Skip to main content
SpringerLink
Log in

Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase-deficient hyperphenylalaninaemia

  • Newborn Screening
  • Published:
Journal of Inherited Metabolic Disease

Summary

In recent years several studies on tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency have been published. The molecular mechanisms of BH4 responsiveness are not conclusively understood, but there is evidence that BH4 responsiveness in hyperphenylalaninaemia (HPA) depends on the patient’s genotype and residual PAH activity. As a BH4 preparation will soon obtain marketing approval as an alternative treatment for phenylketonuria (PKU), it is particularly important to evaluate this treatment and to define criteria to identify patients with a potential benefit from it. Most of the patients found to be BH4-responsive suffered from mild PKU or mild hyperphenylalaninaemia (MHP) and some of these would not be treated at all in many countries. Of patients with moderate and classic forms of PKU, only a few were classified as responders and the clinical significance of the effect size may be small.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abadie V, Berthelot J, Feillet F, et al (2005) Management of phenylketonuria and hyperphenylalaninemia: the French guidelines. Arch Pédiatr 12: 594–601.

    Article  PubMed  CAS  Google Scholar 

  • American Academy of Pediatrics (2001) Committee on Genetics. Pediatrics 107: 427–428.

    Article  Google Scholar 

  • Bélanger-Quintana A, García MJ, Castro M, et al (2005) Spanish BH4-responsive phenylalanine hydroxylase-deficient patients: evolution of seven patients on long-term treatment with tetrahydrobiopterin. Mol Genet Metab 86: S61–66.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Blaskovics ME, Schaeffler GE, Hack S (1974) Phenylalaninemia: differential diagnosis. Arch Dis Child 49: 835–843.

    Article  PubMed  CAS  Google Scholar 

  • Burgard P, Schmidt E, Rupp A, Schneider W, Bremer HJ (1996) Intellectual development of the patients of the German collaborative study of children treated for phenylketonuria. Eur J Pediatr 155: S33–38.

    Article  PubMed  Google Scholar 

  • Blau N (2004) BIOPKU: International Database of Patients and Mutations Causing Tetrahydrobiopterin-responsive HPA/PKU, 2004. Retrieved from <http://www.bh4.org> 19.05.2007.

  • Blau N (2006) Differenzialdiagnose der Hyperphenylalaninämien. Screening auf angeborene Stoffwechselkrankheiten. Kinder- und Jugendmedizin 6: 225–232.

    Google Scholar 

  • Blau N, Erlandsen H (2004) The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 82: 101–111.

    Article  PubMed  CAS  Google Scholar 

  • Burgard P, Bremer HJ, Bührdel P, et al (1999) Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr 158: 46–54.

    Article  PubMed  CAS  Google Scholar 

  • Desviat LR, Perez B, Belanger-Quintana A, et al (2004) Tetrahydrobiopterin responsiveness: results of the BH4 loading in 31 Spanish PKU patients and correlation with their genotype. Mol Genet Metab 83: 157–162.

    Article  PubMed  CAS  Google Scholar 

  • Erlandsen H (2006) Molecular mechanisms of tetrahydrobiopterin-responsiveness. In: Blau N, ed. PKU and BH4, Advances in Phenylketonuria and Tetrahydrobiopterin. Heilbronn: SPS Verlagsgesellschaft, 376–400.

    Google Scholar 

  • Erlandsen H, Stevens RC (1999) The structural basis of phenylketonuria. Mol Genet Metab 68: 103–125.

    Article  PubMed  CAS  Google Scholar 

  • Erlandsen H, Fusetti F, Martinez A, Hough E, Flatmark T, Stevens RC (1997) Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria. Nat Struct Biol 4: 995–1000.

    Article  PubMed  CAS  Google Scholar 

  • Fiege B, Ballhausen D, Kierat L, et al (2004) Plasma tetrahydrobiopterin and its pharmacokinetics following oral administration. Mol Genet Metab 81: 45–51.

