Neuromuscular Disorders In Children Research Articles

Neuromuscular Disorders in Zebrafish: State of the Art and Future Perspectives

Neuromuscular disorders are a broad group of inherited conditions affecting the structure and function of the motor system with polymorphic clinical presentation and disease severity. Although individually rare, collectively neuromuscular diseases have an incidence of 1 in 3,000 and represent a significant cause of disability of the motor system. The past decade has witnessed the identification of a large number of human genes causing muscular disorders, yet the underlying pathogenetic mechanisms remain largely unclear, limiting the developing of targeted therapeutic strategies. To overcome this barrier, model systems that replicate the different steps of human disorders are increasingly being developed. Among these, the zebrafish (Danio rerio) has emerged as an excellent organism for studying genetic disorders of the central and peripheral motor systems. In this review, we will encounter most of the available zebrafish models for childhood neuromuscular disorders, providing a brief overview of results and the techniques, mainly transgenesis and chemical biology, used for genetic manipulation. The amount of data collected in the past few years will lead zebrafish to became a common functional tool for assessing rapidly drug efficacy and off-target effects in neuromuscular diseases and, furthermore, to shed light on new etiologies emerging from large-scale massive sequencing studies.

Phenotypic heterogeneity in skeletal muscle sodium channelopathies: A case report and literature review

Skeletal muscle sodium channelopathies (SMSCs) including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PC), and sodium channel myotonia are caused by sodium channel gene (SCN4A) mutations, with altered sarcolemal excitability, and can present as episodes of skeletal muscle weakness, paralysis, and myotonia. We report a teenage boy, who presented with features of HyperPP, PC, myotonia congenita, and sodium channel myotonia. His electromyography (EMG) revealed myopathic changes, myotonia, and Fournier EMG pattern I, and posed a diagnostic challenge. Genetic analysis showed Thr704Met mutation in SCN4A gene. While with typical clinical phenotypes, the electromyographic patterns can be used to direct genetic testing, atypical phenotypes may pose diagnostic dilemmas. Clinicians dealing with neuromuscular disorders in children need to be aware of the unusual clinical presentations of SMSC, so that focused genetic testing can be carried out.

Test–retest reliability and developmental evolution of the 6-min walk test in Caucasian boys aged 5–12years

The 6-min walk test (6MWT) assesses functional capacity and has been used as outcome measure in therapeutic studies in childhood neuromuscular disorders. The objectives were to evaluate test-retest reliability of the 6MWT and to generate normative data for healthy boys aged 5-12 years. Ninety boys (mean age 8 years 10 months) were recruited over four age subcategories (5-6, 7-8, 9-10, 11-12 years). Mean 6MWT distance and velocity (±standard deviation) for the total group were 555.5±93 m and 92.6±16.6 m/min. The 6MWT distance increased significantly with age. Test-retest reliability (mean interval 12 days) was very high for the total group (ICC>0.95) and for all age subcategories (ICC>0.80) a moderately high reliability (ICC>0.75) was found from 3 min onwards for each age subcategory. There was a mean difference of 5.2 m between test and retest without systematic bias. The standard error of measurement and smallest detectable difference were 20.7 and 57.4 m, respectively. These findings demonstrate the reliability of the 6MWT in young children, underscore its evolution with age, and indicate that a shorter version of the test is also reliable.

Sniff nasal inspiratory pressure and sleep disordered breathing in childhood neuromuscular disorders

The ease of sniff nasal inspiratory pressure testing may extend application of respiratory muscle assessment to younger and cognitively-impaired children. We sought to quantify sniff nasal inspiratory pressure in childhood neuromuscular disorders, and to correlate this measure with conventional pulmonary function tests and overnight polysomnography. Thirty children (mean 9.7±3.8years, range 4.3–16.5years) with diagnosed neuromuscular disorders (Duchenne muscular dystrophy, spinal muscular atrophy, Becker muscular dystrophy, congenital myopathy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, multi-minicore disease) underwent assessment. Thirty-seven percent displayed cognitive impairment. Those with neuromuscular disorders were then compared with 32 volunteer age- and gender-matched controls (mean 10.9±2.9years, range 6.6–17.2years) with normal respiratory function. Twenty-three children with neuromuscular disorders also underwent overnight polysomnography. Children with neuromuscular disorders demonstrated significantly impaired sniff nasal inspiratory pressure, maximal inspiratory pressure, FEV1 and FVC (p<0.05). A positive correlation was identified between daytime sniff nasal inspiratory pressure and maximal inspiratory pressure (r=0.58), FEV1 (r=0.55) and FVC (r=0.46), though not with polysomnography variables (respiratory disturbance index, nadir SpO2, peak CO2). Moderate prevalence of nocturnal hypoxia was observed, and 32% of children demonstrated sleep disordered breathing. Sniff nasal inspiratory pressure assessment was well tolerated, representing a promising surrogate measure for assessment of respiratory function in childhood neuromuscular disorders.

