CHIT1 serum concentration of 151 patients with NMD or primary mitochondriopathy was determined by enzyme-linked immunosorbent assay, and compared to 38 healthy controls and 8 patients with Niemann pick disease type C. Results were controlled for age, sex, CRP and CHIT1 polymorphism, and compared to several established markers (CK, FGF21, GDF15)., Results: CHIT1 levels were not altered in NMDs, but significantly increased in mitochondriopathies, within the range of Niemann-Pick patients. Compared to the established biomarkers, CHIT1 and FGF21 showed a similar diagnostic performance, while better results were found for GDF15. However, there was a tendency for higher CHIT1 concentrations in patients with central nervous system involvement (MELAS syndrome), while FGF21 and GDF15 were not relevantly altered in these patients. Consequently, a combination of biomarkers including CHIT1 provided the best overall diagnostic performance., Conclusions: Serum CHIT1 concentration is significantly elevated in mitochondriopathies compared to healthy controls and other NMD, identifying CHIT1 as potential complementary biomarker in mitochondriopathies., Competing Interests: Declarations. Conflicts of interest: AM has received speaking fees and advisory board honoraria from Hormosan and Sanofi, outside of the submitted work. All other authors report no conflicts of interest. Ethical approval: This study was approved by the institutional research committee of Martin-Luther-University of Halle-Wittenberg (vote no. 2021–101). All subjects included in this study gave their informed consent., (© 2025. The Author(s).)

Neuromuscular diseases (NMD) are a group of neurological diseases that manifest with various clinical symptoms affecting different components of the peripheral nervous system, which play a role in voluntary body movements control. The primary objective of this study is to explore the diagnostic efficacy of a combined genetic and biochemical testing approach for patients with neuromuscular diseases with diverse presentations in a population with high rate of consanguinity. Genetic testing was performed using selected Next Generation Sequencing (NGS) gene panels and whole exome sequencing on the peripheral blood sample from the patients. The study results revealed that the majority of patients in our cohort had a history of consanguinity (83%). Genetic testing through gene panels and Whole Exome Sequencing yielded similar result. Out of the patients tested, 66% underwent gene panels testing, 56% had Whole Exome Sequencing, 32% received array Comparative Genomic Hybridization (CGH) assays, and 40% underwent metabolic testing. Overall, 58 patients (61%) received definitive results after following all tests. Among the remaining 36 patients, 19 exhibited variants of unknown significance (VOUS) (21%)., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Informed consent was obtained from all subjects and/or their legal guardian(s) for participation. The study was carried out in accordance with the code of international and local Ethics (Declaration of Helsinki). This study was reviewed and approved by the local ethics committee of the King Fahad Specialist Hospital Dammam (Dammam, Saudi Arabia). Patient consent for publication: The parents of the patient provided written informed consent for publication. Ethical publication statement: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (© 2024. The Author(s).)

Neuromuscular disorders (NMD) with neonatal or early infantile onset are usually severe and differ in symptoms, complications, and treatment options. The establishment of a diagnosis relies on the combination of clinical examination, morphological analyses of muscle biopsies, and genetic investigations. Here, we re-evaluated and classified a unique collection of 535 muscle biopsies from NMD infants aged 0-6 months examined over a period of 52 years. We aimed to assess the importance and contribution of morphological muscle biopsy analyses for the establishment of a precise and accurate molecular diagnosis. Altogether, 82% of the biopsies showed typical structural myofiber anomalies highly suggestive of specific NMD classes (congenital myopathies, metabolic myopathies, lower motor neuron (LMN) and neuromuscular junction (NMJ) disorders, muscular dystrophies, inflammatory myopathies), while the remaining 18% showed no or only non-specific histological abnormalities. The diagnostic success rate differed among the NMD classes and was particularly high for congenital myopathies as illustrated by the identification of causative genes in 61% of cases. This is essentially due to the presence of characteristic histopathological hallmarks on biopsies visible by light or electron microscopy often pointing to specific genes. In contrast, metabolic myopathies commonly displayed non-specific features on muscle sections, led to the identification of causative genes in only 19% of the patients, and typically required additional enzymatic tests to establish a more precise diagnosis. The evolution of sequencing technologies fundamentally improved molecular diagnosis and also shifted the relevance of muscle biopsies within the diagnostic process. Depending on the clinical presentation of the patients, direct gene or panel sequencing may be the preferred method nowadays. However, histological and ultrastructural examinations of muscle sections are still frequently useful and can constitute an elemental step in the diagnostic process-either by directing purposeful gene sequencing or pointing to genes and pathogenic variants identified by next-generation sequencing (NGS), or by complementing clinical findings and biochemical analysis methods., Competing Interests: Declarations. Ethics approval and consent to participate: All patients and legal guardians consented to the publication of the clinical, histological, and genetic data. Molecular diagnosis was carried out with written informed consent from the patients or legal guardians. Muscle biopsy storage and usage were IRB-approved. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

A 44-year-old woman with a subacute onset of an altered mental status, urinary retention, and fluctuating blood pressure was initially diagnosed with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, meeting the criteria of Graus et al. Cardiac arrest occurred, which required pacemaker placement. She subsequently showed profound flaccid limb paralysis, with magnetic resonance imaging demonstrating focal necrotic lesions localized in the anterior horn of the longitudinal segments of the spinal cord and in the pontine tegmentum. Enteroviruses or autoimmune encephalitis-associated autoantibodies were not detected. We herein report a case of acute flaccid myelitis with profound psychiatric symptoms and dysautonomia, resembling NMDAR encephalitis.

