Disorders of Phenylalanine and Tetrahydrobiopterin Metabolism

  • Nenad BlauEmail author
  • Francjan J. van Spronsen


Hyperphenylalaninemia (HPA), a disorder of phenylalanine catabolism, is caused primarily by a deficiency of the hepatic phenylalanine-4-hydroxylase (PAH) or by one of the enzymes involved in its cofactor tetrahydrobiopterin (BH4) biosynthesis (GTP cyclohydrolase I (GTPCH) and 6-pyruvoyl-tetrahydropterin synthase (PTPS)) or regeneration (dihydropteridine reductase (DHPR) and pterin carbinolamine-4a-dehydratase (PCD)) (Blau et al. 2001). BH4 is known to be the natural cofactor for PAH, all three isoforms of nitric oxide synthase (NOS), tyrosine-3-hydroxylase, as well as tryptophan-5-hydroxylase (Werner et al. 2011), the latter two being the key enzymes in the biosynthesis of the neurotransmitters dopamine and serotonin. Thus, with two exceptions (see below) any cofactor defect will result in a deficiency of biogenic amines accompanied by HPA. Because phenylalanine is a competitive inhibitor of the uptake of tyrosine and tryptophan and other LNAA across the blood-brain barrier and of the hydroxylases of tyrosine and tryptophan, depletion of catecholamines and serotonin occurs in untreated patients with PAH deficiency. Both groups of HPA (PAH and BH4 deficiency) are heterogeneous disorders varying from severe to mild and benign forms. Because of the different clinical and biochemical severities in this group of diseases, the terms “severe” or “mild” will be used based upon the type of treatment and involvement of the CNS. For the BH4 defects, symptoms may manifest during the first weeks of life, but usually are noted within the first 6 months of life. Birth is generally uneventful, except for an increased incidence of prematurity and lower birth weights in severe PTPS deficiency (Opladen et al. 2012).


Phenylalanine Level Dihydropteridine Reductase Sapropterin Dihydrochloride Sepiapterin Reductase Blood Phenylalanine Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Anjema K, van Rijn M, Hofstede FC, et al (2013) Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype. Orphanet J Rare Dis 10:103Google Scholar
  2. Belanger-Quintana A, Burlina A, Harding CO, Muntau AC (2011) Up to date knowledge on different treatment strategies for phenylketonuria. Mol Genet Metab 104(Suppl):S19–25PubMedCrossRefGoogle Scholar
  3. Blau N, Thöny B, Cotton RGH, Hyland K (2001) Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet al, Sly WS, Valle D, Childs B, Vogelstein B (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1725–1776Google Scholar
  4. Blau N, Van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376:1417–1427PubMedCrossRefGoogle Scholar
  5. Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U (2011) Diagnosis, classification and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 104:S2–9PubMedCrossRefGoogle Scholar
  6. Friedman J, Roze E, Abdenur JE et al (2012) Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol 71:520–530PubMedCrossRefGoogle Scholar
  7. Heintz C, Cotton RG, Blau N (2013) Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase and importance of genotypes for pharmacological therapy of phenylketonuria. Hum Mutat 34:927–936PubMedCrossRefGoogle Scholar
  8. Hyland K, Fryburg JS, Wilson WG et al (1997) Oral phenylalanine loading in dopa-responsive dystonia – a possible diagnostic test. Neurology 48:1290–1297PubMedCrossRefGoogle Scholar
  9. Jäggi L, Zurflüh MR, Schuler A et al (2008) Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab 93:295–305PubMedCrossRefGoogle Scholar
  10. Keil S, Anjema K, van Spronsen FJ et al (2013) Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics 131:e1881–e1888PubMedCrossRefGoogle Scholar
  11. Levy HB, Burton S, Cederbaum C, Scriver (2007) “Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH(4)) in phenylketonuria and its use in treatment.” Mol Genet Metab 92(4): 287–291Google Scholar
  12. Opladen T, Okun JG, Burgard P, Blau N, Hoffmann GF (2010) Phenylalanine loading in pediatric patients with dopa-responsive dystonia: revised test protocol and pediatric cut-off values. J Inerit Metab Dis 33:697–703CrossRefGoogle Scholar
  13. Opladen T, Hoffmann FG, Blau N (2012) An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inerit Metab Dis 35:963–73CrossRefGoogle Scholar
  14. Segawa M (2011) Hereditary progressive dystonia with marked diurnal fluctuation. Brain Dev 33:195–201PubMedCrossRefGoogle Scholar
  15. van Spronsen FJ, Huijbregts SC, Bosch AM, Leuzzi V (2011) Cognitive, neurophysiological, neurological and psychosocial outcomes in early-treated PKU-patients: a start toward standardized outcome measurement across development. Mol Genet Metab 104(Suppl):S45–51PubMedCrossRefGoogle Scholar
  16. Werner ER, Blau N, Thöny B (2011) Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 438:397–414PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Division of Inborn Metabolic Diseases, Department of General PediatricsUniversity Children’s HospitalHeidelbergGermany
  2. 2.Division of MetabolismUniversity Children’s HospitalZürichSwitzerland
  3. 3.Section of Metabolic DiseasesBeatrix Children’s Hospital, University Medical Center of Groningen, University of GroningenGroningenThe Netherlands

Personalised recommendations