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Background:The muscular dystrophies are a heterogeneous group of genetic muscle diseases with variable distribution of weakness and mode of inheritance.Methods:We previously performed a systematic review of worldwide population-based studies on Duchenne and Becker muscular dystrophies; the current study focused on the epidemiology of other muscular dystrophies using Medline and EMBASE databases. Two reviewers independently reviewed all abstracts, full-text articles, and abstracted data from 1985 to 2011. Pooling of prevalence estimates was performed using random-effect models.Results:A total of 1104 abstracts and 167 full-text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The overall pooled prevalence of combined muscular dystrophies was 16.14 (confidence interval [CI], 11.21-23.23) per 100,000. The prevalence estimates per 100,000 were 8.26 (CI, 4.99-13.68) for myotonic dystrophy, 3.95 (CI, 2.89-5.40) for facioscapulohumeral dystrophy, 1.63 (CI, 0.94-2.81) for limb girdle muscular dystrophy, and 0.99 (CI, 0.62-1.57) for congenital muscular dystrophies.Conclusions:The studies differed widely in their approaches to case ascertainment, and substantial gaps remain in the global estimates of many other types of muscular dystrophies. Additional epidemiological studies using standardized diagnostic criteria as well as multiple sources of case ascertainment will help address the economic impact and health care burden of muscular dystrophies worldwide.

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.

Summary Background MRI and laboratory features have been incorporated into international diagnostic criteria for multiple sclerosis. We assessed the pattern of MRI lesions and contributions of cerebrospinal fluid (CSF) and serum antibody findings that best identifies children with multiple sclerosis, and the applicability of international diagnostic criteria in the paediatric context. Methods In this prospective cohort study, detailed clinical assessments, serum and CSF studies, and MRI scans were done in youth (aged 0·46–17·87 years) with incidental acquired demyelinating syndrome. Participants were examined prospectively to identify relapsing disease. All MRI scans were assessed using a validated scoring method. A random forest classifier identified imaging and laboratory features that best predicted a multiple sclerosis or monophasic outcome. Performance of the 2001, 2010, and 2017 international McDonald criteria for the diagnosis of multiple sclerosis, the 2016 MRI in multiple sclerosis (MAGNIMS) criteria, and our 2011 proposed (Verhey) criteria were determined; performance was adjudicated with generalised linear models. Findings Between Sept 1, 2004, and June 30, 2017, we included 324 participants with median follow-up of 72 months (range 6–150), 71 (22%) participants with multiple sclerosis, 237 (73%) with monophasic acquired demyelinating syndrome, 14 (4%) with relapsing non-multiple sclerosis, and two (1%) with alternative diagnoses. We scored 2391 brain, 444 spinal, and 67 dedicated orbital MRI scans. One or more T1 hypointense lesions plus one or more periventricular lesions (Verhey criteria) best predicted multiple sclerosis outcome. Performance of the 2017 McDonald criteria was comparable to the 2010 McDonald criteria and was easier to adjudicate. The ability of CSF oligoclonal bands to substitute for the requirement for both enhancing and non-enhancing lesions in the 2017 McDonald criteria improved its performance compared with the 2010 criteria. Myelin oligodendrocyte testing at baseline did not improve performance of the 2017 McDonald criteria. Interpretation The 2017 McDonald criteria for the diagnosis of multiple sclerosis, as applied at the time of incident attack, perform well in identifying children and youth with multiple sclerosis, indicating that the same diagnostic criteria for multiple sclerosis apply across the age span. The presence of so-called black holes on MRI and periventricular lesions at baseline (Verhey criteria) also effectively distinguish children with multiple sclerosis from children with monophasic demyelination. The presence of CSF oligoclonal bands improve diagnostic accuracy. Myelin oligodendrocyte glycoprotein antibodies identify children with acute disseminated encephalomyelitis, and those with relapsing non-multiple sclerosis, most of whom do not meet 2017 McDonald criteria at onset. Funding The Multiple Sclerosis Scientific Research Foundation and The Children's Hospital of Philadelphia.

Aims/hypothesis Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. Methods Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. Results Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p

Background: Advances in medical care for patients with Duchenne muscular dystrophy (DMD) have resulted in improved survival and an increased prevalence of cardiomyopathy. Serial echocardiographic surveillance is recommended to detect early cardiac dysfunction and initiate medical therapy. Clinical anecdote suggests that echocardiographic quality diminishes over time, impeding accurate assessment of left ventricular systolic function. Furthermore, evidence-based guidelines for the use of cardiac imaging in DMD, including cardiac magnetic resonance imaging, are limited. The objective of our single-centre, retrospective study was to quantify the deterioration in echocardiographic image quality with increasing patient age and identify an age at which cardiac magnetic resonance imaging should be considered. Methods: We retrospectively reviewed and graded the image quality of serial echocardiograms obtained in young patients with DMD. The quality of 16 left ventricular segments in two echocardiographic views was visually graded using a binary scoring system. An endocardial border delineation percentage score was calculated by dividing the number of segments with adequate endocardial delineation in each imaging window by the total number of segments present in that window and multiplying by 100. Linear regression analysis was performed to model the relationship between the endocardial border delineation percentage scores and patient age. Results: Fifty-five echocardiograms from 13 patients (mean age 11.6 years, range 3.6-19.9) were systematically reviewed. By 13 years of age, 50% of the echocardiograms were classified as suboptimal with ≥30% of segments inadequately visualized, and by 15 years of age 78% of studies were suboptimal. Linear regression analysis revealed a negative correlation between patient age and endocardial border delineation percentage score (r = -2.49, 95% confidence intervals -4.73, -0.25; p=0.032), with the score decreasing by 2.5% for each 1 year increase in age. Conclusions: Echocardiographic image quality declines with increasing age in DMD. Alternate imaging modalities may play a role in cases of poor echocardiographic image quality.