P1.59 Pre-diagnostic parent experiences in Duchenne and Becker muscular dystrophies, congenital muscular dystrophies, and spinal muscular atrophies: A survey of the national task force for the early identification of childhood neuromuscular disorders

P1.59 Pre-diagnostic parent experiences in Duchenne and Becker muscular dystrophies, congenital muscular dystrophies, and spinal muscular atrophies: A survey of the national task force for the early identification of childhood neuromuscular disorders

骨格筋生検における経皮的針生検の有用性について:生検筋の組織学, 組織化学, 電顕的検討

骨格筋生検における経皮的針生検の有用性について:生検筋の組織学, 組織化学, 電顕的検討

Self-reported quality of life has no correlation with functional status in children and adolescents with spinal muscular atrophy

Background Spinal muscular atrophy is one of the most common neuromuscular disorders in children. Associated with progressive muscular weakness, it may assume a chronic course. In chronic disorders it is of utmost importance to determine the quality of life level. Objective To determine the level of quality of life in a cohort of SMA children and adolescents, and study its relation to motor ability. Methods From the children and adolescents with confirmed SMA diagnosis (presence of deletion) followed at a University Hospital, we selected those that were 4 years or older. They were classified as SMA type II or III according to their best motor ability, evaluated according to the modified Hammersmith functional score, and undertook the AUQEI Portuguese version to determine quality of life. This is an Institutional Review Board approved study and consent was given by all those included. Results Thirty-three children and adolescent with a mean age of 10.28 (±4.71) took part of the study. The fourteen SMA type II had a mean Hammersmith score of 11 (±9.50) and AUQEI of 55.85 (±7.16), while the nineteen SMA type III scored 31.10 (±12.30) and 52.94 (±4.85). No significant difference was found when quality of life scores was compared among those groups. Conclusion On a self-reported scale it seems that regardless the functional status an SMA child and adolescent has a perception of good quality of life.

Sleep and well-being in young men with neuromuscular disorders receiving non-invasive ventilation and their carers

Nocturnal ventilation has improved the physical status and life span of childhood neuromuscular disorders: the purpose of this study was to assess the implications for sleep and well-being in patients and carers. Ten young men (age range 12–25 years) with neuromuscular disorders on assisted ventilation and/or their main carers completed questionnaires on sleep quality, physical and psychological well-being, family burden and function. Both patients and parents expressed satisfaction with ventilation treatment. Compared to standardised values patients reported reduced sleep quality, but their mental health was not substantially affected. Poor sleep quality in carers – but not in patients – was significantly associated with risk for emotional (anxiety and depressive) disorders, reduced physical/emotional health, family burden and difficulty. We conclude that patients were generally well adapted psychologically, but sleep quality was poor and in carers this was linked to reduced well-being and family burden.

Cardiac manifestations of neuromuscular disorders in children

Cardiac abnormalities occur in association with many of the neuromuscular disorders that present in childhood. Genetic defects involving the cytoskeleton, nuclear membrane, and mitochondrial function have all been described in patients with skeletal myopathy and cardiac involvement. The most common classes of neuromuscular disorders with cardiac manifestations are the muscular dystrophies- Duchenne, Becker, limb-girdle and Emery Dreifuss. Friedreich Ataxia and myotonic dystrophy also have important cardiac involvement. The type and extent of cardiac manifestations are specific to the type of neuromuscular disorder. The most common cardiac findings include dilated or hypertrophic cardiomyopathy, atrioventricular conduction defects, atrial fibrillation and ventricular arrhythmias. Screening for cardiac involvement should be performed in all children with neuromuscular disorders that have the potential for cardiac involvement. This review discusses the cardiac findings associated with specific neuromuscular disorders and outlines the indications for evaluation and treatment.

