Neuromuscular Disorders In Children Research Articles

Reoperation, Readmission, and Postoperative Bleeding in Pediatric Cerebral Palsy Patients Undergoing Spinal Arthrodesis.

Background Cerebral palsy (CP) is one of the most common neuromuscular disorders in children, and spinal abnormalities are vastly more common in people with CP compared to the general population. Further investigation is needed to improve our understanding of the perioperative factors that place children with CP at greater risk of postoperative complications.This study aims to investigate (1) whether pediatric CP patients have higher rates of postoperative complications after spinal fusion and (2) risk factors for postoperative bleeding, readmission, and reoperation. Methodology The 2019 American College of Surgeons National Surgical Quality Improvement Program Pediatric database was used for this study. Chi-square tests were used to compare patient demographics, frequency of comorbidities, intraoperative factors, and postoperative complications between CP and non-CP patients. Multivariable logistic regression modeling was conducted to determine if CP was an independent risk factor for the composite variable that included postoperative bleeding, readmission, and reoperation. Results A total of 4,445 patients were included in the study, with 606 CP and 3,839 non-CP patients. Several comorbidities were more prevalent in the CP cohort, most notably asthma, gastrointestinal disease, previous cardiac surgery, and hematologic disorders. Multivariable logistic regression modeling revealed that CP, older age, non-Caucasian race, American Society of Anesthesiologists (ASA) class of 3 or higher, posterior surgical approach, previous cardiac surgery, and ostomy were significantly correlated with higher postoperative complications. Conclusions This study demonstrates that CP, older age, non-Caucasian race, ASA class of 3 or higher, posterior approach, previous cardiac surgery, and ostomy are independent risk factors for postoperative complications, including readmission, reoperation, and postoperative bleeding requiring transfusions. Consequently, there is a pressing need for additional research to establish perioperative strategies that reduce postoperative risks for these patients. Spine surgeons should consider the findings of this study when communicating the potential risks of spinal fusion surgery with patients and their families.

Analysis of spinal muscular atrophy carrier screening results in 32,416 pregnant women and 7,231 prepregnant women.

Spinal muscular atrophy (SMA) is an autosomal recessive disease that is one of the most common in childhood neuromuscular disorders. Our screenings are more meaningful programs in preventing birth defects, providing a significant resource for healthcare professionals, genetic counselors, and policymakers involved in designing strategies to prevent and manage SMA. We screened 39,647 participants from 2020 to the present by quantitative real-time PCR, including 7,231 pre-pregnancy participants and 32,416 pregnancy participants, to detect the presence of SMN1 gene EX7 and EX8 deletion in the DNA samples provided by the subjects. To validate the accuracy of our findings, we also utilized the Multiplex Ligation-dependent Probe Amplification (MLPA) to confirm the reliability of screening results obtained by quantitative real-time PCR. Among the 39,647 participants who were screened, 726 participants were the carriers of SMN1. The overall carrier rate was calculated to be 1.83% (95% confidence interval: 0.86-2.8%). After undergoing screening, a total of 592 pregnancy carriers were provided with genetic counseling and only 503 of their spouses (84.97, 95% confidence interval: 82.09-87.85%) voluntarily underwent SMA screening. This study provides crucial insights into the prevalence and distribution of SMA carriers among the female population. The identification of 726 asymptomatic carriers highlights the necessity of comprehensive screening programs to identify at-risk individuals and ensure appropriate interventions are in place to minimize the impact of SMA-related conditions.

P183 The genetic profile of childhood neuromuscular disorders: a single center experience

P183 The genetic profile of childhood neuromuscular disorders: a single center experience

Special Issue “Neuromuscular Disorders in Children and Adolescents”

Our call for contributions in early 2021 resulted in 10 peer-reviewed publications by the end of the year covering a wide range of topics in the field of neuromuscular diseases in children and adolescents [...]

A Comprehensive Review of Neuromuscular Manifestations of COVID-19 and Management of Pre-Existing Neuromuscular Disorders in Children.

Since the emergence of SARS-CoV-2, several studies have been published describing neuromuscular manifestations of the disease, as well as management of pre-existing pediatric neuromuscular disorders during the COVID-19 pandemic. These disorders include muscular dystrophies, myasthenic syndromes, peripheral nerve disorders, and spinal muscular atrophy. Such patients are a vulnerable population due to frequent complications such as scoliosis, cardiomyopathy, and restrictive lung disease that put them at risk of severe complications of COVID-19. In this review, neuromuscular manifestations of COVID-19 in children and the management of pre-existing pediatric neuromuscular disorders during the COVID-19 pandemic are discussed. We also review strategies to alleviate pandemic-associated disruptions in clinical care and research, including the emerging role of telemedicine and telerehabilitation to address the continued special needs of these patients.

Gene therapy in hereditary neuromuscular diseases

Childhood neuromuscular disorders are devastating conditions associated with major disability and shortened life span. They encompass common muscular dystrophies such as Duchenne muscular dystrophy (DMD); motorneuron diseases such as spinal muscular atrophy (SMA), and less common limb girdle muscular dystrophies and congenital myopathies. Each of these conditions presents its own therapeutic challenges. The major hurdle in muscular dystrophies is the abundance of the target organ (skeletal muscle is ~40% of the body weight), the need to target the heart and, in DMD, the large size of its cDNA that precludes its packaging in commonly used viral vectors.

New diagnostic and therapeutic modalities in neuromuscular disorders in children

Pediatric neuromuscular disorders are a diverse group of conditions that affect how muscle and nerve function. They involve the motor neurons, nerves, neuromuscular junction and muscles. Pathology of any of these regions leads to the inability to perform voluntary movements. Over time, the natural progression of most of these disorders is followed by significant disability, and at the most extreme, almost complete paralysis and death secondary to complications. Diagnostic measures for pediatric neuromuscular disorders, like that of most medical conditions, relies heavily on clinical presentation, history and a detailed physical examination. Primary additional diagnostic measures have included serum creatine kinase (CK) levels, electromyography (EMG), nerve conduction studies (NCS) and muscle or nerve biopsies, which has historically been the gold standard. In the last several decades less invasive testing has become more common such as muscle magnetic resonance imaging (MRI) and genetic testing. The advances of molecular genetics, such as next generation sequencing (NGS) which includes whole-exome sequencing (WES) and whole-genome sequencing (WGS), enable clinicians to pinpoint more accurately exact gene mutations. The advent of genetic testing enhances personalized medicine. The field of pediatric neuromuscular disorders is also undergoing a remarkable evolution in therapeutic modalities including novel targeted therapies such as exon skipping/inclusion and gene replacement therapies. This is a review of the initial approach to suspected neuromuscular disorders in children as well as up to date diagnostic and therapeutic modalities for the most common pediatric neuromuscular disorders. As the world enters the new decade, there are encouraging therapeutic results. However, there remain key challenges to these modalities including limitations in its applicability, optimization for delivery of gene replacement therapies and in its effectiveness.

PRINCIPLES OF IMPROVING THE QUALITY OF CARE FOR CHILDREN WITH NEUROORTHOPEDIC DISORDERS

This article discusses specific approaches to the diagnosis, treatment, and rehabilitation of children with different neuroorthopedic disorders. Particular attention is paid to the experience of foreign specialists in treating neuromuscular disorders in children, as well as the need for a comprehensive and systematic approach to their rehabilitation. In this manuscript, we provided examples of high-tech surgical and conservative treatment, as well as grafting and orthotic support for children with various congenital and acquired diseases of the musculoskeletal system and the central nervous system in the Russian Federation.

Utility and practice of electrodiagnostic testing in the pediatric population: An AANEM consensus statement.

