H Blasco1,2, C Veyrat-Durebex3,4, M Bertrand5, F Patin3,4, F Labarthe6,7, H Henique8, P Emond4, C R Andres3,4, C Antar3,4, C Landon5, L Nadal-Desbarats4, F Maillot7,8. 1. Laboratoire de biochimie et biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours cedex 1, France. helene.blasco@univ-tours.fr. 2. INSERM U930, Université François Rabelais Tours, Tours cedex 1, France. helene.blasco@univ-tours.fr. 3. Laboratoire de biochimie et biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours cedex 1, France. 4. INSERM U930, Université François Rabelais Tours, Tours cedex 1, France. 5. Centre de Biophysique Moléculaire, CNRS UPR4301, Orléans, France. 6. Service de Pédiatrie, CHRU de Tours, Tours cedex 1, France. 7. INSERM U1069, Université François Rabelais Tours, Tours cedex 1, France. 8. Service de médecine interne, CHRU de Tours, Tours cedex 1, France.
Abstract
BACKGROUND: Different pathophysiological mechanisms have been described in phenylketonuria (PKU) but the indirect metabolic consequences of metabolic disorders caused by elevated Phe or low Tyr concentrations remain partially unknown. We used a multiplatform metabolomics approach to evaluate the metabolic signature associated with Phe and Tyr. MATERIAL AND METHODS: We prospectively included 10 PKU adult patients and matched controls. We analysed the metabolome profile using GC-MS (urine), amino-acid analyzer (urine and plasma) and nuclear magnetic resonance spectroscopy (urine). We performed a multivariate analysis from the metabolome (after exclusion of Phe, Tyr and directly derived metabolites) to explain plasma Phe and Tyr concentrations, and the clinical status. Finally, we performed a univariate analysis of the most discriminant metabolites and we identified the associated metabolic pathways. RESULTS: We obtained a metabolic pattern from 118 metabolites and we built excellent multivariate models to explain Phe, Tyr concentrations and PKU diagnosis. Common metabolites of these models were identified: Gln, Arg, succinate and alpha aminobutyric acid. Univariate analysis showed an inverse correlation between Arg, alpha aminobutyric acid and Phe and a positive correlation between Arg, succinate, Gln and Tyr (p < 0.0003). Thus, we highlighted the following pathways: Arg and Pro, Ala, Asp and Glu metabolism. DISCUSSION: We obtain a specific metabolic signature related to Tyr and Phe concentrations. We confirmed the involvement of different pathophysiological mechanisms previously described in PKU such as protein synthesis, energetic metabolism and oxidative stress. The metabolomics approach is relevant to explore PKU pathogenesis.
BACKGROUND: Different pathophysiological mechanisms have been described in phenylketonuria (PKU) but the indirect metabolic consequences of metabolic disorders caused by elevated Phe or low Tyr concentrations remain partially unknown. We used a multiplatform metabolomics approach to evaluate the metabolic signature associated with Phe and Tyr. MATERIAL AND METHODS: We prospectively included 10 PKU adult patients and matched controls. We analysed the metabolome profile using GC-MS (urine), amino-acid analyzer (urine and plasma) and nuclear magnetic resonance spectroscopy (urine). We performed a multivariate analysis from the metabolome (after exclusion of Phe, Tyr and directly derived metabolites) to explain plasma Phe and Tyr concentrations, and the clinical status. Finally, we performed a univariate analysis of the most discriminant metabolites and we identified the associated metabolic pathways. RESULTS: We obtained a metabolic pattern from 118 metabolites and we built excellent multivariate models to explain Phe, Tyr concentrations and PKU diagnosis. Common metabolites of these models were identified: Gln, Arg, succinate and alpha aminobutyric acid. Univariate analysis showed an inverse correlation between Arg, alpha aminobutyric acid and Phe and a positive correlation between Arg, succinate, Gln and Tyr (p < 0.0003). Thus, we highlighted the following pathways: Arg and Pro, Ala, Asp and Glu metabolism. DISCUSSION: We obtain a specific metabolic signature related to Tyr and Phe concentrations. We confirmed the involvement of different pathophysiological mechanisms previously described in PKU such as protein synthesis, energetic metabolism and oxidative stress. The metabolomics approach is relevant to explore PKU pathogenesis.
Authors: Hana Janečková; Karel Hron; Petr Wojtowicz; Eva Hlídková; Anna Barešová; David Friedecký; Lenka Zídková; Petr Hornik; Darina Behúlová; Dagmar Procházková; Hana Vinohradská; Karolína Pešková; Per Bruheim; Vratislav Smolka; Sylvie Sťastná; Tomáš Adam Journal: J Chromatogr A Date: 2011-10-04 Impact factor: 4.759
Authors: Rianne Jahja; Stephan C J Huijbregts; Leo M J de Sonneville; Jaap J van der Meere; Francjan J van Spronsen Journal: J Pediatr Date: 2014-01-30 Impact factor: 4.406