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Untargeted Metabolomics, Targeted Care: The Clinical Utilities of Bedside Metabolomics

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Clinical Metabolomics Applications in Genetic Diseases

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Abstract

The second decade of the twenty-first century saw a quiet revolution in the field of inborn errors of metabolism. Decades of extensive research into metabolic pathways of physiologically active cells and tissues, along with an improved resolution of high-throughput screening capabilities, brought forth the clinical metabolome. Clinicians can now take a metabolic snapshot while assessing their patients and receive invaluable information on pathological processes, rule in or rule out a proposed diagnosis, highlight early signs of decompensation, assess response to treatment, explore new disease biomarkers, and even suggest novel treatment options. In this chapter, we review the major strengths of clinical metabolomics as a diagnostic aid and its capabilities in promoting novel biomarker discovery. We also provide an outlook for how next-gen interpretation modalities (such as machine learning) are expected to revolutionize this field further to benefit patients worldwide.

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Authors and Affiliations

  1. Metabolic Unit, Haim Sheba Medical Center, Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel

    Joshua Manor

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Sarah H. Elsea

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  1. Joshua Manor
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  2. Sarah H. Elsea
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Correspondence to Sarah H. Elsea .

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Editors and Affiliations

  1. Metabolomics Section, Department of Clinical Genomics, Center for Genome Medicine, King Faisal Specialist Hospital & Research Center (KFSHRC), Riyadh, Saudi Arabia

    Anas M. Abdel Rahman

Glossary

Dried blood spot (DBS)

A method of whole blood sample collection in which a small amount of fresh blood is blotted onto an absorbent filter paper, followed by drying. This method provides a convenient storage and shipment platform and is widely used for newborn screening. Typically, a small punch from the DBS paper is eluted with phosphate-buffered saline, availing the sample for testing.

Elevation/reduction (of a metabolite)

In the context of this chapter, a metabolite is considered reduced (insufficient) or elevated (in excess) when UM reveals a Z-score ≥+2 or ≤−2. The Z-score is the number of standard deviations that a data point differs from the population means, representing the relative level of a given metabolite. Raw values for individual metabolites are log2-transformed, and the relative Z-score is calculated compared to a lab-specific reference population [91, 111,112,113].

Inborn error of metabolism (IEM)

A heterogeneous group of mostly inherited disorders involving a failure of the certain metabolic pathway(s) to break down or store biomolecules (typically carbohydrates, lipids, or amino acids) in the cell. Although any given inborn error of metabolism is rare, taken as a group, inborn errors of metabolism occur in 1 in 2000 births [114].

Molecular confirmation

A suspected diagnosis, as suggested by biochemical testing such as UM, is said to be molecularly confirmed when genomic sequencing reveals pathogenic variants, either monoallelic for autosomal dominant or X-linked disorders or biallelic for recessive disorders in the gene associated with the metabolic abnormality. Sequencing can be targeted for the specific gene(s) or untargeted as exome or genome sequencing. In the latter case, further confirmation by Sanger sequencing may be performed to validate the variants identified.

Reference population

A lab-specific reference population created by performing UM on samples received in the clinical laboratory, with careful inclusion and exclusion of clinical samples to ensure pathways and analytes are covered for comprehensive clinical assessment. Raw data for each metabolite are median scaled, log2 transformed, extreme outliers removed, and Z-scores generated based on the mean and standard deviation in this reference population [91, 111,112,113].

Traditional screening methods

Screening tools for certain common abnormalities indicative of diseases. While there is no definition per se for traditional screening methods, they usually include organic acids measured in urine (urine organic acids, UOA); measurements of standard amino acids in plasma (PAA); and carnitine conjugates of fatty acids (acylcarnitine profile, ACP). ACP and PAA are examples of TM where predefined biochemicals are quantitatively measured compared to known standards. UOA is a semiquantitative, untargeted analysis in which analytes are qualitatively compared against a few laboratory-specific internal standards. UOA and PAA are typically performed by liquid chromatography (LC) and/or gas chromatography (GC) coupled with mass spectrometry (MS). In contrast, ACP is performed by tandem MS/MS, where indicators are aimed at detecting carnitine daughter ions.

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Manor, J., Elsea, S.H. (2023). Untargeted Metabolomics, Targeted Care: The Clinical Utilities of Bedside Metabolomics. In: Abdel Rahman, A.M. (eds) Clinical Metabolomics Applications in Genetic Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-99-5162-8_6

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