    Article  PubMed  CAS  Google Scholar 

  • Fiori L, Fiege B, Riva E, Giovannini M (2005) Incidence of BH4-responsiveness in phenylalanine-hydroxylase deficient Italian patients. Mol Genet Metab 86: S67–74.

    Article  PubMed  CAS  Google Scholar 

  • Fusetti F, Erlandsen H, Flatmark T, Stevens RC (1998) Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria. J Biol Chem 273: 16962–16967.

    Article  PubMed  CAS  Google Scholar 

  • Güttler F (1980) Hyperphenylalaninemia: diagnosis and classification of the various types of phenylalanine hydroxylase deficiency. Acta Paediatr Scand 280 (Supplement): 1–80.

    Google Scholar 

  • Güttler F, Azen C, Guldberg P, et al (1999) Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: Report from the Maternal Phenylketonuria Collaborative Study. Pediatrics 104: 258–262.

    Article  PubMed  Google Scholar 

  • Güttler F, Guldberg P (2000) Mutation analysis anticipates dietary requirements in phenylketonuria. Eur J Pediatr 159 (Supplement): S150–S153.

    Article  PubMed  Google Scholar 

  • Guldberg P, Rey F, Zschocke J, et al (1998) A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet 63: 71–79.

    Article  PubMed  CAS  Google Scholar 

  • Hennermann JB, Bührer C, Blau N, Vetter B, Mönch E (2005) Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab 86: S86–90.

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann GF, Machill G (1994) 25 Jahre Neugeborenenscreening auf angeborene Stoffwechselstörungen in Deutschland. Monatsschr Kinderheilkd 142: 857–862.

    Google Scholar 

  • Koch R, Moseley K, Guttler F (2005) Tetrahydrobiopterin and maternal PKU. Mol Genet Metab 86: S139–141.

    Article  PubMed  CAS  Google Scholar 

  • Kure S, Hou DC, Ohura T, et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135: 375–378.

    Article  PubMed  CAS  Google Scholar 

  • Lambruschini N, Perez-Duenaz B, Vilaseca MA, et al (2005) Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab 86: S54–S60.

    Article  PubMed  CAS  Google Scholar 

  • Leitlinien Kinderheilkunde und Jugendmedizin (1997) No. 027/002. Phenylketonurie, Maternale Hyperphenylalaninämie, Tetrahydrobiopterin (BH4)–Stoffwechselstörungen: www.awmf-online.de.

  • Leuzzi V, Carducci C, Chiarotti F, Artiola C, Giovanniello T, Antonozzi I (2006) The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency. J Inherit Metab Dis 29: 38–46.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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(4): 400.

    Article  PubMed  CAS  Google Scholar 

  • Lutz P, Schmidt H, Frey G, Bickel H (1982) Standardized loading test with protein for the differentiation of phenylketonuria from hyperphenylalaninemia. J Inherit Metab Dis 5: 29–35.

    Article  PubMed  CAS  Google Scholar 

  • Lutz P, Schmidt H, Batzler U (1990) Study design and description of patients. Eur J Pediatr 149(Supplement 1): 5–12.

    Article  Google Scholar 

  • MacDonald A (2000) Diet and compliance in phenylketonuria. Eur J Pediatr 159: S136–141.

    Article  PubMed  CAS  Google Scholar 

  • MacDonald A, Harris G, Rylance G, Asplin DA, Booth IW (1997) Abnormal feeding behaviour in phenylketonuria. J Hum Nutr Diet 10: 163–170.

    Article  Google Scholar 

  • Matalon R, Koch R, Michals-Matalon K, et al (2004) Biopterin responsive phenylalanine hydroxylase deficiency. Genet Med 6(1): 27–32.

    Article  PubMed  CAS  Google Scholar 

  • Matalon R, Michals-Matalon K, Koch R, Grady J, Tyring S, Stevens RC (2005) Response of patients with phenylketonuria in the US to tetrahydrobiopterin. Mol Genet Metab 86: S17–21.