Introduction Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments. Methods In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry. Results As of July 25, 2017, there are 658 paediatric participants enrolled in the registry, 249 are dystrophinopathies (229 are Duchenne muscular dystrophy), 57 are myotonic dystrophy participants, 98 spinal muscular atrophy participants and 65 are limb girdle muscular dystrophy. A total of 175 patients have another NM diagnosis. The registry has facilitated 20 clinical trial inquiries, 5 mail-out survey studies and 5 other studies in the paediatric population. Discussion The strengths of the registry are discussed. The registry has proven to be an invaluable tool to NM disease research and has increased Canada's visibility as a competitive location for the conduct of clinical trials for NM therapies.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. Mutations of the DMD gene destabilize the dystrophin associated glycoprotein complex in the sarcolemma. Ongoing mechanical stress leads to unregulated influx of calcium ions into the sarcoplasm, with activation of proteases, release of proinflammatory cytokines, and mitochondrial dysfunction. Cumulative damage and reparative failure leads to progressive muscle necrosis, fibrosis, and fatty replacement. Although there is presently no cure for DMD, scientific advances have led to many potential disease-modifying treatments, including dystrophin replacement therapies, upregulation of compensatory proteins, anti-inflammatory agents, and other cellular targets. Recently approved therapies include ataluren for stop codon read-through and eteplirsen for exon 51 skipping of eligible individuals. The purpose of this chapter is to summarize the clinical features of DMD, to describe current outcome measures used in clinical studies, and to highlight new emerging therapies for affected individuals.

Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832.440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501).In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.

To report the results of a randomized controlled trial using an electronic monitoring device (EM) plus a motivational interviewing (MI) intervention to enhance adherence to disease-modifying therapies (DMT) in pediatric MS.Fifty-two youth with MS (16.03 ± 2.2 years) were randomized to receive either MI (n = 25) (target intervention) or a MS medication video (n = 27) (attention control). Primary endpoint was change in adherence. Secondary outcomes included changes in quality of life, well-being and self-efficacy. Random effects modeling and Cohen's effect size computation evaluated intervention impact.Longitudinal random effect models revealed that the MI group decreased their EM adherence (GroupxTime interaction = -0.19), while increasing frequency of parental DMT reminder (26.01)/administration (11.69). We found decreased EM use in the MI group at 6 months (Cohen's d = -0.61), but increased pharmacy refill adherence (d = 0.23). Parental reminders about medication increased in MI subjects vs controls (d = 0.59 at 3 months; d = 0.70 at 6 months). We found increases in self-reported adherence (d = 0.21) at 3 but not 6 months, fewer barriers to adherence at three (d = -0.58) and six months (d = -0.31), better physical (d = 0.23 at 3 months; d = 0.45 at 6 months), emotional (d = 0.25 at 3 months) and self-efficacy function (d = 0.55 at 3 months; 0.48 at 6 months), but worse well-being, including self-acceptance (d = -0.53 at 6 months) and environmental mastery (d = -0.42 at 3 and 6 months) in intervention as compared to control patients.Participants receiving MI + EM experienced worsening on objective measures of adherence and increased parental involvement, but improved on some self- and parent-reported measures. MI participants reported improvements in quality of life and self-efficacy, but worsened well-being.

We evaluated the relationship of optical coherence tomography (OCT)-measured ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) thickness to other functional measures of afferent visual pathway competence including high-contrast visual acuity (HCVA) and low-contrast visual acuity (LCVA), visual field sensitivity, and color vision perception in a pediatric population with demyelinating disorders.This was a cross-sectional evaluation of 37 children, aged 8-18 years, with pediatric demyelinating disorders (n = 74 eyes), and 18 healthy controls (n = 36 eyes), who were recruited from the University of Toronto, Hospital for Sick Children and the University of Calgary, Alberta Children's Hospital, Canada. A standardized visual battery, including spectral-domain OCT, visual fields, LCVA, and HCVA, was performed in all subjects.Mean RNFL thickness was 26 µm (25.6%) lower in patients with demyelination (76.2 μm [3.7]) compared to controls (102.4 μm [2.1]) (p0.0001). Mean GCL thickness was 20% lower in patients as compared to controls (p0.0001). Mean GCL and RNFL thickness were strongly correlated (r = 0.89; p0.0001), yet in contrast to RNFL thickness, no differences in GCL thickness were noted between optic neuritis (ON) eyes and non-ON eyes of patients. HCVA and LCVA and visual field mean deviation scores decreased linearly with lower RNFL thickness.GCL thickness was decreased in patients regardless of history of ON. The retina may be a site of primary neuronal injury in pediatric demyelination.

