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.

Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma.

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.

Exploring the associations of daily movement behaviours and mid-life cognition: a compositional analysis of the 1970 British Cohort Study.

BACKGROUND: Movement behaviours (eg, sedentary behaviour (SB), moderate and vigorous physical activity (MVPA), light intensity physical activity (LIPA) and sleep) are linked to cognition, yet the relative importance of each component is unclear, and not yet explored with compositional methodologies. OBJECTIVE: To (i) assess the associations of different components of daily movement and participant's overall cognition, memory and executive function, and (ii) understand the relative importance of each individual component for cognition. METHODS: The 1970 British Cohort Study (BCS70) is a prospective birth cohort study of UK-born adults. At age 46, participants consented to wear an accelerometer device and complete tests of verbal memory and executive function. Compositional linear regression was used to examine cross-sectional associations between 24-hour movement behaviours and standardised cognition scores. Isotemporal substitution was performed to model the effect of reallocating time between components of daily movement on cognition. RESULTS: The sample comprised 4481 participants (52% female). Time in MVPA relative to SB, LIPA and sleep was positively associated with cognition after adjustments for education and occupational physical activity, but additional adjustment for health status attenuated associations. SB relative to all other movements was robustly positively associated with cognition. Modelling time reallocation between components revealed an increase in cognition centile after MVPA theoretically replaced 9 min of SB (OR=1.31; 95% CI 0.09 to 2.50), 7 min of LIPA (1.27; 0.07 to 2.46) or 7 min of sleep (1.20; 0.01 to 2.39). CONCLUSIONS: Relative to time spent in other behaviours, greater MVPA and SB was associated with higher cognitive scores. Loss of MVPA time, given its smaller relative amount, appears most deleterious. Efforts should be made to preserve MVPA time, or reinforce it in place of other behaviours.

Longitudinal associations between physical activity and other health behaviours during the COVID-19 pandemic: a fixed effects analysis.

Government enforced restrictions on movement during the COVID-19 pandemic are likely to have had profound impacts on the daily behaviours of many individuals, including physical activity (PA). Given the associations between PA and other health behaviours, changes in PA during the pandemic may have been detrimental for other health behaviours. This study aimed to evaluate whether changes in PA during and after the first national lockdown in the United Kingdom (UK) were associated with concurrent changes in alcohol consumption, sleep, nutrition quality, diet quantity and sedentary time. Data were derived from the UCL COVID-19 Social Study, in which 52,784 adults were followed weekly across 22 weeks of the pandemic from 23rd March to 23rd August 2020. Fixed effects regression models showed that greater PA was positively associated with improved sleep and nutrition quality. However, increases in PA also showed modest associations with increased alcohol consumption and sedentary time. Encouraging people to engage in PA may lead to wider changes in other health behaviours in times of adversity. These associations could be a result of increases in available leisure time for many people during COVID-19 restrictions and are of ongoing importance given the emerging long-term changes to lifestyle and working patterns.

Findings from the Morquio A Registry Study (MARS) after 6 years: Long-term outcomes of MPS IVA patients treated with elosulfase alfa.

BACKGROUND: The Morquio A Registry Study (MARS) is an ongoing, multinational, observational study of patients with MPS IVA. Key objectives of MARS are to characterize the heterogeneity and natural history of disease and to evaluate long-term effectiveness and safety of elosulfase alfa enzyme replacement therapy (ERT). Enrollment began in September 2014; data on medical history, clinical outcomes, and safety assessments are collected as part of routine care. RESULTS: As of February 2021, 381 subjects from 17 countries had enrolled in MARS: 58 ERT-naïve subjects and 323 ERT-treated subjects (≥1 infusion), with a mean ERT exposure of 5.5 years (SD 2.8) and median age at first ERT treatment of 9.8 years. ERT-treated subjects were younger at diagnosis (median 3.4 vs 6.5 years) relative to ERT-naïve subjects. Among ERT-treated subjects, urinary keratan sulfate (uKS) levels declined from pre-ERT baseline to last follow-up on treatment (mean % change [95% confidence interval]: -52.5% [-57.5%, -47.4%]; n = 115) and 6-min walk test distance remained stable (mean change: -6.1 [-27.6, 15.5] m; n = 131) over a mean follow-up of 5.5 years. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) increased in subjects who were < 18 years of age at ERT initiation (mean change: +0.3 [0.1, 0.4] L and + 0.4 [0.3, 0.5] L; mean follow-up: ∼6 years; n = 82) and were stable in subjects ≥18 years (mean change: 0.0 [-0.0, 0.1] L and 0.0 [-0.1, 0.1] L; mean follow-up: 4.6 years; n = 38). Overall, 148 (47.1%) ERT-treated subjects experienced ≥1 adverse event (AE) and 110 subjects (35%) reported ≥1 serious AE. Drug-related AEs were reported in 39 (12.4%) subjects; the most common were hypersensitivity (9 subjects [2.9%]), urticaria (8 subjects [2.5%]), and pyrexia (7 subjects [2.2%]). CONCLUSIONS: MARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified.