Background: Pathogenic variants in the nonmuscle myosin, MYH14, have been associated with several pathologic conditions including a complex phenotype with peripheral neuropathy, myopathy, hoarseness, and hearing loss. Since its first description in a large Korean kindred, this rare neuromuscular disorder has further been characterized in 1 American and 1 Canadian pedigree., Case Presentation: Here, we describe a German patient with atypical MYH14-related neuromuscular disorder. The clinical phenotype included signs of a distal myopathy with early respiratory involvement and a prominent hoarseness and peripheral neuropathy. In contrast to previous reports, no relevant deafness was identified. Muscle biopsy indicated a vacuolated myopathy with excessive autophagy, whereas histology of the sural nerve showed signs of a mixed axonal-demyelinating neuropathy. Next-generation sequencing revealed a loss-of-function variant not identified so far in the MYH14 gene (c.4510del, p.[Arg1504Glyfs*10]). Because of rapid disease progression with respiratory failure, the patient died at the age of 52., Conclusions: We present a novel MYH14 variant resulting in a severe and rapidly progressive MYH14-associated phenotype with predominantly distal myopathy, early respiratory failure, dysphagia, hoarseness, and peripheral neuropathy, without hearing loss. This case expands the clinical spectrum of MYH14-related neuromuscular disorders by providing a new clinical phenotype and disease course and histopathologic features., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Genetic screening of rare diseases allows identification of the responsible gene(s) in about 50% of patients. The remaining cases are in a diagnostic deadlock as current knowledge fails to identify the correct gene or determine if the detected variant on the gene is pathogenic. These are named "variants of unknown significance" (VUS). In the case of neuromuscular diseases, the RYR1 gene is often implicated, with the majority of variants classified as VUS, requiring reliable classification to help patient diagnosis. Our project aims to create an efficient classification pipeline, integrating artificial intelligence, structural biology data, and functional analyses to enhance genetic diagnosis of RYR1-related diseases., (© 2024 médecine/sciences – Inserm.)

Dyspnea is a common symptom in neuromuscular disorders and, although multifactorial, it is usually due to respiratory muscle involvement, associated musculoskeletal changes such as scoliosis or, in certain neuromuscular conditions, cardiomyopathy. Clinical history can elicit symptoms such as orthopnea, trepopnea, sleep disruption, dysphagia, weak cough, and difficulty with secretion clearance. The examination is essential to assist with the diagnosis of an underlying neurologic disorder and determine whether dyspnea is from a cardiac or pulmonary origin. Specific attention should be given to possible muscle loss, use of accessory muscles of breathing, difficulty with neck flexion/extension, presence of thoraco-abdominal paradox, conversational dyspnea, cardiac examination, and should include a detailed neurological examination directed at the suspected differential diagnosis. Pulmonary function testing including sitting and supine spirometry, measures of inspiratory and expiratory muscle strength, cough peak flow, sniff nasal inspiratory pressure, pulse oximetry, transcutaneous CO 2 , and arterial blood gases will help determine the extent of the respiratory muscle involvement, assess for hypercapnic or hypoxemic respiratory failure, and qualify the patient for noninvasive ventilation when appropriate. Additional testing includes dynamic imaging with sniff fluoroscopy or diaphragm ultrasound, and diaphragm electromyography. Polysomnography is indicated for sleep related symptoms that are not otherwise explained. Noninvasive ventilation alleviates dyspnea and nocturnal symptoms, improves quality of life, and prolongs survival. Therapy targeted at neuromuscular disorders may help control the disease or favorably modify its course. For patients who have difficulty with secretion clearance, support of expiratory function with mechanical insufflation-exsufflation, oscillatory devices can reduce the aspiration risk., (© 2024 by the American Association of Neuromuscular & Electrodiagnostic Medicine, Inc. All rights reserved.)

Introduction/aims: Concentric needle electromyography (CNEMG) is an essential examination for evaluating neuromuscular disorders, although pain is a drawback. Clustering Index (CI) method is a non-invasive quantitative analysis for surface electromyography (SEMG) that evaluates whether the signal area is clustered into the few large motor unit potentials (MUPs) or is evenly distributed. However, the diagnostic yield of the CI method in comparison with CNEMG is not known. In this study, we aimed to compare the sensitivity of the CI method with MUP parameters in CNEMG for diagnosing neurogenic or myogenic disorders., Methods: We retrospectively identified patients for whom both SEMG and CNEMG were performed on the same tibialis anterior (TA) muscle. In CNEMG, seven MUP parameters were evaluated, including size index (SI) and revised size indices for neurogenic (rSIn) and myogenic (rSIm) disorders., Results: Identified were 21 patients with neurogenic and 21 patients with myogenic disorders. Control data were constructed from 30 control subjects. The sensitivities of the CI method for the neurogenic and myogenic groups were 76% and 62%, respectively, which were not significantly different from MUP parameters, except for being significantly higher than those of amplitude and duration for myopathy (24%). Among MUP parameters, the sensitivities of rSIn (62%) and rSIm (57%) for myopathy were significantly higher than those of amplitude and duration. The CI method significantly correlated with the strength of the TA muscle in myopathy., Discussion: The CI method, having comparable diagnostic yields to MUP parameters, is promising as a non-invasive diagnostic measure., (© 2024 Wiley Periodicals LLC.)