Introduction: We studied the potential for motor unit number estimation (MUNE) to detect subclinical changes in motor unit numbers in children with type 1 diabetes mellitus (DM). Methods: Blinded observers performed clinical assessment, electrophysiology, and multipoint MUNE of the extensor digitorum brevis muscle in children with DM for ≥5 years and age-matched healthy controls. Results: For 51 DM subjects, the disease duration was 9.1 ± 2.6 years. Subjects with DM and healthy controls (n = 21) had similar demographics. There were no clinical symptoms or signs of peripheral neuropathy in any subject, nor differences in standard electrophysiology between cohorts. Estimated motor unit numbers were decreased significantly in children with DM (224 ± 87 vs. 274 ± 101, P = 0.036). Conclusion: Despite the absence of clinical or standard electrophysiological differences from normal control subjects, MUNE can detect a small significant difference in children with DM, suggesting that motor unit loss begins early and subclinically in the disease. Muscle Nerve 50: 593–598, 2014

It is expected that serum protein biomarkers in Duchenne muscular dystrophy (DMD) will reflect disease pathogenesis, progression and aid future therapy developments. Here, we describe use of quantitative in vivo stable isotope labeling in mammals to accurately compare serum proteomes of wild-type and dystrophin-deficient mdx mice. Biomarkers identified in serum from two independent dystrophin-deficient mouse models (mdx-Δ52 and mdx-23) were concordant with those identified in sera samples of DMD patients. Of the 355 mouse sera proteins, 23 were significantly elevated and 4 significantly lower in mdx relative to wild-type mice (P-value < 0.001). Elevated proteins were mostly of muscle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3 and filamin-C), glycolytic enzymes (aldolase, phosphoglycerate mutase 2, beta enolase and glycogen phosphorylase), transport proteins (fatty acid-binding protein, myoglobin and somatic cytochrome-C) and others (creatine kinase M, malate dehydrogenase cytosolic, fibrinogen and parvalbumin). Decreased proteins, mostly of extracellular origin, included adiponectin, lumican, plasminogen and leukemia inhibitory factor receptor. Analysis of sera from 1 week to 7 months old mdx mice revealed age-dependent changes in the level of these biomarkers with most biomarkers acutely elevated at 3 weeks of age. Serum analysis of DMD patients, with ages ranging from 4 to 15 years old, confirmed elevation of 20 of the murine biomarkers in DMD, with similar age-related changes. This study provides a panel of biomarkers that reflect muscle activity and pathogenesis and should prove valuable tool to complement natural history studies and to monitor treatment efficacy in future clinical trials.

We describe the presenting features and long-term outcome of an unusual cluster of pediatric acute flaccid paralysis cases that occurred in Canada during the 2014 enterovirus D68 outbreak. Children (n = 25; median age 7.8 years) presenting to Canadian centers between July 1 and October 31, 2014, and who met diagnostic criteria for acute flaccid paralysis were evaluated retrospectively. The predominant presenting features included prodromal respiratory illness (n = 22), cerebrospinal fluid lymphocytic pleocytosis (n = 18), pain in neck/back (n = 14) and extremities (n = 10), bowel/bladder dysfunction (n = 9), focal central gray matter lesions found in all regions of the spinal cord within the cohort (n = 16), brain stem lesions (n = 8), and bulbar symptoms (n = 5). Enterovirus D68 was detectable in nasopharyngeal specimens (n = 7) but not in cerebrospinal fluid. Acute therapies (corticosteroids, intravenous immunoglobulins, plasmapheresis) were well tolerated with few side effects. Fourteen of 16 patients who were followed beyond 12 months post onset had neurologic deficits but showed ongoing clinical improvement and motor recovery.

Contains fulltext : 182475.pdf (Publisher’s version ) (Closed access) Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. METHODS: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (

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Contains fulltext : 166520.pdf (Publisher’s version ) (Open Access) BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD; OMIM 158900 & 158901) is a progressive skeletal muscle dystrophy, characterized by an autosomal dominant inheritance pattern. One of the major unsolved questions in FSHD is the marked clinical heterogeneity, ranging from asymptomatic individuals to severely affected patients with an early onset. An estimated 10% of FSHD patients have an early onset (onset before 10 years of age) and are traditionally classified as infantile FSHD. This subgroup is regarded as severely affected and extra-muscular symptoms, such as hearing loss and retinopathy, are frequently described. However, information on the prevalence, natural history and clinical management of early onset FSHD is currently lacking, thereby hampering adequate patient counselling and management. Therefore, a population-based prospective cohort study on FSHD in children is highly needed. METHODS/DESIGN: This explorative study aims to recruit all children (aged 0-17 years) with a genetically confirmed diagnosis of FSHD in The Netherlands. The children will be assessed at baseline and at 2-year follow-up. The general aim of the study is the description of the clinical features and genetic characteristics of this paediatric cohort. The primary outcome is the motor function as measured by the Motor Function Measure. Secondary outcomes include quantitative and qualitative description of the clinical phenotype, muscle imaging, genotyping and prevalence estimations. The ultimate objective will be a thorough description of the natural history, predictors of disease severity and quality of life in children with FSHD. DISCUSSION: The results of this population-based study are vital for adequate patient management and clinical trial-readiness. Furthermore, this study is expected to provide additional insight in the epigenetic and environmental disease modifying factors. In addition to improve counselling, this could contribute to unravelling the aetiology of FSHD. TRIAL REGISTRATION: clinicaltrials.gov NCT02625662.

Corticosteroids are extensively used in pediatrics, yet the burden of side effects is significant. Availability of a simple, fast and reliable biochemical read out of steroidal drug pharmacodynamics could enable a rapid and objective assessment of safety and efficacy of corticosteroids and aid development of corticosteroid replacement drugs. To identify potential corticosteroid responsive biomarkers we performed proteome profiling of serum samples from DMD and IBD patients with and without corticosteroid treatment using SOMAscan aptamer panel testing 1,129 proteins in

• Best practice molecular diagnostic reference standards require international collaboration.

