The clinical value of peripheral biogenic amine metabolites in early-treated phenylketonuria.

BACKGROUND

Brain monoamine depletion is a well-established biochemical consequence of phenylketonuria (PKU). Similar alterations are expected in the peripheral biogenic amines (PBA), which share the same metabolic pathway with the brain. The present cross-sectional study explored the potential prognostic value of PBA by examining their relationship with blood Phe and clinical outcomes in early-treated adult PKU patients (ETPKU).

METHOD

53 ETPKU (age 27.14 ± 8.22 years; 35 female) and 60 age-matched control subjects (age 43 ± 13 years; 43 female) were enrolled in the study. A UPLC-ESI-MS/MS-based method was developed to assess 5-hydroxytryptophan (5-HTP), serotonin (5-HT), 5-hydroxyhyndolacetic acid (5-HIAA), and 3-O-methyldopa (3-OMD) in different blood-derived matrices. Life-long Index of Dietary Control (IDC), concurrent Phe, and Tyr were other parameters included in the analysis. Clinical outcome measures included IQ, executive functions (BRIEF), and psychiatric morbidity (CBCL/ASR and DSM-5-TR).

RESULTS

5-HTP, 5-HIAA, and 3-OMD were significantly lower in PKU patients than in controls. 5-HIAA and 3-OMD were negatively correlated with concurrent Phe levels. Concerning outcome measures, IDC influenced IQ and BRIEF-Shift subscale, 5-HIAA BRIEF-Emotional Control, 3-OMD BRIEF-Initiate subscale, and Tyr BRIEF-Control subscale. In contrast, concurrent plasma Phe did not affect any outcome measures.

CONCLUSION

While confirming the negative influence of Phe on PBA in adult ETPKU, mimicking what happens in the brain, we also found an effect of PBA depletion on clinical outcome measures independent of Phe level. This suggests that PBA could serve as new candidate biomarkers for treatment monitoring in adult ETPKU patients.

Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.