Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders
Burrage LC, Thistlethwaite L, Stroup BM, Sun Q, Miller MJ, Nagamani SCS, Craigen W, Scaglia F, Sutton VR, Graham B, Kennedy AD; Members of the UCDC, Milosavljevic A, Lee BH, Elsea Sarah H
Abstract
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 offtarget effects of medications in UCDs and potentially other IEM.
Genetics in Medicine (2019) https://doi.org/10.1038/s41436-019-0442-0
