Publications by authors named "Hugh J McMillan"

77 Publications

Characterization of physical literacy in children with chronic medical conditions compared to healthy controls: a cross-sectional study.

Appl Physiol Nutr Metab 2021 Mar 9. Epub 2021 Mar 9.

Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.

To determine the physical literacy, defined as the capability for a physically active lifestyle, of children with medical conditions compared with healthy peers, this multicenter cross-sectional study recruited children with medical conditions from cardiology, neurology (including concussion), rheumatology, mental health, respirology, oncology, hematology, and rehabilitation (including cerebral palsy) clinics. Participants aged 8-12 years (N=130; mean age: 10.0±1.44 years; 44% female) were randomly matched to three healthy peers from a normative database, based on age, sex, and month of testing. Total physical literacy was assessed by the Canadian Assessment of Physical Literacy, a validated assessment of physical literacy measuring physical competence, daily behavior, knowledge/understanding, and motivation/confidence. Total physical literacy mean scores(/100) did not differ (t(498)=-0.67; p=0.44) between participants (61.0±14.2) and matched healthy peers (62.0±10.7). Children with medical conditions had lower mean physical competence scores (/30; -6.5 [-7.44, -5.51]; p<0.001) but higher mean motivation/confidence scores (/30; 2.6 [1.67, 3.63]; p<0.001). Mean daily behavior and knowledge/understanding scores did not differ from matches (/30; 1.8 [0.26, 3.33]; p=0.02; /10; -0.04 [-0.38, 0.30]; p=0.81; respectively). Children with medical conditions are motivated to be physically active but demonstrate impaired movement skills and fitness, suggesting the need for targeted interventions to improve their physical competence. Novelty bullets: • Physical literacy in children with diverse chronic medical conditions is similar to healthy peers • Children with medical conditions have lower physical competence than healthy peers, but higher motivation and confidence • Physical competence (motor skill, fitness) interventions, rather than motivation or education, are needed for these youth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1139/apnm-2020-0957DOI Listing
March 2021

Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.

Eur J Hum Genet 2021 Mar 1. Epub 2021 Mar 1.

F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.

Variants in multiple tubulin genes have been implicated in neurodevelopmental disorders, including malformations of cortical development (MCD) and congenital fibrosis of the extraocular muscles (CFEOM). Distinct missense variants in the beta-tubulin encoding genes TUBB3 and TUBB2B cause MCD, CFEOM, or both, suggesting substitution-specific mechanisms. Variants in the alpha tubulin-encoding gene TUBA1A have been associated with MCD, but not with CFEOM. Using exome sequencing (ES) and genome sequencing (GS), we identified 3 unrelated probands with CFEOM who harbored novel heterozygous TUBA1A missense variants c.1216C>G, p.(His406Asp); c.467G>A, p.(Arg156His); and c.1193T>G, p.(Met398Arg). MRI revealed small oculomotor-innervated muscles and asymmetrical caudate heads and lateral ventricles with or without corpus callosal thinning. Two of the three probands had MCD. Mutated amino acid residues localize either to the longitudinal interface at which α and β tubulins heterodimerize (Met398, His406) or to the lateral interface at which tubulin protofilaments interact (Arg156), and His406 interacts with the motor domain of kinesin-1. This series of individuals supports TUBA1A variants as a cause of CFEOM and expands our knowledge of tubulinopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-020-00804-7DOI Listing
March 2021

Costs of Illness of Spinal Muscular Atrophy: A Systematic Review.

Appl Health Econ Health Policy 2021 Feb 12. Epub 2021 Feb 12.

Department of Women's and Children's Health, Karolinska Institutet, Karolinska Vägen 37A, 171 76, Stockholm, Sweden.

Objectives: The objective of our study was to conduct a systematic literature review of estimates of costs of illness of spinal muscular atrophy (SMA).

Methods: We searched MEDLINE (through PubMed), CINAHL, Embase, Web of Science, National Health Service Economic Evaluation Database, and the National Health Service Health Technology Assessment Database for studies published from inception up until 31 August, 2020, reporting direct medical, direct non-medical, and/or indirect costs of any phenotype of SMA. Two reviewers independently screened records for eligibility, extracted the data, and assessed studies for risk of bias using the Newcastle-Ottawa Scale. Costs were adjusted and converted to 2018 US dollars.

