The Effect of Massage Therapy on Autonomic Activity in Critically Ill Children

Objectives. Our main objective was to describe the effect of foot and hand (F&H) massage on the autonomic nervous system (ANS) activity in children hospitalized in a pediatric intensive care unit (PICU); the secondary objectives were to assess the relationship between ANS function and the clinical severity and to explore the effects of repeated massage sessions on the ANS. Methods. Design was a descriptive experimental study. Intervention was single or six session(s) of F&H massage. ANS function was assessed through the frequency-domain analysis of heart rate variability. Main metrics included high and low frequency power (HF and LF), HF + LF, and LF/HF ratio. Results. Eighteen children participated in the study. A strong Spearman’s correlation (ρ=-0.77) was observed between HF + LF and clinical severity. During massage, the parasympathetic activity (measured by HF) increased significantly from baseline (P=0.04) with a mean percentage increase of 75% (95% CI: 20%∼130%). LF increased by 56% (95% CI: 20%∼92%) (P=0.026). Repeated sessions were associated with a persistent effect on HF and LF which peaked at the second session and remained stable thereafter. Conclusions. HF + LF is positively correlated with clinical severity. F&H massage can improve the ANS activity and the effect persists when repeated sessions are offered

Morquio-like dysostosis multiplex presenting with neuronopathic features is a distinct GLB1-related phenotype

Background Morquio B disease (MBD) is a distinct GLB1-related dysostosis multiplex presenting a mild phenocopy of GALNS-related Morquio A disease. Previously reported cases from European countries carry the W273L variant on at least one GLB1 allele and exhibit a pure skeletal phenotype (pure MBD). Only a minority of MBD cases have been described with additional neuronopathic findings (MBD plus). Objectives and Methods With the aim to further describe patterns of MBD-related dysostosis multiplex, we analyzed clinical, biochemical, and genetic features in 17 cases with GLB1-related dysostosis multiplex living and diagnosed in Brazil. Results About 14 of the 17 individuals had three or more skeletal findings characteristic of Morquio syndrome. Two had no additional neuronopathic features (pure MBD) and 12 exhibited additional neuronopathic features (MBD plus). Three of the 17 cases had mild dysostosis without distinct features of MBD. Seven of the 12 MBD plus patients had signs of spinal cord compression (SCC), as a result of progressive spinal vertebral dysostosis. There was an age-dependent increase in the number of skeletal findings and in the severity of growth impairment. GLB1 mutation analysis was completed in 10 of the 14 MBD patients. T500A occurred in compound heterozygosity in 8 of the 19 alleles. Conclusion Our study extends the phenotypic spectrum of GLB1-related conditions by describing a cohort of patients with MBD and GM1-gangliosidosis (MBD plus). Targeting the progressive nature of the skeletal manifestations in the development of new therapies for GLB1-related conditions is warranted

Comprehensive analysis of current PKU management practices and associated patient and parent-reported outcomes in Canada

Phenylketonuria (PKU) is a genetic metabolic disorder requiring life-long treatment to prevent severe neurocognitive disability. Despite early treatment, suboptimal neurobehavioral outcomes are common in individuals with PKU. The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) presented an opportunity to investigate current approaches to care and associated outcomes in children with PKU and their parents. Four studies were conducted herein. The surveys of Canadian metabolic dietitians and physicians, described in Chapter 2, helped to understand current PKU management practices from the perspectives of healthcare providers. Data reflecting practices in metabolic treatment centres and associated outcomes were derived from the CIMDRN clinical longitudinal PKU database (Chapter 3). Finally, parent-reported child’s health and parental quality of life were analyzed in connection to the quality of metabolic control (Chapter 4). Providers’ surveys identified overall compliance with current PKU guidelines. Variation was found in case ascertainment, diagnostic workup (neonatal BH4 loading test), monitoring and follow up tests (neuropsychological assessments), treatment practices (sapropterin and large neutral amino acids, LNAA) and organization of care in metabolic centres. The mean phenylalanine (Phe) levels were within the recommended range of 120-360 µmol/L but increased (to 331±151 µmol/L) beyond 7 years of age for children with classic PKU. Among children with classic PKU, 32% were considered in good metabolic control by the 4th week of life. This increased to 55% by age 4-5 and declined to 28% at 8-9 years. Tiredness, lack of concentration, irritability and moodiness were reported as moderate symptoms in children. Parents reported considerable guilt due to non-adherence to the diet/supplements, their child’s anxiety, and practical impact of dietary protein restriction. Overall, healthcare providers follow the published guidelines in providing care for their patients. However, this work has identified variation in many areas of PKU nutritional and clinical management practices in Canadian metabolic centres, including diagnostic and follow up nutritional and clinical management practices. This variation has the potential to impact patients’ long-term health outcomes. The most variation was in areas of practice that were not strongly supported by empirical evidence. This knowledge will serve to further optimize health and quality of life outcomes in Canadian children with PKU.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat

