Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

Background: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits.

Methods: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes.

Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression.

The metabolic adaptation of eukaryotic cells to hypoxia involves increasing dependence upon glycolytic adenosine triphosphate (ATP) production, an event with consequences for cellular bioenergetics and cell fate. This response is regulated at the transcriptional level by the hypoxia-inducible factor-1(HIF-1)-dependent transcriptional upregulation of glycolytic enzymes (GEs) and glucose transporters. However, this transcriptional upregulation alone is unlikely to account fully for the levels of glycolytic ATP produced during hypoxia.

Rapid carbon accumulation at a saltmarsh restored by managed realignment exceeded carbon emitted in direct site construction.

Increasing attention is being paid to the carbon sequestration and storage services provided by coastal blue carbon ecosystems such as saltmarshes. Sites restored by managed realignment, where existing sea walls are breached to reinstate tidal inundation to the land behind, have considerable potential to accumulate carbon through deposition of sediment brought in by the tide and burial of vegetation in the site. While this potential has been recognised, it is not yet a common motivating factor for saltmarsh restoration, partly due to uncertainties about the rate of carbon accumulation and how this balances against the greenhouse gases emitted during site construction.

Families' healthcare experiences for children with inherited metabolic diseases: protocol for a mixed methods cohort study.

Introduction: Children with inherited metabolic diseases (IMDs) often have complex and intensive healthcare needs and their families face challenges in receiving high-quality, family centred health services. Improvement in care requires complex interventions involving multiple components and stakeholders, customised to specific care contexts. This study aims to comprehensively understand the healthcare experiences of children with IMDs and their families across Canada.

3-Hydroxyisobutyric acid dehydrogenase deficiency: Expanding the clinical spectrum and quantitation of D- and L-3-Hydroxyisobutyric acid by an LC-MS/MS method.

A deficiency of 3-hydroxyisobutyric acid dehydrogenase (HIBADH) has been recently identified as a cause of primary 3-hydroxyisobutyric aciduria in two siblings; the only previously recognized primary cause had been a deficiency of methylmalonic semialdehyde dehydrogenase, the enzyme that is immediately downstream of HIBADH in the valine catabolic pathway and is encoded by the ALDH6A1 gene. Here we report on three additional patients from two unrelated families who present with marked and persistent elevations of urine L-3-hydroxyisobutyric acid (L-3HIBA) and a range of clinical findings. Molecular genetic analyses revealed novel, homozygous variants in the HIBADH gene that are private within each family.

Establishing a core outcome set for mucopolysaccharidoses (MPS) in children: study protocol for a rapid literature review, candidate outcomes survey, and Delphi surveys.

Background: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases characterized by chronic, progressive multi-system manifestations with varying degrees of severity. Disease-modifying therapies exist to treat some types of MPS; however, they are not curative, underscoring the need to identify and evaluate co-interventions that optimize functioning, participation in preferred activities, and quality of life. A Canadian pediatric MPS registry is under development and may serve as a platform to launch randomized controlled trials to evaluate such interventions.

Family Experiences with Care for Children with Inherited Metabolic Diseases in Canada: A Cross-Sectional Survey.

Background And Objective: Children with inherited metabolic diseases often require complex and highly specialized care. Patient and family-centered care can improve health outcomes that are important to families. This study aimed to examine experiences of family caregivers (parents/guardians) of children diagnosed with inherited metabolic diseases with healthcare to inform strategies to improve those experiences.

Core Outcome Sets for Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Phenylketonuria.

Background: Evidence to guide treatment of pediatric medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) is fragmented because of large variability in outcome selection and measurement. Our goal was to develop core outcome sets (COSs) for these diseases to facilitate meaningful future evidence generation and enhance the capacity to compare and synthesize findings across studies.

Methods: Parents and/or caregivers, health professionals, and health policy advisors completed a Delphi survey and participated in a consensus workshop to select core outcomes from candidate lists of outcomes for MCAD deficiency and PKU.

PHKA2 variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only.

Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH.

MITO-FIND: A study in 390 patients to determine a diagnostic strategy for mitochondrial disease.

Mitochondrial diseases, due to nuclear or mitochondrial genome mutations causing mitochondrial dysfunction, have a wide range of clinical features involving neurologic, muscular, cardiac, hepatic, visual, and auditory symptoms. Making a diagnosis of a mitochondrial disease is often challenging since there is no gold standard and traditional testing methods have required tissue biopsy which presents technical challenges and most patients prefer a non-invasive approach. Since a diagnosis invariably involves finding a disease-causing DNA variant, new approaches such as next generation sequencing (NGS) have the potential to make it easier to make a diagnosis.

Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review.

Background: Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study.

Health Care for Mitochondrial Disorders in Canada: A Survey of Physicians.

Background: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care.

Methods: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases.

Mutations in lead to a glycosylation disorder with a variable phenotype.

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. We identified two patients with defective serum transferrin glycosylation and mutations in the gene. These patients present with a phenotype that is mainly characterized by intellectual and developmental disability.

Health services use among children diagnosed with medium-chain acyl-CoA dehydrogenase deficiency through newborn screening: a cohort study in Ontario, Canada.

Background: We describe early health services utilization for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency through newborn screening in Ontario, Canada, relative to a screen negative comparison cohort.

Methods: Eligible children were identified via newborn screening between April 1, 2006 and March 31, 2010. Age-stratified rates of physician encounters, emergency department (ED) visits and inpatient hospitalizations to March 31, 2012 were compared using incidence rate ratios (IRR) and incidence rate differences (IRD).

Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa.

Objective: To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities.

Methods: Morquio A patients aged ≥7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.

Computational Prediction of Position Effects of Apparently Balanced Human Chromosomal Rearrangements.

Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects' phenotypes.

Experiences of caregivers of children with inherited metabolic diseases: a qualitative study.

Background: We sought to understand the experiences of parents/caregivers of children with inherited metabolic diseases (IMD) in order to inform strategies for supporting patients and their families. We investigated their experiences regarding the management of disease, its impact on child and family life, and interactions with the health care system.

Methods: From four Canadian centres, we conducted semi-structured telephone interviews with parents/caregivers of children with an IMD who were born between 2006 and 2015 and who were participating in a larger cohort study.

A novel NDUFS4 frameshift mutation causes Leigh disease in the Hutterite population.

Leigh disease is a progressive, infantile-onset, neurodegenerative disorder characterized by feeding difficulties, failure to thrive, hypotonia, seizures, and central respiratory compromise. Metabolic and neuroimaging investigations typically identify abnormalities consistent with a disorder of mitochondrial energy metabolism. Mutations in more than 35 genes affecting the mitochondrial respiratory chain encoded from both the nuclear and mitochondrial genomes have been associated with Leigh disease.

The health system impact of false positive newborn screening results for medium-chain acyl-CoA dehydrogenase deficiency: a cohort study.

Background: There is no consensus in the literature regarding the impact of false positive newborn screening results on early health care utilization patterns. We evaluated the impact of false positive newborn screening results for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in a cohort of Ontario infants.

Methods: The cohort included all children who received newborn screening in Ontario between April 1, 2006 and March 31, 2010.

Vitamin B12 Deficiency in Infancy: The Case for Screening.

The classic principles put forth by Wilson and Jungner are often applied to determine the suitability of a condition for universal newborn screening. The three cases described here portray the harmful effects of vitamin B12 deficiency in infancy. The challenges and opportunities of early recognition and treatment are highlighted.