Skip to main content
SpringerLink
Log in

Hyperphenylalaninaemia

  • Chapter
Inborn Metabolic Diseases

Abstract

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.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 159.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Folling I (1994) The discovery of phenylketonuria. Acta Paediatr Suppl 407:4–10

    Article  PubMed  CAS  Google Scholar 

  2. The Maternal Phenylketonuria Collaborative Study: a status report (1994) Nutr Rev 52:390–393

    Google Scholar 

  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 147:361–367

    Article  PubMed  CAS  Google Scholar 

  4. Kreis R (2000) Comments on in vivo proton magnetic resonance spectroscopy in phenylketonuria. Eur J Pediatr 159[Suppl 2]:S126–S128

    Article  PubMed  CAS  Google Scholar 

  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 63:71–79

    Article  PubMed  CAS  Google Scholar 

  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 17:362–365

    Article  PubMed  CAS  Google Scholar 

  7. Bartholome K, Lutz P, Bickel H (1975) Determination of phenylalanine hydroxylase activity in patients with phenylketonuria and hyperphenylalaninemia. Pediatr Res 9:899–903

    PubMed  CAS  Google Scholar 

  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 4:101–102

    Article  PubMed  CAS  Google Scholar 

  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 1667–1724

    Google Scholar 

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

    Google Scholar 

  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 158:46–54

    Article  PubMed  CAS  Google Scholar 

  12. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16–18, 2000 (2001) Pediatrics 108:972–982

    Google Scholar 

  13. Ding Z, Harding CO, Thony B (2004) State-of-the-art 2003 on PKU gene therapy. Mol Genet Metab 81:3–8

    Article  PubMed  CAS  Google Scholar 

  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 96:2339–2344

    Article  PubMed  CAS  Google Scholar 

  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 30:243–257

    Article  PubMed  CAS  Google Scholar 

  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 79:110–113

    Article  PubMed  CAS  Google Scholar 

  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):1570–1574

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. 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 

  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–S38

    Article  PubMed  Google Scholar 

  21. 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 

  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 145:53–57

    Article  PubMed  Google Scholar 

  23. Smith I, Beasley MG, Ades AE (1990) Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Child 65:472–478

    PubMed  CAS  Google Scholar 

  24. Smith I, Beasley MG, Ades AE (1991) Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 66:311–316

    Article  PubMed  CAS  Google Scholar 

  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–S168

    Article  PubMed  Google Scholar 

  26. Lundstedt G, Johansson A, Melin L et al (2001) Adjustment and intelligence among children with phenylketonuria in Sweden. Acta Paediatr 90:1147–1152

    Article  PubMed  CAS  Google Scholar 

  27. Welsh M, Pennington B (2000) Phenylketonuria. In: Yeates KO, Ris MD, Taylor HG (eds) Pediatric neuropsychology. Guildford Press, New York, pp 275–299

    Google Scholar 

  28. Cleary MA, Walter JH, Wraith JE et al (1995) Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 127:251–255

    Article  PubMed  CAS  Google Scholar 

  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 51:761–765

    Article  PubMed  Google Scholar 

  30. Thompson AJ, Smith I, Brenton D et al (1990) Neurological deterioration in young adults with phenylketonuria. Lancet 336:602–605

    Article  PubMed  CAS  Google Scholar 

  31. Lee P, Smith I, Piesowicz A et al (1999) Spastic paraparesis after anaesthesia. Lancet 353:554

    Article  PubMed  CAS  Google Scholar 

  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 136:545–547

    Article  PubMed  CAS  Google Scholar 

  33. Discussion of Armstrong MD (1957) The relation of biochemical abnormality to the development of mental defect in phenylketonuria. Columbus Ohio: Ross Laboratories

    Google Scholar 

  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 303:1202–1208

    Article  PubMed  CAS  Google Scholar 

  35. Koch R, Hanley W, Levy H et al (2003) The Maternal Phenylketonuria International Study: 1984–2002. Pediatrics 112(6 Pt 2):1523–1529

    PubMed  Google Scholar 

  36. Lee PJ, Ridout D, Walter JH et al (2005) Maternal phenylketonuria: report from the United Kingdom Registry 1978–97. Arch Dis Child 90:143–146