Sleep and neuromuscular disorders in children

Children suffering from neuromuscular diseases are at an increased risk of sleep-related breathing disorders (SRBD) such as obstructive sleep apnea syndrome (OSAS) and hypoventilation as well as central sleep apnea, which is frequent in these patients due to diaphragmatic weakness. They are at higher risk for developing complications of nocturnal hypoxemia, including pulmonary hypertension, cor pulmonale and neurocognitive dysfunction. Neuromuscular disorders and OSAS are both prevalent disorders and frequently overlap. Sleep-related hypoventilation/hypoxemia due to neuromuscular diseases may be exacerbated in the presence of OSAS; these children are likely to experience greater severity and duration of sleep-related hypoxemia than are children with either disorder alone. Additionally, some of these children have reduced central neural chemoresponsiveness. The development of SRBD in these patients further impairs their quality of life and worsens their respiratory status. We review the literature on the diagnosis and treatment of SRBD in children with a variety of neuromuscular disorders.

Neurophysiology in neuromuscular disorders in children

Neurophysiology in neuromuscular disorders in children

Neuromuscular disorders in children : Diagnosis and treatment

Inherited muscle diseases are heterogeneous with varying genetic etiologies and present with common symptoms and signs, including weakness, motor developmental delay, and hypotonia. To diagnose these various diseases, a meticulous family and clinical history, physical and neurological examinations, laboratory findings with electromyography, muscle biopsy, and genetic testing are needed. Here, I review several inherited muscle diseases, with a focus on muscular dystrophy in children and its genetics and general management.

Muscle echogenicity is increased in fetuses with spina bifida aperta

Background In spina bifida aperta (SBA), movements caudal to the meningomyelocele (MMC) are present in utero, but they disappear shortly after birth. Insight in onset and progression of movement loss is therapeutically relevant. Determination of muscle echogenicity (or density (MD)) is used to estimate onset and progression of various neuromuscular disorders in children. In prenatal SBA, we hypothesized that MD assessment could indicate onset and progression of muscle damage in relation to movement loss. Objective: To estimate onset and progression of muscle changes in fetal SBA by MD assessment.

Quantitative skeletal muscle ultrasound: Diagnostic value in childhood neuromuscular disease

In this study we investigated the diagnostic value of quantitative skeletal muscle ultrasonography in 150 consecutively referred children with symptoms suspect for a neuromuscular disorder. Muscle thickness and quantitatively determined echo intensity of four muscles and the distribution of these variables within the body were examined. Results: Patients with and without a neuromuscular disorder could be discriminated with a positive predictive value of 91% and a negative predictive value of 86%. Patients with a neurogenic disorder could be distinguished from myopathies and non-neuromuscular disorders with a positive predictive value of 86% and a negative predictive of 84%, using the pattern of distribution of pathology within the body. Conclusions: Skeletal muscle ultrasound is a good, practical and non-invasive aid in the diagnosis of neuromuscular disorders in children, that is able to discriminate between children with and without a neuromuscular disorder and between neurogenic disorders and myopathies with high predictive values.

Diagnostic value of muscle, sural nerve and skin biopsies in childhood neuromuscular disorders

To elicit the usefulness of muscle, sural nerve and skin biopsies in neuromuscular disease, including its diagnostic value and indications for biopsy. The authors retrospectively evaluated the clinical data of every patient who underwent muscle, sural nerve and/or skin biopsy in the department between January 1999 and December 2004. One hundred and two patients with the suspected neuromuscular diseases were included. Muscle disease or hereditary metabolic/degenerative diseases with muscular injury were suspected in 82 patients, specific or typical histological findings confirmed diagnosis in 33 of these patients. The diagnosis included muscular dystrophies in 13 patients; inflammatory myopathies in 4 patients; congenital centronuclear myopathies in 2 patients; vacuole myopathy in 1 patient; mitochondrial myopathies in 8 patients; lipid storage myopathy in 1 patient; glycogenosis in 1 patient; spinal muscular atrophy in 3 patients. Nonspecific changes were seen in 25 patients, and in 24 patients nothing abnormal was revealed. Neuropathy or hereditary metabolic/degenerative diseases with peripheral nerve injury were suspected in 23 patients, specific or typical histological findings confirmed diagnosis in 10 of these patients, including hereditary motor and sensory neuropathy in 9 patients and metachromatic leukodystrophy with peripheral nerve abnormality in 1 patient. Nonspecific changes were seen in 11 patients and 2 patients had normal sural nerve. Skin biopsies were performed in 8 patients, specific or typical histological findings confirmed diagnosis in 4 of these patients. The diagnosis included neuronal ceroid lipofuscinosis in 2 patients, infantile axonal dystrophy in 1 patient, vacuole lysosomal disease in 1 patient, and 4 patients had normal skin biopsy. Muscle, sural nerve and skin biopsies play an important role in diagnosis of childhood neuromuscular disease, and should be done only in carefully selected cases after thorough clinical work-up. Muscle biopsy is essential for diagnosis of congenital and metabolic myopathies. Typical pathologic alterations of sural nerve have diagnostic value for hereditary neuropathies. Skin biopsy should be performed to verify neuronal ceroid lipofuscinosis.

