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UnlabelledWe have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).Study designThese analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.ResultsPatients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p

As we identify more and more genetic changes, either through mutation studies or population screens, we need powerful tools to study their potential molecular effects. With these tools, we can begin to understand the contributions of genetic variations to the wide range of human phenotypes. We used our catalogue of molecular changes in patients with carbamyl phosphate synthetase I (CPSI) deficiency to develop such a system for use in eukaryotic cells. We developed the tools and methods for rapidly modifying bacterial artificial chromosomes (BACs) for eukaryotic episomal replication, marker expression, and selection and then applied this protocol to a BAC containing the entire CPSI gene. Although this CPSI BAC construct was suitable for studying nonsynonymous mutations, potential splicing defects, and promoter variations, our focus was on studying potential splicing and RNA-processing defects to validate this system. In this article, we describe the construction of this system and subsequently examine the mechanism of four putative splicing mutations in patients deficient in CPSI. Using this model, we also demonstrate the reversible role of nonsense-mediated decay in all four mutations, using small interfering RNA knockdown of hUPF2. Furthermore, we were able to locate cryptic splicing sites for the two intronic mutations. This BAC-based system permits expression studies in the absence of patient RNA or tissues with relevant gene expression and provides experimental flexibility not available in genomic DNA or plasmid constructs. Our splicing and RNA degradation data demonstrate the advantages of using whole-gene constructs to study the effects of sequence variation on gene expression and function. [ABSTRACT FROM AUTHOR]

Konzo is a neglected paralytic neurological disease associated with food (cassava) poisoning that affects the world's poorest children and women of childbearing ages across regions of sub-Saharan Africa. Despite understanding the dietary factors that lead to konzo, the molecular markers and mechanisms that trigger this disease remain unknown. To identify potential protein biomarkers associated with a disease status, plasma was collected from two independent Congolese cohorts, a discovery cohort (n = 60) and validation cohort (n = 204), sampled 10 years apart and subjected to multiple high-throughput assays. We identified that Glutathione Peroxidase 3 (GPx3), a critical plasma-based antioxidant enzyme, was the sole protein examined that was both significantly and differentially abundant between affected and non-affected participants in both cohorts, with large reductions observed in those affected with konzo. Our findings raise the notion that reductions in key antioxidant mechanisms may be the biological risk factor for the development of konzo, particularly those mediated through pathways involving the glutathione peroxidase family., (© 2024. The Author(s).)

Diversity, equity, inclusion, and accessibility (DEIA) are foundational principles for clinical trials and medical research. In rare diseases clinical research, where numbers of participants are already challenged by rarity itself, maximizing inclusion is of particular importance to clinical trial success, as well as ensuring the generalizability and relevance of the trial results to the people affected by these diseases. In this article, we review the medical and gray literature and cite case examples to provide insights into how DEIA can be proactively integrated into rare diseases clinical research. Here, we particularly focus on genetic diversity. While the rare diseases DEIA literature is nascent, it is accelerating as many patient advocacy groups, professional societies, training and educational organizations, researcher groups, and funders are setting intentional strategies to attain DEIA goals moving forward, and to establish metrics to ensure continued improvement. Successful examples in underserved and underrepresented populations are available that can serve as case studies upon which rare diseases clinical research programs can be built. Rare diseases have historically been innovation drivers in basic, translational, and clinical research, and ultimately, all populations benefit from data diversity in rare diseases populations that deliver novel insights and approaches to how clinical research can be performed., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Child growth measurements are critical vital signs to track, with every individual child growth curve potentially revealing a story about a child's health and well-being. Simply put, every baby born requires basic building blocks to grow and thrive: proper nutrition, love and care, and medical health. To ensure that every child who is missing one of these vital aspects is identified, growth is traditionally measured at birth and each well-child visit. While the blue and pink growth curves appear omnipresent in pediatric clinics, it is surprising to realize that their use only became standard of care in 1977 when the National Center for Health Statistics (NCHS) adopted the growth curve as a clinical tool for health. Behind this practice lies a socioeconomically, culturally, and politically complex interplay of individuals and institutions around the world. In this review, we highlight the often forgotten past, current state of practice, and future potential of this powerful clinical tool: the growth reference chart, with a particular focus on clinical genetics practice. The goal of this article is to understand ongoing work in the field of anthropometry (the scientific study of human measurements) and its direct impact on modern pediatric and genetic patient care., (© 2023 Wiley Periodicals LLC.)