Results: The search identified 14 studies from eight countries (Australia, France, Germany, Italy, Spain, Sweden, the UK, and the USA). The mean per-patient annual direct medical cost of illness was estimated at between $3320 (SMA type III, Italy) and $324,410 (SMA type I, USA), mean per-patient annual direct non-medical cost between $25,880 (SMA types I-III, Spain) and $136,800 (SMA type I, Sweden), and mean per-patient annual indirect cost between $9440 (SMA type I, Germany) and $74,910 (SMA type II, Australia). Most studies exhibited a risk of bias.

Conclusions: The current body of evidence of costs of illness of SMA is relatively scarce and characterized by considerable variability across geographical settings and disease phenotypes. Our review provides data pertaining to the economic impact of SMA, which is of particular relevance in light of emerging treatments and ongoing research in this field, and underscores the substantial unmet medical need in this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40258-020-00624-2DOI Listing
February 2021

Pediatric Hyperacute Arterial Ischemic Stroke Pathways at Canadian Tertiary Care Hospitals.

Can J Neurol Sci 2021 Feb 11:1-8. Epub 2021 Feb 11.

University of Ottawa, Faculty of Medicine, Ottawa, ON, Canada.

Background: Childhood acute arterial ischemic stroke (AIS) is diagnosed at a median of 23 hours post-symptom onset, delaying treatment. Pediatric stroke pathways can expedite diagnosis. Our goal was to understand the similarities and differences between Canadian pediatric stroke protocols with the aim of optimizing AIS management.

Methods: We contacted neurologists at all 16 Canadian pediatric hospitals regarding AIS management. Established protocols were analyzed for similarities and differences in eight domains.

Results: Response rate was 100%. Seven (44%) centers have an established AIS protocol and two (13%) have a protocol under development. Seven centers do not have a protocol; two redirect patients to adult neurology, five rely on a case-by-case approach for management. Analysis of the seven protocols revealed differences in: 1) IV-tPA dosage: age-dependent 0.75-0.9 mg/kg (N = 1) versus age-independent 0.9 mg/kg (N = 6), with maximum doses of 75 mg (N = 1) or 90 mg (N = 6); 2) IV-tPA lower age cut-off: 2 years (N = 5) versus 3 or 10 years (each N = 1); 3) IV-tPA exclusion criteria: PedNIHSS score <4 (N = 3), <5 (N = 1), <6 (N = 3); 4) first choice of pre-treatment neuroimaging: computed tomography (CT) (N = 3), magnetic resonance imaging (MRI) (N = 2) or either (N = 2); 5) intra-arterial tPA use (N = 3) and; 6) mechanical thrombectomy timeframe: <6 hour (N = 3), <24 hour (N = 2), unspecified (N = 2).

Conclusions: Although 44% of Canadian pediatric hospitals have established AIS management pathways, several differences remain among centers. Some criteria (dosage, imaging) reflect adult AIS literature. Canadian expert consensus regarding IV-tPA and endovascular treatment should be established to standardize and implement AIS protocols across Canada.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2021.27DOI Listing
February 2021

Intrinsic peripheral nerve and root tumor and pseudotumoral lesions at a tertiary care pediatric hospital.

Childs Nerv Syst 2021 Apr 6;37(4):1229-1236. Epub 2021 Jan 6.

Department of Pediatrics, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.

Purpose: Tumors affecting peripheral nerves in children are rare. Accurate diagnosis ensures that management is appropriate and timely. A review of intrinsic nerve tumors was completed to differentiate common peripheral nerve lesions based on clinical characteristics and investigations.

Methods: A retrospective review was conducted for children (< 18 years old) diagnosed with an intrinsic tumor affecting peripheral nerve(s) or roots at the Children's Hospital of Eastern Ontario (CHEO) from 2009 to 2019.

