Journal of Inherited Metabolic Disease

, Volume 35, Issue 6, pp 983–992 | Cite as

Tetrahydrobiopterin (BH4) in PKU: effect on dietary treatment, metabolic control, and quality of life

  • B. Ziesch
  • J. Weigel
  • A. Thiele
  • U. Mütze
  • C. Rohde
  • U. Ceglarek
  • J. Thiery
  • W. Kiess
  • S. Beblo
Original Article



Tetrahydrobiopterin (BH4)-sensitive phenylketonuria (PKU) can be treated with sapropterin dihydrochloride. We studied metabolic control and health-related quality of life (HRQoL) in PKU patients treated with BH4.

Subjects and methods

Based on the review of neonatal BH4 test results and mutation analysis in 41 PKU patients, 19 were identified as potentially BH4-sensitive (9 females, 10 males, age 4–18 years). We analyzed phenylalanine (phe) concentrations in dried blood samples, nutrition protocols, and HRQoL questionnaires (KINDL®) beginning from 1 year before, during the first 42 days, and after 3 months of BH4 therapy.


Eight BH4-sensitive patients increased their phe tolerance (629 ± 476 vs. 2131 ± 1084 mg, p = 0.006) while maintaining good metabolic control (phe concentration in dried blood 283 ± 145 vs. 304 ± 136 μM, p = 1.0). Six of them were able to stop dietary protein restriction entirely. BH4-sensitive patients had average HRQoL scores that were comparable to age-matched healthy children. There was no improvement in HRQoL scores after replacing classic dietary treatment with BH4 supply, although personal reports given by the patients and their parents suggest that available questionnaires are inappropriate to detect aspects relevant to inborn metabolic disorders.


BH4 can allow PKU patients to increase their phe consumption significantly or even stop dietary protein restrictions. Unexpectedly, this does not improve HRQoL as assessed with KINDL®, partly due to high scores even before BH4 therapy. Specific questionnaires should be developed for inborn metabolic disorders.