This document provides a comprehensive summary of evidence on the current situation of rare diseases (RDs) globally and regionally, including conditions, practices, policies, and regulations, as well as the challenges and barriers faced by RD patients, their families, and caregivers. The document builds on a review of academic literature and policies and a process of validation and feedback by a group of seven experts from across the globe. Panelists were selected based on their academic merit, expertise, and knowledge regarding the RD environment. The document is divided into five main sections: (1) methodology and objective; (2) background and context; (3) overview of the current situation and key challenges related to RDs covering six dimensions: burden of disease, patient journey, social impact, disease management, RD-related policies, and research and development; (4) recommendations; and (5) conclusions. The recommendations are derived from the discussion undertaken by the experts on the findings of this review and provide a set of actionable solutions to the challenges and barriers to improving access to RD diagnosis and treatment around the world. The recommendations can support critical decision-making, guiding efforts by a broad range of RDs stakeholders, including governments, international organizations, manufacturers, researchers, and patient advocacy groups.

Nitric oxide depletion secondary to arginase induced arginine deficiency has been shown to be important in the pathophysiology of vaso-occlusion in sickle cell pain crisis. Our objective of this study was to perform a comprehensive amino acid evaluation during sickle cell pain crisis. In a total of 58 subjects (29 in steady-state sickle cell disease and 29 with sickle cell pain crisis), the amino acids related to nitric oxide pathway was significantly decreased during sickle cell pain crisis compared to steady-state sickle cell disease: arginine (p = 0.001), citrulline (p = 0.012), and ornithine (p = 0.03). In addition, the amino acids related to energy metabolism was significantly decreased during a pain crisis: asparagine (p < 0.001), serine (p = 0.002), histidine (p = 0.017), alanine (p = 0.004), tyrosine (p = 0.012), methionine (p = 0.007), cystine (p = 0.016), isoleucine (p = 0.016) and lysine (p = 0.006). The amino acid related to oxidative stress were significantly higher during a sickle cell pain crisis (glutamic acid (p < 0.001). Furthermore, multivariate analysis with partial least squares-discriminant analysis (PLS-DA) showed that deficiencies of the amino acids arginine, asparagine, citrulline, methionine and alanine were the most important related to sickle cell pain crisis., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO)., Methods: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated., Results: Abnormal ACP was 73% (95% CI: 56%-86%) and 62% (95% CI: 45%-78%) in the myopathic and nonmyopathic groups, respectively. No significant association was found between myopathy and having an abnormal ACP (OR = 2.10, P = 0.22). In univariate analysis, a 1-year increase in NRTI use was associated with a 20% increase in odds of at least 1 ACP abnormality [OR (95% CI) = 1.20 (1.03-1.41); P = 0.02), and a 1-year increase in protease inhibitor use was associated with 28% increase in the odds of having at least 1 ACP abnormality [OR (95% CI) = 1.28 (1.07-1.52); P = 0.006). Three SNPs, all in the gene for the carnitine transporter ( SLC22A5 ), were associated with the cardiomyopathy phenotype., Conclusion: FAO appears to be altered in HIV-infected children with and without myopathy, but abnormal FAO does not fully explain myopathy in ARV-exposed children. Further study of SLC22A5 variation in ARV-exposed people is warranted carnitine transporter dysfunction-related cardiomyopathy may be treatable., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Concomitant with developing pulmonary hypertension (PH), newborn piglets exposed to chronic hypoxia develop pulmonary vascular NO signaling impairments. PH is reduced and NO signaling is improved in chronically hypoxic piglets treated with the NO-arginine precursor, L-citrulline. Folic acid positively impacts NO signaling. We evaluated whether the effect on NO signaling and PH is greater using co-treatment with folic acid and L-citrulline than either alone. From day 3 to day 10 of hypoxia, piglets were treated solely with folic acid, solely with L-citrulline, or co-treated with both. Catheters were placed to measure in vivo