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. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

Development of the global inflammatory bowel disease visualization of epidemiology studies in the 21st century (GIVES-21).

BACKGROUND: There is a rapid increase in the incidence of inflammatory bowel diseases (IBD) in newly industrialized countries, yet epidemiological data is incomplete. We herein report the methodology adopted to study the incidence of IBD in newly industrialized countries and to evaluate the effect of environmental factors including diet on IBD development. METHODS: Global IBD Visualization of Epidemiology Studies in the 21st Century (GIVES-21) is a population-based cohort of newly diagnosed persons with Crohn's disease and ulcerative colitis in Asia, Africa, and Latin America to be followed prospectively for 12 months. New cases were ascertained from multiple sources and were entered into a secured online system. Cases were confirmed using standard diagnostic criteria. In addition, endoscopy, pathology and pharmacy records from each local site were searched to ensure completeness of case capture. Validated environmental and dietary questionnaires were used to determine exposure in incident cases prior to diagnosis. RESULTS: Through November 2022, 106 hospitals from 24 regions (16 Asia; 6 Latin America; 2 Africa) have joined the GIVES-21 Consortium. To date, over 290 incident cases have been reported. All patients have demographic data, clinical disease characteristics, and disease course data including healthcare utilization, medication history and environmental and dietary exposures data collected. We have established a comprehensive platform and infrastructure required to examine disease incidence, risk factors and disease course of IBD in the real-world setting. CONCLUSIONS: The GIVES-21 consortium offers a unique opportunity to investigate the epidemiology of IBD and explores new clinical research questions on the association between environmental and dietary factors and IBD development in newly industrialized countries.

Diagnostic Outcomes of Childhood ADHD in Chinese Adults.

Objective: We examined adulthood diagnostic, functioning, and social outcomes of childhood ADHD in a Hong Kong Chinese clinical sample. Method: We identified from the central registry 499 Chinese adults clinically diagnosed with ADHD aged 6 to 12 in 2002-2005 in four Hong Kong child psychiatric centers. Assessments included ADHD Clinical Diagnostic Scale (ACDS), Structured Clinical Interview for DSM Disorders (SCID), and World Health Organization Disability Assessment Schedule (WHO-DAS). Results: Eligible participants = 499. One hundred forty-five completed assessments, two deceased, six incarcerated, 100 had invalid contact, 83 declined, 34 emigrated, and 129 unable to attend. Mean follow-up duration = 14.9 years. Nonrespondents were slightly younger (19.78 vs. 20.53, p < .001). In all, 83.1% of all participants currently met Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) ADHD criteria (36.8% inattentive subtype (IA), 43% combined, 3.3% hyperactive/impulsive subtype (H/I) ). One third of persistent ADHD participants currently received care. ADHD persistence was associated with significantly increased psychiatric comorbidity (49.5% vs. 22.7%, p = .02) and poor academic and social outcomes. ADHD persistence and comorbidity independently predicted impairment. Conclusion: Adulthood-persistence of clinically presented childhood ADHD is common and impairing in Hong Kong Chinese.

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.

Two mtDNA mutations 14487T>C (M63V, ND6) and 12297T>C (tRNA Leu) in a Leigh syndrome family.

Mitochondrial cytopathies are characterized by a large variability of clinical phenotypes and severity. The 14487T>C mutation in mtDNA has been recently described to be associated with Leigh syndrome. The 12297T>C mutation has been described in isolated dilated cardiomyopathy patients. Here, we report a family with multiple members who harbor both mutations, with only a few individuals who are affected with Leigh syndrome. Mitochondrial whole genome sequencing analysis in the proband's muscle specimen detected two nearly homoplasmic mutations: 14487T>C (M63V in ND6) and 12297T>C in the tRNA (Leu) (CUN) gene. These two mutations were also detected in the blood, urine sediments, hair follicles, and buccal swab samples of all matrilineal relatives tested. All individuals tested were nearly homoplasmic for the 12297T>C mutation, but had variable degrees of heteroplasmy for 14487T>C. We also screened for the frequency of these two mutations. Of 268 patients with Leigh or Leigh-like disease, one case was found to harbor the 14487T>C mutation (0.3%), and one had the 12297T>C mutation (0.3%). Neither mutation was detected in the 88 patients meeting MELAS syndrome criteria nor in the 56 patients with respiratory chain complex I or I+III deficiency. In conclusion, the 14487T>C mutation appears as the primary etiology of Leigh syndrome in this family, demonstrating the high level of heteroplasmy needed for a clinically significant phenotype with this mutation. The 12297T>C mutation was not associated with dilated cardiomyopathy for the family members who were clinically evaluated and who were shown by testing to be nearly homoplasmic for that mutation.

Heparin cofactor II-thrombin complex: a biomarker of MPS disease.

The mucopolysaccharidoses are a group of lysosomal storage disorders caused by defects in the degradation of glycosaminoglycans. Each disorder is characterized by progressive multi-system disease with considerable clinical heterogeneity. The clinical heterogeneity of these disorders is thought to be related to the degree of the metabolic block in glycosaminoglycan degradation which in turn is related to the underlying mutation at the respective locus. There are currently no objective means other than longitudinal clinical observation, or the detection of a recurrent genetic mutation to accurately predict the clinical course for an individual patient, particularly when diagnosed early. In addition, there are no specific disease biomarkers that reflect the total body burden of disease. The lack of specific biomarkers has made monitoring treatment responses and predicting disease course difficult in these disorders. The recent introduction of enzyme replacement therapy for MPS I, II, and VI highlights the need for objective measures of disease burden and disease responsiveness. We show that serum levels of heparin cofactor II-thrombin complex is a reliable biomarker of the mucopolysaccharidoses. Untreated patients have serum levels that range from 3- to 112-fold above control values. In a series of patients with varying severity of mucopolysaccharidosis I, the serum complex concentration was reflective of disease severity. In addition, serum heparin cofactor II-thrombin levels showed responsiveness to various treatment regimens. We propose that serum levels of heparin cofactor II-thrombin complex may provide an important assessment and monitoring tool for patients with mucopolysaccharidosis.

