Search

Abstract Background Intellectual disability (ID) is a devastating and frequent condition, affecting 2-3% of the population worldwide. Early recognition of treatable underlying conditions drastically improves health outcomes and decreases burdens to patients, families and society. Our systematic literature review identified 81 such inborn errors of metabolism, which present with ID as a prominent feature and are amenable to causal therapy. The WebAPP translates this knowledge of rare diseases into a diagnostic tool and information portal. Methods & results Freely available as a WebAPP via http://www.treatable-id.org and end 2012 via the APP store, this diagnostic tool is designed for all specialists evaluating children with global delay / ID and laboratory scientists. Information on the 81 diseases is presented in different ways with search functions: 15 biochemical categories, neurologic and non-neurologic signs & symptoms, diagnostic investigations (metabolic screening tests in blood and urine identify 65% of all IEM), therapies & effects on primary (IQ/developmental quotient) and secondary outcomes, and available evidence For each rare condition a ‘disease page’ serves as an information portal with online access to specific genetics, biochemistry, phenotype, diagnostic tests and therapeutic options. As new knowledge and evidence is gained from expert input and PubMed searches this tool will be continually updated. The WebAPP is an integral part of a protocol prioritizing treatability in the work-up of every child with global delay / ID. A 3-year funded study will enable an evaluation of its effectiveness. Conclusions For rare diseases, a field for which financial and scientific resources are particularly scarce, knowledge translation challenges are abundant. With this WebAPP technology is capitalized to raise awareness for rare treatable diseases and their common presenting clinical feature of ID, with the potential to improve health outcomes. This innovative digital tool is designed to motivate health care providers to search actively for treatable causes of ID, and support an evidence-based approach to rare metabolic diseases. In our current –omics world with continuous information flow, the effective synthesis of data into accessible, clinical knowledge has become ever more essential to bridge the gap between research and care.

Background: To inform the development of a core outcome set (COS) for children and youth with mucopolysaccharidoses (MPS), we aimed to identify all outcomes and associated outcome measurement instruments that are reported in recent clinical trials and recommended as measurements in clinical management guidelines., Methods: To identify English-language clinical trials and guidelines pertaining to MPS published between 2011 and mid-2021, we applied a comprehensive peer-reviewed search strategy to relevant databases and registers on May 16, 2021. Two reviewers independently screened retrieved citations and then full-text articles to determine eligibility for inclusion. From articles meeting inclusion criteria, we extracted details of the study design, population, intervention, and comparator, along with verbatim outcomes and associated outcome measurement instruments. Outcomes were organized into domains within five a priori core areas: life impact, pathophysiological manifestations, growth and development, resource use, and death. We conducted descriptive analyses at the study level, grouping articles arising from the same study., Results: From 2593 unique citations, 73 articles from 61 unique studies were included in the review, pertaining to all MPS subtypes except for exceptionally rare subtypes. Eighty-four unique outcomes were reported across the studies, 33 (39%) of which were reported by three or fewer studies. Most outcomes (55; 65%) were in the pathophysiological manifestations core area, followed by life impact (17; 20%) and growth and development (10; 12%); one outcome each pertained to resource use and death. The most frequently reported outcomes were general adverse events (45; 74%), immune-related adverse events (39; 64%), and urinary glycosaminoglycans (38; 62%). Substantial variability existed in the reporting of outcome measurement instruments. Some differences in outcome reporting were observed by MPS subtype and publication year., Discussion: Outcomes reported in clinical trials and guidelines for MPS in children and youth vary considerably and largely focus on pathophysiological manifestations. A COS is needed to standardize the selection and measurement of meaningful outcomes across future studies. We will present the outcomes identified in this review to knowledge users as part of a consensus process to select the most critical outcomes for inclusion in the COS. Trial Registration The protocol for this study was registered in PROSPERO (CRD42021267531) and in the COMET Database., (© 2024. The Author(s).)

Purpose: We evaluated DECIDE, an online pretest decision-support tool for diagnostic genomic testing, in nongenetics specialty clinics where there are no genetic counselors (GCs)., Methods: Families of children offered genomic testing were eligible to participate. Fifty-six parents/guardians completed DECIDE at home, at their convenience. DECIDE includes an integrated knowledge quiz and decisional conflict screen. Six months later, parents were offered follow-up questionnaires and interviews about their experiences., Results: Forty parents (71%) had sufficient knowledge and no decisional conflict surrounding their testing decision, but 6 of this group had residual questions. These 6, plus 16 with decisional conflict or insufficient knowledge, saw a GC. At follow-up, little-to-no decisional regret and few negative emotions were identified in any parents. Most chose testing and described their decision as easy, yet stressful, and described many motivations for sequencing. Parents appreciated the simple comprehensive information DECIDE provided and the ability to view it in a low-stress environment., Conclusion: DECIDE provides adequate decision-support to enable most parents to make value-consistent choices about genetic testing for their child. Parents reported that DECIDE helped to clarify motivations for pursuing (or declining) testing. DECIDE is a timely, well-tested, and accessible tool in clinical settings without GCs., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes.