  1. Awiszus D, Unger I (1990) Coping with PKU: results of narrative interviews with parents. Eur J Pediatr 149(Suppl 1):S45–S51Google Scholar
  2. Bernegger C, Blau N (2002) High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002. Mol Genet Metab 77:304–313PubMedCrossRefGoogle Scholar
  3. Bik-Multanowski M, Didycz B, Mozrzymas R et al (2008) Quality of life in noncompliant adults with phenylketonuria after resumption of the diet. J Inherit Metab Dis 31(Suppl 2):S415–418Google Scholar
  4. Bilginsoy C, Waitzman N, Leonard CO, Ernst SL (2005) Living with phenylketonuria: perspectives of patients and their families. J Inherit Metab Dis 28:639–649PubMedCrossRefGoogle Scholar
  5. Bosch AM, Tybout W, van Spronsen FJ, de Valk HW, Wijburg FA, Grootenhuis MA (2007) The course of life and quality of life of early and continuously treated Dutch patients with phenylketonuria. J Inherit Metab Dis 30:29–34PubMedCrossRefGoogle Scholar
  6. Brumm VL, Bilder D, Waisbren SE (2010) Psychiatric symptoms and disorders in phenylketonuria. Mol Genet Metab 99(Suppl 1):S59–S63Google Scholar
  7. Burgard P, Rey F, Rupp A, Abadie V, Rey J (1997) Neuropsychologic functions of early treated patients with phenylketonuria, on and off diet: results of a cross-national and cross-sectional study. Pediatr Res 41:368–374PubMedCrossRefGoogle Scholar
  8. Burlina A, Blau N (2009) Effect of BH(4) supplementation on phenylalanine tolerance. J Inherit Metab Dis 32:40–45PubMedCrossRefGoogle Scholar
  9. Burnett JR (2007) Sapropterin dihydrochloride (Kuvan/phenoptin), an orally active synthetic form of BH4 for the treatment of phenylketonuria. IDrugs 10:805–813PubMedGoogle Scholar
  10. Burton BK, Bausell H, Katz R, Laduca H, Sullivan C (2010) Sapropterin therapy increases stability of blood phenylalanine levels in patients with BH4-responsive phenylketonuria (PKU). Mol Genet Metab 101:110–114PubMedCrossRefGoogle Scholar
  11. Ceglarek U, Muller P, Stach B, Buhrdel P, Thiery J, Kiess W (2002) Validation of the phenylalanine/tyrosine ratio determined by tandem mass spectrometry: sensitive newborn screening for phenylketonuria. Clin Chem Lab Med 40:693–697PubMedCrossRefGoogle Scholar
  12. Elsas LJ, Greto J, Wierenga A (2011) The effect of blood phenylalanine concentration on Kuvan response in phenylketonuria. Mol Genet Metab 102:407–412PubMedCrossRefGoogle Scholar
  13. Fiege B, Blau N (2007) Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr 150:627–630PubMedCrossRefGoogle Scholar
  14. Fiori L, Fiege B, Riva E, Giovannini M (2005) Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. Mol Genet Metab 86(Suppl 1):S67–S74PubMedCrossRefGoogle Scholar
  15. Friedman D, Holmbeck GN, Jandasek B, Zukerman J, Abad M (2004) Parent functioning in families of preadolescents with spina bifida: longitudinal implications for child adjustment. J Fam Psychol 18:609–619PubMedCrossRefGoogle Scholar
  16. Gassio R, Campistol J, Vilaseca MA, Lambruschini N, Cambra FJ, Fuste E (2003) Do adult patients with phenylketonuria improve their quality of life after introduction/resumption of a phenylalanine-restricted diet? Acta Paediatr 92:1474–1478PubMedCrossRefGoogle Scholar
  17. Hartmann B (2009) Bundeslebensmittelschluessel. Max-Rubner-Institut, Karlsruhe
  18. Hatzmann J, Heymans HS, Carbonell A, van Praag BM, Grootenhuis MA (2008) Hidden consequences of success in pediatrics: parental health-related quality of life–results from the Care Project. Pediatrics 122:e1030–e1038PubMedCrossRefGoogle Scholar
  19. Hatzmann J, Maurice-Stam H, Heymans HS, Grootenhuis MA (2009) A predictive model of health related quality of life of parents of chronically ill children: the importance of care-dependency of their child and their support system. Health Qual Life Outcomes 7:72Google Scholar
  20. Hennermann JB, Buhrer C, Blau N, Vetter B, Monch E (2005) Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol Genet Metab 86(Suppl 1):S86–S90PubMedCrossRefGoogle Scholar
  21. Kure S, Hou DC, Ohura T et al (1999) Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J Pediatr 135:375–378PubMedCrossRefGoogle Scholar
  22. Landolt MA, Nuoffer JM, Steinmann B, Superti-Furga A (2002) Quality of life and psychologic adjustment in children and adolescents with early treated phenylketonuria can be normal. J Pediatr 140:516–521PubMedCrossRefGoogle Scholar