Nerve conduction studies and needle electromyography, collectively known as electrodiagnostic (EDX) studies, have been available for pediatric patients for decades, but the accessibility of this diagnostic modality and the approach to testing vary significantly depending on the physician and institution. The maturation of molecular diagnostic approaches and other diagnostic technologies such as neuromuscular ultrasound indicate that an analysis of current needs and practices for EDX studies in the pediatric population is warranted. The American Association of Neuromuscular & Electrodiagnostic Medicine convened a consensus panel to perform literature searches, share collective experiences, and develop a consensus statement. The panel found that electrodiagnostic studies continue to have high utility for the diagnosis of numerous childhood neuromuscular disorders, and that standardized approaches along with the use of high-quality reference values are important to maximize the diagnostic yield of these tests in infants, children, and adolescents.

Gene therapy for childhood neuromuscular and neurodegenerative disorders: An update

The central nervous system is a rather complex site for gene therapy as it contains neurons, astrocytes, and oligodendrocytes, and they have discrete and intricate interconnections between them, establishing a delicate balance. However, with significant advances in scientific technology and development of new viral vectors, now, gene therapy has a greater promise for pediatric neurological disorders, especially for certain neurodegenerative diseases, which still remains to be invincible by other pharmacological modalities. Adeno-associated virus (AAV) vector is the predominant vector used for gene therapy currently. Gene editing therapy using antisense oligonucleotides has been successfully implemented in neuromuscular diseases such as dystrophinopathy and spinal muscular atrophy (SMA). Recently, an AAV-mediated gene therapy is approved by the Food and Drug Administration for SMA, and it is considered to be the most expensive drug in the world. Gene therapy for dystrophinopathy has also been safely tried in two clinical studies, although its efficacy is yet to be demonstrated. In Xlinked adrenoleukodystrophy, late infantile metachromatic leukodystrophy, late infantile neuronal ceroid lipofuscinosis and Canavan disease results of human trials are very much promising. Ongoing clinical trials in several lysosomal storage disorders such as mucopolysaccharidosis type III, Fabry disease, and Pompeii disease are currently active. In mouse models, several other neurodevelopmental disorders have also been tested successfully for gene therapy.

Exercise biology of neuromuscular disorders.

Neuromuscular disorders (NMDs) are chronic conditions that affect the neuromuscular system. Many NMDs currently have no cure; however, as more effective therapies become available for NMD patients, these individuals will exhibit improved health and/or prolonged lifespans. As a result, persons with NMDs will likely desire to engage in a more diverse variety of activities of daily living, including increased physical activity or exercise. Therefore, there is a need to increase our knowledge of the effects of acute exercise and chronic training on the neuromuscular system in NMD contexts. Here, we discuss the disease mechanisms and exercise biology of Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy type 1 (DM1), which are among the most prevalent NMDs in children and adults. Evidence from clinical and preclinical studies are reviewed, with emphasis on the functional outcomes of exercise, as well as on the putative cellular mechanisms that drive exercise-induced remodelling of the neuromuscular system. Continued investigation of the molecular mechanisms of exercise adaptation in DMD, SMA, and DM1 will assist in enhancing our understanding of the biology of these most prevalent NMDs. This information may also be useful for guiding the development of novel therapeutic targets for future pursuit.