Introduction: Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family-centred care need information about the characteristics of existing interventions, their development and the domains of family-centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family-centred interventions designed to improve experiences with care for children with chronic conditions., Methods: We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7-20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family-centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full-text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family-centred care., Results: Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed-methods studies (n = 9 each). The most frequently addressed domains of family-centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30)., Conclusion: This review, which identified 61 unique interventions aimed at improving family-centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high-needs population., Patient or Public Contribution: This study was co-developed with three patient partner co-investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co-investigators contributed to this study at all stages, from conceptualization to dissemination., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Hypomyelinating Leukodystrophy 22 (HLD22) is caused by a stoploss mutation in CLDN11. To study the molecular mechanisms underlying HLD22, human induced pluripotent stem cells (hiPSCs) were generated from patient fibroblasts carrying the stop-loss mutation in CLDN11., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Glycogen storage disease type Ib (GSD Ib) is an autosomal recessively inherited deficiency of the glucose-6-phosphate translocase (G6PT). Clinical features include a combination of a metabolic phenotype (fasting hypoglycemia, lactic acidosis, hepatomegaly) and a hematologic phenotype with neutropenia and neutrophil dysfunction. Dietary treatment involves provision of starches such as uncooked cornstarch (UCCS) and Glycosade® to provide prolonged enteral supply of glucose. Granulocyte colony-stimulating factor (G-CSF) is the treatment of choice for neutropenia. Because long-term stimulation of hematopoiesis with G-CSF causes serious complications such as splenomegaly, hypersplenism, and osteopenia; hematopoietic stem cell transplantation (HSCT) has been considered in some patients with GSD Ib to correct neutropenia and avoid G-CSF related adverse effects. Whether HSCT also has an effect on the metabolic phenotype and utilization of carbohydrate sources has not been determined., Objective: Our objective was to measure the utilization of starch in a patient with GSD Ib before and after HSCT using the minimally invasive 13 C-glucose breath test ( 13 C-GBT)., Design: A case of GSD Ib (18y; female) underwent 13 C-GBT four times: UCCS (pre-HSCT), UCCS (3, 5 months post-HSCT) and Glycosade® (6 months post-HSCT) with a dose of 80 g administered via nasogastric tube after a 4 h fast according to our patient's fasting tolerance. Breath samples were collected at baseline and every 30 min for 240 min. Rate of CO 2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Biochemical and clinical data were obtained from the medical records as a post-hoc chart review., Results: UCCS utilization was significantly higher in GSD Ib pre-HSCT, which reduced and stabilized 5 months post-HSCT. UCCS and Glycosade® utilizations were low and not different at 5 and 6 months post-HSCT. Blood glucose concentrations were not significantly different at any time point., Conclusions: Findings show that HSCT stabilized UCCS utilization, as reflected by lower and stable glucose oxidation. The results also illustrate the application of 13 C-GBT to examine glucose metabolism in response to various carbohydrate sources after other treatment modalities like HSCT in GSD Ib., Competing Interests: None., (© 2023 The Author(s).)

Background: A wealth of human and experimental studies document a causal and aggravating role of iron deficiency in neurodevelopmental disorders. While pre-, peri-, and early postnatal iron deficiency sets the stage for the risk of developing neurodevelopmental disorders, iron deficiency acquired at later ages aggravates pre-existing neurodevelopmental disorders. Yet, the association of iron deficiency and neurodevelopmental disorders in childhood and adolescence has not yet been explored comprehensively. In this scoping review, we investigate 1) the association of iron deficiency in children and adolescents with the most frequent neurodevelopmental disorders, ADHD, ASD, and FASD, and 2) whether iron supplementation improves outcomes in these disorders., Method: Scoping review of studies published between 1994 and 2021 using "iron deficiency / iron deficiency anemia" AND "ADHD" OR "autism" OR "FASD" in four biomedical databases. The main inclusion criterion was that articles needed to have quantitative determination of iron status at any postnatal age with primary iron markers such as serum ferritin being reported in association with ADHD, ASD, or FASD., Results: For ADHD, 22/30 studies and 4/4 systematic reviews showed an association of ADHD occurrence or severity with iron deficiency; 6/6 treatment studies including 2 randomized controlled trials demonstrated positive effects of iron supplementation. For ASD, 3/6 studies showed an association with iron deficiency, while 3/6 and 1/1 systematic literature review did not; 4 studies showed a variety of prevalence rates of iron deficiency in ASD populations; 1 randomized controlled trial found no positive effect of iron supplementation on behavioural symptoms of ASD. For FASD, 2/2 studies showed an association of iron deficiency with growth retardation in infants and children with prenatal alcohol exposure., Conclusion: Evidence in favor of screening for iron deficiency and using iron supplementation for pediatric neurodevelopmental disorders comes primarily from ADHD studies and needs to be further investigated for ASD and FASD. Further analysis of study methodologies employed and populations investigated is needed to compare studies against each other and further substantiate the evidence created., Competing Interests: The authors have declared that no competing interests exist.

