Journal
AMERICAN JOURNAL OF CLINICAL NUTRITION
Volume 115, Issue 3, Pages 811-821Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ajcn/nqab400
Keywords
phenylketonuria; PKU; metabolomics; metabolic control; choline; oxidative stress
Categories
Funding
- Georgia Clinical and Translational Science Alliance - National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR002378]
- David H. Murdock Institute for Business and Culture
- Duke's Clinical and Translational Science Award from the National Center for Advancing Translational Sciences from the National Institutes of Health [UL1TR002553]
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This study used untargeted metabolomics to identify significant disruptions in amino acid and lipid metabolites in females with phenylketonuria (PKU), which were associated with bioenergetic impairment and oxidative stress. Choline-conjugated lipids were found to play a fundamental role in these pathways, and had not been previously evaluated in PKU. Short-term intervention at a metabolic camp effectively improved or normalized the abundance of the identified metabolites.
Background: There remains a limited understanding of the metabolic perturbations, beyond phenylalanine (Phe) metabolism, that contribute to phenotypic variability in phenylketonuria (PKU). Objectives: This study aimed to characterize changes in the PKU plasma metabolome following a 5-d metabolic camp intervention and to compare PKU profiles with those of matched healthy controls. Methods: In 28 females (aged 12-57 y). fasting plasma samples were collected on the first (day 1) and final (day 5) days of camp to measure metabolic control and to complete untargeted metabolomic profiling. Three-day dietary records were collected to assess changes in dietary adherence and composition. Univariate (Wilcoxon signed-rank and Mann-Whitney U test) and multivariate (random forest, hierarchical clustering) analyses were performed to identify clinical and metabolic features that were associated with the intervention and disease state. Results: Relative to healthy controls. Phe catabolites, ketones. and carnitine- and glycine-conjugated fatty acids were elevated in females with PKU at baseline, whereas fatty acylcholine metabolites were substantially lower. After the camp intervention, plasma Phe concentrations decreased [median change: -173 mu mol/L (IQR: -325. -28 mu mol/L)] and 70% of PKU participants demonstrated improved dietary adherence by decreasing Phe intake and/or increasing medical food consumption. This was accompanied by a shift in abundance for 223 metabolites (q < 0.05). Compounds associated with the metabolism of Phe, fatty acids, and choline contributed most to profile differences between camp days 1 and 5. Conclusions: In females with PKU, untargeted metabolomics identified prominent perturbations in amino acid and lipid metabolites associated with bioenergetic impairment and oxidative stress. Choline-conjugated lipids could have fundamental roles in these pathways and they have not been previously evaluated in PKU. A short-term camp intervention was effective for improving or fully normalizing the abundance of the identified discriminatory metabolites.
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