hemodynamics. NO production was measured in vitro in dissected pulmonary arteries. Compared to normoxic piglets, pulmonary vascular resistance (PVR) was elevated and NO production was reduced in untreated hypoxic piglets. Regardless of treatment strategy, PVR was less in all three treated groups of hypoxic piglets when compared to the untreated hypoxic group. In addition, for all three groups of treated hypoxic piglets, NO production was higher than the untreated group. Improvements in PVR and NO production did not differ between piglets co-treated with folic acid and L-citrulline and those treated solely with either. Thus, the impact on NO production and PVR was not augmented by combining folic acid and L-citrulline treatments. Nonetheless, treatment with folic acid, either singly or when combined with L-citrulline, increases NO production and inhibits PH in chronically hypoxic newborn piglets. Folic acid merits consideration as a therapy for PH in human infants with chronic heart and lung conditions that are associated with chronic hypoxia., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Delays in the diagnosis of genetic syndromes are common, particularly in low and middle-income countries with limited access to genetic screening services. We, therefore, aimed to develop and evaluate a machine learning-based screening technology using facial photographs to evaluate a child's risk of presenting with a genetic syndrome for use at the point of care., Methods: In this retrospective study, we developed a facial deep phenotyping technology based on deep neural networks and facial statistical shape models to screen children for genetic syndromes. We trained the machine learning models on facial photographs from children (aged <21 years) with a clinical or molecular diagnosis of a genetic syndrome and controls without a genetic syndrome matched for age, sex, and race or ethnicity. Images were obtained from three publicly available databases (the Atlas of Human Malformations in Diverse Populations of the National Human Genome Research Institute, Face2Gene, and the dataset available from Ferry and colleagues) and the archives of the Children's National Hospital (Washington, DC, USA), in addition to photographs taken on a standard smartphone at the Children's National Hospital. We designed a deep learning architecture structured into three neural networks, which performed image standardisation (Network A), facial morphology detection (Network B), and genetic syndrome risk estimation, accounting for phenotypic variations due to age, sex, and race or ethnicity (Network C). Data were divided randomly into 40 groups for cross validation, and the performance of the model was evaluated in terms of accuracy, sensitivity, and specificity in both the total population and stratified by race or ethnicity, age, and sex., Findings: Our dataset included 2800 facial photographs of children (1318 [47%] female and 1482 [53%] male; 1576 [56%] White, 432 [15%] African, 430 [15%] Hispanic, and 362 [13%] Asian). 1400 children with 128 genetic conditions were included (the most prevalent being Williams-Beuren syndrome [19%], Cornelia de Lange syndrome [17%], Down syndrome [16%], 22q11.2 deletion [13%], and Noonan syndrome [12%] syndrome) in addition to 1400 photographs of matched controls. In the total population, our deep learning-based model had an accuracy of 88% (95% CI 87-89) for the detection of a genetic syndrome, with 90% sensitivity (95% CI 88-92) and 86% specificity (95% CI 84-88). Accuracy was greater in White (90%, 89-91) and Hispanic populations (91%, 88-94) than in African (84%, 81-87) and Asian populations (82%, 78-86). Accuracy was also similar in male (89%, 87-91) and female children (87%, 85-89), and similar in children younger than 2 years (86%, 84-88) and children aged 2 years or older (eg, 89% [87-91] for those aged 2 years to <5 years)., Interpretation: This genetic screening technology could support early risk stratification at the point of care in global populations, which has the potential accelerate diagnosis and reduce mortality and morbidity through preventive care., Funding: Children's National Hospital and Government of Abu Dhabi., Competing Interests: Declaration of interests This technology is protected by US patent numbers 9443132 (to MGL, MS, and KR), and 10204260 (to MGL and MS). The software is also protected by the copyright with assigned case and SR number 1–8317833951 (to ARP and MGL). All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)