Purpose Respiratory management of Duchenne muscular dystrophy (DMD) is not well studied and may vary across centers and practitioners. Our objective was to describe and compare the respiratory management practices of Canadian Pediatric Respirologists and Neuromuscular specialists for children with DMD. Methods A web-based survey was sent to all 56 practicing Canadian Pediatric Respirologists and to all 24 members of the Canadian Pediatric Neuromuscular Group (CPNG) who follow children with neuromuscular diseases. The survey included 28 questions about timing and indications for respiratory consultation, sleep disordered breathing (SDB) assessments, and treatments. Results Thirty eight (68%) pediatric respirologists and 17 (71%) CPNG members responded. Respirologists provide initial consultation after a patient's first admission to hospital with respiratory complications (14/38, 37%) and when symptoms of SDB are present (14/38, 37%). Half of the CPNG members request initial Respirology consultation at the time of DMD diagnosis. Both groups request routine pulmonary function tests. Ninety-six percent of respirologists use maximal inspiratory (MIP) and expiratory pressures (MEP) to assess respiratory muscle strength, whereas 82% of CPNG members additionally use peak cough flow. Assessment for SDB is requested by both groups when pulmonary function is abnormal or patients are symptomatic. Respirologists favor polysomnography, whereas CPNG members use overnight pulse oximetry. Nocturnal non-invasive ventilation and lung volume recruitment (LVR) are used in a minority of patients. Conclusions Respirologists and CPNG members provide similar respiratory management of DMD patients, but differ in timing of consultation and choice of tests for pulmonary function and SDB. Canadian practices differ from the American Thoracic Society and Centre for Disease Control guidelines. Pediatr Pulmonol. 2013; 48:59–66. © 2012 Wiley Periodicals, Inc.

Summary Background HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children. Methods In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15 , Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use. Findings Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61–4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99–222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25–4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00–1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99–4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26–273·85) or CSF oligoclonal bands (6·33, 3·35–11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%. Interpretation Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness. Funding Canadian Multiple Sclerosis Scientific Research Foundation.

Vitamin D is essential for bone mineralization and maintenance of bone strength. Vitamin D deficiency results in rickets in children and osteomalacia in adults. There have been increasing numbers of reports regarding the prevalence of hypovitaminosis D in North America (1,2). Furthermore, vitamin D-deficiency rickets is an ongoing concern among children living in Canada (3). Beyond its effects on bone health, vitamin D may also protect against type I diabetes, multiple sclerosis, hypertension and cancer (4). Vitamin D formed in the skin and from dietary sources is transported to the liver, where it is converted to 25-hydroxyvitamin D (25[OH]D). Serum 25(OH)D is a reliable biomarker of vitamin D status, and it is used to define vitamin D deficiency or intoxication (5–8). Laboratory reference ranges traditionally have set the lower normal limits for serum 25(OH)D concentrations at 37.5 nmol/L to 40 nmol/L. However, it has been suggested that at concentrations between 50 nmol/L and 100 nmol/L, the body store of vitamin D is already depleted, with compensatory elevation of parathyroid hormone (PTH) indicative of hypovitaminosis D (9). In adult populations, it has been shown that intestinal calcium absorption increases as serum 25(OH)D concentration rises, up to approximately 80 nmol/L, where it reaches a plateau (10). While it is generally agreed that 25(OH)D concentrations of 50 nmol/L can prevent rickets, higher concentrations may be necessary to affect the prevalence of diabetes, multiple sclerosis, fractures and various types of cancer. Many authors have focused on the assessment of vitamin D status in children suffering from various chronic diseases (11–15) or severe burns (16). There are only a few studies on vitamin D status among healthy children (17–22). Therefore, the objectives of the present study were to determine the 25(OH)D concentrations in a healthy paediatric population living in Calgary, Alberta, and to identify risk factors associated with suboptimal vitamin D.

Contexte: La dystrophie musculaire de Duchenne (DMD) est la forme la plus frequente de dystrophie musculaire dans l'enfance. Methode: Nous avons poste un questionnaire a 17 medecins membres du Canadian Paediatric Neuromuscular Group afin d'evaluer les soins actuels donnes aux patients d'âge pediatrique atteints de DMD au Canada. L'enquete portait sur les aspects suivants: 1) la composition des equipes multidisciplinaires; 2) les moyens diagnostiques utilises pour poser le diagnostic de DMD; 3) l'utilisation de corticosteroides; la surveillance et le traitement des complications 4) orthopediques, 5) respiratoires et 6) cardiaques et 7) les soins de sante usuels (nutrition et immunisations). Resultats: Quatorze des 17 medecins (82%) ont retourne le questionnaire complete. Douze d'entre eux suivaient des patients atteints de DMD. Tous les centres avaient des equipes multidisciplinaires qui incluaient des pneumologues (11/12), des neurologues ou physiatres pediatriques (11), des physiotherapeutes (9), des ergotherapeutes (9) et des orthopedistes (7). Tous les centres utilisaient le deflazacort a 0,9 mg/kg/j. Cette medication etait maintenue apres le passage au fauteuil roulant (11) ainsi que la prise de routine de calcium et de vitamine D (10). Des attelles nocturnes etaient prescrites dans tous les centres. La surveillance de routine comprenait des epreuves de fonction pulmonaire (11), des etudes du sommeil (10), un EKG/echocardiogramme (10), mesure de la densite osseuse (DEXA) (10), radiographie de la colonne vertebrale (9) et consultation en dietetique (4). Conclusion: Les patients pediatriques atteints de DMD recoivent des soins relativement uniformes dans toutes les cliniques multidisciplinaires au Canada, conformement aux recommandations enoncees dans les lignes directrices sur la prise en charge de la DMD.