Morquio B Disease. Disease Characteristics and Treatment Options of a Distinct GLB1-Related Dysostosis Multiplex

Morquio B disease (MBD) is an autosomal recessive GLB1-gene-related lysosomal storage disease, presenting with a peculiar type of dysostosis multiplex which is also observed in GALNS-related Morquio A disease. MBD may present as pure skeletal phenotype (pure MBD) or in combination with the neuronopathic manifestations seen in type 2 (juvenile) or type 3 (late onset) GM1 gangliosidosis (MBD plus). The main skeletal features are progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly and odontoid hypoplasia. The main neuronopathic features are dystonia, ataxia, and intellectual/developmental/speech delay. Spinal cord compression occurs as a complication of spinal dysostosis. Chronic pain is reported, along with mobility issues and challenges with daily living and self-care activities, as the most common health concern. The most commonly reported orthopedic surgeries are hip and knee replacements. Keratan sulphate-derived oligosaccharides are characteristic biomarkers. Residual β-galactosidase activities measured against synthetic substrates do not correlate with the phenotype. W273 L and T500A are the most frequently observed GLB1 variants in MBD, W273L being invariably associated with pure MBD. Cytokines play a role in joint destruction and pain, providing a promising treatment target. In the future, patients may benefit from small molecule therapies, and gene and enzyme replacement therapies, which are currently being developed for GM1 gangliosidosis.Other UBCNon UBCReviewedFacult

Morquio B patient/caregiver survey: First insight into the natural course of a rare GLB1 related condition

Morquio B disease (MBD) or Mucopolysaccharidosis type IV B (MPS IV B) is caused by particular GLB1 mutations specifically affecting the affinity of beta-galactosidase to keratan sulphate, resulting in dysostosis multiplex resembling Morquio A (MPS IV A) disease (GALNS deficiency). Additional neuronopathic features of GM1 II/III (juvenile/adult) gangliosidosis have been reported in some patients. Our patient/caregiver online survey was aimed at elucidating the clinical manifestations of this ultra-rare condition.Comparing to previously published data on MPS IV A, the 30 respondents in our MBD group presented with greater growth chart values (weight and height) and with lesser effects of odontoid hypoplasia. The most common concerns are: (1) mobility issues - 84% having difficulty walking; (2) chronic pain - 96%; (3) surgeries - average 3 per person, 80% for hip problems; (4) hip dysplasia, knee/ankle concerns, and scoliosis. Approximately 50% of MBD participants live independently and actively contributing to society.Evidence from our survey results supports the notion that skeletal manifestations in MBD are milder than in the majority of patients with MPS IV A. The data collected will help with the establishment of clinically meaningful outcomes for future therapeutic trials, and with the counseling of newly diagnosed patients about their health expectations. Keywords: Skeletal dysplasia, GM1 gangliosidosis, Lysosome, Natural histor

