Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism

Abstract

Global metabolic profiling currently achievable by untargeted mass spectrometry-based metabolomic platforms has great potential to advance our understanding of human disease states, including potential utility in the detection of novel and known inborn errors of metabolism (IEMs). There are few studies of the technical reproducibility, data analysis methods, and overall diagnostic capabilities when this technology is applied to clinical specimens for the diagnosis of IEMs. We explored the clinical utility of a metabolomic workflow capable of routinely generating semi-quantitative z-score values for ~900 unique compounds, including ~500 named human analytes, in a single analysis of human plasma. We tested the technical reproducibility of this platform and applied it to the retrospective diagnosis of 190 individual plasma samples, 120 of which were collected from patients with a confirmed IEM. Our results demonstrate high intra-assay precision and linear detection for the majority compounds tested. Individual metabolomic profiles provided excellent sensitivity and specificity for the detection of a wide range of metabolic disorders and identified novel biomarkers for some diseases. With this platform, it is possible to use one test to screen for dozens of IEMs that might otherwise require ordering multiple unique biochemical tests. However, this test may yield false negative results for certain disorders that would be detected by a more well-established quantitative test and in its current state should be considered a supplementary test. Our findings describe a novel approach to metabolomic analysis of clinical specimens and demonstrate the clinical utility of this technology for prospective screening of IEMs.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-015-9843-7) contains supplementary material, which is available to authorized users.

Aromatic l-amino acid decarboxylase deficiency diagnosed by clinical metabolomic profiling of plasma

“…It uses a state-ofthe-art mass spectrometry platform, and the resulting spectra are compared against a library of~2500 metabolites, both human and xenobiotic. On average, Global MAPS tests for~900 human compounds and includes many of the analytes that are routinely tested in patients with inborn errors of metabolism, as well as analytes for which no clinical testing is available in the United States [5]. We report a case of AADC deficiency that was detected using this large-scale metabolomic platform.…”

Chronic Oral l-Carnitine Supplementation Drives Marked Plasma TMAO Elevations in Patients with Organic Acidemias Despite Dietary Meat Restrictions

“…In a prior study, we explored the clinical utility of an untargeted metabolomic platform in the retrospective analysis of plasma specimens collected from patients with a wide range of IEMs, as well as individuals without a biochemical diagnosis (Miller et al 2015). This sample set included specimens from multiple unrelated patients receiving treatment for organic acidemias, including glutaric acidemia type 1 (OMIM#231670), methylmalonic acidemia, and propionic acidemia.…”

“…The methods and a general overview of findings from the metabolomic analyses in this report have been previously described (Miller et al 2015). Briefly, an untargeted MS/ MS-based metabolomic platform was used to semiquantitatively analyze~900 unique small molecule plasma analytes in each of 190 patient specimens including 69 patients without a diagnosed genetic disorder.…”

“…To test the hypothesis that chronic oral supplemental Lcarnitine could lead to TMAO production in patients undergoing standard treatment for an organic acidemia, we mined a metabolomic dataset previously generated by our lab, which contains metabolic information on patients with a wide variety of IEMs (Miller et al 2015). Findings from this analysis were correlated with clinical data and confirmed using a targeted tandem mass spectrometry (MS/ MS) assay that allowed absolute quantification of TMAO.…”

Elucidation of the complex metabolic profile of cerebrospinal fluid using an untargeted biochemical profiling assay

“…We recently demonstrated the utility of metabolomics to identify biochemical signatures of disease in plasma [23] and urine [24] for diverse classes of IEMs. This approach identified and assisted in the diagnosis of aromatic amino acid decarboxylase deficiency through the metabolomic and genomic analyses of plasma [22].…”