Characterization and treatment monitoring of ureagenesis disorders using stable isotopes
Urea cycle disorders (UCDs) are a group of rare conditions, possibly life-threatening and without definitive cure besides liver transplantation. Traditional biochemical analyses/biomarkers cannot reliably determine changes in the UC-function from baseline to post-intervention. We describe a UHPLC-HRMS method to assess ureagenesis in plasma and dried blood spots for [<sup>15</sup>N]urea and [<sup>15</sup>N]amino acids, using [<sup>15</sup>N]ammonium chloride as tracer. [<sup>15</sup>N]enrichment of urea and amino acids was studied in controls (<i>n</i> = 22) and patients (<i>n</i> = 59), the latter showing characteristic ureagenesis variations according to their underlying metabolic defect. Follow-up of therapies was successful, as we observed restoration of [<sup>15</sup>N]urea production and lowering of [<sup>15</sup>N]glutamine. There were no adverse events, and only minimal amounts of tracer and samples required with a short sample preparation time and analysis. Thus, the method proved to be safe and efficient to monitor UCD patients of variable severity pre- and post-therapy, being suitable as physiological endpoint for development of therapies.
Authors
- Ralf A. Husain (ORCID: https://orcid.org/0000-0003-0798-6346)
- Véronique Rüfenacht
- Dominique Roland (ORCID: https://orcid.org/0000-0002-4074-849X)
- Gabriella Allegri
- Daniela Karall (ORCID: https://orcid.org/0000-0002-4846-1047)
- Beat Thöny (ORCID: https://orcid.org/0000-0002-5001-086X)
- Déborah Mathis (ORCID: https://orcid.org/0000-0002-2326-7782)
- Johannes Häberle (ORCID: https://orcid.org/0000-0003-0635-091X)
- Francesco Porta (ORCID: https://orcid.org/0000-0003-3899-4867)
- Nicole Rimann
- Matthias Gautschi (ORCID: https://orcid.org/0000-0003-1358-1759)
- Martin Poms (ORCID: https://orcid.org/0000-0002-4426-314X)
- Barbara Siri (ORCID: https://orcid.org/0000-0002-2876-4745)
- René Santer (ORCID: https://orcid.org/0000-0002-3670-5657)
- Carlo Dionisi‐Vici (ORCID: https://orcid.org/0000-0002-0007-3379)
- Nadia Zürcher
- Karolina Orchel-Szastak
Institutions
- University of Bern (CH)
- Innsbruck Medical University (AT)
- Universität Hamburg (DE)
- University Hospital of Bern (CH)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- Institute of Pathology and Genetics (BE)
- University Medical Center Hamburg-Eppendorf (DE)
- Bambino Gesù Children's Hospital (IT)
- University Children's Hospital Zurich (CH)
- Jena University Hospital (DE)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
Publication Details
- Journal
- npj Metabolic Health and Disease
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1038/s44324-025-00051-8
- Primary Topic
- Metabolism and Genetic Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Universität Zürich
- Citrin Foundation