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Classical phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism. It results in severe mental retardation and additional neurological problems when treatment does not begin within the first few weeks of life. However, when a very strict diet is begun early and carefully maintained, affected children can be expected to show normal development and experience a normal life span. The worldwide overall incidence is approximately 1:10,000 with a large national/ethnic variability (1:20,000 live births in South America, 1:4500 in Ireland, 1:2600 in Turkey, 1:11,000 in China, and 1:200,000 in Finland).1 In Europe, the estimated prevalence in the general population is 1:8500.2 Because of the severity of the disease if untreated and the excellent outcome when children are treated early and well, newborn screening for PKU has been instituted in many countries.

PKU is caused by a defect in a single enzyme, phenylalanine hydroxylase, that converts the essential amino acid phenylalanine into tyrosine (a non-essential amino acid which becomes essential in PKU) (Figure 15-1). At physiological concentrations 75% to 90% of phenylalanine intake is hydroxylated to tyrosine and about 10% to 25% is used for protein synthesis.1,3,4,5 The failure of this conversion results in an increase of phenylalanine in the blood and in bodily tissues, notably the brain. Through a mechanism that is not well understood, excess of brain phenylalanine is neurotoxic.

FIGURE 15-1.

Defect and accumulating metabolites in phenylketonuria. Left column: Blood phenylalanine concentration is fed by food intake or by breakdown of body protein due to catabolism. Outflow results from protein synthesis, hydroxylation to tyrosine, and transamination (predominantly when phenylalanine concentrations are unphysiologically high). Phenylalanine is actively transported into the brain, competing with other LNAAs for the same transporter. Increased concentrations of phenylalanine and decreased concentrations of LNAAs, particularly tyrosine and subsequently dopamine in the brain, result in neurological damage and impaired cognitive, behavioral, and emotional development. Therapeutic phenylalanine intake is directly operated by compliance, by behavior of the patient, as well as by social and family variables. Right column: Tyrosine hydroxylated from phenylalanine is used for protein synthesis but is also a substrate for neurotransmitters and melanine. Center: The PAH gene codes for phenylalanine hydroxylase, with different genotypes resulting in different degrees of the metabolic block. Different phenotypes can be distinguished for the analysis of genotype-phenotype associations. Accumulating metabolites are in blue font. Metabolites that may be deficient are in green font. PAH, phenylalanine hydroxylase; PHE, phenylalanine; BH4, tetrahydrobiopterin; BH2, dihydrobiopterin; L-Tyr, tyrosine; LNAA, large neutral amino acids.

Normal phenylalanine metabolism is regulated by the apoenzyme phenylalanine hydroxylase (PAH; EC1.14.16.1) in association with its cofactor tetrahydrobiopterin (BH4). The gene coding for PAH is located on the long arm of chromosome 12. The enzyme is primarily expressed in liver, and the amount of enzyme protein expressed is regulated by ...

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