Results: We report 14 children with perineurioma (N = 6), neurofibroma (N = 4), intraneural ganglion cyst (N = 2), or lipomatosis (N = 2). Mean age of symptom onset was 8.2 years (range 0.3 to 17.3 years). Presenting symptoms included muscle weakness (7/14), painless muscle wasting (2/14), contracture (1/14), pain (1/14), or the identification of a painless mass (3/14). Nerve conduction studies (NCS) or electromyography (EMG) were performed in 11/14 patients. MRI was useful at differentiating between these pediatric nerve tumors. Biopsies were performed in nine patients with additional surgical management pursued in four patients.

Conclusion: The rare nature of peripheral nerve tumors in children can pose diagnostic challenges. NCS/EMG are important to assist with localization, and MRI is useful to distinguish more benign tumors. Key MRI, clinical, and NCS features can in some cases guide management, potentially avoiding the need for invasive procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00381-020-04995-8DOI Listing
April 2021

Newborn Screening for Spinal Muscular Atrophy: Ontario Testing and Follow-up Recommendations.

Can J Neurol Sci 2020 Oct 16:1-8. Epub 2020 Oct 16.

Children's Hospital of Eastern Ontario Research Institute, Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.

Background: Spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons causing muscle atrophy and weakness. Nusinersen, the first effective SMA therapy was approved by Health Canada in June 2017 and has been added to the provincial formulary of all but one Canadian province. Access to this effective therapy has triggered the inclusion of SMA in an increasing number of Newborn Screening (NBS) programs. However, the range of disease-modifying SMN2 gene copy numbers encountered in survival motor neuron 1 (SMN1)-null individuals means that neither screen-positive definition nor resulting treatment decisions can be determined by SMN1 genotype alone. We outline an approach to this challenge, one that specifically addresses the case of SMA newborns with four copies of SMN2.

Objectives: To develop a standardized post-referral evaluation pathway for babies with a positive SMA NBS screen result.

Methods: An SMA NBS pilot trial in Ontario using first-tier MassARRAY and second-tier multi-ligand probe amplification (MLPA) was launched in January 2020. Prior to this, Ontario pediatric neuromuscular disease and NBS experts met to review the evidence regarding the diagnosis and treatment of children with SMA as it pertained to NBS. A post-referral evaluation algorithm was developed, outlining timelines for patient retrieval and management.

Conclusions: Ontario's pilot NBS program has created a standardized path to facilitate early diagnosis of SMA and initiation of treatment. The goal is to provide timely access to those SMA infants in need of therapy to optimize motor function and prolong survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2020.229DOI Listing
October 2020

Inhaled Solvent Abuse Mimicking Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Child Neurol Open 2020 Jan-Dec;7:2329048X20934914. Epub 2020 Jun 19.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ontario, Canada.

Exposure to n-hexane or toluene-containing solvents such as glue or gasoline can produce clinical symptoms and neurophysiological findings that can mimic chronic inflammatory demyelinating polyneuropathy. The authors present a case of a boy with severe sensorimotor polyneuropathy with demyelinating features. Cerebrospinal fluid testing and magnetic resonance imaging spine did not show findings typical of chronic inflammatory demyelinating polyneuropathy. His lack of response to immunosuppressive therapy prompted a nerve biopsy which was instrumental in confirming a diagnosis of chronic organic solvent exposure, subsequently confirmed on history. This case highlights the importance of additional testing to ensure diagnostic certainty which allows appropriate treatment and/or disease management to be tailored appropriately including in this instance, the involvement of mental health counseling and avoidance of immunosuppressant medication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2329048X20934914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307582PMC
June 2020

A splice variant in expands the clinical and genetic spectrum of Harel-Yoon syndrome.

Neurol Genet 2020 Aug 3;6(4):e452. Epub 2020 Jun 3.

Division of Neurology (I.H., H.J.M.), Children's Hospital of Eastern Ontario, Children's Hospital of Eastern Ontario Research Institute (H.J.M., Y.I., D.A.D.), University of Ottawa; Newborn Screen Ontario (K.D.K.), Ottawa; Department of Clinical Genetics (J.L., D.A.D.), and Division of Metabolics (M.A.L.), Children's Hospital of Eastern Ontario, University of Ottawa.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286657PMC
August 2020

Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature.