S90 Quantified electromyography in children

In spite of recent advantages in molecular genetics, electromyography (EMG) still has diagnostic value, especially in children. Neuromuscular disorders in children are not common compared to in adults but they are important. Many of them are disabling disorders in which there is no cure, only supportive treatment. Such neuromuscular disorders affect not only the patient, but the whole family, often because of increased care load. In addition to these chronic disorders, of which many have a genetic background, there are acute and subacute traumatic disorders and immunopathies. In children, every medical procedure may induce anxiety. It is therefore important that one or both parents are present at the investigation in order to support their child. It is advisable to apply a local anaesthetic prior to EMG. Pain relief may be needed to give before EMG (e.g. morphine). Controlled conscious sedation may sometimes be needed (e.g. midazolam, ketamine, nitrous oxide). In the majority of children, conventional needle EMG is used in order to study the motor unit properties. In a normal muscle at rest no abnormal spontaneous activity is identified. Thus, after the insertion activity has subsided, the muscle at rest is investigated for abnormal spontaneous activity which may occur in single muscle fibres or in a group of fibres. There may be abnormal spontaneous activity of different kinds in one and the same diseased muscle of neurogenic or myogenic origin. Ten different places in each muscle are examined, and the amount of abnormal spontaneous activity in these ten needle positions is measured. At slight voluntary activation motor unit potentilas (MUPs) are recruited. Preferably, about 20 MUPs are collected from each muscle in order to allow a thorough assessment. However, in children with severe disorders, and who activate only sporadically, it may not be possible to obtain more than a few MUPs. The MUPs are collected by quantitative method, sometimes mixed with a semiquantitative method, depending on the child’s co-operation. For each MUP there are different parameters to consider, e.g. amplitude, duration, shape and stability. Strong voluntary activation is used to study the interference pattern. It is difficult to perform this adequately in children, but, when feasible, it gives much information and complements the MUP analysis. Single-fbre EMG is a very useful and sensitive tool in the diagnosis of neuromuscular transmission disorders. It can be studied under voluntary activation or, particularly in children, with electrical stimulation. The oral communication will further elaborate on EMG and give practical tips.

Advances in neuromuscular disorders – an update

Abstract There have been several significant recent advances in the diagnosis and management of children with neuromuscular disorders. These have been accompanied by an increased understanding of the basic defects seen, in particular how genotype relates to phenotype. In this article we aim to review the advances in commonly seen neuromuscular disorders in children including spinal muscular atrophy, Duchenne muscular dystrophy, myotonic dystrophy, the congenital myopathies, myaesthenic syndromes, limb-girdle muscular dystrophies and Charcot–Marie–Tooth hereditary neuropathies. We explain what treatments have been shown to be effective and where research efforts are currently concentrated for each group of disorders.

Mitochondrial oxidative phosphorylation disorders in children: Phenotypic, genotypic and biochemical correlations in 85 patients from South India

Mitochondrial oxidative phosphorylation (OXPHOS) disorders account for a variety of neuromuscular disorders in children. In this study mitochondrial respiratory chain enzymes were assayed in muscle tissue in a large cohort of children with varied neuromuscular presentations from June 2011 to December 2013. The biochemical enzyme deficiencies were correlated with the phenotypes, magnetic resonance imaging, histopathology and genetic findings to reach a final diagnosis. There were 85 children (mean age: 6.9±4.7years, M:F:2:1) with respiratory chain enzyme deficiency which included: isolated complex I (n=50, 60%), multiple complexes (n=24, 27%), complex IV (n=8, 9%) and complex III deficiencies (n=3, 4%). The most common neurological findings were ataxia (59%), hypotonia (59%) and involuntary movements (49%). A known mitochondrial syndrome was diagnosed in 27 (29%) and non-syndromic presentations in 57 (71%). Genetic analysis included complete sequencing of mitochondrial genome, SURF1, POLG1&2. It revealed variations in mitochondrial DNA (n=8), SURF1 (n=5), and POLG1 (n=3). This study, the first of its kind from India, highlights the wide range of clinical and imaging phenotypes and genetic heterogeneity in children with mitochondrial oxidative phosphorylation disorders.

Ultrasound in the Assessment of Myopathic Disorders.