Purpose of Review: Obstructive sleep apnea (OSA) is common in children. Phenotyping pediatric OSA has a crucial role in personalized diagnosis and treatment to improve outcomes for this population. This review sets forth a clinical approach that allows for phenotyping pediatric OSA., Recent Findings: The emerging concept of phenotyping pediatric OSA is based on identifying a primary cause, which leads to a more precise understanding of the pathogenesis in any individual patient. Phenotyping enables treatment focusing on the primary cause, but does not exclude the need for supplemental management strategies based on other recognizable traits. The identification of pediatric OSA phenotypes (POP) relies on observable characteristics with significant prevalence. This review will concentrate on the most important phenotypes seen in clinical practice: pediatric OSA with craniofacial abnormalities (POPCA); OSA with upper airway disease (POPUAD); OSA with obesity (POPO), and OSA associated with neuromuscular disease (POPNED)., Summary: Phenotyping pediatric OSA is a form of personalized medicine. By identifying clinical subtypes, individualized treatment plans can be devised in order to choose therapies that are associated with predictable responses. Moreover, it is rare that a therapeutic modality is devoid of possible complications; knowledge of the phenotype being treated can enable early intervention should those occur. Finally, all of the aforementioned phenotypes require personalized support incorporating individualized care plans so as to optimize the quality of life and overall sleep health of children with OSA., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Neuromuscular and vascular hamartoma (NMVH) is an infrequent gastrointestinal lesion described in human and veterinary medical literature. The histologic features of this entity are haphazardly arranged fascicles of smooth muscle, nerve fibers, scattered ganglion cells, and hemangiomatous blood vessels. Here we describe 2 putative cases of NMVH in a 1.7-y-old, intact female Anatolian mixed-breed dog and a 4-mo-old intact male Akita dog. Both animals had gastrointestinal clinical signs, including hematochezia, and on exploratory laparotomy, intussusception was confirmed. Histologic examination confirmed NMVH within the cecal wall in both cases using a panel of immunohistochemical (IHC) markers for vascular structures (CD31), smooth muscle (alpha-smooth muscle actin [α-SMA]), and nerves (glial fibrillary acidic protein [GFAP] and S100). The complete surgical excision of the lesion in both animals was considered curative without persistent clinical signs 14 mo and 12 mo, respectively, after surgery., Competing Interests: Declaration of conflicting interestsTatiane Terumi Negrão Watanabe and Linda Huang are employed by Antech Diagnostics, Mars Petcare Science & Diagnostics. The remaining authors declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article.

Neuromuscular disorders (NMDs) encompass a broad range of hereditary and acquired conditions that affect motor units, significantly impacting patients' quality of life and reproductive health. This narrative review aims to explore in detail the reproductive challenges associated with major hereditary NMDs, including Charcot-Marie-Tooth disease (CMT), dystrophinopathies, Myotonic Dystrophy (DM), Facioscapulohumeral Muscular Dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Limb-Girdle Muscular Dystrophy (LGMD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, it discusses the stages of diagnosis and genetic testing, recurrence risk estimation, options for preimplantation genetic testing (PGT) and prenatal diagnosis (PND), the reciprocal influence between pregnancy and disease, potential obstetric complications, and risks to the newborn., Competing Interests: The authors have no conflicts of interest to declare.

