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

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.

Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

“…In this study, the cohort of IEM was found in eight patients and, consistent with the literature, it was mainly caused by mitochondrial disorders (7/8) [41,42].…”

The impact of COVID-19 pandemic on the diagnosis and management of inborn errors of metabolism: A global perspective

“…Inborn errors of metabolism (IEM) are a vast group of genetic disorders caused by pathogenic variants in genes controlling enzymes, structural proteins or cofactors affecting various metabolic pathways [ 2 ]. Although most IEM are individually rare, more than 1000 well-characterized IEM disorders have been recently classified [ 3 ], with an estimated overall incidence of 1:800–2500 live births [ 2 ].…”

“…Inborn errors of metabolism (IEM) are a vast group of genetic disorders caused by pathogenic variants in genes controlling enzymes, structural proteins or cofactors affecting various metabolic pathways [ 2 ]. Although most IEM are individually rare, more than 1000 well-characterized IEM disorders have been recently classified [ 3 ], with an estimated overall incidence of 1:800–2500 live births [ 2 ]. Despite the great diversity in the clinical presentations and management strategies of different IEM, they mostly share in common their need for challenging diagnostic procedures requiring specialized labs and for multidisciplinary collaborative medical teams for acute and long-term treatment and patient monitoring.…”

Toward a Standardized Strategy of Clinical Metabolomics for the Advancement of Precision Medicine

“…MS is the primary analytical method on which the emerging omics fields such as proteomics and metabolomics are based. Owing to its potential as a multi-platform analytical method and its diverse applicability from diagnosis and prognosis to the discovery of novel biomarkers for targeted therapies, MS has been routinely applied in omics studies, especially cancer and metabolism-related omics research, for a better insight into human diseases [19][20][21][22][23][24][25][26]. Table 1 displays the main findings of some major studies among the initial achievements of the field.…”