  23. Lee P, Treacy EP, Crombez E et al (2008) Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet A 146A:2851–2859PubMedCrossRefGoogle Scholar
  24. Levy HL, Waisbren SE (1994) PKU in adolescents: rationale and psychosocial factors in diet continuation. Acta Paediatr Suppl 407:92–97PubMedCrossRefGoogle Scholar
  25. Lindner M, Haas D, Mayatepek E, Zschocke J, Burgard P (2001) Tetrahydrobiopterin responsiveness in phenylketonuria differs between patients with the same genotype. Mol Genet Metab 73:104–106PubMedCrossRefGoogle Scholar
  26. Macdonald A (2000) Diet and compliance in phenylketonuria. Eur J Pediatr 159(Suppl 2):S136–S141Google Scholar
  27. Macdonald A, Gokmen-Ozel H, van Rijn M, Burgard P (2010) The reality of dietary compliance in the management of phenylketonuria. J Inherit Metab Dis 33:665–670PubMedCrossRefGoogle Scholar
  28. Muntau AC, Roschinger W, Habich M et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347:2122–2132PubMedCrossRefGoogle Scholar
  29. Mütze U, Roth A, Weigel JF et al (2011) Transition of young adults with phenylketonuria from pediatric to adult care. J Inherit Metab Dis 34(3):701–709Google Scholar
  30. Pey AL, Perez B, Desviat LR et al (2004) Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations. Hum Mutat 24:388–399PubMedCrossRefGoogle Scholar
  31. Pietz J, Dunckelmann R, Rupp A et al (1998) Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 157:824–830PubMedCrossRefGoogle Scholar
  32. Prince AP, McMurray MP, Buist NR (1997) Treatment products and approaches for phenylketonuria: improved palatability and flexibility demonstrate safety, efficacy and acceptance in US clinical trials. J Inherit Metab Dis 20:486–498PubMedCrossRefGoogle Scholar
  33. Ravens-Sieberer U, Ellert U, Erhart M (2007) Health-related quality of life of children and adolescents in Germany. Norm data from the German Health Interview and Examination Survey (KiGGS). Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 50:810–818PubMedCrossRefGoogle Scholar
  34. Scriver CR, Kaufman S, Eisensmith RC, Woo SLC (1998) The hyperphenylalaninemias. In: Scriver RC, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 1015–1075Google Scholar
  35. Shintaku H, Kure S, Ohura T et al (2004) Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene. Pediatr Res 55:425–430PubMedCrossRefGoogle Scholar
  36. Simon E, Schwarz M, Roos J et al (2008) Evaluation of quality of life and description of the sociodemographic state in adolescent and young adult patients with phenylketonuria (PKU). Health Qual Life Outcomes 6:25Google Scholar
  37. Stemerdink BA, Kalverboer AF, van der Meere JJ et al (2000) Behaviour and school achievement in patients with early and continuously treated phenylketonuria. J Inher Metab Dis 23:548–562PubMedCrossRefGoogle Scholar
  38. Ten Hoedt AE, Maurice-Stam H, Boelen CC et al (2011) Parenting a child with phenylketonuria or galactosemia: implications for health-related quality of life. J Inherit Metab Dis 34:391–398PubMedCrossRefGoogle Scholar
  39. Thompson AJ, Smith I, Brenton D et al (1990) Neurological deterioration in young adults with phenylketonuria. Lancet 336:602–605PubMedCrossRefGoogle Scholar
  40. Trefz FK, Burton BK, Longo N et al (2009) Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr 154:700–707PubMedCrossRefGoogle Scholar
  41. Wallander JL, Varni JW (1998) Effects of pediatric chronic physical disorders on child and family adjustment. J Child Psychol Psychiatry 39:29–46PubMedCrossRefGoogle Scholar
  42. Weglage J, Funders B, Wilken B et al (1992) Psychological and social findings in adolescents with phenylketonuria. Eur J Pediatr 151:522–525PubMedCrossRefGoogle Scholar
  43. Zurfluh MR, Zschocke J, Lindner M et al (2008) Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat 29:167–175PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • B. Ziesch
    • 1
  • J. Weigel
    • 1
  • A. Thiele
    • 3
  • U. Mütze
    • 1
  • C. Rohde
    • 1
  • U. Ceglarek
    • 2
  • J. Thiery
    • 2
  • W. Kiess
    • 1
  • S. Beblo
    • 1
    • 4
  1. 1.University Hospital for Children and AdolescentsUniversity of LeipzigLeipzigGermany
  2. 2.Institute of Laboratory Medicine, Clinical Chemistry and Molecular DiagnosticsUniversity of LeipzigLeipzigGermany
  3. 3.Institute for Nutritional SciencesUniversity of Halle-WittenbergHalleGermany
  4. 4.Universitätskinderklinik und PoliklinikLeipzigGermany

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