Objective: Diagnostic assessment of ADHD is challenging due to comorbid psychopathologies and symptoms overlapping with other psychiatric disorders. In this study, we investigate if a distinct pattern of neuromuscular dysregulation previously reported in ADHD, can help identifying ADHD in psychiatric patients with diverse and complex symptoms., Method: We explored the impact of neuromuscular dysregulation, as measured by The Motor Function Neurologic Assessment (MFNU), on the likelihood of being diagnosed with ADHD, affective disorder, anxiety disorder, or personality disorder among adults ( n  = 115) referred to a psychiatric outpatient clinic., Results: Logistic regression revealed that neuromuscular dysregulation was significantly associated with ADHD diagnosis only ( OR 1.15, p  < .01), and not with affective-, anxiety-, or personality disorders. Sensitivity and specificity for ADHD at different MFNU scores is provided., Conclusions: A test of neuromuscular dysregulation may promote diagnostic accuracy in differentiating ADHD from other psychiatric disorders in patients with an overlapping symptom picture. This may have important implications for clinical practice. More studies are needed., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The MFNU manual is edited by LLS and TS. The other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective . The measurement of electromyography (EMG) signals with needle electrodes is widely used in clinical settings for diagnosing neuromuscular diseases. Patients experience pain during needle EMG testing. It is significant to develop alternative diagnostic modalities. Approach . This paper proposes a portable magnetomyography (MMG) measurement system for neuromuscular disease auxiliary diagnosis. Firstly, the design and operating principle of the system are introduced. The feasibility of using the system for auxiliary diagnosis of neuromuscular diseases is then studied. The magnetic signals and needle EMG signals of thirty subjects were collected and compared. Main results . It is found that the amplitude of muscle magnetic field signal increases during mild muscle contraction, and the signal magnitudes of the patients are smaller than those of normal subjects. The diseased muscles tested in the experiment can be distinguished from the normal muscles based on the signal amplitude, using a threshold value of 6 pT. The MMG diagnosis results align well with the needle EMG diagnosis. In addition, the MMG measurement indicates that there is a persistence of spontaneous activity in the diseased muscle. Significance. The experimental results demonstrate that it is feasible to auxiliary diagnose neuromuscular diseases using the portable MMG system, which offers the advantages of non-contact and painless measurements. After more in-depth, systematic, and quantitative research, the portable MMG could potentially be used for auxiliary diagnosis of neuromuscular diseases. The clinical trial registration number is ChiCTR2200067116., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Neuromuscular diseases impact on children's health related quality of life but there is a lack of studies in Latin America that measured this construct. To respond to this need, this study aimed to explore quality of life and its relationship with age, functional dependence and specific diagnosis in children and adolescents in Latin America. A cross-sectional correlation study was carried out with 133 caregivers on children (2-18 years old) with various neuromuscular disorders. Parents reported on their children's health related quality of life through the PedsQL GCS and the PedsQL NMM. Differences in quality of life were found when comparing children with high functional dependence with those with mild dependence (p = 0.05). No significant differences were found regarding the child diagnosis. Finally, quality of life was highly correlated with the child's age, even when controlling for functional dependence differences between ages. Children and adolescents with neuromuscular show a diminished health related quality of life, not only in physical functioning but in their psychosocial functioning. Health related quality of life may vary according to the child's age and functional dependence., (Copyright © 2024 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Early diagnosis of neosporosis in dogs is challenging., Objectives: To evaluate the feasibility of a compound multimodal testing approach for diagnosing in dogs neuromuscular and combined forms of neosporosis., Animals: A total of 16 dogs diagnosed with solely neuromuscular neosporosis or with a combination of neuromuscular and central nervous system neosporosis., Methods: Retrospective review of clinical signs, laboratory findings, treatment, and outcome with focus on the diagnostic utility of different tests. Development of a chromogenic in situ hybridization (ISH) assay for the identification of Neospora caninum in paraffin-embedded muscle samples., Results: 13/16 dogs had only neuromuscular signs of neosporosis, 3/16 had disease signs with concomitant central nervous system (CNS) involvement. Serology was performed in 15/16, with 10/15 showing titers >1 : 160 at admission. PCR on muscle samples detected N. caninum DNA in 11/16. Immunohistochemistry (IHC) detected N. caninum in 9/16 and ISH in 9/16. Histopathology revealed inflammatory myopathy in 10/16, necrotizing myopathy in 5/16, borderline changes in 1/16 and tachyzoites in 9/16. In 4 cases, N. caninum infection was confirmed with all 5 diagnostic methods, 3 cases with 4, 2 with 3, 6 with 2, and 1 animal with 1., Conclusions and Clinical Importance: Diagnosis of N. caninum infection should rely on a multimodal diagnostic approach and negativity of 1 single test should not allow for exclusion. Serology in combination with direct parasite identification via histopathology, DNA via PCR, or both modalities, appears a reliable diagnostic approach., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Introduction/aims: Fatigue is a common and debilitating symptom encountered in the neuromuscular clinic. The 7-item Fatigue Severity Scale (FSS-7) is a Rasch-modified assessment validated in inflammatory neuropathies but not across a typical neuromuscular patient population. The aim of this study was to validate this measure in neuromuscular disorders and to compare between patient sex, age and diagnoses., Methods: The modified FSS-7 was mailed to patients recruited from a specialist neuromuscular clinic at the Walton Centre. Responses were subjected to Rasch analysis and descriptive statistics were performed on the Rasch converted data., Results: The mFSS-7 met the Rasch model expectations with an overall Chi-square probability of 0.4918, a strict unidimensional scale free from differential item functioning (DIF) that satisfied the model with substantial test-retest reliability using Lin's concordance correlation coefficient 0.71 (95% CI 0.63-0.77). A 15.7% ceiling effect was observed in this patient cohort. Post hoc analysis did not show any significant difference in fatigue between sex, age or neuromuscular diagnoses., Discussion: The self-completed Rasch mFSS-7 showed acceptable test-retest reliability across patients with varied disorders under follow-up in a specialist neuromuscular clinic. The ceiling effect constrains its use for those with the most severe fatigue. Future considerations could include assessment of the benefits of clinical interventions, particularly multidisciplinary team input or dedicated fatigue clinics., (© 2024 Wiley Periodicals LLC.)

Respiratory sequelae are a frequent cause of morbidity and mortality in children with NMD. Impaired cough strength and resulting airway clearance as well as sleep disordered breathing are the two main categories of respiratory sequelae. Routine clinical evaluation and diagnostic testing by pulmonologists is an important pillar of the multidisciplinary care required for children with NMD. Regular surveillance for respiratory disease and timely implementation of treatment including pulmonary clearance techniques as well as ventilation can prevent respiratory related morbidity including hospital admissions and improve survival. Additionally, novel disease modifying therapies for some NMDs are now available which has significantly improved the clinical trajectories of patients resulting in a paradigm shift in clinical care. Pulmonologists are 'learning' the new natural history for these diseases and adjusting clinical management accordingly., Competing Interests: Disclosure The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rare neuromuscular diseases (NMDs) encompass various disorders of the nervous system and skeletal muscles, and present intricate challenges in diagnosis, treatment, and research due to their low prevalence and often diverse multisystemic manifestations. Leveraging collected patient data for secondary use and analysis holds promise for advancing medical understanding in this field. However, a certain level of data quality is a prerequisite for the methods that can be used to analyze data. The heterogeneous nature of NMDs poses a significant obstacle to the creation of standardized documentation, as there are still many challenges to accurate diagnosis and many discrepancies in the diagnostic process between different countries. This paper proposes the development of an information model tailored to NMDs, aiming to augment visibility, address deficiencies in documentation, and facilitate comprehensive analysis and research endeavors. By providing a structured framework, this model seeks to propel advancements in understanding and managing NMD, ultimately benefiting patients and healthcare providers worldwide.

