• John H. Walter
  • Philip J. Lee
  • Peter Burgard


Mutations within the gene for the hepatic enzyme phenylalanine hydroxylase (PAH) and those involving enzymes of pterin metabolism are associated with hyperphenylalaninaemia (HPA). Phenylketonuria (PKU) is caused by a severe deficiency in PAH activity and untreated leads to permanent central nervous system damage. Dietary restriction of phenylalanine (PHE) along with aminoacid, vitamin and mineral supplements, started in the first weeks of life and continued through childhood, is an effective treatment and allows for normal cognitive development. Continued dietary treatment into adulthood with PKU is generally recommended but, as yet, there is insufficient data to know whether this is necessary. Less severe forms of PAH deficiency may or may not require treatment depending on the degree of HPA. High blood levels in mothers with PKU leads to fetal damage. This can be prevented by reducing maternal blood PHE throughout the pregnancy with dietary treatment. Disorders of pterin metabolism lead to both HPA and disturbances in central nervous system amines. Generally they require treatment with oral tetrahydrobiopterin and neurotransmitters.


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  1. 1.
    Folling I (1994) The discovery of phenylketonuria. Acta Paediatr Suppl 407:4–10PubMedCrossRefGoogle Scholar
  2. 2.
    The Maternal Phenylketonuria Collaborative Study: a status report (1994) Nutr Rev 52:390–393Google Scholar
  3. 3.
    Pietz J, Benninger C, Schmidt H et al (1988) Long-term development of intelligence (IQ) and EEG in 34 children with phenylketonuria treated early. Eur J Pediatr 147:361–367PubMedCrossRefGoogle Scholar
  4. 4.
    Kreis R (2000) Comments on in vivo proton magnetic resonance spectroscopy in phenylketonuria. Eur J Pediatr 159[Suppl 2]:S126–S128PubMedCrossRefGoogle Scholar
  5. 5.
    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 pre diction of metabolic phenotype. Am J Hum Genet 63:71–79PubMedCrossRefGoogle Scholar
  6. 6.
    Lichter Konecki U, Rupp A, Konecki DS et al (1994) Relation between phenylalanine hydroxylase genotypes and phenotypic parameters of diagnosis and treatment of hyperphenylalaninaemic disorders. German Collaborative Study of PKU. J Inherit Metab Dis 17:362–365PubMedCrossRefGoogle Scholar
  7. 7.
    Bartholome K, Lutz P, Bickel H (1975) Determination of phenylalanine hydroxylase activity in patients with phenylketonuria and hyperphenylalaninemia. Pediatr Res 9:899–903PubMedGoogle Scholar
  8. 8.
    Trefz FK, Bartholome K, Bickel H et al (1981) In vivo residual activities of the phenylalanine hydroxylating system in phenylketonuria and variants. J Inherit Metab Dis 4:101–102PubMedCrossRefGoogle Scholar
  9. 9.
    Scriver CR, Kaufman S (2001) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1667–1724Google Scholar
  10. 10.
    Anonymous (1993) Recommendations on the dietary management of phenylketonuria. Report of Medical Research Council Working Party on Phenylketonuria. Arch Dis Child 68:426–427Google Scholar
  11. 11.
    Burgard P, Bremer HJ, Buhrdel P et al (1999) Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr 158:46–54PubMedCrossRefGoogle Scholar
  12. 12.
    National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16–18, 2000 (2001) Pediatrics 108:972–982Google Scholar
  13. 13.
    Ding Z, Harding CO, Thony B (2004) State-of-the-art 2003 on PKU gene therapy. Mol Genet Metab 81:3–8PubMedCrossRefGoogle Scholar
  14. 14.
    Sarkissian CN, Shao Z, Blain F et al (1999) A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc Natl Acad Sci U S A 96:2339–2344PubMedCrossRefGoogle Scholar
  15. 15.
    Liu J, Jia X, Zhang J et al (2002) Study on a novel strategy to treatment of phenylketonuria. Artif Cells Blood Substit Immobil Biotechnol 30:243–257PubMedCrossRefGoogle Scholar
  16. 16.
    Koch R, Moseley KD, Yano S et al (2003) Large neutral amino acid therapy and phenylketonuria: a promising approach to treatment. Mol Genet Metab 79:110–113PubMedCrossRefGoogle Scholar
  17. 17.
    Matalon R, Surendran S, Matalon KM et al (2003) Future role of large neutral amino acids in transport of phenylalanine into the brain. Pediatrics 112(6 Pt 2):1570–1574PubMedGoogle Scholar
  18. 18.
    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
  19. 19.
    Blau N, Erlandsen H (2004) The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 82:101–111PubMedCrossRefGoogle Scholar
  20. 20.
    Burgard P, Schmidt E, Rupp A et al (1996) Intellectual development of the patients of the German Collaborative Study of children treated for phenylketonuria. Eur J Pediatr 155[Suppl 1]:S33–S38PubMedCrossRefGoogle Scholar
  21. 21.
    Walter JH, White FJ, Hall SK et al (2002) How practical are recommendations for dietary control in phenylketonuria? Lancet 360: 55–57PubMedCrossRefGoogle Scholar
  22. 22.
    Camfield CS, Joseph M, Hurley T et al (2004) Optimal management of phenylketonuria: a centralized expert team is more successful than a decentralized model of care. J Pediatr 145:53–57PubMedCrossRefGoogle Scholar
  23. 23.