In this mixed-methods study, utilization data for disease-modifying therapies were reviewed to determine the adherence rate among our pediatric multiple sclerosis cohort. Adolescents were interviewed to explore their experiences with multiple sclerosis and the impact of peer relationships on adherence to treatment. Seventeen adolescents (6 male, 11 female) started interferon beta or glatiramer acetate before age 18. The mean age at first drug start date was 15.8 years. Eight of the adolescents (47%) discontinued treatment after a median duration of 20 months. Many of the adolescents struggled to integrate the injections into their daily lives, with peers either facilitating or impeding this transition. In conclusion, adolescents in this cohort had difficulty adhering to disease-modifying therapies, and peers played an important role in mediating their adjustment to multiple sclerosis. Specific strategies are required to improve adolescents' adherence to treatment, including less intrusive options and enhancing peer support.

We describe the experience of parents caring for children with neuromuscular disease (NMD) on home mechanical ventilation (HMV). Data was obtained from semi-structured interviews and analyzed using a phenomenological framework. Fifteen families including 19 parents of children with DMD ( n =3), SMA ( n =5), and other NMD ( n =7) participated. The central theme of these parents' experience was being the "lifeline" for their child's life and quality of life. The families' lives changed significantly with the decision to place their child on HMV; over time, these changes became part of their new "normal". Despite becoming expert caregivers, the parents experienced a recurrent sense of loss and uncertainty. Those who perceived insufficient support felt the weight of responsibility as sole care providers for their child with NMD. Beyond recognizing the parents as experts, more support by health care professionals, their extended family, and their community are needed to enable parents to fulfill their vital role.

ACE-031 is a fusion protein of activin receptor type IIB and IgG1-Fc, which binds myostatin and related ligands. It aims to disrupt the inhibitory effect on muscle development and provide potential therapy for myopathies like Duchenne muscular dystrophy (DMD).ACE-031 was administered subcutaneously every 2-4 weeks to DMD boys in a randomized, double-blind, placebo-controlled, ascending-dose trial. The primary objective was safety evaluation. Secondary objectives included characterization of pharmacokinetics and pharmacodynamics.ACE-031 was not associated with serious or severe adverse events. The study was stopped after the second dosing regimen due to potential safety concerns of epistaxis and telangiectasias. A trend for maintenance of the 6-minute walk test (6MWT) distance in the ACE-031 groups compared with a decline in the placebo group (not statistically significant) was noted, as was a trend for increased lean body mass and bone mineral density (BMD) and reduced fat mass.ACE-031 use demonstrated trends for pharmacodynamic effects on lean mass, fat mass, BMD, and 6MWT. Non-muscle-related adverse events contributed to the decision to discontinue the study. Myostatin inhibition is a promising therapeutic approach for DMD. Muscle Nerve 55: 458-464, 2017.

Meckel syndrome (MKS) is a rare lethal autosomal recessive disorder characterized by the presence of occipital encephalocele, cystic kidneys, fibrotic changes of the liver and polydactyly. Joubert syndrome (JS)-related disorders (JSRDs) or cerebello-oculo-renal syndromes (CORS) are a group of recessively inherited conditions characterized by a molar tooth sign (MTS) on cranial MRI, a set of core clinical features (developmental delay/mental retardation, hypotonia, ataxia, episodic breathing abnormalities, abnormal eye movements) and variable involvement of other systems including renal, ocular, central nervous system, craniofacial, hepatic, and skeletal. A significant clinical overlap between MKS and JSRD/CORS has been recognized in the literature. We describe a group of 10 Hutterite patients, of which 7 had been previously diagnosed with MKS, with a JSRD. Clinical features include variable early mortality, cognitive handicap, a characteristic dysmorphic facial appearance, hypotonia, ataxia, abnormal breathing pattern, nystagmus, and MTS on MRI. Additional features include occipital encephalocele, posterior fossa fluid collections resembling Dandy-Walker malformation, hydrocephalus, coloboma, and renal disease. This JSRD is a recognizable dysmorphic syndrome characterized by hypertelorism, deep-set eyes, down-slanting palpebral fissures, ptosis, arched eyebrows with medial sparseness, square nasal tip, short philtrum with tented upper lip, open mouth with down-turned corners, and posteriorly rotated low-set ears. Renal disease is present in 70% of patients and is characterized by cystic kidneys, abnormalities in renal function and hypertension. Homozygous deletions of NPHP1 and the known loci for JS/JSRD and MKS were excluded by identity-by-descent mapping studies suggesting that this condition in the Hutterites represents yet another locus for a JSRD.

PURPOSE To assess the image and patient level interrater agreement and repeatability within 1 month for corneal nerve fiber length (CNFL) measured using in vivo corneal confocal microscopy (IVCCM) in children. METHODS Seventy-one subjects (mean [SD] age 14.3 [2.6] years, range 8-18 years; 44 with type 1 diabetes and 27 controls; 36 males and 35 females) were included. 547 images (∼6 images per subject) were analyzed manually by two independent and masked observers. One-month repeat visit images were analyzed by a single masked observer in 21 patients. Automated image analysis was then performed using a specialized computerized software (ACCMetrics). RESULTS For CNFL, the ICC (95% CI) were 0.94 (0.93-0.95) for image-level, 0.86 (0.78-0.91) for patient-level, and 0.88 (0.72-0.95) for the 1-month repeat assessment, and the Bland-Altman plots showed minimal bias between observers. Although there was excellent agreement between manual and automated analysis according to an ICC 0.89 (0.82-0.93), the Bland-Altman plot showed a consistent bias with manual measurements providing higher readings. CONCLUSIONS In vivo corneal confocal microscopy image analysis shows good reproducibility with excellent intraindividual and interindividual variability in pediatric subjects. Since the image-level reproducibility is stronger than the patient-level reproducibility, refinement of the method for image selection will likely further increase the robustness of this novel, rapid, and noninvasive approach to detect early neuropathy in children with diabetes. Further studies on the use of IVCCM to identify early subclinical neuropathy in children are indicated.