    Article  PubMed  CAS  Google Scholar 

  37. Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. Medical Research Council Working Party on Phenylketonuria (1993) BMJ 306:115–119

    Google Scholar 

  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 19:91–93

    PubMed  CAS  Google Scholar 

  39. Lee PJ, Lilburn M, Baudin J (2003) Maternal phenylketonuria: experiences from the United Kingdom. Pediatrics 112(6 Pt 2):1553–1556

    PubMed  Google Scholar 

  40. American Academy of Pediatrics: Maternal phenylketonuria (2001) Pediatrics 107:427–428

    Article  Google Scholar 

  41. Koch R, Hanley W, Levy H et al (2000) Maternal phenylketonuria: an international study. Mol Genet Metab 71:233–239

    Article  PubMed  CAS  Google Scholar 

  42. Levy HL, Waisbren SE, Guttler F et al (2003) Pregnancy experiences in the woman with mild hyperphenylalaninemia. Pediatrics 112(6 Pt 2):1548–1552

    PubMed  Google Scholar 

  43. Ponzone A, Guardamagna O, Spada M et al (1993) Differential diagnosis of hyperphenylalaninaemia by a combined phenylalaninetetrahydrobiopterin loading test. Eur J Pediatr 152:655–661

    Article  PubMed  CAS  Google Scholar 

  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 34:10–14

    PubMed  CAS  Google Scholar 

  45. Smith I, Hyland K, Kendall B (1985) Clinical role of pteridine therapy in tetrahydrobiopterin deficiency. J Inherit Metab Dis 8[Suppl 1]:39–45

    Article  PubMed  Google Scholar 

  46. Hyland K (1993) Abnormalities of biogenic amine metabolism. J Inherit Metab Dis 16:676–690

    Article  PubMed  CAS  Google Scholar 

  47. Spada M, Ferraris S, Ferrero GB et al (1996) Monitoring treatment in tetrahydrobiopterin deficiency by serum prolactin. J Inherit Metab Dis 19:231–233

    Article  PubMed  CAS  Google Scholar 

  48. Schuler A, Kalmanchey R, Barsi P et al (2000) Deprenyl in the treatment of patients with tetrahydrobiopterin deficiencies. J Inherit Metab Dis 23:329–332

    Article  PubMed  CAS  Google Scholar 

  49. Ponzone A, Spada M, Ferraris S et al (2004) Dihydropteridine reductase deficiency in man: from biology to treatment. Med Res Rev 24:127–150

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Hospital Road, Pendlebury, Manchester, M27 4HA, UK

    John H. Walter

  2. Charles Dent Metabolic Unit, National Hospital for Neurology & Neurosurgery, Post Box 92, Queens Square, London, WC1N 3BG, UK

    Philip J. Lee

  3. Department of General Pediatrics, Universitäts-Kinderklinik, Im Neuenheimer Feld 150, 69120, Heidelberg, Germany

    Peter Burgard

Authors
  1. John H. Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philip J. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Burgard
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Pediatrics, University Hospital Groningen, Burgemeester Weertslaan 31, 8162 DP, Epe, The Netherlands

    John Fernandes

  2. Unité de Métabolisme, Département de Pédiatrie, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75043, Paris Cedex 15, France

    Jean-Marie Saudubray

  3. Metabolic Research Group, Christian de Duve Institute of Cellular Pathology, University of Louvain Medical School, Avenue Hippocrate 75-39, 1200, Brussels, Belgium

    Georges van den Berghe

  4. Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Hospital Road, Pendlebury, Manchester, M27 4HA, UK

    John H. Walter

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer Medizin Verlag Heidelberg

About this chapter

Cite this chapter

Walter, J.H., Lee, P.J., Burgard, P. (2006). Hyperphenylalaninaemia. In: Fernandes, J., Saudubray, JM., van den Berghe, G., Walter, J.H. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg . https://doi.org/10.1007/978-3-540-28785-8_17

Download citation

  • DOI: https://doi.org/10.1007/978-3-540-28785-8_17

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-28783-4

  • Online ISBN: 978-3-540-28785-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation