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BackgroundMovement 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.ObjectiveTo (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.MethodsThe 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.ResultsThe 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).ConclusionsRelative 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.

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.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 (FEVMARS 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.

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

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 (MAPKi) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiates the pro-apoptotic effects of MAPKi via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Co-targeting PEX3 and UGCG selectively eliminates a subset of metabolically active, drug-tolerant CD36+melanoma persister cells, thereby sensitizing melanoma to MAPKi and delaying resistance. Increased levels of peroxisomal genes andUGCGare found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restores MAPKi sensitivity in multiple models of therapy resistance. Finally, triple therapy comprised of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor and a MAPKi demonstrates potent anti-tumor activity in pre-clinical melanoma models, thus representing a promising approach for melanoma treatment.HighlightsInhibiting peroxisome biogenesis uncovers a metabolic vulnerability in melanomaCD36+persister melanoma cells tolerate MAPK-targeted therapy through peroxisome/UGCG mediated metabolic rewiringDual blockade of PEX3 and UGCG potentiates melanoma response to MAPK-targeted therapies and restores therapeutic sensitivity in MAPKi-resistant tumorsNNC 55-0396 is a PEX3-PEX19 binding inhibitor with potent anti-tumor activity in melanoma

BackgroundGovernment 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 pre-pandemic evidence for 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 other health behaviours, namely alcohol consumption, sleep, nutrition quality, diet quantity and sedentary time.MethodsData were derived from the UCL COVID-19 Social Study. The analytical sample consisted of 52,784 adults followed weekly across 22 weeks of the pandemic from 23rd March to 23rd August 2020. Data were analysed using fixed effects regression.ResultsThere was significant within-individual variation in both PA and other health behaviours throughout the study period. Increased 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.ConclusionOur findings indicate that, whilst the first wave of COVID-19 restrictions were in place, increases in PA were associated with improved sleep and better diet. Encouraging people to engage in PA may therefore lead to positive change in other health behaviours in times of adversity. However, increases in PA were also associated with more engagement in the negative health behaviours of alcohol consumption and sedentary time. These associations could be a result of increases in available leisure time for many people during COVID-19 restrictions and require further investigation to inform future public health guidance.

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. Supplementary Information The online version contains supplementary material available at 10.1007/s40271-021-00538-8.

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.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index–4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index–4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.

IntroductionChildren 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 analysisA 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 disseminationThe 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.

BackgroundThe COVID-19 pandemic has seen government enforced restrictions on movement, with ‘stay-at-home’ orders in place for a second and third time in many nations. Such restrictions have altered physical activity (PA) habits. This study aimed to evaluate longitudinal trends in PA in a self-selected UK-based sample and the key predictors of these trends.MethodsFrom 23 April 2020 to 30 January 2021, an online survey collected detailed measures of PA engagement in a sample of 1,947 UK-based adults. Generalised estimating equations (GEE) were fitted to explore trends in PA engagement over time, and how sociodemographic, health, lifestyle and contextual factors impacted participant’s attainment of Word Health Organisation (WHO) recommended levels of PA (constituting muscle strengthening activity (MSA), and moderate or vigorous PA (MVPA)).ResultsAttainment of WHO recommended levels of total PA showed a decline. While one in five achieved the recommended levels of total 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 significantly 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%). The same trends were observed for MSA and MVPA individually. Better quality of life, higher socioeconomic position and higher pre-COVID-19 PA levels were associated with meeting WHO recommended PA levels, while having overweight or obesity, a limiting chronic health condition, or being in strict isolation showed the inverse associations. Time-specific associations with MSA or MVPA were observed for gender, age, ethnicity, and other health behaviours.ConclusionAmong a self-selected sample of UK-based adults, there were reductions in PA levels throughout the first UK lockdown without reversal during the ensuing period. Based on observed associations of reduced PA with socioeconomic and health-related indices, such changes may point towards deepening health inequities during the pandemic.