J Inherit Metab Dis 2020 11 3;43(6):1321-1332. Epub 2020 Aug 3.

Research Center, CHU Sainte Justine, University of Montreal, Montreal, Quebec, Canada.

We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jimd.12278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689772PMC
November 2020

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

Can J Neurol Sci 2020 11 4;47(6):810-815. Epub 2020 Jun 4.

Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.

Background: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population.

Methods: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials.

Results: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner.

Conclusion: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2020.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656664PMC
November 2020

Corrigendum: Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L796V Mutation in .

Front Neurol 2020;11:181. Epub 2020 Mar 20.

Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.

[This corrects the article DOI: 10.3389/fneur.2020.00077.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099287PMC
March 2020

Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L769V Mutation in .

Front Neurol 2020 13;11:77. Epub 2020 Feb 13.

Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.

The phenotypic spectrum associated with the skeletal muscle voltage-gated sodium channel gene () has expanded with advancements in genetic testing. Autosomal dominant mutations were first linked to hyperkalemic periodic paralysis, then subsequently included paramyotonia congenita, several variants of myotonia, and finally hypokalemic periodic paralysis. Biallelic recessive mutations were later identified in myasthenic myopathy and in infants showing a severe congenital myopathy with hypotonia. We report a patient with a pathogenic variant, c.2386C>G p.L769V at a highly conserved leucine. The phenotype was manifest at birth with arthrogryposis multiplex congenita, severe episodes of bronchospasm that responded immediately to carbamazepine therapy, and electromyographic evidence of widespread myotonia. Another case of p.L769V has been reported with hip dysplasia, scoliosis, myopathy, and later paramyotonia. Expression studies of L796V mutant channels showed predominantly gain-of-function changes, that included defects of slow inactivation. Computer simulations of muscle excitability reveal a strong predisposition to myotonia with exceptionally prolonged bursts of discharges, when the L796V defects are included. We propose L769V is a pathogenic variant, that along with other cases in the literature, defines a new dominant disorder of myotonic myopathy with secondary congenital joint and skeletal involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031655PMC
February 2020

Life expectancy at birth in Duchenne muscular dystrophy: a systematic review and meta-analysis.

Eur J Epidemiol 2020 Jul 27;35(7):643-653. Epub 2020 Feb 27.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.

Several studies indicate that prognosis for survival in Duchenne muscular dystrophy (DMD) has improved in recent decades. However, published evidence is inconclusive and some estimates may be obsolete due to improvements in standards of care, in particular the routine use of mechanical ventilatory support in advanced stages of the disease. In this systematic review and meta-analysis (PROSPERO identifier: CRD42019121800), we searched MEDLINE (through PubMed), CINAHL, Embase, PsycINFO, and Web of Science for studies published from inception up until December 31, 2018, reporting results of life expectancy in DMD. We pooled median survival estimates from individual studies using the median of medians, and weighted median of medians, methods. Risk of bias was established with the Newcastle-Ottawa Scale. Results were stratified by ventilatory support and risk of bias. We identified 15 publications involving 2662 patients from 12 countries from all inhabited continents except Africa. Median life expectancy without ventilatory support ranged between 14.4 and 27.0 years (pooled median: 19.0 years, 95% CI 18.0-20.9; weighted pooled median: 19.4 years, 18.2-20.1). Median life expectancy with ventilatory support, introduced in most settings in the 1990s, ranged between 21.0 and 39.6 years (pooled median: 29.9 years, 26.5-30.8; weighted pooled median: 31.8 years, 29.3-36.2). Risk of bias had little impact on pooled results. In conclusion, median life expectancy at birth in DMD seems to have improved considerably during the last decades. With current standards of care, many patients with DMD can now expect to live into their fourth decade of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-020-00613-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387367PMC
July 2020

Drisapersen associated with elevated serum factor VIII levels in Duchenne muscular dystrophy.

Neurology 2020 03 19;94(12):538-540. Epub 2020 Feb 19.

