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.

Diagnostic yield of clinical exome sequencing in adulthood in medical genetics clinics.

Clinical exome sequencing (ES) is the most comprehensive genomic test to identify underlying genetic diseases in Canada. We performed this retrospective cohort study to investigate the diagnostic yield of clinical ES in adulthood. Inclusion criteria were: (1) Adult patients ≥18 years old; (2) Patients underwent clinical ES between January 1 and December 31, 2021; (3) Patients were seen in the Department of Medical Genetics. We reviewed patient charts. We applied American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification guidelines for interpretation of variants. Non-parametric Fisher's exact statistical test was used. Seventy-seven patients underwent clinical ES. Fourteen different genetic diseases were confirmed in 15 patients: FBXO11, MYH7, MED13L, NSD2, ANKRD11 (n = 2), SHANK3, RHOBTB2, CDKL5, TRIO, TCF4, SCN1, SMAD3, POGZ, and EIF2B3 diseases. The diagnostic yield of clinical ES was 19.5%. Patients with a genetic diagnosis had a significantly higher frequency of neurodevelopmental disorders than those with no genetic diagnosis (p = 0.00339). The diagnostic yield of clinical ES was the highest in patients with seizures (35.7%), and with progressive neurodegenerative diseases (33.3%). Clinical ES is a helpful genomic test to provide genetic diagnoses to the patients who are referred to medical genetic clinics due to suspected genetic diseases in adulthood to end their diagnostic odyssey. Targeted next generation sequencing panels for specific phenotypes may decrease the cost of genomic test in adulthood.

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. METHODS AND ANALYSIS: A two-stage explanatory sequential mixed methods design will be used. Stage 1: quantitative data on healthcare networks and encounter experiences will be collected from 100 parent/guardians through a care map, 2 baseline questionnaires and 17 weekly diaries over 5-7 months. Care networks will be analysed using social network analysis. Relationships between demographic or clinical variables and ratings of healthcare experiences across a range of family centred care dimensions will be analysed using generalised linear regression. Other quantitative data related to family experiences and healthcare experiences will be summarised descriptively. Ongoing analysis of quantitative data and purposive, maximum variation sampling will inform sample selection for stage 2: a subset of stage 1 participants will participate in one-on-one videoconference interviews to elaborate on the quantitative data regarding care networks and healthcare experiences. Interview data will be analysed thematically. Qualitative and quantitative data will be merged during analysis to arrive at an enhanced understanding of care experiences. Quantitative and qualitative data will be combined and presented narratively using a weaving approach (jointly on a theme-by-theme basis) and visually in a side-by-side joint display. ETHICS AND DISSEMINATION: The study protocol and procedures were approved by the Children's Hospital of Eastern Ontario's Research Ethics Board, the University of Ottawa Research Ethics Board and the research ethics boards of each participating study centre. Findings will be published in peer-reviewed journals and presented at scientific conferences.

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. METHODS: A cross-sectional mailed survey was conducted of family caregivers recruited from an ongoing cohort study. Participants rated their healthcare experiences during their child's visits to five types of healthcare settings common for inherited metabolic diseases: the metabolic clinic, the emergency department, hospital inpatient units, the blood laboratory, and the pharmacy. Participants provided narrative descriptions of any memorable negative or positive experiences. RESULTS: There were 248 respondents (response rate 49%). Caregivers were generally very or somewhat satisfied with the care provided at each care setting. Appropriate treatment, provider knowledge, provider communication, and care coordination were deemed essential aspects of satisfaction with care by the majority of participants across many settings. Memorable negative experiences were reported by 8-22% of participants, varying by setting. Among participants who reported memorable negative experiences, contributing factors included providers' demeanor, lack of communication, lack of involvement of the family, and disregard of an emergency protocol letter provided by the family. CONCLUSIONS: While caregivers' satisfaction with care for children with inherited metabolic diseases was high, we identified gaps in family-centered care and factors contributing to negative experiences that are important to consider in the future development of strategies to improve pediatric care for inherited metabolic diseases.

