Skip to main content

Advertisement

SpringerLink
Log in

Altered tetrahydrobiopterin metabolism in patients with phenylalanine hydroxylase deficiency

  • Original Article
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ANCOVA:

Analysis of covariance

BH4 :

6R-l-erythro-5,6,7,8-tetrahydrobiopterin

ESI-MS/MS:

Electro-spray ionization tandem mass spectrometry

GTPCH:

GTP cyclohydrolase 1

GFRP:

GTPCH feedback regulatory protein

Phe:

Phenylalanine

Tyr:

Tyrosine

VIF:

Variance inflation factor

References

  1. Antonozzi I, Carducci C, Vestri L, Pontecorvi A, Moretti F (1988) Rapid and sensitive method for high-performance liquid chromatographic analysis of pterins in biological fluids. J Chromatogr 459:319–324

    Article  CAS  PubMed  Google Scholar 

  2. Blau N, Van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376:1417–1427

    Article  CAS  PubMed  Google Scholar 

  3. Chace DH, Millington DS, Terada N, Kahler SG, Roe CR, Hofman LF (1993) Rapid diagnosis of phenylketonuria by quantitative analysis for phenylalanine and tyrosine in neonatal blood spots by tandem mass spectrometry. Clin Chem 39(1):66–71

    CAS  PubMed  Google Scholar 

  4. Dhondt JL, Ardouin P, Hayte JM, Farriaux JP (1981) Developmental aspects of pteridine metabolism and relationships with phenylalanine metabolism. Clin Chim Acta 116(2):143–152

    Article  CAS  PubMed  Google Scholar 

  5. Dobrowolski SF, Lyons-Weiler J, Spridik K, Biery A, Breck J, Vockley J, Yatsenko S, Sultana T (2015) Altered DNA methylation in PAH deficient phenylketonuria. Mol Genet Metab 115(2–3):72–77. doi:10.1016/j.ymgme.2015.04.002

    Article  CAS  PubMed  Google Scholar 

  6. Häberle DA, Schiffl H, Mayer G, Hennings G, Rembold H (1978) Renal balance of pterin cofactors in the rat. A clearance and micropuncture study. Pflugers Arch 375(1):9–16

    Article  PubMed  Google Scholar 

  7. Harada T, Kagamiyama H, Hatakeyama K (1993) Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity. Science 260:1507–1510

    Article  CAS  PubMed  Google Scholar 

  8. Kaufman S (1963) The structure of the phenylalanine-hydroxylation cofactor. Proc Natl Acad Sci U S A 50:1085–1093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Leeming RJ, Blair JA, Green A, Raine DN (1976) Biopterin derivatives in normal and phenylketonuric patients after oral loads of L-phenylalanine, L-tyrosine, and L-tryptophan. Arch Dis Child 51(10):771–777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Leeming RJ, Hall SK, Surplice IM, Green A (1990) Relationship between plasma and red cell biopterins in acute and chronic hyperphenylalaninaemia. J Inherit Metab Dis 13(6):883–887

    Article  CAS  PubMed  Google Scholar 

  11. Bitsori M (2012) The development of renal function. Essentials in pediatric urology, pp 9–20. ISBN: 978-81-308-0511-5 Editor: George Sakellaris

  12. Mastrangelo M, Chiarotti F, Berillo L, Caputi C, Carducci C, Di Biasi C, Manti F, Nardecchia F, Leuzzi V (2015) The outcome of white matter abnormalities in early treated phenylketonuric patients: a retrospective longitudinal long-term study. Mol Genet Metab 116(3):171–177

    Article  CAS  PubMed  Google Scholar 

  13. Murr C, Widner B, Wirleitner B, Fuchs D (2002) Neopterin as a marker for immune system activation. Curr Drug Metab 3(2):175–187

    Article  CAS  PubMed  Google Scholar 

  14. Nardecchia F, Manti F, Chiarotti F, Carducci C, Carducci C, Leuzzi V (2015) Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: a longitudinal study. Mol Genet Metab 115(2):84–90