From the Department of Pediatrics (H.J.M., A.A.), Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa; Department of Pediatrics (H.G.), Sick Kids Hospital, University of Toronto, Toronto; and Department of Pediatrics (S.A., C.C.), London Children's Hospital, University of Western Ontario, London, Ontario, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009139DOI Listing
March 2020

Risk of Intracranial Hemorrhage Following Intravenous tPA (Tissue-Type Plasminogen Activator) for Acute Stroke Is Low in Children.

Stroke 2020 02 17;51(2):542-548. Epub 2019 Dec 17.

Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia (R.N.I.).

Background and Purpose- Data regarding the safety and efficacy of intravenous tPA (tissue-type plasminogen activator) in childhood acute arterial ischemic stroke are inadequate. The TIPS trial (Thrombolysis in Pediatric Stroke; National Institutes of Health grant R01NS065848)-a prospective safety and dose-finding trial of intravenous tPA in acute childhood stroke-was closed for lack of accrual. TIPS sites have subsequently treated children with acute stroke in accordance with established institutional protocols supporting data collection on outcomes. Methods- Data on children treated with intravenous tPA for neuroimaging-confirmed arterial ischemic stroke were collected retrospectively from 16 former TIPS sites to establish preliminary safety data. Participating sites were required to report all children who were treated with intravenous tPA to minimize reporting bias. Symptomatic intracranial hemorrhage (SICH) was defined as ECASS (European Cooperative Acute Stroke Study) II parenchymal hematoma type 2 or any intracranial hemorrhage associated with neurological deterioration within 36 following tPA administration. A Bayesian beta-binomial model for risk of SICH following intravenous tPA was fit using a prior distribution based on the risk level in young adults (1.7%); to test for robustness, the model was also fit with uninformative and conservative priors. Results- Twenty-six children (age range, 1.1-17 years; median, 14 years; 12 boys) with stroke and a median pediatric National Institutes of Health Stroke Scale score of 14 were treated with intravenous tPA within 2 to 4.5 hours (median, 3.0 hours) after stroke onset. No patient had SICH. Two children developed epistaxis. Conclusions- The estimated risk of SICH after tPA in children is 2.1% (95% highest posterior density interval, 0.0%-6.7%; mode, 0.9%). Regardless of prior assumption, there is at least a 98% chance that the risk is <15% and at least a 93% chance that the risk is <10%. These results suggest that the overall risk of SICH after intravenous tPA in children with acute arterial ischemic stroke, when given within 4.5 hours after symptom onset, is low.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.119.027225DOI Listing
February 2020

Developmental delay and neuropsychiatric comorbidities associated with Duchenne and Becker muscular dystrophy.

Muscle Nerve 2020 02 23;61(2):127-128. Epub 2019 Dec 23.

Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26775DOI Listing
February 2020

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

Muscle Nerve 2020 02;61(2):143-155

Centre de Référence Maladies Neuromusculaires, Service de Neurologie, Réanimation et Réeducation Pédiatriques, Hôpital Raymond Poincaré, Garches, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26752DOI Listing
February 2020

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Nat Med 2019 11 21;25(11):1748-1752. Epub 2019 Oct 21.

Department of Pediatric Infectious Diseases, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF). CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-019-0613-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858576PMC
November 2019

Nusinersen: Evidence of sustained clinical improvement and lessened fatigue in older ambulatory patients with spinal muscular atrophy.

Authors:
Hugh J McMillan

Muscle Nerve 2020 01 22;61(1):1-2. Epub 2019 Oct 22.

Division of Neurology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26735DOI Listing
January 2020

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy.

Ann Clin Transl Neurol 2019 08 26;6(8):1519-1532. Epub 2019 Jul 26.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Objective: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease.

Methods: We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA.

Results: We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation.

Interpretation: This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acn3.50855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689695PMC
August 2019

A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset.

J Neuromuscul Dis 2019 ;6(3):333-339

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.