Cognitive Impairment In Treatment-Naïve Bipolar II and Unipolar Depression.

Cognition dysfunction may reflect trait characteristics of bipolarity but cognitive effects of medications have confounded previous comparisons of cognitive function between bipolar II and unipolar depression, which are distinct clinical disorders with some overlaps. Therefore, we examined the executive function (WCST), attention, cognitive speed (TMT-A) and memory (CAVLT, WMS-Visual reproduction) of 20 treatment-naïve bipolar II patients (BPII), 35 treatment-naïve unipolar depressed (UD) patients, and 35 age/sex/education matched healthy controls. The subjects were young (aged 18-35), and had no history of psychosis or substance use, currently depressed and meeting either RDC criteria for Bipolar II Disorder or DSM-IV-TR criteria for Major Depressive Disorder. The patients were moderately depressed (MADRS) and anxious(HAM-A), on average within 3.44 years of illness onset. Sociodemographic data and IQ were similar between the groups. UD patients had significantly slower cognitive speed and cognitive flexibility (WCST perseverative error). BPII depressed patients showed relatively intact cognitive function. Verbal memory (CAVLT List A total) correlated with illness chronicity only in BPII depression, but not UD. In conclusion, young and treatment-naïve BPII depressed patients differed from unipolar depression by a relatively intact cognitive profile and a chronicity-cognitive correlation that suggested a stronger resemblance to Bipolar I Disorder than Unipolar Depression.

Subcutaneous fat necrosis of the newborn and lactic acidosis.

Subcutaneous fat necrosis of the newborn (SFN) is an uncommon, self-limited condition of neonates and infants. However, hypercalcemia may be a potentially life-threatening complication of the otherwise self-healing process. Rare complications such as thrombocytopenia, hypertriglyceridemia, hypoglycemia, calcium deposits in the liver, inferior vena cava, atrial septum of the heart, and nephrocalcinosis have been reported. To our knowledge, this is the first description of a patient in whom lactic acidosis was encountered in an infant along with the other known complications of SFN.

Vanishing white matter disease with periodic (paroxysmal) hemiparesis.

Vanishing white matter disease is a chronically progressive leukodystrophy with periods of acute deterioration after head trauma and febrile illness. This report describes a child with genetically and clinically confirmed vanishing white matter disease exhibiting frequent episodes of right-sided hemiplegia, aphasia, and headache resolving fully within hours to days. This report describes a case of this condition presenting with episodes of hemiparesis with full discovery to baseline. Some possible mechanisms explaining this unusual presentation are provided.

Metabolic Clinic Atlas: Organization of Care for Children with Inherited Metabolic Disease in Canada.

INTRODUCTION: Nearly all children in Canada with an inherited metabolic disease (IMD) are treated at one of the country's Hereditary Metabolic Disease Treatment Centres. We sought to understand the system of care for paediatric IMD patients in Canada in order to identify sources of variation and inform future research priorities. METHODS: Treatment centres were contacted by email and invited to complete a web-based survey. The questionnaire addressed, for each centre, the population size served and scope of practice, available human resources and clinic services and research capacity. Survey responses were analyzed descriptively. RESULTS: We received responses from 13 of the 14 treatment centres invited to participate. These centres represent at least 85% of the Canadian population, with over half of the centres located in southern Ontario and Quebec. All centres reported paediatric patients with IMDs as their main patient population. A variety of dedicated staff was identified; every centre reported having at least one physician and one dietician. The most common ancillary services available included telehealth (11/12 respondents) and biochemical genetic laboratory testing (10/12), with a high variability of access to on-site laboratory tests. A majority of centres indicated access to additional off-site services, but barriers to these were reported. All but one centre indicated previous experience with research. CONCLUSIONS: The variation we identified in the organization of care highlights the need to investigate the association between practice differences and health outcomes for paediatric IMD patients to inform policies that establish equitable access to services that are beneficial.

Influenza B acute necrotizing encephalopathy: a case report and literature review.

The case of a 9-year-old girl with acute encephalopathy with evidence of influenza B virus infection and bilateral basal ganglia lesions is reported. The literature on acute necrotizing encephalopathy is reviewed, and other causes of bilateral basal ganglia lesions are discussed.

Familial recurrence of cerebral palsy with multiple risk factors.

The recurrence of cerebral palsy in the same family is uncommon. We, however, report on two families with two or more affected siblings. In both families, numerous potential risk factors were identified including environmental, obstetric, and possible maternal effects. We hypothesize that multiple risk factors may lead to the increased risk of recurrence of cerebral palsy in families. Intrinsic and maternal risk factors should be investigated in all cases of cerebral palsy to properly counsel families on the risk of recurrence. Recent studies of genetic polymorphisms associated with cerebral palsy are considered with reference to our observations in these two families.

A Case of Dilated Cardiomyopathy Associated with 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG CoA) Lyase Deficiency.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) lyase deficiency is an inborn error of metabolism characterized by impairment of ketogenesis and leucine catabolism resulting in an organic acidopathy. In 1994, a case of dilated cardiomyopathy and fatal arrhythmia was reported in a 7-month-old infant. We report a case of dilated cardiomyopathy in association with HMG CoA lyase deficiency in a 23-year-old man with the acute presentation of heart failure. To our knowledge, this is the first case reported in an adult.