Journal of Inherited Metabolic Disease

, Volume 29, Issue 1, pp 38–46 | Cite as

The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency

  • V. Leuzzi
  • C. Carducci
  • C. Carducci
  • F. Chiarotti
  • C. Artiola
  • T. Giovanniello
  • I. Antonozzi
Original Article

Summary

A fall in blood phenylalanine (Phe) after tetrahydrobiopterin (BH4) administration is a common trait in phenylalanine hydroxylase (PAH, EC 1.14.16.1) deficiency (McKusick 261600). To explore the extent and biological correlates of this phenomenon we studied: (a) the spectrum of BH4 response in patients with PAH deficiency; (b) the variability of BH4 response according to the severity of the biochemical phenotype; and (c) the variability of the response to BH4 in subjects with the same genotype. Fifty PAH-deficient subjects (age 1 month–35 years) were enrolled for the study (5 with mild hyperphenylalaninaemia (MHPHE), 15 with mild phenylketonuria (MPKU) and 30 with classic phenylketonuria (CPKU) and underwent an identical schedule of blood samplings 24 h before and after oral BH4 challenge (6(R)-BH4, 20 mg/kg per day), leaving Phe intake unchanged. The effect of BH4 on blood Phe concentration was evaluated according to the percent decrease of Phe during the 24 h following the challenge (criterion a), and as variation exceeding the individual variability of blood Phe (criterion b). The number of BH4-responders according to criterion b was 31 (including all the 14 detected by criterion a): 17 out of 30 CPKU (57%), 9 out of 15 MPKU (60%), and all the MHPHE subjects (χ2 = 3.45, df = 2, p = 0.178). The effect of BH4 showed a large interindividual variability unrelated to diagnostic classification, basal value of blood Phe, maximum percentage of Phe reduction, Phe intake, and genotype. Some inconsistencies were found in patients with identical genotype. The first responsive case homozygous for the severe R408W mutation was found. Two new mutations, Y387X and G352C, were identified (the former was BH4-responsive), and the responsiveness of three already reported mutations (R261Q, D338Y, T92I) was substantiated.