Charcot-Marie-Tooth disease is a phenotypically and genetically heterogeneous group of disorders affecting both motor and sensory neurons. Exome sequencing has driven discovery of genes responsible for Charcot-Marie-Tooth disease with more than 70 genes now associated with this neuromuscular disease. The MARS gene was recently reported as the cause of Charcot-Marie-Tooth 2U, a slowly progressive axonal sensorimotor polyneuropathy with adult-onset reported in six patients. We report here a patient with a progressive, early childhood-onset, motor-predominant form of Charcot-Marie-Tooth disease. Exome sequencing identified a novel MARS variant (c.1189G>A; p.Ala397Thr) that was not present in her unaffected mother; her unaffected father was unavailable. Further studies using structural modeling and a yeast humanization assay support pathogenicity of the variant. Our study expands the phenotype of Charcot-Marie-Tooth 2U, while highlighting the utility of functional assays to evaluate variant pathogenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-190404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889022PMC
February 2020

"Owl's Eye" Sign in Acute Flaccid Paralysis.

Can J Neurol Sci 2019 11;46(6):756-757

Department of Pediatrics, Division of Neurology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.

A 4-year-old boy presented with asymmetric acute flaccid paralysis (AFP) of his right arm and both legs. He was alert with no oculobulbar weakness or incontinence. He had fever and diarrhea 5 days earlier. He was fully immunized with no travel history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2019.250DOI Listing
November 2019

Pediatric Neurology Workforce in Canada: A 5-Year Update.

Can J Neurol Sci 2019 09 26;46(5):566-574. Epub 2019 Jul 26.

Division of Pediatric Neurology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada.

Background: In 2013, a task force was developed to discuss the future of the Canadian pediatric neurology workforce. The consensus was that there was no indication to reduce the number of training positions, but that the issue required continued surveillance. The current study provides a 5-year update on Canadian pediatric neurology workforce data.

Methods: Names, practice types, number of weekly outpatient clinics, and dates of certification of all physicians currently practicing pediatric neurology in Canada were obtained. International data were used to compute comparisons between countries. National data sets were used to provide information about the number of residency positions available and the number of Canadian graduates per year. Models for future projections were developed based on published projected population data and trends from the past decade.

Results: The number of pediatric neurologists practicing in Canada has increased 165% since 1994. During this period, wait times have not significantly shortened. There are regional discrepancies in access to child neurologists. The Canadian pediatric neurology workforce available to see outpatient consultations is proportionally less than that of USA. After accounting for retirements and emigrations, the number of child neurologists being added to the workforce each year is 4.9. This will result in an expected 10-year increase in Canadian pediatric neurologists from 151 to 200.

Conclusions: Despite an increase in the number of Canadian child neurologists over the last two decades, we do not predict that there will be problems with underemployment over the next decade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2019.229DOI Listing
September 2019

Muscle problems in juvenile-onset acid maltase deficiency (Pompe disease).

Paediatr Child Health 2019 Jul 8;24(4):270-271. Epub 2019 May 8.

Department of Neurology Paediatrics, Children's Hospital London Health Science Centre, London, Ontario.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/pch/pxy153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587424PMC
July 2019

Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy.

Channels (Austin) 2019 12;13(1):153-161

b Institute of Organic Chemistry and Biochemistry , Czech Academy of Sciences , Prague , Czech Republic.

Neuromuscular disorders encompass a wide range of conditions often associated with a genetic component. In the present study, we report a patient with severe infantile-onset amyotrophy in whom two compound heterozygous variants in the gene CACNA1H encoding for Ca3.2 T-type calcium channels were identified. Functional analysis of Ca3.2 variants revealed several alterations of the gating properties of the channel that were in general consistent with a loss-of-channel function. Taken together, these findings suggest that severe congenital amyoplasia may be related to CACNA1H and would represent a new phenotype associated with mutations in this gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19336950.2019.1614415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527065PMC
December 2019

Intermittent glucocorticoid regimes for younger boys with duchenne muscular dystrophy: Balancing efficacy with side effects.

Authors:
Hugh J McMillan

Muscle Nerve 2019 06 25;59(6):638-639. Epub 2019 Apr 25.

Division of Neurology, Children's Hospital of Eastern Ontario, University of Ottawa, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mus.26490DOI Listing
June 2019

Obesity and Endocrine Management of the Patient With Duchenne Muscular Dystrophy.

