Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders

Genet Med. 2019 Sep;21(9):1977-1986. doi: 10.1038/s41436-019-0442-0. Epub 2019 Jan 23.


Purpose: Untargeted metabolomic analysis is increasingly being used in the screening and management of individuals with inborn errors of metabolism (IEM). We aimed to test whether untargeted metabolomic analysis in plasma might be useful for monitoring the disease course and management of urea cycle disorders (UCDs).

Methods: Untargeted mass spectrometry-based metabolomic analysis was used to generate z-scores for more than 900 metabolites in plasma from 48 individuals with various UCDs. Pathway analysis was used to identify common pathways that were perturbed in each UCD.

Results: Our metabolomic analysis in plasma identified multiple potentially neurotoxic metabolites of arginine in arginase deficiency and, thus, may have utility in monitoring the efficacy of treatment in arginase deficiency. In addition, we were also able to detect multiple biochemical perturbations in all UCDs that likely reflect clinical management, including metabolite alterations secondary to dietary and medication management.

Conclusion: In addition to utility in screening for IEM, our results suggest that untargeted metabolomic analysis in plasma may be beneficial for monitoring efficacy of clinical management and off-target effects of medications in UCDs and potentially other IEM.

Keywords: arginase deficiency; branched-chain amino acids; guanidino compounds; metabolomics; urea cycle disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers / blood*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Male
  • Mass Spectrometry
  • Metabolic Networks and Pathways / genetics
  • Metabolism, Inborn Errors / blood*
  • Metabolism, Inborn Errors / genetics
  • Metabolism, Inborn Errors / pathology
  • Metabolomics*
  • Urea / metabolism
  • Urea Cycle Disorders, Inborn / blood*
  • Urea Cycle Disorders, Inborn / genetics
  • Urea Cycle Disorders, Inborn / pathology
  • Young Adult


  • Biomarkers
  • Urea