Metabolomics in diagnostics of inborn metabolic disorders

Finding a diagnosis for patients with a rare inborn metabolic disorder can be a long and difficult path. Whereas next generation sequencing is now a commonly used modality, which has significantly impacted the diagnostic yield and speed, next generation metabolic screening through untargeted metabolomics is next in line to prove its value in the diagnostic trajectory.

Untargeted metabolomics, often based on mass spectrometry platforms, is a well-established technology for the identification of novel disease markers. However, untargeted metabolomics as first line diagnostics for rare disease is now only gradually making its way into clinical practice. Most retrospective studies show that the majority of inborn metabolic disorder can be detected through untargeted metabolomics. Some diseases will still go undetected, which diagnoses are missed depends on the specific metabolomics method chosen; there is no single all-encompassing platform. Therefore, careful assessments of the opportunities and limitations are currently undertaken in prospective studies, combining untargeted metabolomics in the diagnostics setting with the current gold standard genetic and biochemical diagnostic modalities. These studies show an increased diagnostic yield when implementing untargeted metabolomics. Given the continuing technological advances, defining the optimal timing, place, and order of the various diagnostic modalities will keep on evolving in the foreseen future.