Congenital lumbar hernias are rare malformations caused by defects in the development of the posterior abdominal wall. A known association exists with lumbocostovertebral syndrome; however other associated anomalies, including one case with arthrogryposis, have been previously reported. We present an infant girl with bilateral congenital lumbar hernias, multiple joint contractures, decreased muscle bulk and symptoms of malignant hyperthermia. Molecular testing revealed an R4861C mutation in the ryanodine receptor 1 (RYR1) gene, known to be associated with central core disease. This is the first reported case of the co-occurrence of congenital lumbar hernias and central core disease. We hypothesize that ryanodine receptor 1 mutations may interrupt muscle differentiation and development. Further, this case suggests an expansion of the ryanodine receptor 1-related myopathy phenotype to include congenital lumbar hernias.

Background: Neuropathy is an important complication and contributes to the morbidity of diabetes mellitus. The availability of simple and non-invasive tests for screening of early diabetic neuropathy (DN) in children with diabetes may prevent further progression of this complication. The purpose of this study was to compare conventional nerve conduction studies (NCS) with non-invasive techniques, including vibration perception thresholds (VPT) and tactile perception thresholds (TPT) for the detection of DN in children and adolescents with type 1 diabetes. Methods: Children from the Alberta Children’s Hospital Diabetes Clinic with at least 5 yr duration of type 1 diabetes underwent detailed evaluations, including neurologic exam, NCS, VPT, and TPT testing. Information on duration of diabetes, height, and mean glycosylated hemoglobin (A1C) were also collected. Descriptive statistics, including Student’s t-test and chi-squared test, were used for analysis. Results: Seventy-three children (mean age of 13.7 ± 2.6 yr) completed the study. The mean duration of diabetes was 8.1 ± 2.6 yr, and the mean A1C was 9.0 ± 1.0%. Forty-two (57%) children had DN based on NCS. Using NCS as a gold standard, the sensitivity and specificity of VPT were 62 and 65%, while the sensitivity and specificity of TPT were 19 and 64%, respectively. Conclusions: Subclinical DN is common among children and adolescents with type 1 diabetes, and there is a need for better metabolic control in this population. VPT and TPT may not be adequate screening tools for the detection of DN in children.

Poliomyelitis is a historically devastating neurological complication of poliovirus infection. Poliovirus vaccines have decreased the incidence of poliomyelitis to 209 global cases in 2014, with new cases of acute flaccid myelitis primarily associated with nonpolio enteroviruses. Recently, during outbreaks of enterovirus D68 throughout North America and Europe, cases of acute flaccid myelitis have been reported, suggesting another nonpolio enterovirus associated with acute flaccid myelitis. The authors describe 3 patients diagnosed with acute flaccid myelitis during a province-wide outbreak of enterovirus D68 with the virus detected in 2 of the patients. Given the significant morbidity associated with acute flaccid myelitis and potential for nonpolio enterovirus to cause outbreaks, prompt identification and notification of public health authorities are warranted.

Duchenne and Becker MD are allelic disorders caused by mutations of the DMD gene located on Xp21, which encodes for the dystrophin protein. DMD is the most common form of muscular dystrophy in childhood, with an estimated incidence of 1 per 3,500 live-born males, and a pooled prevalence of DMD of 4.78 per 100,000 males worldwide. BMD is a generally milder and more variable form of dystrophinopathy, with an incidence of 1 in 18,518 male births, and a pooled prevalence of 1.53 per 100,000 males worldwide. Diagnosis is based on careful review of the clinical features and confirmed by additional investigations including muscle biopsy and/or genetic testing. Suspicion of the diagnosis of DMD is usually triggered in one of three ways, including (1) most commonly, the observation of abnormal muscle function with signs of proximal muscle weakness in a male child; (2) the detection of elevated serum creatine kinase as part of routine screening; or (3) the presence of elevated liver enzymes including aspartate aminotransferase and alanine aminotransferase. Current strategies include promoting proper nutrition, delaying onset of complications, and optimizing health outcomes through on-going support. Pharmaceutical interventions include corticosteroids for skeletal muscle weakness and afterload reduction for cardiomyopathy. Early recognition and precise genetic diagnosis will allow for new therapeutic options for DMD. Even though there is currently no cure, respiratory intervention and other supportive strategies have led to improved survival and better health-related quality of life for many affected individuals.

Muscular dystrophies (MD) refer to a heterogeneous group of disorders associated with ongoing muscle degeneration and regeneration, leading to progressive weakness. The distribution of weakness includes a limb-girdle pattern, with shoulder and hip girdle muscle involvement; a humeroperoneal pattern, with predominantly triceps, biceps, and peroneal muscles weakness; or a distal pattern, with distal weakness in the legs and arms. Traditionally, the classification of MD is based on a combination of clinical and pathological criteria, including age of onset and distribution of muscle weakness, the extent of disease progression, associated symptoms, systemic features, family history, serum creatine kinase, muscle histology, as well as electromyography and nerve conduction studies. Increasingly, the diagnosis of MD requires genetic confirmation, as there can be considerable variations and overlaps in the clinical phenotypes. This chapter aims to provide an overview of the myotonic dystrophies, limb-girdle muscular dystrophies, and congenital muscular dystrophies. Duchenne and Becker muscular dystrophy as well as facioscapulohumeral dystrophy are discussed in other chapters.