Neuromuscular ultrasound (US) augments a careful physical examination and electrodiagnostic evaluation in the evaluation of suspected myopathy. Ultrasound evaluation of muscle can identify abnormal echo intensity, size, and movement. Because it is painless and noninvasive, US can be used to evaluate multiple muscles to direct the electrodiagnostic examination or muscle biopsy. Some patterns of muscle involvement can suggest specific etiologies. Most muscular dystrophies show homogenously increased muscle echo intensity with attenuation of the US signal, likely resultant from increased intramuscular fat and fibrosis. Inflammatory myopathies can also show homogenously increased echogenicity but lack the signal attenuation seen in muscular dystrophies. In contrast, denervation can show "moth-eaten," atrophic muscles with fasciculations. Advanced age and obesity also impacts muscle size and echo intensity and can hamper efforts to detect mild pathologies. The sensitivity and specificity of US for detecting neuromuscular disease have been best studied in children and depend on the type and severity of the disorder. In general, muscle US yields sensitivities and specificities of 67% to 100% for detecting neuromuscular disorders in children and is similar to electromyogram for detection of myopathy. Ultrasound is most sensitive for detecting muscular dystrophies and is less sensitive in metabolic myopathies and very young children.

Neuromuscular disorders in children in South-Eastern Norway

To describe the group of patients under the age of 18 who have neuromuscular disorders and are from a region with 1.65 million inhabitants in South-Eastern Norway. Patients with known or suspected neuromuscular disorders were identified by neuropediatricians/rehabilitation teams in the region. We registered a total of 141 patients under the age of 18 who had a neu- romuscular diagnosis, giving a prevalence of 35.6 × 10 −5 in this population. It was possible to check the diagnoses of 122 pa- tients. Duchenne muscular dystrophy was the largest group, followed by peripheral neuropathies, myotonic dystrophy and spinal muscular atrophy. The prevalence figures for the different diagnostic entities are discussed on the basis of previously reported studies from the same area, from a comparable Swedish area and from other countries. We registered patients with a broad spectrum of neuromuscular diagnoses in our health region. The classical, well-known entities were the most prevalent condi- tions. It was difficult to make a very specific diagnosis in quite a few cases.

G.P.195: BMP signaling controls satellite cell dependent postnatal muscle growth

Postnatal/juvenil muscle growth is achieved by both an increase in myofiber size and the addition of further myonuclei, whereas myofiber number does not increase further. Satellite cells are the resident muscle stem cells which proliferate in growing muscle to supply new myonuclei. Little is known of how satellite cell function is controlled during the postnatal/juvenil growth phase to permit correct muscle mass development and the generation of the adult satellite cell pool. We previously have shown that signaling by Bone morphogenetic proteins (BMP) regulates embryonic myogenesis by determining the entry of embryonic muscle precursors into differentiation. Here we demonstrate that this pathway also defines postnatal/juvenil muscle growth. We found that juvenile satellite cells express elements of the BMP signaling cascade such as BMP ligands, BMP receptor, and the intracellular BMP responsive element P-Smad1/5/8, showing that BMP signaling is active in these cells. Abrogating BMP signaling targeted to satellite cells in juvenile Rosa26-Lox-Stop-Lox-Smad6-IRES-GFP:Pax7CreERT2/+ mice decreased the pool of satellite cells and muscle fibres contained less myonuclei and were smaller than those from control mice. We show that blockade of BMP signaling decreased satellite cell proliferation and diminished the myonuclear recruitment during myofiber growth as the underlying cellular mechanism, and this severely retarded muscle growth. In addition, failure of satellite cell proliferation strongly reduced the final satellite cell reservoir in mature muscle. In conclusion, these results show that correct BMP signaling in satellite cells is required for satellite cell dependent myofiber growth and for the generation of the adult satellite cell pool. In future it will be of large interest to determine whether the BMP signaling pathway is altered in childhood neuromuscular disorders and whether this inflicts satellite cell dependent muscle growth.

Muscle magnetic resonance imaging of the lower limbs: valuable diagnostic tool in the investigation of childhood neuromuscular disorders.

