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Review
. 2019 Oct 21;9(10):242.
doi: 10.3390/metabo9100242.

Inborn Errors of Metabolism in the Era of Untargeted Metabolomics and Lipidomics

Israa T Ismail  1   2 , Megan R Showalter  3 , Oliver Fiehn  4
Affiliations
Review

Inborn Errors of Metabolism in the Era of Untargeted Metabolomics and Lipidomics

Israa T Ismail et al. Metabolites. .

Erratum in

Abstract

Inborn errors of metabolism (IEMs) are a group of inherited diseases with variable incidences. IEMs are caused by disrupting enzyme activities in specific metabolic pathways by genetic mutations, either directly or indirectly by cofactor deficiencies, causing altered levels of compounds associated with these pathways. While IEMs may present with multiple overlapping symptoms and metabolites, early and accurate diagnosis of IEMs is critical for the long-term health of affected subjects. The prevalence of IEMs differs between countries, likely because different IEM classifications and IEM screening methods are used. Currently, newborn screening programs exclusively use targeted metabolic assays that focus on limited panels of compounds for selected IEM diseases. Such targeted approaches face the problem of false negative and false positive diagnoses that could be overcome if metabolic screening adopted analyses of a broader range of analytes. Hence, we here review the prospects of using untargeted metabolomics for IEM screening. Untargeted metabolomics and lipidomics do not rely on predefined target lists and can detect as many metabolites as possible in a sample, allowing to screen for many metabolic pathways simultaneously. Examples are given for nontargeted analyses of IEMs, and prospects and limitations of different metabolomics methods are discussed. We conclude that dedicated studies are needed to compare accuracy and robustness of targeted and untargeted methods with respect to widening the scope of IEM diagnostics.

Keywords: LC-MS; aminoacidemia.; lysosomal storage disease; mass spectrometry; mitochondrial disorders; organic aciduria; phenylketonuria.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Percentage of each category of inborn errors of metabolism (IEMs) according to inclusion criteria reported by [43].
Figure 2
Figure 2
The prevalence of IEMs diseases globally and among different countries. Numbers on x-axes are given per 100,000 live births (Table S1).
Figure 3
Figure 3
Mechanism of IEM diseases. Enzyme AB converts metabolite A to product B. A defect in enzyme BC leads to an accumulation of metabolite B that may cause an activation of the pathway BD. This causes an abnormal concentration of metabolite D and a deficiency in the end product C. Alterations in these compounds are called the metabolic signature of the “ABCD disease” which can be used for diagnosis if all compounds are detected.
Figure 4
Figure 4
Pathophysiological classification of IEMs adopted from [55].
Figure 5
Figure 5
Improvement of IEM diagnosis tests using untargeted metabolomics.
Figure 6
Figure 6
Workflow for diagnosis of IEMs comparing targeted versus untargeted metabolomics.
See this image and copyright information in PMC

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