The worldwide burden of diabetes and its complications in children continues to increase due to the rise in type 1 and type 2 diabetes. Although overt diabetic neuropathy is rarely present in children and adolescents with diabetes, subclinical diabetic neuropathy has been estimated to occur in approximately half of all children with type 1 diabetes with a duration of 5 years or longer and up to 25% of pediatric patients with newly diagnosed diabetes have abnormal findings on nerve conduction studies. The present review on the state of pediatric diabetic neuropathy covers the definition, prevalence, pathogenesis, diagnosis, risk factors, and possible treatment approaches specific to children and adolescents with diabetes. It also highlights the many unknowns in this field. Nonetheless, new emerging interventions that can either prevent or delay the progression of diabetic microvascular and macrovascular complications may become available in the near future. Until specific interventions for diabetic neuropathy are available for use in children, it will be hard to justify screening for neuropathy other than through clinical assessment. Meanwhile, the search for quicker, easily administered, and quantifiable tests for diabetic neuropathy and efforts to establish valid pediatric norms for well-established measures used in adults will need to continue.

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disorder of the central nervous system that is increasingly recognized in children and adolescents. This realization comes with additional concerns about existing therapeutic options and the impact of the disease on health-related outcomes of adolescents with MS. This five-part review provides an update on management strategies relevant to the pediatric MS population. The first section gives an overview on the epidemiology and natural history of early onset MS. The second section outlines currently available MS treatments, including medications during acute relapses and long-term immunomodulatory therapies. The third section highlights adherence issues pertaining to MS, including the challenges uniquely faced by adolescents. The fourth section provides a summary of research into quality of life and psychosocial consequences of pediatric onset MS. Attention is drawn to the grief experience of affected adolescents and the importance of peer relationships. Finally, the family resilience framework is presented as a conceptual model to facilitate optimal adaptation of adolescents with MS. Healthcare professionals can promote resilience and treatment adherence by ensuring that these individuals and their families are sufficiently informed about available MS treatments, providing instrumental support for managing potential medication side effects, and addressing age-appropriate developmental needs.

The purpose of this study was to assess risk factors and management of status epilepticus and non-status epilepticus seizures at a community hospital in Saudi Arabia. The research design was a prevalence study of a convenience sample of pediatric seizure episodes admitted to a 350-bed hospital from 1992 to 1997. The mean age at presentation was 2 years, 10 months, 43% of patients had no history of seizures, and 17% were transferred from other hospitals. Fifty-nine (28%) of 212 seizure episodes were status epilepticus (SE). These SE episodes were significantly more likely than non-SE episodes to be associated with a history of seizures, prior antiepileptic drug (AED) therapy, the presence of an acute etiology, and prolonged duration of seizures before hospitalization. SE episodes were also significantly more likely than non-SE episodes to receive an inappropriate AED, to require intensive care unit admission, to suffer morbidity, and to have SE recurrence at follow-up; however, the difference in mortality was not significant. In conclusion, children with SE were more likely than those with non-SE seizures to have a history of seizures and acute brain insults, prolonged seizure duration before hospitalization, and less optimal management and outcomes. Management of SE in this referral population can be improved by more rapid access to appropriate medical care.

Background Duchenne muscular dystrophy is an X-linked recessive muscular dystrophy. Clinical management primarily involves rehabilitation strategies aimed at preserving functional mobility as long as possible. Side-alternating vibration therapy is a rehabilitation intervention that has shown promise in a number of different neuromuscular disorders, and has the potential to preserve strength, functional mobility, and bone mass. There has been little research regarding the tolerance to side-alternating vibration therapy in muscle diseases such as Duchenne muscular dystrophy. Methods Four patients were recruited for a pilot study assessing the safety and tolerance of side-alternating vibration therapy in individuals with Duchenne muscular dystrophy. All patients participated in a 4-week training period involving side-alternating vibration therapy sessions three times per week. Serum creatine kinase was measured, and adverse effects reviewed at each session with functional mobility assessed before and after the training period. Results All patients tolerated the training protocol well, and there were no major changes in functional mobility. One patient had a transient increase in creatine kinase during the study; however, levels of this enzyme were stable overall when comparing the pretraining and posttraining values. Some patients reported subjective improvement during the training period. Conclusions Side-alternating vibration therapy is well tolerated in children with Duchenne muscular dystrophy and may have potential to improve or maintain functional mobility and strength in these patients.

The worldwide burden of diabetes and its complications in children continues to increase due to the rise in type 1 and type 2 diabetes. Although overt diabetic neuropathy is rarely present in children and adolescents with diabetes, subclinical diabetic neuropathy has been estimated to occur in approximately half of all children with type 1 diabetes with a duration of 5 years or longer and up to 25% of pediatric patients with newly diagnosed diabetes have abnormal findings on nerve conduction studies. The present review on the state of pediatric diabetic neuropathy covers the definition, prevalence, pathogenesis, diagnosis, risk factors, and possible treatment approaches specific to children and adolescents with diabetes. It also highlights the many unknowns in this field. Nonetheless, new emerging interventions that can either prevent or delay the progression of diabetic microvascular and macrovascular complications may become available in the near future. Until specific interventions for diabetic neuropathy are available for use in children, it will be hard to justify screening for neuropathy other than through clinical assessment. Meanwhile, the search for quicker, easily administered, and quantifiable tests for diabetic neuropathy and efforts to establish valid pediatric norms for well-established measures used in adults will need to continue.