Genomics in Cerebral Palsy phenotype across the lifespan: Comparison of diagnostic yield between children and adult population.

PURPOSE: The presentation and underlying etiology of Cerebral Palsy (CP) in general are heterogenous. Clinical features present differently in pediatric versus adult patient populations. Many metabolic and genetic conditions present with clinical symptoms suggestive of CP. Precision medicine practices are currently a standard of care, and Next-Generation-Sequencing (NGS) tools are used for the purpose of diagnosis and management. We describe the diagnostic yield and impact on management of NGS comparing a cohort of 102 children and 37 adults with CP, referred to two tertiary care centres between 2015 and 2020 (adult cohort) and 2017-2020 (pediatric cohort) respectively. PRINCIPAL RESULTS: In the adult cohort, 28 patients had a positive genetic diagnosis, giving a yield of 75.6%. Their age varied between 18 and 59 years, with a median of 28 years. Out of the positive diagnoses, 12 were consistent with an inborn error of metabolism and in 9 patients (32.1%) some form of treatment or management guideline was recommended. In the pediatric cohort 21 patients had a positive genetic diagnosis and 22 results are still pending, giving a yield of 32.8%. Age at diagnosis ranged between 18 months and 12 years. In 15 patients (71.4%) there was some form of management recommendation. All families benefited from genetic counseling. MAJOR CONCLUSIONS: Given the combined high yield of positive genetic diagnosis in pediatric and adult cases presenting with symptoms of Cerebral Palsy, and the more readily available Next Generation Sequencing testing in major academic centres, we recommend that either a referral to a pediatric or adult neurometabolic centre to be made, or genetic testing to be initiated where this is available.

Brain-lung-thyroid syndrome in a neonate with argininosuccinate lyase deficiency.

Argininosuccinate lyase (ASL) deficiency is a rare autosomal recessive urea cycle disorder. The severe neonatal-onset form is characterised by hyperammonaemia in the first days of life and manifests with a variety of severe symptoms. However, an index of suspicion for additional or alternative diagnoses must be maintained when the patient's presentation is out of keeping with expected manifestations and course. We present a case of a neonate with ASL deficiency and concomitant hypotonia, severe respiratory distress, pulmonary hypertension, systemic hypotension and congenital hypothyroidism. The patient was investigated and subsequently diagnosed with brain-lung-thyroid syndrome, caused by a mutation in the NKX2-1 gene.

Outcomes of patients with cobalamin C deficiency: A single center experience.

Biallelic variants in MMACHC results in the combined methylmalonic aciduria and homocystinuria, called cobalamin (cbl) C (cblC) deficiency. We report 26 patients with cblC deficiency with their phenotypes, genotypes, biochemical parameters, and treatment outcomes, who were diagnosed and treated at our center. We divided all cblC patients into two groups: group 1: SX group: identified after manifestations of symptoms (n = 11) and group 2: NB group: identified during the asymptomatic period via newborn screening (NBS) or positive family history of cblC deficiency (n = 15). All patients in the SX group had global developmental delay and/or cognitive dysfunction at the time of the diagnosis and at the last assessment. Seizure, stroke, retinopathy, anemia, cerebral atrophy, and thin corpus callosum in brain magnetic resonance imaging (MRI) were common in patients in the SX group. Global developmental delay and cognitive dysfunction was present in nine patients in the NB group at the last assessment. Retinopathy, anemia, and cerebral atrophy and thin corpus callosum in brain MRI were less frequent. We report favorable outcomes in patients identified in the neonatal period and treated pre-symptomatically. Identification of cblC deficiency by NBS is crucial to improve neurodevelopmental outcomes.

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.

Pre-school neurocognitive and functional outcomes after liver transplant in children with early onset urea cycle disorders, maple syrup urine disease, and propionic acidemia: An inception cohort matched-comparison study.

