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

• Published in: Genetics in medicine Vol. 21; no. 9; pp. 1977 - 1986
• Main Authors: Burrage, Lindsay C., Thistlethwaite, Lillian, Stroup, Bridget M., Sun, Qin, Miller, Marcus J., Nagamani, Sandesh C.S., Craigen, William, Scaglia, Fernando, Sutton, V. Reid, Graham, Brett, Kennedy, Adam D., Milosavljevic, Aleksandar, Lee, Brendan H., Elsea, Sarah H.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.09.2019; Nature Publishing Group US; Elsevier Limited
• Subjects: Adolescent; Adult; arginase deficiency; Biomarkers - blood; Biomedical and Life Sciences; Biomedicine; branched-chain amino acids; Child; Child, Preschool; Female; guanidino compounds; Human Genetics; Humans; Laboratory Medicine; Male; Mass Spectrometry; Metabolic Networks and Pathways - genetics; Metabolism, Inborn Errors - blood; Metabolism, Inborn Errors - genetics; Metabolism, Inborn Errors - pathology; Metabolites; Metabolomics; Urea - metabolism; urea cycle disorder; Urea Cycle Disorders, Inborn - blood; Urea Cycle Disorders, Inborn - genetics; Urea Cycle Disorders, Inborn - pathology; Young Adult; arginase deficiency; branched-chain amino acids; metabolomics; urea cycle disorder; guanidino compounds
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-019-0442-0

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). 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. 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. 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.