Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase (PAH). Demonstration of mutations in the PAH gene establishes PAH deficiency as the cause of hyperphenylalaninaemia in the newborn and provides a basis for predicting the metabolic phenotype and anticipating the dietary requirements of the patient. Mutations in the PAH gene are well archived in the PAH Locus Knowledgebase. Loss of PAH protein is a consequence of misfolding, aggregation and accelerated degradation of the enzyme. BH4 rescues the activity of mutant PAH enzymes by functioning as a chaperone to stabilise enzyme structure or by overcoming defects that alter the Km for BH4. Defects in BH4 metabolism can be divided into those associated with hyperphenylalaninaemia and those presenting without hyperphenylalaninaemia. The diagnosis of BH4 deficiencies has to be considered for all conditions with hyperphenylalaninaemia. The measurement of pteridines in urine discriminates BH4 synthesis deficiency from PKU children. Therapy is aimed at normalising Phe levels and brain neurotransmitters (Matalon et al., 2006). Treatment includes a special diet and/or BH4 supplements.

Key Concepts:

  • Deficiency of phenylalanine hydroxylase (PAH; E.C. is caused by mutations in the PAH gene.

  • PAH is inherited in an autosomal recessive pattern (MIM #261600).

  • PAH deficiency is a highly heterogeneous disorder that has been divided into four arbitrary phenotype categories: classic, moderate and mild PKU, and mild hyperphenylalninaemia (MHP).

  • More than 450 mutated versions of PAH have been reported worldwide, each producing a protein with partial or total loss of enzyme activity.

  • A clear correlation between genotype and phenylalanine tolerance has been documented and genotype/phenotype correlations are established on the basis of patient data.

Keywords: phenylketonuria; phenylalanine hydroxylase; genotype–phenotype correlations; mutation; tetrahydrobiopterin

Figure 1.

A continuum of phenylalanine hydroxylase‐deficiency phenotypes. Arbitrary phenotype categories may be defined on the basis of phenylalanine tolerance, that is, the amount of dietary phenylalanine tolerated while keeping serum phenylalanine concentrations within the desired therapeutic range. Pretreatment phenylalanine levels broadly correlate with disease severity, but cannot be used reliably for anticipating dietary requirements in individual patients. MHP, mild hyperphenylalaninaemia.

Figure 2.

Concept of functional hemizygosity in phenylalanine hydroxylase (PAH) deficiency. Functionally hemizygous patients carry on one of their chromosomes a null PAH mutation, that is, a mutation that produces no PAH activity. Like the homozygous constellation, the functionally hemizygous constellation produces only homopolymeric enzyme. Accordingly, the mutation on the nonnull allele determines the phenylalanine‐hydroxylating capacity and hence the phenotypic outcome.



Gjetting T, Petersen M, Guldberg P and Güttler F (2001) Missense mutations in the N‐terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine. American Journal of Human Genetics 68: 1353–1360.

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 prediction of metabolic phenotype. American Journal of Human Genetics 63: 71–79.

Güttler F (1980) Hyperphenylalaninemia: diagnosis and classification of the various types of phenylalanine hydroxylase deficiency. Acta Paediatrica Scandinavica 280(suppl.): 1–80.

Güttler F and Guldberg P (2006) Genotype/phenotype correlations in phenylalanine hydroxylase deficiency. In: Blau N (ed.) PKU and BH4 – Advances in Phenylketonuria and Tetrahydrobiopterin, pp. 211–320. Heilbronn, Germany: SPS Verlagsgesellschaft mbH.

Güttler F, Guldberg P and Henriksen KF (1993) Mutation genotype of mentally retarded patients with phenylketonuria. Developmental Brain Dysfunction 6: 92–96.

Kaufman S (1993) The phenylalanine hydroxylating system. Advances in Enzymology and Related Areas of Molecular Biology 67: 77–264.

Kayaalp E, Treacy E, Waters PJ et al. (1997) Human PAH mutation and hyperphenylalaninemia phenotypes: a metanalysis of genotype–phenotype correlations. American Journal of Human Genetics 61: 1309–1317.

Kobe B, Jennings IG, House CM et al. (1999) Structural basis of autoregulation of phenylalanine hydroxylase. Nature Structural Biology 6: 442–448.

Ledley FD, Grenett HE, DiLella AG, Kwok SCM and Woo SLC (1985) Gene transfer and expression of human phenylalanine. Science 228: 77–79.

Matalon R, Michals‐Matalon K, Bhatia G et al. (2006) Large neutral amino acids in the treatment of phenylketonuria. Journal of Inherited Metabolic Diseases 29: 732–738.

Scriver CR and Kaufman S (2001) The hyperphenylalaninemias. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, pp. 1667–1724. New York: McGraw‐Hill.

Further Reading

Eisensmith RC and Woo SL (1995) Molecular genetics of phenylketonuria: from molecular anthropology to gene therapy. Advances in Genetics 32: 199–271.

Fusetti F, Erlandsen H, Flatmark T and Stevens RC (1998) Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria. Journal of Biological Chemistry 273: 16962–16967.

Koch R, Hanley W, Levy H et al. (2000) Maternal phenylketonuria: an international study. Molecular Genetics and Metabolism 71: 233–239.

Levy HL, Waisbren SE, Lobbregt D et al. (1994) Maternal mild hyperphenylalaninaemia: an international survey of offspring outcome. Lancet 344: 1589–1594.

Lyman FL (ed.) (1963) Phenylketonuria. Springfield, IL: Charles C Thomas.

Martinez A, Knappskog PM, Olafsdottir S et al. (1995) Expression of recombinant human phenylalanine hydroxylase as fusion protein in Escherichia coli circumvents proteolytic degradation by host cell proteases: isolation and characterization of the wild‐type enzyme. Biochemical Journal 306: 589–597.

Moats RA, Koch R, Moseley K et al. (2000) Brain phenylalanine concentration in the management of adults with phenylketonuria. Journal of Inherited Metabolic Diseases 23: 7–14.

Pietz J, Kreis R, Rupp A et al. (1999) Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. Journal of Clinical Investigation 103: 1169–1178.

Scriver CR and Waters PJ (1999) Monogenic traits are not simple: lessons from phenylketonuria. Trends in Genetics 15: 267–272.

Ullrich K, Moller H, Weglage J et al. (1994) White matter abnormalities in phenylketonuria: results of magnetic resonance measurements. Acta Paediatrica 407(suppl.): 78–82.

Web Links

PAH (Phenylalanine Hydroxylase); Locus ID: 5053. LocusLink:

PAH (Phenylalanine Hydroxylase); MIM number: 261600. OMIM:‐post/Omim/dispmim?261600

PAHdb Provides Users with Access to Information about Mutations at the Phenylalanine Hydroxylase Locus.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Güttler, Flemming, and Guldberg, Per(Aug 2011) Phenylketonuria. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006027.pub2]