BACKGROUND: Urea cycle disorders (UCD) and organic acid disorders classically present in the neonatal period. In those who survive, developmental delay is common with continued risk of regression. Liver transplantation improves the biochemical abnormality and patient survival is good. We report the neurocognitive and functional outcomes post-transplant for nine UCD, three maple syrup urine disease, and one propionic acidemia patient. METHODS: Thirteen inborn errors of metabolism (IEM) patients were individually one-to-two matched to 26 non-IEM patients. All patients received liver transplant. Wilcoxon rank sum test was used to compare full-scale intelligence-quotient (FSIQ) and Adaptive Behavior Assessment System-II General Adaptive Composite (GAC) at age 4.5 years. Dichotomous outcomes were reported as percentages. RESULTS: FSIQ and GAC median [IQR] was 75 [54, 82.5] and 62.0 [47.5, 83] in IEM compared with 94.5 [79.8, 103.5] and 88.0 [74.3, 97.5] in matched patients (P-value <.001), respectively. Of IEM patients, 6 (46%) had intellectual disability (FSIQ and GAC <70), 5 (39%) had autism spectrum disorder, and 1/13 (8%) had cerebral palsy, compared to 1/26 (4%), 0, 0, and 0% of matched patients, respectively. In the subgroup of nine with UCDs, FSIQ (64[54, 79]), and GAC (56[45, 75]) were lower than matched patients (100.5 [98.5, 101] and 95 [86.5, 99.5]), P = .005 and .003, respectively. CONCLUSION: This study evaluated FSIQ and GAC at age 4.5 years through a case-comparison between IEM and matched non-IEM patients post-liver transplantation. The neurocognitive and functional outcomes remained poor in IEM patients, particularly in UCD. This information should be included when counselling parents regarding post-transplant outcome.

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. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities. RESULTS: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend "mitochondrial cocktails" for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority. CONCLUSIONS: While Canadian physicians' views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols.

Les soins de santé prodigués au Canada à des individus atteints de troubles mitochondriaux : une enquête menée auprès de médecins. Contexte: Dans le cas de patients atteints de troubles mitochondriaux rares, il est permis de croire qu'une meilleure compréhension des pratiques en matière de diagnostic et de traitement peut contribuer, au moyen des lignes directrices, à l'étalonnage et à l'établissement de priorités en ce qui regarde la recherche évaluative. Notre intention a été de décrire les soins prodigués au Canada par des médecins, notamment leur variabilité, dans le cas de ces patients. Méthodes: Pour ce faire, nous avons effectué une enquête transversale auprès de médecins canadiens qui posent des diagnostics de troubles mitochondriaux et qui prodiguent des soins continus aux patients qui en sont atteints. À cet effet, nous avons fait appel à la méthode d'enquête dite « en boule de neige ¼ (snowball sampling) afin d'identifier des participants possiblement admissibles. Ces derniers ont été ensuite contactés par la poste, et ce, à cinq reprises au maximum. Ils ont été invités à remplir un questionnaire et à le retourner par la poste ou en ligne. Ce questionnaire abordait les aspects suivants : leur expérience personnelle à titre de prestataire de soins ; leurs pratiques en matière de diagnostic et de traitement ; les défis se présentant à eux au moment d'avoir accès à des tests ou à des traitements ; et finalement leurs points de vue en ce qui regarde les priorités de la recherche. Résultats: Dans le cadre de cette enquête, nous avons reçu 58 réponses, ce qui représente un taux de 52 %. Une majorité de répondants (83 %) ont indiqué allouer 20 % ou moins de leur temps de pratique clinique aux soins de patients atteints de ces troubles. Nous avons également noté d'importantes variations concernant les soins et les diagnostics, et ce, même si les outils d'évaluation fréquemment considérés utiles sur le plan diagnostic (p. ex. : des IRM du cerveau/la spectroscopie par RM) étaient également recommandés dans des lignes directrices déjà publiées. Environ la moitié de nos répondants (49 %) recommanderaient volontiers un « cocktail ¼ de vitamines pour tous leurs patients ou la plupart d'entre eux. Quand il est question de vitamines spécifiques et de cofacteurs, nous avons cependant identifié une variation dans leurs réponses. Interrogés quant à la priorité numéro un en matière de recherche, une majorité de répondants a dit recommander la poursuite d'études portant sur la mise sur pied de traitements thérapeutiques efficaces. Conclusions: Bien que les points de vue de ces médecins canadiens en ce qui regarde les diagnostics et la prise en charge des troubles mitochondriaux soient en phase avec des recommandations publiées, d'importantes variations reflètent la persistance d'aspects incertains ainsi qu'un besoin de données empiriques afin de renforcer et de mettre à jour les protocoles de rééférence.