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References

  1. Antonozzi I, Carducci C, Vestri L, Pontecorvi A, Moretti F (1998) Rapid and sensitive method for high-performance liquid chromatographic analysis of pterins in biological fluids. J Chromatogr 459: 319–324.Google Scholar
  2. Bardelli T, Donati MA, Gasperini S, et al (2002) Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in Italian patients with hyperphenylalaninemia. Mol Genet Metab 77: 260–266.CrossRefPubMedGoogle Scholar
  3. Bernegger C, Blau N (2002) High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1919 patients observed from 1988 to 2002. Mol Genet Metab 77: 304–313.CrossRefPubMedGoogle Scholar
  4. Blau N, Erlandsen H(2004) The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 82: 101–111.CrossRefPubMedGoogle Scholar
  5. Blau N, Trefz FK (2002) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency: possible regulation of gene expression in a patient with the homozygous L48S mutation. Mol Genet Metab 75: 186–187.CrossRefPubMedGoogle Scholar
  6. Chehin R, Thorolfsson M, Knappskog PM, et al (1998) Domain structure and stability of human phenylalanine hydroxylase inferred from infrared spectroscopy. FEBS Lett 422: 225–230.CrossRefPubMedGoogle Scholar
  7. Desviat LR, Perez B, Belanger-Quintana A, et al (2004) Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlations with their genotype. Mol Genet Metab 83: 157–162.PubMedGoogle Scholar
  8. Dhondt JL, Ogier H, Benoist JF, Belhesme C, Giraud M (2003) The interpretation of tetrahydrobiopterin loading test in hyperphenylalaninaemia. J Inherit Metab Dis 26 (supplement 2): 18.Google Scholar
  9. Erlandsen H, Stevens RC (2001) A structural hypothesis for BH4 responsiveness in patients with mild forms of hyperphenylalaninaemia and phenylketonuria. J Inherit Metab Dis 24: 213–230.CrossRefPubMedGoogle Scholar
  10. Erlandsen H, Pey AL, Gámez A, et al (2004) Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc Nat Acad Sci USA 101(48): 16903–16908.Google Scholar
  11. Fiege B, Ballhausen D, Kierat L, et al (2003) Plasma tetrahydrobiopterin and its pharmacokinetics following oral administration. Mol Genet Metab 81: 45–51.Google Scholar
  12. Guldberg P, Romano V, Ceratto N, et al (1993) Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for the diagnosis of hyperphenylalaninemia in Southern Europe. Hum Mol Genet 2: 1703–1707.PubMedGoogle Scholar
  13. Hennermann JB, Vetter B, Kulozik AE, Mönch E (2002) Partial and total tetrahydrobiopterin-responsiveness in classical and mild phenylketonuria (PKU). J Inherit Metab Dis 25(supplement 11): 21.Google Scholar
  14. Koch R, Güttler F, Blau N (2002) Mental illness in mild PKU responds to biopterin. Mol Genet Metab 75: 284–286.CrossRefPubMedGoogle Scholar
  15. Kure S, Hou D-C, Ohura T, et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135: 375–378.PubMedGoogle Scholar
  16. Lässker FU, Zschocke J, Blau N, Santer R (2002) Tetrahydrobiopterin responsiveness in phenylketonuria. Two new cases and a review of molecular genetic findings. J Inherit Metab Dis 25: 65–70.CrossRefPubMedGoogle Scholar
  17. Lindner M, Haas D, Zschocke J, Burgard P (2001) Tetrahydrobiopterin responsiveness in phenylketonuria differs between patients with the same genotype. Mol Genet Metab 73: 104–106.CrossRefPubMedGoogle Scholar
  18. Lindner M, Steinfeld R, Burgard P, Schulze A, Mayatepek E, Zschocke J (2003) Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency. Hum Mutat 21: 400.CrossRefPubMedGoogle Scholar
  19. MacDonald A, Rylance GW, Asplin D, Hall SK, Booth IW (1998) Does a single plasma phenylalanine predict quality of control in phyenlketonuria? Arch Dis Child 78: 122–126.PubMedGoogle Scholar
  20. Matalon R, Koch R, Michals-Matalon K, Mosley K, Stevens R (2002) Tretrahydrobiopterin-responsive phenylalanine hydroxylase mutations. J Inherit Metab Dis 25: (supplement I): 23.Google Scholar
  21. Matalon R, Koch R, Michals-Matalon K, et al (2004) Biopterin responsive phenylalanine hydroxylase deficiency. Genet Med 6: 27–32.PubMedGoogle Scholar
  22. Moretti F, Birarelli M, Carducci C, Pontecorvi A, Antonozzi I (1990) Simultaneous high-performance liquid chromatographic determination of amino acids in a dried spot as a neonatal screening test. J Chromatogr 511: 131–136.CrossRefPubMedGoogle Scholar
  23. Muntau AC, Röschinger W, Habich M, et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347: 2122–2132.CrossRefPubMedGoogle Scholar
  24. Scriver CR, Kaufman S (2001) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beadudet Al, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B. assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, vol. 2. New York: McGraw-Hill 1667–1724.Google Scholar
  25. Spaapen LJM, Bakker JA, Velter C, et al (2001) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates. J Inherit Metab Dis 24: 352–358.CrossRefPubMedGoogle Scholar
  26. Spaapen LJM, Rubio-Gozalbo ME (2003) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, state of the art. Mol Genet Metab 77: 260–266.Google Scholar
  27. Steinfeld R, Kohlschutter A, Ullrich K, Lukacs Z (2003) A hypothesis on the biochemical mechanism of BH(4)-responsiveness in phenylalanine hydroxylase deficiency. Amino Acids 25: 63–68.PubMedGoogle Scholar
  28. Trefz FK, Aulea-Scholz C, Blau N (2001) Successful treatment of phenylketonuria by tetrahydrobiopterin. Eur J Pediatr 160: 315.CrossRefPubMedGoogle Scholar
  29. Weglage JM, Grenzebach A, Teeffelen-Heithoff T, et al (2002) Tetrahydrobiopterin responsiveness in a large series of phenylketonuria patients. J Inherit Metab Dis 25: 321–322.PubMedGoogle Scholar

Copyright information

© SSIEM and Springer 2006

Authors and Affiliations

  • V. Leuzzi
    • 1
  • C. Carducci
    • 2
  • C. Carducci
    • 2
  • F. Chiarotti
    • 3
  • C. Artiola
    • 2
  • T. Giovanniello
    • 2
  • I. Antonozzi
    • 2
  1. 1.Department of Child Neurology and PsychiatryUniversity of Rome ‘La Sapienza’RomaItaly
  2. 2.Department of Experimental Medicine and PathologyUniversity of Rome ‘La Sapienza’Rome
  3. 3.Department of Cell Biology and NeurosciencesNational Health InstituteRomeItaly

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