European Journal of Pediatrics

, Volume 176, Issue 7, pp 917–924 | Cite as

Altered tetrahydrobiopterin metabolism in patients with phenylalanine hydroxylase deficiency

  • Francesca Nardecchia
  • Flavia Chiarotti
  • Claudia Carducci
  • Silvia Santagata
  • Giulia Valentini
  • Antonio Angeloni
  • Nenad Blau
  • Vincenzo LeuzziEmail author
Original Article


The tetrahydrobiopterin (BH4) cofactor is essential for the activity of various enzymes, including phenylalanine (Phe) hydroxylase. In phenylketonuria (PKU) patients, who are chronically exposed to high Phe levels, high urinary excretion of BH4 metabolites neopterin and biopterin is observed. The aim of this longitudinal study was to investigate consistence and variability of the urinary excretion of pterins (neopterin and biopterin) in PKU patients in relation to age and concomitant blood Phe and tyrosine levels. The study was based on the result of 274 pterin examinations (3–13 exams per subject) performed in 47 PKU patients (aged 6 days to 37 years). Multivariate analysis showed that urinary biopterin and neopterin excretion was affected by age and concomitant blood Phe concentration. The influence of blood Phe on both biopterin and neopterin levels was greater in patients younger than 4 months. Later on, interindividual variability was higher than intraindividual variability for both biopterin and neopterin.

Conclusion: Common metabolic (blood Phe levels) and individual (age) factors implicated in the assessment of PKU outcome account only marginally and transiently for the variability of neopterin and biopterin excretion in PKU patients. Other unknown homeostatic factors may probably affect the individual response to chronically elevated Phe levels.

What is Known:

• In PKU patients, a high urinary excretion of biopterin and neopterin is found.

• Biopterin and neopterin excretion is influenced by age and phenylalanine levels.

W hat is New:

• Blood phenylalanine concentration is the major determinant on pterin excretion in PKU patients in the first months of life.

• In older PKU patients, the influence of phenylalanine on pterin excretion is less prominent.


Phenylketonuria Tetrahydrobiopterin (BH4Biochemical variability in PKU Biopterin Neopterin 



Analysis of covariance




Electro-spray ionization tandem mass spectrometry


GTP cyclohydrolase 1


GTPCH feedback regulatory protein






Variance inflation factor



This study is supported in part by the Sapienza University AWARDS project Grant prot No. C26H148C2P (to FN, CC, and VL) and the FP7-HEALTH-2012-INNOVATION-1 EU Grant No. 305444 (to NB).

Authors’ Contributions

All authors have seen and agree with the contents of the manuscript and state that the work is not and will not be submitted to any other journal while under consideration by the European Journal of Pediatrics and that there are no prior publications or submissions with any overlapping information.

All authors have each made a substantial contribution so as to qualify for authorship. In details, Francesca Nardecchia wrote the first draft of the manuscript and contributed to the development of the experimental design, the acquisition of data, and the analysis and interpretation of biochemical data; Flavia Chiarotti contributed to the statistical data analysis, the analysis and interpretation of data, and the draft and revision of the manuscript; Claudia Carducci performed the metabolic analysis, contributed to the drafting, and critically revised the manuscript; Silvia Santagata performed the metabolic analysis, contributed to the drafting, and critically revised the manuscript; Giulia Valentini contributed to the acquisition of data, the analysis and interpretation of biochemical data, and the revision of the manuscript; Antonio Angeloni contributed to the interpretation of the data, and critically revised the manuscript; Nenad Blau contributed to the interpretation of the data, and critically revised the manuscript; and Vincenzo Leuzzi contributed to the development of the experimental design, the analysis and interpretation of biochemical data, and the revision of the manuscript.

Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


This study was supported in part by the Sapienza University AWARDS project Grant prot No. C26H148C2P (to FN, CC, and VL) and the FP7-HEALTH-2012-INNOVATION-1 EU Grant No. 305444 (to NB).

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Francesca Nardecchia
    • 1
  • Flavia Chiarotti
    • 2
  • Claudia Carducci
    • 3
  • Silvia Santagata
    • 3
  • Giulia Valentini
    • 1
  • Antonio Angeloni
    • 3
  • Nenad Blau
    • 4
  • Vincenzo Leuzzi
    • 1
    Email author
  1. 1.Department of Pediatrics, Child Neurology and PsychiatrySAPIENZA University of RomeRomeItaly
  2. 2.Department of Cell Biology and NeuroscienceIstituto Superiore di SanitàRomeItaly
  3. 3.Department of Experimental MedicineSAPIENZA University of RomeRomeItaly
  4. 4.Dietmar-Hopp-Metabolic CenterUniversity Children’s HospitalHeidelbergGermany

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