P.P.1 07 Limitation of neck movement may be a feature of most of the childhood neuromuscular disorders

Neck rigidity with reduced neck flexion is often reported in some forms of Congenital Muscular Dystrophy (CMD) including Ullrich and Merosin Deficient CMD, Rigid Spine Syndrome and in Emery-Dreifuss MD. Reduced neck flexion causes major functional difficulties. Non-ambulant children need to flex their trunk to look forward whereas in ambulant children, safe walking is compromised by inability to look down. We have previously observed deteriorating neck posture in children with Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy, (SMA) especially after spinal surgery.

FC7.2 Using high-density surface electromyography (HD-sEMG) in detecting neuromuscular disorders in children

FC7.2 Using high-density surface electromyography (HD-sEMG) in detecting neuromuscular disorders in children

Cardiac monitoring and treatment for children and adolescents with neuromuscular disorders

Dilated cardiomyopathy, hypertrophic cardiomyopathy, and cardiac rhythm disturbances are important features of certain neuromuscular disorders in children, adolescents, and young adults. This article summarizes the cardiac features seen in patients with Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy, Friedreich's ataxia, and Emery-Dreifuss muscular dystrophy. The optimal management of these cardiac features remains contentious, but increasingly these patients are referred for routine cardiological assessment in the absence of symptoms. This article examines the value of routine screening and drug interventions for cardiac complications in asymptomatic and symptomatic individuals with neuromuscular disorders. We recommend a pragmatic approach, actively looking for cardiac conditions which will benefit from early intervention, but avoiding routine screening for asymptomatic conditions in which there is no evidence of benefit from early intervention.

Comparison of Clinical Characteristics Between Congenital Fiber Type Disproportion Myopathy and Congenital Myopathy with Type 1 Fiber Predominance

Congenital myopathies are clinical and genetic heterogeneous disorders characterized by skeletal muscle weakness and specific structural changes in muscle fiber. Congenital myopathy with fiber type disproportion (CFTD) is an established disorder of congenital myopathy. CFTD is characterized by non-progressive childhood neuromuscular disorders with a relatively good prognosis and type 1 fiber predominance and smallness. Congenital myopathy with type 1 fiber predominance (CMT1P) is also a distinct entity of congenital myopathy characterized by non-progressive childhood neuromuscular disorders and type 1 fiber predominance without smallness. Little is known about CMT1P. Clinical characteristics, including dysmorphic features such as hip dislocation, kyphoscoliosis, contracture, and high arch palate, were analyzed along with laboratory and muscle pathologies in six patients with CMT1P and three patients with CFTD. The clinical manifestations of CFTD and CMT1P were similar. However, the frequency of dysmorphic features is less in CMT1P than in CFTD. Long term observational studies of CMT1P are needed to determine if it will change to another form of congenital myopathy or if CMT1P is a distinct clinical entity.

Muscle ultrasound in children: Normal values and application to neuromuscular disorders

In this study, 105 healthy children (45 to 156 months old, 57 girls) were examined using ultrasound (US) imaging to obtain reference values of muscle dimensional and aspect parameters. We measured biceps and quadriceps sizes and subcutaneous tissue thickness. To quantify muscle aspect, we calculated muscle density, inhomogeneity and white-area index by digital image analysis. Age-, weight- and gender-dependencies were discussed. We demonstrated earlier that the complete set of parameters allows for differentiation between myopathies and neuropathies in adults, with high sensitivity. In this study, we investigated if these parameters have additional value in the diagnostic evaluation of 36 children with proven neuromuscular disease (20 Duchenne muscular dystrophy, 16 neuropathies). We found that density analysis provides a sensitive method for distinguishing between healthy children and children with neuromuscular disorders. We have also found that more detailed aspect analysis is necessary to further distinguish between these types of neuromuscular disorders in children. In conclusion, this set of normal muscle parameters can be used to help diagnose neuromuscular disorders in children. It will also facilitate follow-up in disease progression and therapy. (E-mail: n.m.maurits@neuro.azg.nl)