Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Phenylketonuria: a 21st century perspective

Nature Reviews Endocrinology volume 6, pages 509–514 (2010)Cite this article

Subjects

Abstract

Phenylketonuria is the most prevalent inherited defect in amino acid metabolism. Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. Untreated, phenylketonuria causes severe mental retardation, epilepsy and behavioral problems. The combined effect of neonatal screening and treatment has, however, meant that phenylketonuria is now a biochemical rather than a clinical diagnosis. Treatment consists of stringent dietary restriction of natural protein intake and supplementation of amino acids other than phenylalanine by a chemically manufactured protein substitute. Although clinical outcome on a phenylalanine-restricted diet is good, neuropsychological deficits are now known to exist in dietary-treated patients with phenylketonuria, and quality of life, nutritional condition and psychosocial outcome could probably also be improved. The need for new therapeutic approaches is being met by supplementation with tetrahydrobiopterin or large neutral amino acids, whilst development of the use of phenylalanine ammonia lyase, and, in the longer term, gene therapy and chaperone treatment holds promise. This Review provides an overview of the history of phenylketonuria, the challenges of treatment today and the treatment possibilities in the near future.

Key Points

  • Phenylketonuria was the first successfully treated inborn error of metabolism, and with treatment, prevention from mental retardation became possible

  • Essentially, phenylketonuria is now a biochemical rather than a clinical diagnosis, which is largely based on high blood phenylalanine concentrations or phenylalanine to tyrosine ratio found at neonatal screening

  • Conventional treatment for phenylketonuria consists of dietary restriction of phenylalanine, which necessitates a stringent restriction of natural protein with supplementation of all amino acids apart from phenylalanine

  • Problems in the outcome of phenylketonuria are almost completely restricted to the brain, which suggests that the blood–brain barrier is of major importance in the pathophysiology of phenylketonuria

  • Notwithstanding the enormous improvement of neurocognitive outcome on dietary treatment, intelligence quotient and neuropsychological tests show deficits that necessitate improvements in diagnosis and new treatment strategies

  • New therapeutic modalities, including large neutral amino acids and tetrahydrobiopterin, may in part replace dietary restriction, while phenylalanine ammonia lyase, chaperone treatment and gene therapy are in development

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The metabolism of phenylalanine.

Similar content being viewed by others

Article 20 May 2021

Francjan J. van Spronsen, Nenad Blau, … Annet M. Bosch

References

  1. Zschocke, J. Phenylketonuria mutations in Europe. Hum. Mutat. 21, 345–356 (2003).

    Article  CAS  Google Scholar 

  2. Følling I. The discovery of phenylketonuria. Acta Paediatr. 83 (Suppl. 407), S4–S10 (1994).

    Article  Google Scholar 

  3. Bickel, H., Gerrard, J. & Hickmans, E. M. Influence of phenylalanine intake on phenylketonuria. Lancet 265, 812–813 (1953).

    Article  CAS  Google Scholar 

  4. Guthrie, R. & Susi, A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 32, 338–343 (1963).

    CAS  PubMed  Google Scholar 

  5. Loeber, J. G. Neonatal screening in Europe; the situation in 2004. J. Inherit. Metab. Dis. 30, 430–438 (2007).

    Article  Google Scholar 

  6. Zurflüh, M. R. et al. Screening for tetrahydrobiopterin deficiencies using dried blood spots on filter paper. Mol. Genet. Metab. 86 (Suppl. 1), S96–S103 (2005).

    Article  Google Scholar 

  7. van Spronsen, F. J. & Enns, G. M. Future treatment strategies in phenylketonuria. Mol. Gen. Metab. 99 (Suppl. 1), S90–S95 (2010).

    Article  CAS  Google Scholar 

  8. Smith, I., Beasley, M. G. & Ades, A. E. Intelligence and quality of dietary treatment in phenylketonuria. Arch. Dis. Child. 65, 472–478 (1990).

    Article  CAS  Google Scholar 

  9. Verkerk, P. H., Vaandrager, G. J. & Sengers R. C. 15 years of national screening for phenylketonuria in The Netherlands; 4th Report of the National Commission for Management of Phenylketonuria [in Dutch]. Ned Tijdschr Geneeskd. 134, 2533–2536 (1990).

    CAS  PubMed  Google Scholar 

  10. Gassió, R. et al. School performance in early and continuously treated phenylketonuria. Pediatr. Neurol. 33, 267–271 (2005).

    Article  Google Scholar 

  11. Huijbregts, S. C. et al. Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria. Neuropsychology 17, 369–379 (2003).

