We describe an inborn error of metabolism called phenylketonuria (PKU; MIM No. 261600). The disease has been called an epitome of human biochemical genetics (Scriver and Clow, 1980a, 1980b). The disorder reflects a disadaptive interaction between nature and nurture. The component in nurture is an essential amino acid, L-phenylalanine; the one in nature is mutation in the phenylalanine hydroxylase gene (PAH) encoding the enzyme L-phenylalanine hydroxylase (EC 220.127.116.11). The discordance between nature and nurture leads to hyperphenylalaninemia (HPA), which can have a toxic effect on brain development and function. The “proximal” phenotype (phenylalanine hydroxylase dysfunction) is under the control of one locus encoding the phenylalanine hydroxylase enzyme and additional loci encoding several other enzymes necessary for synthesis and recycling of the tetrahydrobiopterin cofactor essential for the catalytic reaction; locus heterogeneity thus enters the interpretation of HPA. The intermediate (metabolic) and distal (cognitive) phenotypes of PKU disease both behave as complex traits that elude consistent interindividual genotype-phenotype correlations. The phenylalanine hydroxylase gene harbors great allelic diversity; several hundred mutations, both disease-causing and polymorphic, are recorded in PAHdb, a public-locus-specific mutation database (www.pahdb.mcgill.ca).
The HPAs are disorders of phenylalanine hydroxylation. The minimum requirements for the normal reaction, which occurs in both liver and kidney in human subjects, are phenylalanine hydroxylase enzyme (a monooxygenase, EC 18.104.22.168), oxygen, L-phenylalanine substrate, and the 6R isomer of the tetrahydrobiopterin (BH4) cofactor. For the pterin cofactor to function as a catalyst, BH4 must be regenerated from the carbinolamine byproduct (4a-hydroxytetrahydropterin) of the hydroxylation reaction. This is achieved by a recycling pathway in which 4α-carbinolamine dehydratase (formerly known as phenylalanine hydroxylase–stimulating protein) converts the carbinolamine to the quinonoid dihydropterin, which, as the substrate for dihydropteridine reductase in the presence of reduced pyridine nucleotide, is converted back to BH4. A pathway exists for biosynthesis of this obligatory cofactor involved both here and in the function of other aromatic monooxygenases and of nitric oxide synthase; the enzymes in the pathway are guanosine triphosphate cyclohydrolase, 6- pyruvoyltetrahydropterin synthase, and sepiapterin reductase. Diseases of BH4 synthesis and recycling are discussed in Chap. 102.
Hyperphenylalaninemia is defined as a plasma phenylalanine value greater than 120 µmol/liter (>2 mg/dl). Whether forms of HPA owing to altered integrity of the enzyme should be subdivided into different forms—notably phenylketonuria (plasma phenylalanine >1000 µmol/liter, diet phenylalanine tolerance < 500 mg/day) and non-PKU forms (plasma phenylalanine < 1000 µmol/liter, diet tolerance > 500 mg/day)—is a moot point. Evidence suggests that mild degrees of persistent untreated HPA (<600 µmol/liter) may not be harmful to cognitive development (as yet an unproven hypothesis). For purposes of diagnosis, counseling and correct treatment of the non-PAH enzyme deficiencies affecting BH4 homeostasis must be ruled out.
The human PAH gene covers approximately 100 kb of genomic DNA on chromosome 12, band region q23.2, and is embedded in a region of 1.5 Mbp harboring five other genes. The nucleotide sequences, both genomic (GenBank accession number AF404777) and cDNA (U49897.1), are now known (see www.pahdb.mcgill.ca); PAH has 13 exons and a complex 5′ untranslated region containing cis-acting, trans-activated regulatory elements. The gene is rich in intragenic ...