Special Issue "Genetic Metabolic Diagnostics"

A special issue of Metabolites (ISSN 2218-1989).

Deadline for manuscript submissions: closed (31 August 2019).

Special Issue Editors

Dr. J.J.M. (Judith) Jans
E-Mail Website
Guest Editor
University Medical Center Utrecht, Center for Molecular Medicine, Utrecht, Netherlands
Interests: inborn errors of metabolism; untargeted metabolomics; genetic metabolic diagnostics; disease discovery
Prof. Dr. N.M. (Nanda) Verhoeven-Duif
E-Mail Website
Guest Editor
University Medical Center Utrecht, Center for Molecular Medicine, Utrecht, Netherlands
Interests: : inborn errors of metabolism; untargeted metabolomics; genetic metabolic diagnostics; vitamin B6

Special Issue Information

Dear Colleagues,

With unprecedented pace, the number of known inborn errors of metabolism (IEM) is expanding. Whole-exome sequencing and whole-genome sequencing are swiftly finding their way into diagnostic practice. Similarly, the possibilities offered by recent technical improvements in metabolic diagnostics are enormous. These improvements include, amongst others, the implementation of untargeted metabolomics in metabolic diagnostics and the integration of the various -omics methodologies. These developments have led to the discovery of novel IEM and to faster and better diagnostics.

This Special Issue is devoted to the most recent advances in genetic metabolic diagnostics, and is now open for submissions. Topics that will be covered by this Special Issue include, but are not limited to: developments in novel metabolic diagnostic methods, the identification of metabolites with clinical relevance for patients with IEM, -omics data integration, and novel pathophysiological insights into IEM. Manuscripts including reviews dealing with other challenging issues with respect to genetic metabolic diagnostics will also be considered. We are looking forward to receiving your submissions.

Dr. J.J.M. (Judith) Jans
Prof. Dr. N.M. (Nanda) Verhoeven-Duif
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • inborn errors of metabolism
  • genetic metabolic diagnostics
  • metabolomics
  • biochemical genetics
  • untargeted metabolomics

Published Papers (5 papers)