Children presenting with neuromuscular symptoms are subject to exhaustive investigations. As it is noninvasive, muscle magnetic resonance imaging (MRI) is an important diagnostic tool in children, yet its impact has so far been mainly studied in small groups of genetically defined diseases, where specific MRI patterns are known. To assess the contribution of muscle MRI of the lower limbs in a diverse cohort of patients, we reviewed the diagnostic findings in 39 patients with a suspected neuromuscular disorder that underwent muscle MRI (28/39), biopsy (26/39), or both (18/39). MRI was performed without sedation in 26 of 28 patients at a mean age of 10 years (range, 1-27 years). In 10 of 28 cases (35%), MRI significantly contributed to the final diagnosis, and in 7 of 28 cases (25%), muscle MRI directly instructed genetic testing. These cases included Bethlem myopathy, laminopathy, calpainopathy, and RYR1-related myopathies. Muscle MRI serves as a valuable additional tool to guide diagnosis in suspected neuromuscular disorders in children, especially in cases with nonspecific biopsy findings.

184th ENMC international workshop: Pain and fatigue in neuromuscular disorders: 20–22 May 2011, Naarden, The Netherlands

This European Neuromuscular Centre (ENMC) care workshop was attended by 19 professionals working in the field of neuromuscular disorders (pediatric and adult), pain or fatigue from 8 different countries (USA, Great Britain, Germany, France, Italy, Sweden, Denmark and the Netherlands), and 3 patient representatives coming from the Netherlands. This ENMC organized workshop aimed to achieve consensus on the definition of pain and fatigue in NMD, to define a core set of measurement instruments for pain and fatigue in NMD, and to discuss possible interventions. Prior to the workshop, all participants received a questionnaire on the assessment instruments and interventions that they regularly used to, respectively, assess and treat pain and fatigue. Two experts on (chronic) pain and fatigue in general (Henriet van Middendorp and Hans Knoop) were invited to present an overview of definitions, mechanisms, and measurement instruments for pain and fatigue. Next to that, several participants presented data on the prevalence of pain and fatigue in the various NMD populations. Through group discussions with all participants, consensus was reached on the definition and core set of measurement instruments (to be used)/for use in future research and clinical practice in NMD.

Intérêt de la biopsie musculaire chez l’enfant en 2012

Muscle biopsy is a mainstay diagnostic tool for investigating neuromuscular disorders in children. We report the yield of pediatric muscle biopsy in a population of 415 children by a retrospective study of 419 biopsies performed between 1/01/2000 and 31/12/2009 in a neuropediatric department, including mitochondrial respiratory chain analysis for 87 children. Two hundred and fifty-five biopsies were from boys (61%) 164 from girls (39%). Their mean age at biopsy was 6.5years; 155 (37%) biopsies were obtained before the child was 5years old. Final histopathological diagnoses were: congenital myopathy (n=193, including 15 structural congenital myopathies); progressive muscular dystrophy (n=75 [18%] including 57 dystrophinopathies); congenital muscular dystrophy (n=17, including six primary merosinopathies); dermatomyositis (n=11); spinal muscular atrophy (n=9, including six atypical spinal muscular atrophies); metabolic myopathy (n=32, including 19 mitochondrial myopathies); encephalomyopathy (n=53 [13%], including 27 with a mitochondrial respiratory chain defect). Pathological diagnosis remained undetermined in 16 cases. In 184 patients (44%), the muscle biopsy revealed specific histopathological anomalies (dystrophic process; specific ultrastructural abnormalities; perifascicular atrophy; neurogenic atrophy; metabolic anomalies) enabling a precise etiological diagnosis. For 85% of progressive muscular dystrophies, the biopsy resulted in a genetic diagnosis after identification of the protein defect. In 15% of the congenital myopathies, histopathological anomalies focused attention on one or several genes. Concerning dystrophinopathies, quantification of dystrophin deficiency on the biopsy specimen contributed to the definition of the clinical phenotype: Duchenne, or Becker. In children with a myopathy, muscle biopsy is often indispensable to establish the etiological diagnosis. Based on the results from this series, muscle biopsy can provide a precise orientation in 45% of patients, leading to a genetic hypothesis.