Advances in DNA sequencing technologies, especially next-generation sequencing (NGS), which is the basis for whole-exome sequencing (WES) and whole-genome sequencing (WGS), have profoundly transformed immune-mediated rheumatic disease diagnosis. Recently, substantial cost reductions have facilitated access to these diagnostic tools, expanded the capacity of molecular diagnostics and enabled the pursuit of precision medicine in rheumatology. Understanding the fundamental principles of genetics and diversity in genetic variant classification is a crucial milestone in rheumatology. However, despite the growing availability of DNA sequencing platforms, a significant number of autoinflammatory diseases (AIDs), neuromuscular disorders, hereditary collagen diseases, and monogenic bone diseases remain unsolved, and variants of uncertain significance (VUS) pose a formidable challenge to addressing these unmet needs in the coming decades. This article aims to provide an overview of the clinical indications and interpretation of comprehensive genetic testing in the medical field, addressing the related complexities and implications., (© 2024. The Author(s).)

Conventional electrophysiological methods, i.e. nerve conduction studies and electromyography are suitable methods for the diagnosis of neuromuscular disorders, however, they provide limited information about muscle fibre membrane properties and underlying disease mechanisms. Muscle excitability testing is a technique that provides in vivo information about muscle fibre membrane properties such as membrane potential and ion channel function. Since the 1960s, various methodologies have been suggested to examine muscle membrane properties but technical difficulties have limited its use. In 2009, an automated, fast and simple application, the so-called multi-fibre muscle velocity recovery cycles (MVRC) has accelerated the use of muscle excitability testing. Later, frequency ramp and repetitive stimulation protocols have been developed. Though this method has been used mainly in research for revealing disease mechanisms across a broad range of neuromuscular disorders, it may have additional diagnostic uses; value has been shown particularly in muscle channelopathies. This review will provide a description of the state-of-the art of methodological and clinical studies for muscle excitability testing., (Copyright © 2024 International Federation of Clinical Neurophysiology. All rights reserved.)

Systemic diseases can cause heart block owing to the involvement of the myocardium and thereby the conduction system. Younger patients (<60) with heart block should be evaluated for an underlying systemic disease. These disorders are classified into infiltrative, rheumatologic, endocrine, and hereditary neuromuscular degenerative diseases. Cardiac amyloidosis owing to amyloid fibrils and cardiac sarcoidosis owing to noncaseating granulomas can infiltrate the conduction system leading to heart block. Accelerated atherosclerosis, vasculitis, myocarditis, and interstitial inflammation contribute to heart block in rheumatologic disorders. Myotonic, Becker, and Duchenne muscular dystrophies are neuromuscular diseases involving the myocardium skeletal muscles and can cause heart block., Competing Interests: Disclosure Dr W.Z. Tzou is a consultant for or has received speaker honoraria, or research funding from Abbott, American Heart Association, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. Dr S.R.A. Sabzwari has no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction/aims: Self-efficacy reflects a person's perceptions of their capabilities for specific tasks and influences motivation and performance. The Unidimensional Self-Efficacy in Neuromuscular Disorders (USE-NM) was modified from the Multiple Sclerosis (MS) USE-MS scale and administered to patients attending a specialist neuromuscular clinic. The aim was to investigate this measure in neuromuscular disorders and to compare between patient sex, age, and diagnosis., Methods: The USE-NM was posted to patients recruited from a specialist neuromuscular clinic at the Walton Centre. Responses were subjected to Rasch analysis using RUMM2030 software and descriptive statistics were performed using SPSS version 28., Results: One hundred and ninety-eight patients (56.1% male) grouped by age (<50; 50-59; 60-69; and >69 years) and with varied NM disorders returned the USE-NM. It did not meet the Rasch model expectations due to disordered thresholds of items 6 and 8 ("Sometimes I feel inadequate as a person because of my neuromuscular disorder" and "I feel that my social life would be better if I did not have a neuromuscular disorder"). Following item re-scoring, the modified USE-NM satisfied the Rasch model with a unidimensional scale free from differential item functioning and an overall chi-square probability of 0.146 with good reliability and validity. Post hoc nonparametric testing showed no significant difference in fatigue between sex, age, and neuromuscular diagnoses., Discussion: The Rasch-modified USE-NM offers a measure of self-efficacy for neuromuscular disorders encountered in a typical specialist clinic. Future considerations could be given to assessing any benefits of multidisciplinary team input, across a specialist neuromuscular service., (© 2024 Wiley Periodicals LLC.)

Objective: This article reviews autoimmune neuromuscular disorders and includes an overview of the diagnostic approach, especially the role of antibody testing in a variety of neuropathies and some other neuromuscular disorders., Latest Developments: In the past few decades, multiple antibody biomarkers associated with immune-mediated neuromuscular disorders have been reported. These biomarkers are not only useful for better understanding of disease pathogenesis and allowing more timely diagnosis but may also aid in the selection of an optimal treatment strategy., Essential Points: Recognition of autoimmune neuromuscular conditions encountered in inpatient or outpatient neurologic practice is very important because many of these disorders are reversible with prompt diagnosis and early treatment. Antibodies are often helpful in making this diagnosis. However, the clinical phenotype and electrodiagnostic testing should be taken into account when ordering antibody tests or panels and interpreting the subsequent results. Similar to other laboratory investigations, understanding the potential utility and limitations of antibody testing in each clinical setting is critical for practicing neurologists., (Copyright © 2024 American Academy of Neurology.)