    Article  CAS  PubMed  Google Scholar 

  15. Niederwieser A, Curtius HC, Gitzelmann R, Otten A, Baerlocher K, Blehovà B, Berlow S, Gröbe H, Rey F, Schaub J, Scheibenreiter S, Schmidt H, Viscontini M (1980) Excretion of pterins in phenylketonuria and phenylketonuria variants. Helv Paediatr Acta 35(4):335–342

    CAS  PubMed  Google Scholar 

  16. Opladen T, Abu Seda B, Rassi A, Thöny B, Hoffmann GF, Blau N (2011) Diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots: further development of the method and 5 years experience. J Inherit Metab Dis 34(3):819–826. doi:10.1007/s10545-011-9300-1

    Article  CAS  PubMed  Google Scholar 

  17. Ponzone A, Guardamagna O, Spada M, Ponzone R, Sartore M, Kierat L, Heizmann CW, Blau N (1993) Hyperphenylalaninemia and pterin metabolism in serum and erythrocytes. Clin Chim Acta 216(1–2):63–71

    Article  CAS  PubMed  Google Scholar 

  18. Scriver CR, Waters PJ (1999) Monogenic traits are not simple: lessons from phenylketonuria. Trends Genet 15(7):267–272

    Article  CAS  PubMed  Google Scholar 

  19. van Spronsen FJ, van Wegberg AM, Ahring K, Belanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Gizewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, Trefz FK, van Rijn M, Walter JH, MacDonald A (2017) Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(16)30320-5

  20. van Vliet D, Anjema K, Jahja R, de Groot MJ, Liemburg GB, Heiner-Fokkema MR, van der Zee EA, Derks TG, Kema IP, van Spronsen FJ (2015) BH4 treatment in BH4-responsive PKU patients: preliminary data on blood prolactin concentrations suggest increased cerebral dopamine concentrations. Mol Genet Metab 114(1):29–33. doi:10.1016/j.ymgme.2014.11.009

    Article  PubMed  Google Scholar 

  21. Yano S, Moseley K, Fu X, Azen C (2016) Evaluation of tetrahydrobiopterin therapy with large neutral amino acid supplementation in phenylketonuria: effects on potential peripheral biomarkers, melatonin and dopamine, for brain monoamine neurotransmitters. PLoS One 11(8):e0160892. doi:10.1371/journal.pone.0160892

    Article  PubMed  PubMed Central  Google Scholar 

  22. Yoneyama T, Hatakeyama K (1998) Decameric GTP cyclohydrolase I forms complexes with two pentameric GTP cyclohydrolase I feedback regulatory proteins in the presence of phenylalanine or of a combination of tetrahydrobiopterin and GTP. J Biol Chem 273:20102–20108

    Article  CAS  PubMed  Google Scholar 

  23. Zurflüh MR, Giovannini M, Fiori L, Fiege B, Gokdemir Y, Baykal T, Kierat L, Gärtner KH, Thöny B, Blau N (2005) Screening for tetrahydrobiopterin deficiencies using dried blood spots on filter paper. Mol Genet Metab (Suppl 1):S96–103

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Child Neurology and Psychiatry, SAPIENZA University of Rome, Via dei Sabelli 108, 00185, Rome, Italy

    Francesca Nardecchia, Giulia Valentini & Vincenzo Leuzzi

  2. Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Flavia Chiarotti

  3. Department of Experimental Medicine, SAPIENZA University of Rome, Viale del Policlinico 155, 00161, Rome, Italy

    Claudia Carducci, Silvia Santagata & Antonio Angeloni

  4. Dietmar-Hopp-Metabolic Center, University Children’s Hospital, Heidelberg, Germany

    Nenad Blau

Authors
  1. Francesca Nardecchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Flavia Chiarotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia Carducci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvia Santagata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giulia Valentini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Angeloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nenad Blau
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vincenzo Leuzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Vincenzo Leuzzi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

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.

Additional information

Communicated by Peter de Winter

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nardecchia, F., Chiarotti, F., Carducci, C. et al. Altered tetrahydrobiopterin metabolism in patients with phenylalanine hydroxylase deficiency. Eur J Pediatr 176, 917–924 (2017). https://doi.org/10.1007/s00431-017-2932-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-017-2932-x

Keywords

Search

Navigation