Plasma metabolomic profile changes in females with phenylketonuria following a camp intervention

There remains a limited understanding of the metabolic perturbations, beyond phenylalanine (Phe) metabolism, that contribute to phenotypic variability in phenylketonuria (PKU).

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.

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.

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 µmol/L (IQR: -325, -28 µmol/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.

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.