We aimed to describe the effects of whole body vibration training on serum creatine kinase and motor function in two brothers with Duchenne muscular dystrophy using standardized measurements. Whole body vibration was delivered using a side-alternating vibration platform at a starting frequency of 7.5 Hz, increasing up to 20 Hz for 5 minutes three times weekly for three months. The baseline serum creatine kinase of the 7 and 10 years old boys was 33,105 U/L and 14,984 U/L. After vibration training, their levels dropped significantly, reaching a nadir of 7,383 U/L and 536 U/L respectively during treatment. There was a modest increase in their 6-minute walk distance but their overall North Star Ambulatory Assessment scores were unchanged. Whole body vibration appeared to be safe and well-tolerated. The reduction in serum creatine kinase as observed in these two boys suggests a potential benefit of brief high frequency vibration on muscle function.

The muscular dystrophies are a broad group of hereditary muscle diseases with variable severity. Population-based prevalence estimates have been reported but pooled estimates are not available. We performed a systematic review of worldwide population-based studies reporting muscular dystrophies prevalence and/or incidence using MEDLINE and EMBASE databases. The search strategy included key terms related to muscular dystrophies, incidence, prevalence and epidemiology. Two reviewers independently reviewed all abstracts, full text articles and abstracted data using standardized forms. Pooling of prevalence estimates was performed using random effect models. 1104 abstracts and 167 full text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The studies differed widely in their approaches to case ascertainment, resulting in significant methodological heterogeneity and varied data quality. The pooled prevalence of DMD and BMD was 4.78 (95% CI 1.94-11.81) and 1.53 (95% CI 0.26-8.94) per 100,000 males respectively. The incidence of DMD ranged from 10.71 to 27.78 per 100,000. This is the first meta-analysis of worldwide prevalence estimates for muscular dystrophies. There is a need for more epidemiological studies addressing global estimates on incidence and prevalence of muscular dystrophies, utilizing standardized diagnostic criteria as well as multiple sources of case ascertainment.

OBJECTIVE: To evaluate the incidence, clinical features, diagnostic, and treatment trends of pediatric myasthenia in Canada. METHODS: Through established Canadian Pediatric Surveillance Program methodology, physicians were anonymously surveyed for cases of pediatric myasthenia using a standardized clinical questionnaire containing deidentified data. Inclusion criteria were any child RESULTS: In 2 years of surveillance, 57 confirmed cases were reported. There were 34 generalized and 18 ocular reports of juvenile myasthenia gravis plus 5 congenital myasthenic syndrome cases. There were 14 incident cases in 2010 and 6 in 2011. Age of onset ranged from “birth” to 17 years for the generalized form compared with 18 months to 11 years for the ocular subtype. Positive acetylcholine receptor titers were found in 22 (67%) of 33 generalized cases and 8 (44%) of 18 ocular patients. Of patients started on pyridostigmine, improvement was noted in 33 (100%) of 33 generalized cases and 15 (88%) of 17 ocular cases. CONCLUSIONS: This study represents the largest descriptive series of pediatric myasthenia in North America and provides valuable information about clinical characteristics. A high index of suspicion is important for this treatable disease. Children generally respond promptly to readily available therapies.

We studied the potential for motor unit number estimation (MUNE) to detect subclinical changes in motor unit numbers in children with type 1 diabetes mellitus (DM).Blinded observers performed clinical assessment, electrophysiology, and multipoint MUNE of the extensor digitorum brevis muscle in children with DM for ≥ 5 years and age-matched healthy controls.For 51 DM subjects, the disease duration was 9.1 ± 2.6 years. Subjects with DM and healthy controls (n=21) had similar demographics. There were no clinical symptoms or signs of peripheral neuropathy in any subject, nor differences in standard electrophysiology between cohorts. Estimated motor unit numbers were decreased significantly in children with DM (224 ± 87 vs. 274 ± 101, P=0.036).Despite the absence of clinical or standard electrophysiological differences from normal control subjects, MUNE can detect a small significant difference in children with DM, suggesting that motor unit loss begins early and subclinically in the disease.

Background:Patient registries represent an important method of organizing “real world” patient information for clinical and research purposes. Registries can facilitate clinical trial planning and recruitment and are particularly useful in this regard for uncommon and rare diseases. Neuromuscular diseases (NMDs) are individually rare but in aggregate have a significant prevalence. In Canada, information on NMDs is lacking. Barriers to performing Canadian multicentre NMD research exist which can be overcome by a comprehensive and collaborative NMD registry.Methods:We describe the objectives, design, feasibility and initial recruitment results for the Canadian Neuromuscular Disease Registry (CNDR).Results:The CNDR is a clinic-based registry which launched nationally in June 2011, incorporates paediatric and adult neuromuscular clinics in British Columbia, Alberta, Ontario, Quebec, New Brunswick and Nova Scotia and, as of December 2012, has recruited 1161 patients from 12 provinces and territories. Complete medical datasets have been captured on 460 “index disease” patients. Another 618 “non-index” patients have been recruited with capture of physician-confirmed diagnosis and contact information. We have demonstrated the feasibility of blended clinic and central office-based recruitment. “Index disease” patients recruited at the time of writing include 253 with Duchenne and Becker muscular dystrophy, 161 with myotonic dystrophy, and 71 with ALS.Conclusions:The CNDR is a new nationwide registry of patients with NMDs that represents an important advance in Canadian neuromuscular disease research capacity. It provides an innovative platform for organizing patient information to facilitate clinical research and to expedite translation of recent laboratory findings into human studies.