Objective: To summarize the clinical manifestations, diagnosis, treatment and prognosis of acute flaccid myelitis (AFM) in children. Methods: Clinical characteristics of 4 AFM cases from Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics, from September 2018 to November 2022, were analyzed retrospectively. Results: The age of 4 children with AFM was 7 years, 4 years and 3 months, 7 years and 1 month, 6 years and 5 months, respectively. There were 2 boys and 2 girls. Prodromal infection status showed 3 children of respiratory tract infection and 1 child of digestive tract infection. The main manifestation was asymmetrical limb weakness after infection, and the affected limb range was from monoplegia to quadriplegia. Cranial nerve injury was involved in 1 child, no encephalopathy. Magnetic resonance imaging in the spinal cord of all 4 children showed long T1 and T2 signals, mainly involving gray matter. Cerebrospinal fluid cell-protein separation was observed in 2 children. Pathogen detected in 1 child pharyngeal swab was enterovirus D68. Antibody IgM to adenovirus was positive in the blood of 1 child. Antibody IgG against Echo and Coxsackie B virus were positive in the blood of another child. After glucocorticoid, human immunoglobulin or simple symptomatic treatment and at the same time under later rehabilitation training, muscle strength recovered to different degrees, but there were disabilities left in 3 children. Conclusions: AFM should be considered in children with acute and asymmetrical flaccid paralysis accompanied by abnormal magnetic resonance imaging signal in the central region of spinal cord, especially post-infection. The effective treatment is limited and the prognosis is poor.

Neuromuscular disorders (NMDs) include a wide range of diseases affecting the peripheral nervous system. The genetic diagnoses are increasingly obtained with using the next generation sequencing (NGS). We applied the custom-design targeted NGS panel including 89 genes, together with genotyping and multiplex ligation-dependent probe amplification (MLPA) to identify a genetic spectrum of NMDs in 52 Polish patients. As a result, the genetic diagnosis was determined by NGS panel in 29 patients so its diagnostic utility is estimated at 55.8%. The most pathogenic variants were found in CLCN1, followed by CAPN3, SCN4A, and SGCA genes. Genotyping of myotonic dystrophy type 1 and 2 (DM1 and DM2) as a secondary approach has been performed. The co-occurrence of CAPN3 and CNBP mutations in one patient as well as DYSF and CNBP mutations in another suggests possibly more complex inheritance as well as expression of a phenotype. In 7 individuals with single nucleotide variant found in NGS testing, the MLPA of the CAPN3 gene was performed detecting the deletion encompassing exons 2-8 in the CAPN3 gene in one patient, confirming recessive limb-girdle muscular dystrophy type 1 (LGMDR1). Thirty patients obtained a genetic diagnosis (57.7%) after using NGS testing, genotyping and MLPA analysis. The study allowed for the identification of 27 known and 4 novel pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) associated with NMDs.In conclusion, the diagnostic approach with diverse molecular techniques enables to broaden the mutational spectrum and maximizes the diagnostic yield. Furthermore, the co-occurrence of DM2 and LGMD has been detected in 2 individuals., (© 2024. The Author(s).)

Human rhinovirus (HRV) has been sporadically detected in patients with acute flaccid myelitis (AFM). We report a case of AFM in a 2-year-old boy with severe neurologic sequelae, whose nasopharyngeal and stool samples tested positive for HRV-A19. Clinical information related to AFM with HRV is limited. Further study of the association of AFM with HRV is warranted., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Although existing guidelines address electrodiagnostic (EDX) testing in identifying neuromuscular conditions, guidance regarding the uses and limitations of serial (or repeat) EDX testing is limited. By assessing neurophysiological change longitudinally across time, serial electrodiagnosis can clarify a diagnosis and potentially provide valuable prognostic information. This monograph presents four broad indications for serial electrodiagnosis in adult peripheral neurological disorders. First, where clinical change has raised suspicion for a new or ongoing lesion, EDX reassessment for spatial spread of abnormality, involvement of previously normal muscle or nerve, and/or evolving pathophysiology can clarify a diagnosis. Second, where diagnosis of a progressive neuromuscular condition is uncertain, electrophysiological data from a second time point can confirm or refute suspicion. Third, to establish prognosis after a static nerve injury, a repeat study can assess the presence and extent of reinnervation. Finally, faced with a limited initial study (as when complicated by patient or environmental factors), a repeat EDX study can supplement missing or limited data to provide needed clarity. Repeat EDX studies carry certain limitations, however, such as with prognostication in the setting of remote or chronic lesions, sensory predominant fascicular injury, or mild axonal injury. Nevertheless, serial electrodiagnosis remains a valuable and underused tool in the diagnostic and prognostic evaluation of neuromuscular conditions., (© 2024 by the American Association of Neuromuscular & Electrodiagnostic Medicine, Inc. All rights reserved.)

Objective: This article aims to familiarize the reader with the clinical approach, diagnostic considerations, and treatment strategies for patients presenting with abrupt-onset or acutely worsening weakness due to neuromuscular disorders., Latest Developments: Neuromuscular weakness is often the result of an inflammatory process. In recent years, there has been growing recognition of pathologic antibodies that cause neuromuscular injury. This has allowed clinicians to make a more accurate diagnosis. Additionally, neuromuscular junction disorders and myopathies are increasingly identified as the adverse effects of novel anticancer therapies, namely immune checkpoint inhibitors. More data are being incorporated into frameworks for neuroprognostication after neuromuscular emergencies, especially for commonly encountered disorders such as Guillain-Barré syndrome., Essential Points: Care of patients with neuromuscular emergencies requires prompt attention to respiratory status. Once supportive measures are in place to protect the airway and facilitate effective ventilation, diagnostic considerations should hinge on appropriate neurologic localization. Aggressive immunosuppression is often required for immune-mediated neuromuscular disorders, and clinicians must be thoughtful in selecting a strategy that best aligns with each patient's risk factors and comorbidities., (Copyright © 2024 American Academy of Neurology.)

