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      Untargeted Metabolomic Profiling Reveals Multiple Pathway Perturbations and New Clinical Biomarkers in Urea Cycle Disorders

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          Abstract

          Purpose:

          Untargeted metabolomic analysis is increasingly being used in the screening and management of individuals with inborn errors of metabolism (IEM). We aimed to test whether untargeted metabolomic analysis in plasma might be useful for monitoring the disease course and management of urea cycle disorders (UCDs).

          Methods:

          Untargeted mass spectrometry-based metabolomic analysis was used to generate z-scores for more than 900 metabolites in plasma from 48 individuals with various UCDs. Pathway analysis was used to identify common pathways that were perturbed in each UCD.

          Results:

          Our metabolomic analysis in plasma identified multiple potentially neurotoxic metabolites of arginine in arginase deficiency and, thus, may have utility in monitoring the efficacy of treatment in arginase deficiency. In addition, we were also able to detect multiple biochemical perturbations in all UCDs that likely reflect clinical management, including metabolite alterations secondary to dietary and medication management.

          Conclusions:

          In addition to utility in screening for IEM, our results suggest that untargeted metabolomic analysis in plasma may be beneficial for monitoring efficacy of clinical management and off-target effects of medications in UCDs and potentially other IEM.

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          Most cited references34

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          Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.

          Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.
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            Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.

            Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.
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              High Resolution Mass Spectrometry Improves Data Quantity and Quality as Compared to Unit Mass Resolution Mass Spectrometry in High-Throughput Profiling Metabolomics

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                Author and article information

                Journal
                9815831
                22061
                Genet Med
                Genet. Med.
                Genetics in medicine : official journal of the American College of Medical Genetics
                1098-3600
                1530-0366
                13 February 2019
                23 January 2019
                24 July 2019
                : 10.1038/s41436-019-0442-0
                Affiliations
                [1 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
                [2 ]Texas Children’s Hospital, Houston, TX 77030
                [3 ]Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030
                [4 ]BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, ShaTin, Hong Kong SAR
                [5 ]Metabolon, Inc. Durham, NC 27560
                [6 ]Members of the UCDC are listed in the appendix
                Author notes
                [* ]Corresponding Authors: Lindsay C. Burrage, M.D., Ph.D., Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, MS 225, Houston TX, 77030, burrage@ 123456bcm.edu ; Sarah H. Elsea, Ph.D., Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB2015, Houston TX, 77030, elsea@ 123456bcm.edu

                Current Address:

                [^]

                Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202

                [#]

                Baebies, Inc. Durham, NC

                Article
                NIHMS1521483
                10.1038/s41436-019-0442-0
                6650380
                30670878
                3fbe97ff-9383-4817-bb05-3dc2852dc63f

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                History
                Categories
                Article

                Genetics
                metabolomics,urea cycle disorder,arginase deficiency,branched-chain amino acids,guanidino compounds

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