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.

Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.

Kidney disease and organ transplantation in methylmalonic acidaemia.

OBJECTIVES: MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre-, peri-, and post-transplant course of all children with MMA who underwent liver or combined liver-kidney transplant in our centers. DESIGN AND METHODS: Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years. RESULTS: Five children with MMA underwent liver transplant (4/5) and combined liver-kidney transplant (1/5). Three were Mut0 and two had a cobalamin B disorder. Four of five were transplanted between ages 3 and 5 years. Renal dysfunction prior to transplant was seen in 2/5 patients. Post-transplant (one liver transplant and one combined transplant) renal function improved slightly when using creatinine-based GFR formula. We noticed in 2 patients a big discrepancy between creatinine- and cystatin C-based GFR calculations. One patient with no renal disease developed renal failure post-liver transplantation. Serum MMA levels have decreased in all to <300 µmol/L. Four patients remain on low protein diet, carnitine, coenzyme Q, and vitamin E post-transplant. CONCLUSIONS: MMA is a complex metabolic disorder. Renal disease can continue to progress post-liver transplant and close follow-up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post-transplant can halt the progression of renal disease remains unclear.

Genetic landscape of pediatric movement disorders and management implications.

OBJECTIVE: To identify underlying genetic causes in patients with pediatric movement disorders by genetic investigations. METHODS: All patients with a movement disorder seen in a single Pediatric Genetic Movement Disorder Clinic were included in this retrospective cohort study. We reviewed electronic patient charts for clinical, neuroimaging, biochemical, and molecular genetic features. DNA samples were used for targeted direct sequencing, targeted next-generation sequencing, or whole exome sequencing. RESULTS: There were 51 patients in the Pediatric Genetic Movement Disorder Clinic. Twenty-five patients had dystonia, 27 patients had ataxia, 7 patients had chorea-athetosis, 8 patients had tremor, and 7 patients had hyperkinetic movements. A genetic diagnosis was confirmed in 26 patients, including in 20 patients with ataxia and 6 patients with dystonia. Targeted next-generation sequencing panels confirmed a genetic diagnosis in 9 patients, and whole exome sequencing identified a genetic diagnosis in 14 patients. CONCLUSIONS: We report a genetic diagnosis in 26 (51%) patients with pediatric movement disorders seen in a single Pediatric Genetic Movement Disorder Clinic. A genetic diagnosis provided either disease-specific treatment or effected management in 10 patients with a genetic diagnosis, highlighting the importance of early and specific diagnosis.

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment.

Glutaric aciduria type 3 (GA3) is associated with decreased conversion of free glutaric acid to glutaryl-coA, reflecting deficiency of succinate-hydroxymethylglutarate coA-transferase, caused by variants in the SUGCT (C7orf10) gene. GA3 remains less well known, characterised and understood than glutaric aciduria types 1 and 2. It is generally considered a likely "non-disease," but this is based on limited supporting information, with only nine individuals with GA3 described in the literature. Clinicians encountering a patient with GA3 therefore still face a dilemma of whether or not this should be dismissed as irrelevant.We have identified three unrelated Canadian patients with GA3. Two came to clinical attention because of symptoms, while the third was identified by a population urine-based newborn screening programme and has so far remained asymptomatic. We describe the clinical histories, biochemical characterisation and genotypes of these individuals. Examination of allele frequencies underlines the fact that GA3 is underdiagnosed. While one probable factor is that some GA3 patients remain asymptomatic, we highlight other plausible reasons whereby this diagnosis might be overlooked.Gastrointestinal disturbances were previously reported in some GA3 patients. In one of our patients, severe episodes of cyclic vomiting were the major problem. A trial of antibiotic treatment, to minimise bacterial GA production, was followed by significant clinical improvement.At present, there is insufficient evidence to define any specific clinical phenotype as attributable to GA3. However, we consider that it would be premature to assume that this condition is completely benign in all individuals at all times.