The type, distribution pattern and time course of spontaneous muscular activity are important for the diagnostics of neuromuscular diseases in the clinical practice. In neurogenic lesions with motor axonal involvement, pathologic spontaneous activity (PSA) is usually reliably detectable by needle electromyography (EMG) 2-4 weeks after occurrence of the lesion. The distribution pattern correlates with the lesion location. The focus of the present work is the description of the different forms of PSA in myogenic diseases., (© 2024. The Author(s).)

Objective: Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence-based recommendations for their integration into practice., Methods: In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research-led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required., Results: Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice-altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene-panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today., Interpretation: Our results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post-exome auxiliary investigations extended our diagnostic yield by 81% overall (34-62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Electrophysiologic testing plays an important role in evaluating peripheral nerve, muscle, and neuromuscular junction diseases, aiding in diagnosis and treatment strategies by offering real-time assessment. Demyelination of peripheral nerves results in increased conduction delay, temporal dispersion, conduction block, and stimulation threshold. The localization or diffusion of these changes is crucial in understanding disease pathogenesis, necessitating stimulation at multiple points along nerve pathways. When axonal degeneration occurs, the amplitude is reduced, with mild conduction delay. Acute axonal degeneration may require 1 week to develop into Wallerian degeneration. During this time, conductivity was preserved in the nerve peripheral to the lesion. When MG or LEMS is suspected, repetitive nerve stimulation tests and single-fiber EMG are valuable for the diagnosis and pathophysiological evaluation. Notably, the latter is highly sensitive but not specific. Needle electromyography (EMG) assists in differentiating between myopathies and neurogenic diseases, and in determining whether the patient is in an acute or chronic stage. Integration of these tests contribute to an accurate diagnosis when considering the presenting symptoms.

Neuromuscular ultrasound has become an integral part of the diagnostic workup of neuromuscular diseases in neurology. Neuromuscular ultrasound can detect nerve enlargement, selective muscle damage, and fasciculation easily and non-invasively, which allows differentiation between auto-immune/inflammatory and degenerative/hereditary diseases. It is significant and essential for all neurologists to master the neuromuscular ultrasound technique.

Background: Neuromuscular disorders (NMDs) are heterogeneous conditions with a considerable fraction attributed to monogenic defects. Despite the advancements in genomic medicine, many patients remain without a diagnosis. Here, we investigate whether a comprehensive reassessment strategy improves the diagnostic outcomes., Methods: We analyzed 263 patients with NMD phenotypes that underwent diagnostic exome or genome sequencing at our tertiary referral center between 2015 and 2023. We applied a comprehensive reassessment encompassing variant reclassification, re-phenotyping and NGS data reanalysis. Multivariable logistic regression was performed to identify predictive factors associated with a molecular diagnosis., Results: Initially, a molecular diagnosis was identified in 53 cases (20%), while an additional 23 (9%) had findings of uncertain significance. Following comprehensive reassessment, the diagnostic yield increased to 23%, revealing 44 distinct monogenic etiologies. Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4). Male sex reduced the odds of receiving a molecular diagnosis (OR 0.42; 95%CI 0.21-0.82), while a positive family history (OR 5.46; 95%CI 2.60-11.76) and a myopathy phenotype (OR 2.72; 95%CI 1.11-7.14) increased the likelihood. 7% were resolved through targeted genetic testing or classified as acquired etiologies., Conclusion: Our findings reinforce the use of NGS in NMDs of suspected monogenic origin. We show that a comprehensive reassessment enhances diagnostic accuracy. However, one needs to be aware that genetic diagnoses are often made with uncertainty and can even be downgraded based on new evidence., (© 2023. The Author(s).)

Acute neuromuscular disorders occasionally occur in the Pediatric Neurologic Intensive Care Unit. Many of these are primary disorders of the motor unit that may present acutely or exacerbate during an intercurrent illness. Additionally, acute neuromuscular disorders may develop during an acute systemic illness requiring intensive care management that predispose the child to another set of acute motor unit disorders. This chapter discusses acute neuromuscular crises in the infant, toddler, and adolescent, as well as neuromuscular disorders resulting from critical illness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diagnosis of neuromuscular diseases (NMD) can be challenging because of the heterogeneity of this group of diseases. This review aimed to describe the diagnostic yield of whole exome sequencing (WES) for pediatric-onset neuromuscular disease diagnosis, as well as other benefits of this approach in patient management since WES can contribute to appropriate treatment selection in NMD patients. WES increases the possibility of reaching a conclusive genetic diagnosis when other technologies have failed and even exploring new genes not previously associated with a specific NMD. Moreover, this strategy can be useful when a dual diagnosis is suspected in complex congenital anomalies and undiagnosed cases., (© 2023. The Author(s).)