Background: Terms currently used to describe the so-called challenging and disruptive behaviors (CBDs) of children with intellectual disabilities (ID) have different connotations depending on guiding contextual frameworks, such as academic and cultural settings in which they are used. A non-judgmental approach, which does not attempt to establish existing categorical diagnoses, but which describes in a neutral way, is missing in the literature. Therefore, we tried to describe CDBs in youth with ID in an explorative study., Methods: Interviews with families investigated the CDBs of five youth with Down syndrome. At home, families tracked youth's sleep/wake behaviors and physical activity. Youth were observed in a summer school classroom. The collected information and suggested explanatory models for observed CDBs were reviewed with the families., Results: We grouped CDBs as challenging , if they were considered to be reactive or triggered, or unspecified , if no such explanatory model was available. A third category was created for light-hearted CDBs: goofy , acknowledging the right to laugh together with peers. We found some relationships between sleep, physical activity, and CDBs and developed an explorative approach, supporting a child-centered perspective on CDBs., Conclusion: The controversial discussions on terminology and management of CDBs in the literature demonstrate the need for a non-judgmental approach. Such an explorative approach, allowing non-professionals to not label, has been missing. The fact that, up to now, the light-hearted behaviors of an individual with ID have not been integrated in commonly-used behavioral checklists as their natural right , proves our concept and indicates that a paradigm change from judgment-based to exploratory-driven approaches is needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chan, Campbell, Beyzaei, Stockler and Ipsiroglu.)

Background: Glycogen storage disease type Ia (GSD Ia) is an autosomal recessive disorder caused by deficiency of glucose-6-phosphatase (G6Pase), resulting in fasting hypoglycemia. Dietary treatment with provision of uncooked cornstarch (UCCS) or a novel modified cornstarch ( Glycosade® ) is available to treat hypoglycemia, yet choice of carbohydrate to achieve a desirable glycemic control is debated. 13 C-glucose breath test ( 13 C-GBT) can be used to examine glucose metabolism from different carbohydrate sources via 13 CO 2 in breath., Objectives: Our objectives were: 1) establishing the use of a minimally invasive 13 C-GBT to examine in vivo glucose metabolism in healthy adults, and 2) using 13 C-GBT to measure utilization of the standard UCCS vs. Glycosade® in GSD Ia and healthy controls., Design: Experiment 1- Ten healthy adults (6F: 4 M, 22-33y) underwent 13 C-GBT protocol twice as a proof-of-principle, once with oral isotope dose (glucose 75 g + [U- 13 C 6 ] d-glucose 75 mg) and once without isotope (only glucose 75 g) to test sensitivity of natural 13 C-enrichment. Breath samples were collected at baseline and every 20 min for 240 min. Rate of CO 2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Experiment 2- Three GSD Ia (12y, 13y, and 28y) and six healthy controls (2F: 4 M, 10-32y) underwent 13 C-GBT protocol twice: with UCCS or Glycosade® (based on their current prescribed dose 42-100 g) after ~4 h fast based on our GSD Ia patients with fasting tolerance., Results: Findings 1- Maximum 13 C-enrichments occurred at 200 min without and with [U- 13 C 6 ] d-glucose in all healthy adults, suggesting natural enrichment is sensitive for the 13 C-GBT. Findings 2- Glycosade® utilization was lower than UCCS utilization in 12y and 13y GSD Ia, but was similar in the 28y GSD Ia., Conclusions: 13 C-GBT is a novel minimally invasive functional test to examine glucose metabolism in GSD Ia, and test new products like Glycosade® , which has the potential to improve nutritional management and individualized carbohydrate supply in GSD., Competing Interests: None., (© 2022 The Authors.)

Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual's full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results. Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals' primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)