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Phenotypic and genotypic spectrum of congenital disorders of glycosylation type I and type II.

BACKGROUND: Congenital disorders of glycosylation (CDG) are inborn defects of glycan metabolism. They are multisystem disorders. Analysis of transferrin isoforms is applied as a screening test for CDG type I (CDG-I) and type II (CDG-II). We performed a retrospective cohort study to determine spectrum of phenotype and genotype and prevalence of the different subtypes of CDG-I and CDG-II. MATERIAL AND METHODS: All patients with CDG-I and CDG-II evaluated in our institution's Metabolic Genetics Clinics were included. Electronic and paper patient charts were reviewed. We set-up a high performance liquid chromatography transferrin isoelectric focusing (TIEF) method to measure transferrin isoforms in our Institution. We reviewed the literature for the rare CDG-I and CDG-II subtypes seen in our Institution. RESULTS: Fifteen patients were included: 9 with PMM2-CDG and 6 with non-PMM2-CDG (one ALG3-CDG, one ALG9-CDG, two ALG11-CDG, one MPDU1-CDG and one ATP6V0A2-CDG). All patients with PMM2-CDG and 5 patients with non-PMM2-CDG showed abnormal TIEF suggestive of CDG-I or CDG-II pattern. In all patients, molecular diagnosis was confirmed either by single gene testing, targeted next generation sequencing for CDG genes, or by whole exome sequencing. CONCLUSION: We report 15 new patients with CDG-I and CDG-II. Whole exome sequencing will likely identify more patients with normal TIEF and expand the phenotypic spectrum of CDG-I and CDG-II.

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. Participants were selected with the aim of achieving a diverse sample with respect to treatment centre, IMD, and age of the child. Interviews emphasized the impacts of the disease and its treatment on the child and family and explicitly queried perceptions of interactions with the health care system. We identified emergent themes from the interview data. RESULTS: We completed interviews with 21 parents/caregivers. The 21 children were aged <1 to 7 years old with IMD that included amino acid disorders, urea cycle disorders, fatty acid oxidation disorders, and organic acid disorders or 'other' IMD. Most parents reported that they and their families had adapted well to their child's diagnosis. Parents used proactive coping strategies to integrate complex disease management protocols into routine family life. An important source of stress was concern about the social challenges faced by their children. Participants reported positive interactions with their most involved health care providers within the metabolic clinic. However, they reported challenges associated with the health care system outside of disease-specific metabolic care, when encountering systems and providers unfamiliar with the child's disease. CONCLUSIONS: The successful use of proactive coping strategies among parents of children with IMD in this study suggests the potential value of promoting positive coping and is an important direction for future study. Parents' social concerns for their children were important stressors that warrant consideration by health care providers positioned to support families. Our results with respect to experiences with care highlight the important role of specialized metabolic clinics and point to a need for better coordination of the care that takes place outside the disease-specific management of IMD.

Progressive Cerebellar Atrophy and a Novel Homozygous Pathogenic DNAJC19 Variant as a Cause of Dilated Cardiomyopathy Ataxia Syndrome.