    Article  CAS  Google Scholar 

  12. Christ, S. E, Huijbregts, S. C., de Sonneville, L. M. & White, D. A. Executive function in early-treated phenylketonuria: Profile and underlying mechanisms. Mol. Gen. Metab. 99 (Suppl. 1), S22–S32 (2010).

    Article  CAS  Google Scholar 

  13. Gentile J. K., Ten Hoedt, A. E. & Bosch, A. M. Psychosocial aspects of PKU: hidden disabilities. Mol. Gen. Metab. 99 (Suppl. 1), S64–S67 (2010).

    Article  CAS  Google Scholar 

  14. van Spronsen, F. J. & Burgard, P. The truth of treating patients with phenylketonuria after childhood: the need for a new guideline. J. Inherit. Metab. Dis. 31, 673–679 (2008).

    Article  CAS  Google Scholar 

  15. Albrecht, J., Garbade, S. F. & Burgard, P. Neuropsychological speed tests and blood phenylalanine levels in patients with phenylketonuria: a meta-analysis. Neurosci. Biobehav. Rev. 33, 414–421 (2009).

    Article  CAS  Google Scholar 

  16. Koch, R. et al. Phenylketonuria in adulthood: A collaborative study. J. Inherit. Metab. Dis. 25, 333–346 (2002).

    Article  CAS  Google Scholar 

  17. Pietz, J. et al. Psychiatric disorders in adult patients with early-treated phenylketonuria. Pediatrics 99, 345–350 (1997).

    Article  CAS  Google Scholar 

  18. Lee, P. J., McKitterick, K., Channon, S. & Leach, A. Improvements in neuropsychometric outcome when re-introducing diet in adulthood in phenylketonuria (PKU). J. Inherit. Metab. Dis. 30 (Suppl. 1), 14 (2007).

    Google Scholar 

  19. Koch, R., Trefz, F. & Waisbren, S. Psychosocial issues and outcomes in maternal PKU. Mol. Gen. Metab. 99 (Suppl. 1), S68–S74 (2010).

    Article  CAS  Google Scholar 

  20. Laclair, C. E., Ney, D. M., MacLeod, E. L. & Etzel, M. R. Purification and use of glycomacropeptide for nutritional management of phenylketonuria. J. Food Sci. 74, E199–E206 (2009).

    Article  CAS  Google Scholar 

  21. Ney, D. M. et al. Nutritional management of PKU with glycomacropeptide from cheese whey. J. Inherit. Metab. Dis. 32, 32–39 (2009).

    Article  CAS  Google Scholar 

  22. Lim, K., van Calcar, S. C., Nelson, K. L., Gleason, S. T. & Ney, D. M. Acceptable low-phenylalanine foods and beverages can be made with glycomacropeptide from cheese whey for individuals with PKU. Mol. Genet. Metab. 92, 176–178 (2007).

    Article  CAS  Google Scholar 

  23. van Calcar, S. C. et al. Improved nutritional management of phenylketonuria by using a diet containing glycomacropeptide compared with amino acids. Am. J. Clin. Nutr. 89, 1068–1077 (2009).

    Article  CAS  Google Scholar 

  24. Andersen, A. E. & Avins, L. Lowering brain phenylalanine levels by giving other large neutral amino acids. A new experimental therapeutic approach to phenylketonuria. Arch. Neurol. 33, 684–686 (1976).

    Article  CAS  Google Scholar 

  25. Pietz, J. et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J. Clin. Invest. 103, 1169–1178 (1999).

    Article  CAS  Google Scholar 

  26. Moats, R. A., Moseley, K. D., Koch, R. & Nelson, M. Jr. Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults. Pediatrics 112, 1575–1579 (2003).

    PubMed  Google Scholar 

  27. Schindeler, S. et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol. Genet. Metab. 91, 48–54 (2007).

    Article  CAS  Google Scholar 

  28. Lou, H. Large doses of tryptophan and tyrosine as potential therapeutic alternative to dietary phenylalanine restriction in phenylketonuria. Lancet 2, 150–151 (1985).

    Article  CAS  Google Scholar 

  29. Matalon, R. et al. Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. J. Inherit. Metab. Dis. 30, 153–158 (2007).

    Article  CAS  Google Scholar 

  30. Kaufman, S. & Milstien, S. Phenylketonuria and its variants. Ann. Clin. Lab. Sci. 7, 178–185 (1977).

    CAS  PubMed  Google Scholar 

  31. Kure, S. et al. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J. Pediatr. 135, 375–378 (1999).

    Article  CAS  Google Scholar 

  32. Burton, B. K. et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study. J. Inherit. Metab. Dis. 30, 700–707 (2007).