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Research

Open AccessArticle
Untargeted Metabolomics-Based Screening Method for Inborn Errors of Metabolism using Semi-Automatic Sample Preparation with an UHPLC- Orbitrap-MS Platform
Metabolites 2019, 9(12), 289; https://doi.org/10.3390/metabo9120289 - 26 Nov 2019
Abstract
Routine diagnostic screening of inborn errors of metabolism (IEM) is currently performed by different targeted analyses of known biomarkers. This approach is time-consuming, targets a limited number of biomarkers and will not identify new biomarkers. Untargeted metabolomics generates a global metabolic phenotype and [...] Read more.
Routine diagnostic screening of inborn errors of metabolism (IEM) is currently performed by different targeted analyses of known biomarkers. This approach is time-consuming, targets a limited number of biomarkers and will not identify new biomarkers. Untargeted metabolomics generates a global metabolic phenotype and has the potential to overcome these issues. We describe a novel, single platform, untargeted metabolomics method for screening IEM, combining semi-automatic sample preparation with pentafluorophenylpropyl phase (PFPP)-based UHPLC- Orbitrap-MS. We evaluated analytical performance and diagnostic capability of the method by analysing plasma samples of 260 controls and 53 patients with 33 distinct IEM. Analytical reproducibility was excellent, with peak area variation coefficients below 20% for the majority of the metabolites. We illustrate that PFPP-based chromatography enhances identification of isomeric compounds. Ranked z-score plots of metabolites annotated in IEM samples were reviewed by two laboratory specialists experienced in biochemical genetics, resulting in the correct diagnosis in 90% of cases. Thus, our untargeted metabolomics platform is robust and differentiates metabolite patterns of different IEMs from those of controls. We envision that the current approach to diagnose IEM, using numerous tests, will eventually be replaced by untargeted metabolomics methods, which also have the potential to discover novel biomarkers and assist in interpretation of genetic data. Full article
(This article belongs to the Special Issue Genetic Metabolic Diagnostics)
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Open AccessArticle
Urea Cycle Related Amino Acids Measured in Dried Bloodspots Enable Long-Term In Vivo Monitoring and Therapeutic Adjustment
Metabolites 2019, 9(11), 275; https://doi.org/10.3390/metabo9110275 - 12 Nov 2019
Abstract
Background: Dried bloodspots are easy to collect and to transport to assess various metabolites, such as amino acids. Dried bloodspots are routinely used for diagnosis and monitoring of some inherited metabolic diseases. Methods: Measurement of amino acids from dried blood spots by liquid [...] Read more.
Background: Dried bloodspots are easy to collect and to transport to assess various metabolites, such as amino acids. Dried bloodspots are routinely used for diagnosis and monitoring of some inherited metabolic diseases. Methods: Measurement of amino acids from dried blood spots by liquid chromatography-tandem mass spectrometry. Results: We describe a novel rapid method to measure underivatised urea cycle related amino acids. Application of this method enabled accurate monitoring of these amino acids to assess the efficacy of therapies in argininosuccinate lyase deficient mice and monitoring of these metabolites in patients with urea cycle defects. Conclusion: Measuring urea cycle related amino acids in urea cycle defects from dried blood spots is a reliable tool in animal research and will be of benefit in the clinic, facilitating optimisation of protein-restricted diet and preventing amino acid deprivation. Full article
(This article belongs to the Special Issue Genetic Metabolic Diagnostics)
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Open AccessArticle
Assessing the Pre-Analytical Stability of Small-Molecule Metabolites in Cerebrospinal Fluid Using Direct-Infusion Metabolomics
Metabolites 2019, 9(10), 236; https://doi.org/10.3390/metabo9100236 - 18 Oct 2019
Abstract
Metabolomics studies aiming to find biomarkers frequently make use of historical or multicenter cohorts. These samples often have different pre-analytical conditions that potentially affect metabolite concentrations. We studied the effect of different storage conditions on the stability of small-molecule metabolites in cerebrospinal fluid [...] Read more.
Metabolomics studies aiming to find biomarkers frequently make use of historical or multicenter cohorts. These samples often have different pre-analytical conditions that potentially affect metabolite concentrations. We studied the effect of different storage conditions on the stability of small-molecule metabolites in cerebrospinal fluid to aid a reliable interpretation of metabolomics data. Three cerebrospinal fluid pools were prepared from surplus samples from the Amsterdam Dementia Cohort biobank. Aliquoted pools were exposed to different storage conditions to assess the temperature and freeze/thaw stability before final storage at −80 °C: storage up to four months at −20 °C and up to one week at either 5–8 °C or 18–22 °C and exposure to up to seven freeze/thaw cycles. Direct-infusion high-resolution mass spectrometry was performed, resulting in the identification of 1852 m/z peaks. To test the storage stability, principal component analyses, repeated measures analysis of variance, Kruskal–Wallis tests, and fold change analyses were performed, all demonstrating that small-molecule metabolites in the cerebrospinal fluid (CSF) are relatively unaffected by 1–3 freeze/thaw cycles, by storage at −20 °C up to two months, by storage at 5–8 °C for up to 72 h, or by storage at 18–22 °C for up to 8 h. This suggests that these differences do not affect the interpretation of potential small-molecule biomarkers in multicenter or historical cohorts and implies that these cohorts are suitable for biomarker studies. Full article
(This article belongs to the Special Issue Genetic Metabolic Diagnostics)
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Open AccessCommunication
Sphingolipid Metabolism Perturbations in Rett Syndrome
Metabolites 2019, 9(10), 221; https://doi.org/10.3390/metabo9100221 - 10 Oct 2019
Abstract
Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the MECP2 gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features [...] Read more.
Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the MECP2 gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features of Rett syndrome. We performed a semi-quantitative tandem mass spectrometry-based analysis that measured over 900 metabolites on blood samples from 14 female subjects with Rett syndrome carrying MECP2 mutations. The metabolic profiling revealed alterations in lipids, mostly involved in sphingolipid metabolism, and sphinganine/sphingosine, that are known to have a neurotrophic role. Further investigations are required to understand the mechanisms underlying such perturbations and their significance in the disease pathogenesis. Nevertheless, these metabolites are attractive for studies on the disease pathogenesis and as potential disease biomarkers. Full article
(This article belongs to the Special Issue Genetic Metabolic Diagnostics)
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Open AccessArticle
Oxygraphy Versus Enzymology for the Biochemical Diagnosis of Primary Mitochondrial Disease
Metabolites 2019, 9(10), 220; https://doi.org/10.3390/metabo9100220 - 10 Oct 2019
Abstract
Primary mitochondrial disease (PMD) is a large group of genetic disorders directly affecting mitochondrial function. Although next generation sequencing technologies have revolutionized the diagnosis of these disorders, biochemical tests remain essential and functional confirmation of the critical genetic diagnosis. While enzymological testing of [...] Read more.
Primary mitochondrial disease (PMD) is a large group of genetic disorders directly affecting mitochondrial function. Although next generation sequencing technologies have revolutionized the diagnosis of these disorders, biochemical tests remain essential and functional confirmation of the critical genetic diagnosis. While enzymological testing of the mitochondrial oxidative phosphorylation (OXPHOS) complexes remains the gold standard, oxygraphy could offer several advantages. To this end, we compared the diagnostic performance of both techniques in a cohort of 34 genetically defined PMD patient fibroblast cell lines. We observed that oxygraphy slightly outperformed enzymology for sensitivity (79 ± 17% versus 68 ± 15%, mean and 95% CI), and had a better discriminatory power, identifying 58 ± 17% versus 35 ± 17% as “very likely” for oxygraphy and enzymology, respectively. The techniques did, however, offer synergistic diagnostic prediction, as the sensitivity rose to 88 ± 11% when considered together. Similarly, the techniques offered varying defect specific information, such as the ability of enzymology to identify isolated OXPHOS deficiencies, while oxygraphy pinpointed PDHC mutations and captured POLG mutations that were otherwise missed by enzymology. In summary, oxygraphy provides useful information for the diagnosis of PMD, and should be considered in conjunction with enzymology for the diagnosis of PMD. Full article
(This article belongs to the Special Issue Genetic Metabolic Diagnostics)
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