BACKGROUND: The dilated cardiomyopathy with ataxia syndrome is a rare autosomal recessive multisystem disorder caused by mutations in DNAJC19. We present a new patient with a novel pathogenic variant in DNAJC19 with novel neuroimaging finding of progressive cerebellar atrophy. PATIENT DESCRIPTION AND RESULTS: We describe a new patient with dilated cardiomyopathy with ataxia syndrome presenting with global developmental delay, hypotonia, ataxia, and dilated cardiomyopathy. During follow-up, her cardiac phenotype improved but she exhibited progressive cerebellar atrophy and developed bilateral increased T2 signal intensities in the thalami, parietal lobes, and pons on magnetic resonance imaging. Dilated cardiomyopathy and 3-methylglutaconic aciduria in her urine organic acid analysis also improved. CONCLUSIONS: This child with dilated cardiomyopathy with ataxia syndrome developed progressive cerebellar atrophy, a novel feature of this syndrome. In individuals with global developmental delay, hypotonia, ataxia, the dilated cardiomyopathy with ataxia syndrome should be considered even in the differential diagnosis in the absence of cardiomyopathy or 3-methylglutaconic aciduria.

Child and family experiences with inborn errors of metabolism: a qualitative interview study with representatives of patient groups.

BACKGROUND: Patient-centered health care for children with inborn errors of metabolism (IEM) and their families is important and requires an understanding of patient experiences, needs, and priorities. IEM-specific patient groups have emerged as important voices within these rare disease communities and are uniquely positioned to contribute to this understanding. We conducted qualitative interviews with IEM patient group representatives to increase understanding of patient and family experiences, needs, and priorities and inform patient-centered research and care. METHODS: We developed a sampling frame of patient groups representing IEM disease communities from Canada, the United States, and United Kingdom. With consent, we interviewed participants to explore their views on experiences, needs, and outcomes that are most important to children with IEM and their families. We analyzed the data using a qualitative descriptive approach to identify key themes and sub-themes. RESULTS: We interviewed 18 organizational representatives between February 28 and September 17, 2014, representing 16 IEMs and/or disease categories. Twelve participants voluntarily self-identified as parents and/or were themselves patients. Three key themes emerged from the coded data: managing the uncertainty associated with raising and caring for a child with a rare disease; challenges associated with the affected child's life transitions, and; the collective struggle for improved outcomes and interventions that rare disease communities navigate. CONCLUSION: Health care providers can support children with IEM and their families by acknowledging and reducing uncertainty, supporting families through children's life transitions, and contributing to rare disease communities' progress toward improved interventions, experiences, and outcomes.

Scoping review of patient- and family-oriented outcomes and measures for chronic pediatric disease.

BACKGROUND: Improvements in health care for children with chronic diseases must be informed by research that emphasizes outcomes of importance to patients and families. To support a program of research in the field of rare inborn errors of metabolism (IEM), we conducted a broad scoping review of primary studies that: (i) focused on chronic pediatric diseases similar to IEM in etiology or manifestations and in complexity of management; (ii) reported patient- and/or family-oriented outcomes; and (iii) measured these outcomes using self-administered tools. METHODS: We developed a comprehensive review protocol and implemented an electronic search strategy to identify relevant citations in Medline, EMBASE, DARE and Cochrane. Two reviewers applied pre-specified criteria to titles/abstracts using a liberal accelerated approach. Articles eligible for full-text review were screened by two independent reviewers with discrepancies resolved by consensus. One researcher abstracted data on study characteristics, patient- and family-oriented outcomes, and self-administered measures. Data were validated by a second researcher. RESULTS: 4,118 citations were screened with 304 articles included. Across all included reports, the most-represented diseases were diabetes (35%), cerebral palsy (23%) and epilepsy (18%). We identified 43 unique patient- and family-oriented outcomes from among five emergent domains, with mental health outcomes appearing most frequently. The studies reported the use of 405 independent self-administered measures of these outcomes. CONCLUSIONS: Patient- and family-oriented research investigating chronic pediatric diseases emphasizes mental health and appears to be relatively well-developed in the diabetes literature. Future research can build on this foundation while identifying additional outcomes that are priorities for patients and families.