    Article  PubMed  CAS  Google Scholar 

  • Medical Research Council Working Party on Phenylketonuria (1993) Recommendations on the dietary management of phenylketonuria. Arch Dis Child 68: 426–427.

    Google Scholar 

  • Muntau A, Roschinger W, Habich M, et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylkentonuria. N Engl J Med 347: 2122–2132.

    Article  PubMed  CAS  Google Scholar 

  • Muntau AC, Gersting SW (2006) Treatment of patients with tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. In: Blau N, ed. PKU and BH4, Advances in Phenylketonuria and Tetrahydrobiopterin. Heilbronn: SPS Verlagsgesellschaft, 104–119.

    Google Scholar 

  • National Institutes of Health Consensus Developement Conference Statement (2001) Phenylketonuria: screening and management. 2000 Oct. 16–18. Pediatrics 108: 972–982.

    Article  Google Scholar 

  • Niederwieser A, Matasovic A, Staudenmann W, Wang M, Curtius HC (1982) Screening for tetrahydrobiopterin deficiency. In: Wachter H, Curtius HC, Pfleiderer W, eds. Biochemical and Clinical Aspects of Pteridines, vol. 1. Berlin: De Gruyter, 293–306.

    Google Scholar 

  • Niederwieser A, Ponzone A, Curtius HC (1985) Differential diagnosis of tetrahydrobiopterin deficiency. J Inherit Metab Dis 8(Supplement 1): 34–38.

    Article  PubMed  CAS  Google Scholar 

  • Perez-Duenas B, Vilaseca MA, Mas A, et al (2004) Tetrahydrobiopterin responsiveness in patients with phenylketonuria. Clin Biochem 37: 1083–1090.

    Article  PubMed  CAS  Google Scholar 

  • Scriver CR, Kaufman S (2001) Hyperphenylalaninemias: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 1667–1724.

    Google Scholar 

  • Shintaku H, Kure S, Ohura T, et al (2003) Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene. Pediatr Res 55: 1–6.

    Google Scholar 

  • Trefz F, Blau N (2003) Potential role of tetrahydrobiopterin in the treatment of maternal phenylketonuria. Pediatrics 112: 1566–1569.

    PubMed  Google Scholar 

  • Walter JH, White FJ, Hall SK, et al (2002) How practical are recommendations for dietary control in phenylketonuria? Lancet 360: 55–57.

    Article  PubMed  CAS  Google Scholar 

  • Weglage J, Funders B, Ullrich K, Rupp A, Schmidt E (1996) Psychosocial aspects in phenylketonuria. Eur J Pediatr 155: S101–104.

    Article  PubMed  Google Scholar 

  • Zurflüh MR, Fiori L, Fiege B, et al (2006) Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency. J Inherit Metab Dis 29(6): 725–731.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Zentrum für Kinder- und Jugendmedizin, Heidelberg, Germany

    G. Gramer, P. Burgard, S. F. Garbade & M. Lindner

  2. METABNET: Netzwerk für im Neugeborenen-Screening erfassbare seltene genetische Stoffwechselstörungen, Heidelberg, Germany

    G. Gramer, P. Burgard, S. F. Garbade & M. Lindner

  3. Stoffwechselzentrum Heidelberg, Sektion für angeborene Stoffwechselkrankheiten, Zentrum für Kinder- und Jugendmedizin, INF 150, D-69120, Heidelberg, Germany

    M. Lindner

Authors
  1. G. Gramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Burgard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. F. Garbade
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Lindner.

Additional information

Communicating editor: Rodney Pollitt

Competing interests: None declared

References to electronic databases: Phenylketonuria (PKU), OMIM #261600; phenylalanine hydroxylase (PAH),EC 1.14.16.1).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gramer, G., Burgard, P., Garbade, S.F. et al. Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase-deficient hyperphenylalaninaemia. J Inherit Metab Dis 30, 556–562 (2007). https://doi.org/10.1007/s10545-007-0651-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-007-0651-6

Keywords

Search

Navigation