Pediatrics 2018 10;142(Suppl 2):S43-S52

Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada; and

Duchenne muscular dystrophy (DMD) is associated with an increased risk of endocrine complications due to the effects of prolonged glucocorticoid therapy as well as progressive muscle weakness. Categories of complications include obesity and its comorbidities, short stature, pubertal delay, and adrenal insufficiency. Obesity prevention is important for long-term management of patients with DMD. Preventing glucocorticoid-induced weight gain fosters patient mobility, ease of transfer, and reduces sleep-disordered breathing. Metabolic complications from obesity (glucose intolerance, dyslipidemia) also can be avoided. Short stature and pubertal delay may negatively affect self-esteem and peer relationships, and careful monitoring of growth and pubertal development can allow anticipatory counseling. Adrenal insufficiency, a potentially life-threatening complication associated with prolonged glucocorticoid use, must be recognized so as to allow prompt treatment. In this article, we provide a summary of current guidance to ensure comprehensive endocrine management is followed in patients with DMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2018-0333FDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460463PMC
October 2018

Bone Health and Osteoporosis Management of the Patient With Duchenne Muscular Dystrophy.

Pediatrics 2018 10;142(Suppl 2):S34-S42

Golisano Children's Hospital, School of Medicine and Dentistry, University of Rochester, Rochester, New York.

Duchenne muscular dystrophy is associated with an increased risk of bone fragility due to the adverse effects of prolonged glucocorticoid therapy and progressive muscle weakness on bone strength. Osteoporosis manifests clinically as low-trauma long-bone and vertebral fractures (VFs), with VFs frequent, particularly in those treated with glucocorticoid therapy. It is increasingly recognized that bone pain, medical complications of osteoporosis (such as fat embolism syndrome), and the potential for permanent, fracture-induced loss of ambulation can be mitigated with timely bone health surveillance and management. This includes periodic spine radiographs for VF detection because VFs can be asymptomatic in their early phases and thereby go undetected in the absence of monitoring. With this article, we provide a comprehensive review of the following 4 phases of bone health management: (1) bone health monitoring, which is used to identify early signs of compromised bone health; (2) osteoporosis stabilization, which is aimed to mitigate back pain and interrupt the fracture-refracture cycle through bone-targeted therapy; (3) bone health maintenance, which has the goal to preserve the clinical gains realized during the stabilization phase through ongoing bone-targeted therapy; and (4) osteoporosis therapy discontinuation, which places those who are eligible for discontinuation of osteoporosis treatment back on a health monitoring program. In the course of reviewing these 4 phases of management, we will discuss the criteria for diagnosing osteoporosis, along with detailed recommendations for osteoporosis intervention including specific drugs, dose, length of therapy, contraindications, and monitoring of treatment efficacy and safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2018-0333EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442478PMC
October 2018

Phosphoserine aminotransferase deficiency: imaging findings in a child with congenital microcephaly.

J Matern Fetal Neonatal Med 2020 Mar 19;33(6):1033-1035. Epub 2018 Sep 19.

Department of Medical Imaging, Children's Hospital of Eastern Ontario, Ottawa, Canada.

Serine deficiency disorders can result from deficiency in one of three enzymes. Deficiency of the second enzyme, 3-phosphoserine aminotransferase (PSAT), has been reported in two siblings; the eldest investigated for acquired microcephaly, spasticity and epilepsy. Our patient had neurological symptoms at birth. Fetal magnetic resonance imaging (MRI) at 35-week gestation demonstrated microencephaly and gyral simplification (anterior > posterior) which was confirmed upon postnatal MRI. Congenital microcephaly was apparent at birth. PSAT deficiency was confirmed when exome sequencing identified biallelic mutations in and biochemical testing noted low plasma serine and cerebral spinal fluid serine. Despite oral serine and glycine supplementation at 4 months old, the patient showed little neurodevelopmental progress and developed epileptic spasms at 10 months old. PSAT deficiency should be considered for patients with congenital microcephaly. Although further characterization of MRI findings in other patients is required, microencephaly with simplified gyral pattern could provide imaging clues for this rare metabolic disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14767058.2018.1514375DOI Listing
March 2020