    Smith I, Beasley MG, Ades AE (1990) Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Child 65:472–478PubMedGoogle Scholar
  24. 24.
    Smith I, Beasley MG, Ades AE (1991) Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 66:311–316PubMedCrossRefGoogle Scholar
  25. 25.
    Burgard P, Link R, Schweitzer-Krantz S (2000) Phenylketonuria: evidence-based clinical practice. Summary of the roundtable discussion. Eur J Pediatr 159[Suppl 2]:S163–S168PubMedCrossRefGoogle Scholar
  26. 26.
    Lundstedt G, Johansson A, Melin L et al (2001) Adjustment and intelligence among children with phenylketonuria in Sweden. Acta Paediatr 90:1147–1152PubMedCrossRefGoogle Scholar
  27. 27.
    Welsh M, Pennington B (2000) Phenylketonuria. In: Yeates KO, Ris MD, Taylor HG (eds) Pediatric neuropsychology. Guildford Press, New York, pp 275–299Google Scholar
  28. 28.
    Cleary MA, Walter JH, Wraith JE et al (1995) Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 127:251–255PubMedCrossRefGoogle Scholar
  29. 29.
    Feldmann R, Denecke J, Pietsch M et al (2002) Phenylketonuria: no specific frontal lobe-dependent neuropsychological deficits of early-treated patients in comparison with diabetics. Pediatr Res 51:761–765PubMedCrossRefGoogle Scholar
  30. 30.
    Thompson AJ, Smith I, Brenton D et al (1990) Neurological deterioration in young adults with phenylketonuria. Lancet 336:602–605PubMedCrossRefGoogle Scholar
  31. 31.
    Lee P, Smith I, Piesowicz A et al (1999) Spastic paraparesis after anaesthesia. Lancet 353:554PubMedCrossRefGoogle Scholar
  32. 32.
    Robinson M, White FJ, Cleary MA et al (2000) Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. J Pediatr 136:545–547PubMedCrossRefGoogle Scholar
  33. 33.
    Discussion of Armstrong MD (1957) The relation of biochemical abnormality to the development of mental defect in phenylketonuria. Columbus Ohio: Ross LaboratoriesGoogle Scholar
  34. 34.
    Lenke RR, Levy HL (1980) Maternal phenylketonuria and hyperphenylalaninaemia. An international survey of the outcome of of untreated and treated pregnancies. N Engl J Med 303:1202–1208PubMedCrossRefGoogle Scholar
  35. 35.
    Koch R, Hanley W, Levy H et al (2003) The Maternal Phenylketonuria International Study: 1984–2002. Pediatrics 112(6 Pt 2):1523–1529PubMedGoogle Scholar
  36. 36.
    Lee PJ, Ridout D, Walter JH et al (2005) Maternal phenylketonuria: report from the United Kingdom Registry 1978–97. Arch Dis Child 90:143–146PubMedCrossRefGoogle Scholar
  37. 37.
    Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. Medical Research Council Working Party on Phenylketonuria (1993) BMJ 306:115–119Google Scholar
  38. 38.
    Soltesz G, Harris D, Mackenzie IZ et al (1985) The metabolic and endocrine milieu of the human fetus and mother at 18–21 weeks of gestation. I. Plasma amino acid concentrations. Pediatr Res 19:91–93PubMedGoogle Scholar
  39. 39.
    Lee PJ, Lilburn M, Baudin J (2003) Maternal phenylketonuria: experiences from the United Kingdom. Pediatrics 112(6 Pt 2):1553–1556PubMedGoogle Scholar
  40. 40.
    American Academy of Pediatrics: Maternal phenylketonuria (2001) Pediatrics 107:427–428CrossRefGoogle Scholar
  41. 41.
    Koch R, Hanley W, Levy H et al (2000) Maternal phenylketonuria: an international study. Mol Genet Metab 71:233–239PubMedCrossRefGoogle Scholar
  42. 42.
    Levy HL, Waisbren SE, Guttler F et al (2003) Pregnancy experiences in the woman with mild hyperphenylalaninemia. Pediatrics 112(6 Pt 2):1548–1552PubMedGoogle Scholar
  43. 43.
    Ponzone A, Guardamagna O, Spada M et al (1993) Differential diagnosis of hyperphenylalaninaemia by a combined phenylalaninetetrahydrobiopterin loading test. Eur J Pediatr 152:655–661PubMedCrossRefGoogle Scholar
  44. 44.
    Hyland K, Surtees RA, Heales SJ et al (1993) Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr Res 34:10–14PubMedGoogle Scholar
  45. 45.
    Smith I, Hyland K, Kendall B (1985) Clinical role of pteridine therapy in tetrahydrobiopterin deficiency. J Inherit Metab Dis 8[Suppl 1]:39–45PubMedCrossRefGoogle Scholar
  46. 46.
    Hyland K (1993) Abnormalities of biogenic amine metabolism. J Inherit Metab Dis 16:676–690PubMedCrossRefGoogle Scholar
  47. 47.
    Spada M, Ferraris S, Ferrero GB et al (1996) Monitoring treatment in tetrahydrobiopterin deficiency by serum prolactin. J Inherit Metab Dis 19:231–233PubMedCrossRefGoogle Scholar
  48. 48.
    Schuler A, Kalmanchey R, Barsi P et al (2000) Deprenyl in the treatment of patients with tetrahydrobiopterin deficiencies. J Inherit Metab Dis 23:329–332PubMedCrossRefGoogle Scholar
  49. 49.
    Ponzone A, Spada M, Ferraris S et al (2004) Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev 24:127–150PubMedCrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag Heidelberg 2006

Authors and Affiliations

  • John H. Walter
    • 1
  • Philip J. Lee
    • 2
  • Peter Burgard
    • 3
  1. 1.Willink Biochemical Genetics UnitRoyal Manchester Children’s HospitalPendlebury, ManchesterUK
  2. 2.Charles Dent Metabolic UnitNational Hospital for Neurology & NeurosurgeryLondonUK
  3. 3.Department of General PediatricsUniversitäts-KinderklinikHeidelbergGermany

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