Untargeted Metabolomic Study for Urinary Characterization of Adult Patients with Phenylketonuria
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.
Authors
- Adriana Pané (ORCID: https://orcid.org/0000-0002-7810-1827)
- Mireia Urpí-Sardà (ORCID: https://orcid.org/0000-0002-4064-5175)
- C. Carbonell (ORCID: https://orcid.org/0009-0009-3917-0334)
- Glòria Garrabou (ORCID: https://orcid.org/0000-0001-8973-9933)
- José C. Milisenda (ORCID: https://orcid.org/0000-0003-0151-7872)
- Rosa Maria López Galera
- Pedro Moreno (ORCID: https://orcid.org/0000-0002-5501-5272)
- Judit García‐Villoria (ORCID: https://orcid.org/0000-0003-2132-4138)
- Mariona Guitart‐Mampel (ORCID: https://orcid.org/0000-0002-9768-4706)
- Rafaël Llorach (ORCID: https://orcid.org/0000-0002-5215-4445)
- Olga Jáuregui (ORCID: https://orcid.org/0000-0002-5834-3829)
- María de Talló Forga Visa
- Ana Matas-García (ORCID: https://orcid.org/0000-0002-9184-8079)
- Blanca Barrau-Martínez (ORCID: https://orcid.org/0000-0002-5700-5262)
- Ester Tobías
- Arnau Gonzalez-Rodriguez (ORCID: https://orcid.org/0009-0004-5057-5416)
- Regina Roca-Vives
Institutions
- Instituto de Salud Carlos III (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Centro de Investigación Biomédica en Red (ES)
- Hospital Clínic de Barcelona (ES)
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (ES)
- Fundació Clínic per a la Recerca Biomèdica (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-12-06
- DOI
- https://doi.org/10.3390/ijms262411808
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable
- Generalitat de Catalunya
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III
- European Regional Development Fund