COVID-19 pandemic restrictions impacted dietary habits during the initial months of the pandemic, but long-term effects are unclear. In this longitudinal study, self-selected UK adults (n=1,733) completed three online surveys (May-June, August-September and November-December 2020, with a retrospective pre-pandemic component in the baseline survey), self-reporting sociodemographics, lifestyle and behaviours, including high fat, salt and sugar (HFSS) snacks, HFSS meals and fruit and vegetable (FV) intake. Data were analysed using generalised estimating equations. Monthly HFSS snacks portion intake increased from pre-pandemic levels (48.3) in May-June (57.6, pWhat is currently known from previous studiesThe introduction of lockdown restrictions impacted on diet behaviours during the initial months of the pandemic.Changes in dietary behaviours have been wide ranging, with individuals making healthy and unhealthy dietary changes in high fat, salt and sugar (HFSS) snacks, HFSS meals and fruit and vegetable (FV) intake.These dietary changes are associated with multiple sociodemographic, lifestyle and behavioural factors.Whether dietary changes persist across longer periods of the pandemic, and which factors are associated with any long-term dietary behaviour change is yet to be identified.What this paper addsAverage UK adult intakes of HFSS snacks and meals fluctuated across the pandemic, with the former returning to pre-pandemic levels and the latter remaining below pre-pandemic levels.FV intake was stable until the end of 2020, when the proportion meeting recommended intakes declined.Across the first year of the pandemic, being female and having a lower quality of life were associated with an increase in HFSS snacks intake, whereas the association of age and HFSS meals intake with HFSS snacks intake varied across the pandemic. Living with adults only and having a higher intake of HFSS snacks were associated with an increase in HFSS meals intake. A higher BMI and lower physical activity level were associated with reduced FV intake.

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 &lt, 0.001, respectively), and then significantly decreased to November–December (to 75.06 kg/26.27 kg/m2, p &lt, 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.

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.

BackgroundRecent 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.MethodsData 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.FindingsOur 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.InterpretationThere 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 linked 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.FundingNuffield Foundation, UK Research and Innovation, Wellcome Trust

Introduction Musculoskeletal findings in MPS can progress after enzyme replacement. Our aim was to examine synovial recesses, tendons, retinacula and pulleys using ultrasonography for structural and inflammatory changes. Material and methods The wrist, metacarpophalangeal (MCP), proximal and distal interphalangeal (PIP and DIP) joints, the finger flexor tendons and the knee including entheses of quadriceps and patella tendons were assessed clinically. Ultrasonography of the various synovial recesses of the wrist as well as the extensor retinaculum, carpal tunnel, MCP, PIP and DIP joints of the second finger, extensor and flexor tendons, A1-5 pulleys and the knee joint including relevant entheses followed. Significance of differences between patient values and available normative data were assessed using t-tests. Results Ultrasonography showed significant abnormal intraarticular material in the wrist without a clear distribution to synovial recesses and without effusions. Doppler signals were found in a perisynovial distribution and not intrasynovial as expected in in inflammatory arthritis. Findings were similar in the knee but not the fingers. Flexor and extensor tendons were also mostly normal in their structure but significant thickening of retinaculae and the flexor tendon pulleys was seen (p Conclusion MPS I patients showed intraarticular deposition of abnormal material in the wrist and knee but not in the finger joints where significant thickening of retinaculae/pulleys controlling tendon position was dominant. No ultrasound findings of inflammatory pathology were demonstrated but rather a secondary reaction to abnormal deposition and direct damage of GAG.

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.

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.

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.

Psychosis is a symptomatic endpoint with many causes, complicating its pathophysiological characterization and treatment. Our study applies unsupervised clustering techniques to analyze metabolomic data, acquired using 2 different tandem mass spectrometry (MS-MS) methods, from an unselected group of 120 patients with psychosis. We performed an independent analysis of each of the 2 datasets generated, by both hierarchical clustering and k-means. This led to the identification of biochemically distinct groups of patients while reducing the potential biases from any single clustering method or datatype. Using our newly developed robust clustering method, which is based on patients consistently grouped together through different methods and datasets, a total of 20 clusters were ascertained and 78 patients (or 65% of the original cohort) were placed into these robust clusters. Medication exposure was not associated with cluster formation in our study. We highlighted metabolites that constitute nodes (cluster-specific metabolites) vs hubs (metabolites in a central, shared, pathway) for psychosis. For example, 4 recurring metabolites (spermine, C0, C2, and PC.aa.C38.6) were discovered to be significant in at least 8 clusters, which were identified by at least 3 different clustering approaches. Given these metabolites were affected across multiple biochemically different patient subgroups, they are expected to be important in the overall pathophysiology of psychosis. We demonstrate how knowledge about such hubs can lead to novel antipsychotic medications. Such pathways, and thus drug targets, would not have been possible to identify without patient stratification, as they are not shared by all patients, due to the heterogeneity of psychosis.

Introduction Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders.Methods: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD.Results: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/ 774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol.Conclusions: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.

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.

