Untargeted Metabolomic Study for Urinary Characterization of Adult Patients with Phenylketonuria

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Abstract
Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by phenylalanine hydroxylase deficiency, leading to phenylalanine (Phe) accumulation and neurological dysfunction if untreated. While metabolomics holds promise for biomarker discovery in PKU, few studies have examined urinary metabolites using untargeted approaches. This study applied untargeted metabolomics using HPLC-QTOF-MS to analyze urine from 36 adult patients with PKU and 34 healthy controls. Biomarker Analysis was performed with MetaboAnalyst 6.0. A total of 73 significant metabolites (FDR < 0.05; VIP > 1) were identified, with 29 upregulated and 44 downregulated in PKU. A 23% of these metabolites were related to Phe metabolism, while 77% were associated with alterations across more than 10 metabolic pathways, including leucine and tryptophan metabolism, acylcarnitines, vitamins, and diet- or microbiota-derived compounds, among others. Specifically, upregulated metabolites with an AUC > 0.9 included several Phe-derived compounds, the nucleoside 8-hydroxy-7-methylguanine, and indole compounds (1H-indole-3-carboxaldehyde). Conversely, downregulated metabolites with an AUC > 0.9 included N-acetyl(iso)leucine and a heptenoylcarnitine isomer. The Random Forest-based model demonstrated enhanced predictive performance when integrating 10 metabolites, supporting their potential utility as biomarkers for PKU. These findings improve the biological understanding of metabolic disturbances beyond Phe, and may support the development of new therapeutic and dietary strategies.
Funding Information
  • Fundació la Marató de TV3 (202014-32, 202014-30)
  • Ministerio de Ciencia, Innovación y Universidades, Fondo Europeo de Desarrollo Regional
  • Agencia Estatal de Investigación (EQC2019-005533-P)
  • INSA joINT rEseaRch ACTions INTERACT 2024
  • Instituto de Salud Carlos III (ER24P3AC722, ER25PE04)
  • AGAUR-Generalitat de Catalunya (2022 FI_B 01012, 2024 FI-1 00408)
  • FPU predoctoral program from the Spanish Ministry of Science, Innovation and Universities (FPU23/03478)
  • INSA-UB recognized as a María de Maeztu Unit of Excellence (CEX2021-001234-M, MICIU/AEI/10.13039/501100011033)

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