Longitudinal changes and correlates of meeting WHO recommended levels of physical activity in the UK during the COVID-19 pandemic: Findings from the HEBECO study.

BACKGROUND: The COVID-19 pandemic has seen repeated government enforced restrictions on movement. This study aimed to evaluate longitudinal trends in physical activity (PA) in a self-selected UK-based sample and identify the key correlates of these trends. METHODS: From 23 April 2020 to 30 January 2021, measures of PA engagement were collected in a sample of 1,947 UK-based adults. Generalised estimating equations (GEE) explored trends in PA engagement over time, and how sociodemographic, health and contextual factors impacted participant's attainment of World Health Organization (WHO) recommended levels of PA (constituting muscle strengthening activity (MSA), and moderate or vigorous PA (MVPA)). RESULTS: While one in five achieved the recommended levels of PA in the first UK lockdown in April-June 2020 (19.5%, 95%CI: 17.8-21.3%) and a similar proportion in June-July 2020 (17.7%, 95%CI: 16.1-19.5%), this reduced during the period of eased restrictions in August-September 2020 (15.2%, 95%CI: 13.7-16.9%) and the second UK lockdown in November 2020-January 2021 (14.1%, 95%CI: 12.6-15.9%). Similar trends were observed for MSA and MVPA individually. Better quality of life, higher socioeconomic position and pre-COVID-19 PA levels were associated with meeting the WHO recommended levels of PA, while those living with overweight or obesity, a limiting health condition, or isolating showed the inverse associations. Time-specific associations with MSA or MVPA were observed for gender and age. CONCLUSION: Reductions in PA levels throughout the first strict lockdown continued without reversal during the ensuing period. The association of negative change with socioeconomic and health-related indices points towards deepening health inequities during the pandemic.

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.

Liver-Directed Adeno-Associated Virus-Mediated Gene Therapy for Mucopolysaccharidosis Type VI.

Gene Therapy for Mucopolysaccharidosis Type VIIn this open-label gene therapy study, infusions for MPS type VI occurred without severe adverse events. In the high-dose cohort, serum active arylsulfatase B reached 30% to 100% of normal. A modest urinary GAG increase did not require reintroduction of enzyme replacement therapy. Clinical deterioration was not noted for up to 2 years after therapy.

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. To promote the standardized collection of patient/family-reported and clinical outcomes considered important to patients/families, health care providers (HCPs), and policymakers, the choice of outcomes to include in the registry will be informed by a core outcome set (COS). We aim to establish a patient-oriented COS for pediatric MPS using a multi-stakeholder approach. METHODS: In step 1 of the six-step process to develop the COS, we will identify relevant outcomes through a rapid literature review and candidate outcomes survey. A two-phase screening approach will be implemented to identify eligible publications, followed by extraction of outcomes and other pre-specified data elements. Simultaneously, we will conduct a candidate outcomes survey with children with MPS and their families to identify outcomes most important to them. In step 2, HCPs experienced in treating patients with MPS will be invited to review the list of outcomes generated in step 1 and identify additional clinically relevant outcomes. We will then ask patients/families, HCPs, and policymakers to rate the outcomes in a set of Delphi Surveys (step 3), and to participate in a subsequent consensus meeting to finalize the COS (step 4). Step 5 involves establishing a set of outcome measurement instruments for the COS. Finally, we will disseminate the COS to knowledge users (step 6). DISCUSSION: The proposed COS will inform the choice of outcomes to include in the MPS registry and, more broadly, promote the standardized collection of patient-oriented outcomes for pediatric MPS research. By involving patients/families from the earliest stage of the research, we will ensure that the COS will be relevant to those who will ultimately benefit from the research. TRIAL REGISTRATION: PROSPERO CRD42021267531 , COMET.

Longitudinal changes in physical activity during and after the first national lockdown due to the COVID-19 pandemic in England.