Background Glycemic control in hepatic glycogen storage diseases (GSDs) relies on specific nutritional recommendations, including strict avoidance of a fasting period. Uncooked cornstarch (UCCS) is an important therapeutic component. A new modified UCCS, Glycosade™, was created with the objective of prolonging euglycemia. We aimed to determine the length of euglycemia on Glycosade™ using a continuous glucose monitor (CGM) and to evaluate whether longer euglycemia and thus less nighttime interruptions would improve sleep and quality of life (QoL) after the introduction of the modified cornstarch. Methods We conducted a prospective cohort study to assess quality and quantity of sleep and quality of life (QoL) in patients with GSDs on standard UCCS and after the introduction of Glycosade™. Sleep and QoL evaluation was done for patients using validated questionnaires, a standardized sleep diary and actigraphy. Length of fast and glucose variability were determined with CGM. Results Nine adults with GSD Ia took part in the study. Glycosade™ introduction was done under close supervision during a hospital admission. Comparison of sleep in 9 patients showed sleep disturbances on standard UCCS that were improved with Glycosade™. QoL was normal both pre and post Glycosade™. The CGM confirmed maintenance of a longer fasting period with Glycosade™ at home. Conclusion Glycosade™ represents an alternative option for GSD patients. We showed possible benefits in terms of sleep quality. We also confirmed the longer length of fast on Glycosade™. Synopsis A new modified form of uncooked starch for patients with glycogen storage disease represents an alternative option as it showed a longer length of fast and improvements in sleep quality.

The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders in which accumulation of glycosaminoglycans (GAGs) leads to progressive tissue and organ dysfunction. In addition to a variety of somatic signs and symptoms, patients with rapidly progressing MPS I (Hurler), II, III, and VII can present with significant neurological manifestations, including impaired cognitive abilities, difficulties in language and speech, behavioral abnormalities, sleep problems, and/or seizures. Neurological symptoms have a substantial impact on the quality of life of MPS patients and their families. Due to the progressive nature of cognitive impairment in these MPS patients, neurocognitive function is a sensitive indicator of disease progression, and a relevant outcome when testing efficacy of therapies for these disorders. In order to effectively manage and develop therapies that address neurological manifestations of MPS, it is important to use appropriate neurocognitive assessment tools that are sensitive to changes in neurocognitive function in MPS patients. This review discusses expert opinions on key issues and considerations for effective neurocognitive testing in MPS patients. In addition, it describes the neurocognitive assessment tools that have been used in clinical practice for these patients. The content of this review is based on existing literature and information from a meeting of international experts with extensive experience in managing and treating MPS disorders.

The mucopolysaccharidoses (MPS) represent a heterogeneous group of lysosomal storage disorders, each one associated with a deficiency in one of the enzymes involved in glycosaminoglycan degradation. Sleep disorders are a frequent manifestation of all types of MPS. Underlying causes are diverse and comprised of both respiratory and central nervous system (CNS) abnormalities. Sleep disordered breathing such as obstructive sleep apnea and nocturnal hypoventilation can arise in patients with upper airway obstruction and/or with alterations in respiratory mechanics, causing restrictive pulmonary disease. MPS patients with CNS disease can also develop sleep disturbances unrelated to ventilatory impairments, often associated with severe behavioral problems or night-time epileptic seizures. The present review discusses the pathophysiology, evaluation, and management of sleep disorders in MPS based on information from a meeting on the brain in MPS, attended by an international group of experts (April 28-30, 2016, Stockholm, Sweden), and additional literature searches.

To increase accessibility to genetics services for low-urgency patients seeking Ashkenazi Jewish (AJ) carrier screening, we designed an interactive computer (IC) module that provides pre-test genetics education and allows genetics professionals to order the test without meeting the patients beforehand. We compared this module with in-person genetic counseling (GC) using a randomized trial. AJ individuals were randomized to undergo genetics education via the IC module (n = 26) or GC (n = 28). We compared post-interventional genetics knowledge, perceived genetic risk, and anxiety between the two groups, after accounting for pre-interventional scores, using ANCOVA. Wilcoxon Rank-Sum test was used to compare post-interventional satisfaction. Post-interventional genetics knowledge, risk perception, or anxiety were not significantly different between the two groups after accounting for baseline scores (p = 0.50-0.54), although the data are inconclusive regarding the module's non-inferiority at a 5% margin. Post-intervention satisfaction scores were generally higher in the GC group than the IC module group. Our IC module has the potential to improve access to clinical genetics services for patients and staff, but it is not suitable for all AJ patients and cannot completely replace the benefits of in-person consultations.