Developments in evidence creation for treatments of inborn errors of metabolism

Inborn errors of metabolism (IEM) represent the first group of genetic disorders, amenable to causal therapies. In addition to traditional medical diet and cofactor treatments, new treatment strategies such as enzyme replacement and small molecule therapies, solid organ transplantation, and cell-and gene-based therapies have become available. Inherent to the rare nature of the single conditions, generating high-quality evidence for these treatments in clinical trials and under real-world conditions has been challenging. Guidelines developed with standardized methodologies have contributed to improve the practice of care and long-term clinical outcomes. Adaptive trial designs allow for changes in sample size, group allocation and trial duration as the trial proceeds. n-of-1 studies may be used in small sample sized when participants are clinically heterogeneous. Multicenter observational and registry-based clinical trials are promoted via international research networks. Core outcome and standard data element sets will enhance comparative analysis of clinical trials and observational studies. Patient-centered outcome-research as well as patient-led research initiatives will further accelerate the development of therapies for IEM

Nutritional management of phenylalanine hydroxylase (PAH) deficiency in pediatric patients in Canada: a survey of dietitians’ current practices

Background: Phenylalanine hydroxylase (PAH) deficiency is one of 31 targeted inherited metabolic diseases (IMD) for the Canadian Inherited Metabolic Diseases Research Network (CIMDRN). Early diagnosis and initiation of treatment through newborn screening has gradually shifted treatment goals from the prevention of disabling complications to the optimization of long term outcomes. However, clinical evidence demonstrates that subtle suboptimal neurocognitive outcomes are present in the early and continuously diet-treated population with PAH deficiency. This may be attributed to variation in blood phenylalanine levels to outside treatment range and this, in turn, is possibly due to a combination of factors; disease severity, dietary noncompliance and differences in practice related to the management of PAH deficiency. One of CIMDRN’s goals is to understand current practices in the diagnosis and management of PAH deficiency in the pediatric population, from the perspective of both health care providers and patients/families. Objectives: We investigated Canadian metabolic dietitians’ perspectives on the nutritional management of children with PAH deficiency, awareness of recently published North American treatment and nutritional guidelines in relation to PAH deficiency, and nutritional care practices within and outside these guidelines. Methods: We invited 33 dietitians to participate in a survey, to ascertain their use of recently published guidelines and their practices in relation to the nutritional care of pediatric patients with PAH deficiency. Results: We received 19 responses (59% response rate). All participants reported awareness of published guidelines for managing PAH deficiency. To classify disease severity, 89% of dietitians reported using pre-treatment blood phenylalanine (Phe) levels, alone or in combination with other factors. 74% of dietitians reported using blood Phe levels ≥360 μmol/L (6 mg/dL) as the criterion for initiating a Phe-restricted diet. All respondents considered 120-360 μmol/L (2–6 mg/dL) as the optimal treatment range for blood Phe in children 0–9 years old, but there was less agreement on blood Phe targets for older children. Most dietitians reported similar approaches to diet assessment and counseling: monitoring growth trends, use of 3 day diet records for intake analysis, individualization of diet goals, counseling patients to count grams of dietary natural protein or milligrams of dietary Phe, and monitoring blood Phe, tyrosine and ferritin. Conclusion: While Canadian dietitians’ practices in managing pediatric PAH deficiency are generally aligned with those of the American College of Medical Genetics and Genomics (ACMG), and with the associated treatment and nutritional guidelines from Genetic Metabolic Dietitians International (GMDI), variation in many aspects of care reflects ongoing uncertainty and a need for robust evidence.Other UBCNon UBCReviewedFacult

Guanidinoacetate Methyltransferase (Gamt) Deficiency: Outcomes In 48 Individuals And Recommendations For Diagnosis, Treatment And Monitoring

We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, L-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of t-ornithine and/or an arginine-restricted diet (250 mg/kg/d L-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.WoSScopu

Evaluation of the quality of clinical data collection for a pan-Canadian cohort of children affected by inherited metabolic diseases : lessons learned from the Canadian Inherited Metabolic Diseases Research Network

Background The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases. Methods At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN’s clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data. Results As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method – 0% missing). Discussion Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.Other UBCReviewedFacultyResearche