Introduction: Acute presentations and emergencies in neuromuscular disorders (NMDs) often challenge clinical acumen. The objective of this review is to refine the reader's approach to history taking, clinical localization and early diagnosis, as well as emergency management of neuromuscular emergencies., Methods: An extensive literature search was performed to identify relevant studies. We prioritized meta-analysis, systematic reviews, and position statements where possible to inform any recommendations., Summary: The spectrum of clinical presentations and etiologies ranges from neurotoxic envenomation or infection to autoimmune disease such as Guillain-Barré Syndrome (GBS) and myasthenia gravis (MG). Delayed diagnosis is not uncommon when presentations occur "de novo," respiratory failure is dominant or isolated, or in the case of atypical scenarios such as GBS variants, severe autonomic dysfunction, or rhabdomyolysis. Diseases of the central nervous system, systemic and musculoskeletal disorders can mimic presentations in neuromuscular disorders., Conclusions: Fortunately, early diagnosis and management can improve prognosis. This article provides a comprehensive review of acute presentations in neuromuscular disorders relevant for the emergency physician., (© 2024 The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Objectives: Neuromuscular disorders could have respiratory involvement early or late into illness. Rarely, patients may present with a hypercapnic respiratory failure (with minimal motor signs) unmasking an underlying disease. There are hardly any studies which have addressed the spectrum and challenges involved in management of this subset, especially in the real-world scenario., Methods: A retrospective study comprising consecutive patients hospitalized with hypercapnic respiratory failure as the sole/dominant manifestation. The clinical-electrophysiological spectrum, phrenic conductions, diaphragm thickness, and outcomes were analyzed., Results: Twenty-seven patients were included, the mean age was 47.29 (SD 15.22) years, and the median duration of respiratory symptoms was 2 months (interquartile range [IQR] 1-4). Orthopnea was present in 23 patients (85.2%) and encephalopathy in 8 patients (29.6%). Phrenic nerve latencies and amplitudes were abnormal in 83.3% and 95.6%, respectively. Abnormal diaphragm thickness was noted in 78.5%. Based on a comprehensive electrophysiological strategy and paraclinical tests, an etiology was established in all. Reversible etiologies were identified in 17 patients (62.9%). These included myasthenia gravis (anti-AChR and MuSK), inflammatory myopathy, riboflavin transporter deficiency neuronopathy, Pompe disease, bilateral phrenic neuritis, and thyrotoxicosis. Respiratory onset motor neuron disease was diagnosed in 8 patients (29.6%). Despite diaphragmatic involvement, a functional respiratory recovery was noted at discharge (45%) and last follow-up (60%). Predictors for good outcomes included female sex, normal nerve conductions, and recent-onset respiratory symptoms., Discussion: A good functional recovery was noted in most of the patients including respiratory onset motor neuron disease. A systematic algorithmic approach helps in proper triaging, early diagnosis, and treatment. Clinical and electrodiagnostic challenges and observations from a tertiary care referral center are discussed., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Gait abnormalities are frequent in children and can be caused by different pathologies, such as cerebral palsy, neuromuscular disease, toe walker syndrome, etc. Analysis of the "gait pattern" (i.e., the way the person walks) using 3D analysis provides highly relevant clinical information. This information is used to guide therapeutic choices; however, it is underused in diagnostic processes, probably because of the lack of standardization of data collection methods. Therefore, 3D gait analysis is currently used as an assessment rather than a diagnostic tool. In this work, we aimed to determine if deep learning could be combined with 3D gait analysis data to diagnose gait disorders in children. We tested the diagnostic accuracy of deep learning methods combined with 3D gait analysis data from 371 children (148 with unilateral cerebral palsy, 60 with neuromuscular disease, 19 toe walkers, 60 with bilateral cerebral palsy, 25 stroke, and 59 typically developing children), with a total of 6400 gait cycles. We evaluated the accuracy, sensitivity, specificity, F1 score, Area Under the Curve (AUC) score, and confusion matrix of the predictions by ResNet, LSTM, and InceptionTime deep learning architectures for time series data. The deep learning-based models had good to excellent diagnostic accuracy (ranging from 0.77 to 0.99) for discrimination between healthy and pathological gait, discrimination between different etiologies of pathological gait (binary and multi-classification); and determining stroke onset time. LSTM performed best overall. This study revealed that the gait pattern contains specific, pathology-related information. These results open the way for an extension of 3D gait analysis from evaluation to diagnosis. Furthermore, the method we propose is a data-driven diagnostic model that can be trained and used without human intervention or expert knowledge. Furthermore, the method could be used to distinguish gait-related pathologies and their onset times beyond those studied in this research., Competing Interests: Declaration of competing interest None of the authors have any financial or personal conflict of interest with regard to this work., (Copyright © 2024. Published by Elsevier Ltd.)

Rare or novel missense variants in large genes such as TTN and NEB are frequent in the general population, which hampers the interpretation of putative disease-causing biallelic variants in patients with sporadic neuromuscular disorders. Often, when the first initial genetic analysis is performed, the reconstructed haplotype, i.e. phasing information of the variants is missing. Segregation analysis increases the diagnostic turnaround time and is not always possible if samples from family members are lacking. To overcome this difficulty, we investigated how well the linked-read technology succeeded to phase variants in these large genes, and whether it improved the identification of structural variants. Linked-read sequencing data of nemaline myopathy, distal myopathy, and proximal myopathy patients were analyzed for phasing, single nucleotide variants, and structural variants. Variant phasing was successful in the large muscle genes studied. The longest continuous phase blocks were gained using high-quality DNA samples with long DNA fragments. Homozygosity increased the number of phase blocks, especially in exome sequencing samples lacking intronic variation. In our cohort, linked-read sequencing added more information about the structural variation but did not lead to a molecular genetic diagnosis. The linked-read technology can support the clinical diagnosis of neuromuscular and other genetic disorders., (© 2024. The Author(s).)