    Article  CAS  Google Scholar 

  33. Muntau, A. C. et al. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N. Engl. J. Med. 347, 2122–2132 (2002).

    Article  CAS  Google Scholar 

  34. Levy, H., Burton, B., Cederbaum, S. & Scriver, C. Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment. Mol. Genet. Metab. 92, 287–291 (2007).

    Article  CAS  Google Scholar 

  35. Bernegger, C. & Blau, N. High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002. Mol. Genet. Metab. 77, 304–313 (2002).

    Article  CAS  Google Scholar 

  36. Hennermann, J. B., Bührer, C., Blau, N., Vetter, B. & Mönch, E. Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria. Mol. Genet. Metab. 86 (Suppl. 1), S86–S90 (2005).

    Article  CAS  Google Scholar 

  37. Dobrowolski, S. F. et al. A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin. J. Hum. Genet. 54, 335–339 (2009).

    Article  CAS  Google Scholar 

  38. Pérez, B. et al. Kinetic and stability analysis of PKU mutations identified in BH4-responsive patients. Mol. Genet. Metab. 86 (Suppl. 1), S11–S16 (2005).

    Article  Google Scholar 

  39. Gersting, S. W. et al. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am. J. Hum. Genet. 83, 5–17 (2008).

    Article  CAS  Google Scholar 

  40. Blau, N. et al. Optimizing the use of sapropterin (BH4) in the management of phenylketonuria. Mol. Genet. Metab. 96, 158–163 (2009).

    Article  CAS  Google Scholar 

  41. Sarkissian, C. N. et al. A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc. Natl Acad. Sci. USA 96, 2339–2344 (1999).

    Article  CAS  Google Scholar 

  42. Sarkissian, C. N. et al. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria. Proc. Natl Acad. Sci. USA 105, 20894–20899 (2008).

    Article  CAS  Google Scholar 

  43. Kang, T. S. et al. Converting an injectable protein therapeutic into an oral form: phenylalanine ammonia lyase for phenylketonuria. Mol. Genet. Metab. 99, 4–9 (2010).

    Article  CAS  Google Scholar 

  44. Harding, C. O. et al. Complete correction of hyperphenylalaninemia following liver-directed, recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria. Gene Ther. 13, 457–462 (2006).

    Article  CAS  Google Scholar 

  45. Ding, Z., Georgiev, P. & Thöny, B. Administration-route and gender-independent long-term therapeutic correction of phenylketonuria (PKU) in a mouse model by recombinant adeno-associated virus 8 pseudotyped vector-mediated gene transfer. Gene Ther. 13, 587–593 (2006).

    Article  CAS  Google Scholar 

  46. Ding, Z. et al. Correction of murine PKU following AAV-mediated intramuscular expression of a complete phenylalanine hydroxylating system. Mol. Ther. 16, 673–681 (2008).

    Article  CAS  Google Scholar 

  47. Rebuffat, A., Harding, C. O., Ding, Z. & Thöny, B. Comparison of adeno-associated virus pseudotype 1, 2, and 8 vectors administered by intramuscular injection in the treatment of murine phenylketonuria. Hum. Gene Ther. 21, 463–477 (2010).

    Article  CAS  Google Scholar 

  48. Thöny, B. Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle. J. Inherit. Metab. Dis. doi:10.1007/s10545-010-9044-3.

  49. Gregersen, N., Bross, P., Vang, S. & Christensen, J. H. Protein misfolding and human disease. Annu. Rev. Genomics Hum. Genet. 7, 103–124 (2006).

    Article  CAS  Google Scholar 

  50. Cohen, F. E. & Kelly, J. W. Therapeutic approaches to protein-misfolding diseases. Nature 426, 905–909 (2003).

    Article  CAS  Google Scholar 

  51. Pey, A. L. et al. Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria. J. Clin. Invest. 118, 2858–2867 (2008).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Beatrix Children's Hospital, University Medical Center of Groningen, PO Box 30.001, Groningen, 9700, RB, The Netherlands

    Francjan J. van Spronsen

Authors
  1. Francjan J. van Spronsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares associations with the following companies: Merck Serono (Consultant, Speakers Bureau, Grant/research support), Nutricia (Consultant, Speakers Bureau, Grant/research support).

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Spronsen, F. Phenylketonuria: a 21st century perspective. Nat Rev Endocrinol 6, 509–514 (2010). https://doi.org/10.1038/nrendo.2010.125

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2010.125

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research