Recent studies have shown reduced physical activity at early stages of the COVID-19 pandemic. However, there is a lack of investigation on longitudinal changes in physical activity beyond lockdowns and stay-at-home orders. Moreover, it is unclear if there is heterogeneity in physical activity growth trajectories. This study aimed to explore longitudinal patterns of physical activity and factors associated with them. Data were from the UCL COVID-19 Social Study. The analytical sample consisted of 35,915 adults in England who were followed up for 22 weeks from 24th March to 23rd August 2020. Data were analysed using growth mixture models. Our analyses identified six classes of growth trajectories, including three stable classes showing little change over time (62.4% in total), two classes showing decreasing physical activity (28.6%), and one class showing increasing physical activity over time (9%). A range of factors were found to be associated the class membership of physical activity trajectories, such as age, gender, education, income, employment status, and health. There is substantial heterogeneity in longitudinal changes in physical activity during the COVID-19 pandemic. However, a substantial proportion of our sample showed persistent physical inactivity or decreasing physical activity. Given the well-established link between physical activity and health, persistent or increased physical inactivity is likely to have both immediate and long-term implications for people's physical and mental health, as well as general wellbeing. More efforts are needed to promote physical activity during the pandemic and beyond.

Impact of COVID-19 Pandemic on Weight and BMI among UK Adults: A Longitudinal Analysis of Data from the HEBECO Study.

COVID-19-related restrictions impacted weight and weight-related factors during the initial months of the pandemic. However, longitudinal analyses are scarce. An online, longitudinal study was conducted among self-selected UK adults (n = 1818), involving three surveys (May-June, August-September, November-December 2020), covering anthropometric, sociodemographic, COVID-19-related and behavioural measures. Data were analysed using generalised estimating equations. Self-reported average weight/body mass index (BMI) significantly increased between the May-June period and the August-September period (74.95 to 75.33 kg/26.22 kg/m2 to 26.36kg/m2, p < 0.001, respectively), and then significantly decreased to November-December (to 75.06 kg/26.27 kg/m2, p < 0.01), comparable to May-June levels (p = 0.274/0.204). However, there was great interindividual variation, 37.0%/26.7% increased (average 3.64 kg (95% confidence interval: 3.32, 3.97)/1.64 kg/m2 (1.49, 1.79)), and 34.5%/26.3% decreased (average 3.59 kg (3.34, 3.85)/1.53 kg/m2 (1.42, 1.63)) weight/BMI between May-June and November-December. Weight/BMI increase was significantly negatively associated with initial BMI, and positively associated with monthly high fat, salt and sugar (HFSS) snacks intake and alcohol consumption, and for BMI only, older age. Associations were time-varying; lower initial BMI, higher HFSS snacks intake and high-risk alcohol consumption were associated with maintaining weight/BMI increases between August-September and November-December. The average weight/BMI of UK adults fluctuated between May-June and November-December 2020. However, the substantial interindividual variation in weight/BMI trajectories indicates long-term health impacts from the pandemic, associated with food and alcohol consumption.

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. Delphi participants rated the importance of outcomes on a nine-point scale (1-3: not important, 4-6: important but not critical, 7-9: critical). Candidate outcomes were progressively narrowed down over 3 survey rounds. At the workshop, participants evaluated the remaining candidate outcomes using an adapted nominal technique, open discussion, and voting. After the workshop, we finalized the COSs and recommended measurement instruments for each outcome. RESULTS: There were 85, 61, and 53 participants across 3 Delphi rounds, respectively. The candidate core outcome lists were narrowed down to 20 outcomes per disease to be discussed at the consensus workshop. Voting by 18 workshop participants led to COSs composed of 8 and 9 outcomes for MCAD deficiency and PKU, respectively, with measurement recommendations. CONCLUSIONS: These are the first known pediatric COSs for MCAD deficiency and PKU. Adoption in future studies will help to ensure best use of limited research resources to ultimately improve care for children with these rare diseases.

Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study.

BACKGROUND: Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa. RESULTS: A total of 33 patients, aged 5-63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease. CONCLUSIONS: In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.

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.

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. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes. METHODS: We used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death. RESULTS: For MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles. CONCLUSIONS: Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies.

Hematopoietic stem cell transplant does not prevent neurological deterioration in infants with Farber disease: Case report and literature review.

Farber disease (FD) is an inherited autosomal recessive disorder of lipid metabolism. The hallmark of the disease is systemic accumulation of ceramide due to lysosomal acid ceramidase deficiency. The involvement of the central nervous system is critical in this disorder leading to rapid deterioration and death within a few years after birth. Efforts to treat patients by hematopoietic stem cell transplant (HSCT) have resulted in favorable results in the absence of neurological manifestations. We report the outcomes of HSCT in two patients with FD who received early HSCT and had neurological deterioration posttransplant. We also present a new understanding of the limitations of HSCT in FD management based on our observations of the clinical course of the two patients after therapy.

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.

INTRODUCTION: Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA. METHODS: Twenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. RESULTS: A total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). CONCLUSION: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.