Introduction
Background
Phenylketonuria (PKU) was discovered and described by Folling in 1934. It is the most common inborn error of amino acid metabolism. Deficiency of the enzyme phenylalanine hydroxylase (PAH) leads to accumulation of phenylalanine (Phe) in the plasma (>1200 µmol/L; reference range, 35-90 µmol/L) and to excretion of phenylpyruvic acid (approximately 1 g/d) and phenylacetic acid in the urine. Phe has ketogenic and gluconeogenic intermediates that contribute to the glucose pool, which can play a role in normal brain development and function. In many countries, phenylketonuria is detected by screening newborns. Patients treated with a diet low in Phe can lead a normal life.
Pathophysiology
In most patients, the classic type of phenylketonuria (PKU) is caused by a deficiency of PAH, resulting in increased levels of Phe in body fluids. PAH catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the oxidative degradation of Phe. PAH requires a nonprotein cofactor termed tetrahydrobiopterin (BH4), and the rate-limiting step in the synthesis of BH4 is guanosine triphosphate cyclohydrolase I (GTP-CH I). PAH crystallizes as a tetramer, with each monomer consisting of a catalytic domain and a tetramerization domain. Examination of the mutations causing phenylketonuria reveals that some of the most frequent mutations are located at the interface of the catalytic and tetramerization domains.
Other types of phenylketonuria include phenylketonuria caused by impaired synthesis of BH4, GTP-CH I, 6-pyruvoyl tetrahydropterin (6-PTS), or dihydropteridine reductase (DHPR). Patients with the BH4 cofactor deficiency have more severe neurologic problems that are not completely corrected by the dietary reduction of Phe.
The learning disabilities in patients with phenylketonuria who are adequately treated may result from reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membranes.
Frequency
United States
The incidence of classic phenylketonuria (PKU) is approximately 1 case per 15,000 births.
International
The prevalence in the general population is approximately 4 cases per 100,000 individuals, and the incidence is 350 cases per million live births. Approximately 0.04-1% of the residents in mental retardation clinics are affected by phenylketonuria (PKU). A high incidence is reported in Turkey (approximately 1 case in 2,600 births), the Yemenite Jewish population (1:5,300), Scotland (1:5,300), Estonia (1:8,090),1 Hungary (1:11,000), Denmark (1:12,000), France (1:13,500), United Kingdom (1:14,300), Norway (1:14,500), China (1:17,000), Italy (1:17,000), Canada (1:20,000), Minas Gerais State in Brazil (1:20,000),2 and former Yugoslavia (1:25,042).3 A low incidence is reported in African Americans (1:50,000), Finland (<1:100,000),4 and Japan (1:125,000).5
Mortality/Morbidity
Patients with phenylketonuria (PKU) who have not been treated have severe mental retardation. Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment.
Race
Phenylketonuria (PKU) is common in whites and Asians and is rare in blacks.
Sex
No sexual predilection exists for phenylketonuria (PKU). Untreated maternal PKU increases the risk for developmental problems in offspring.
Age
Phenylketonuria (PKU) can commonly be recognized in newborns with the help of newborn screening programs.
Clinical
History
Most patients appear healthy at birth. In adult patients who stop dietary treatment, neurologic dysfunction may occur.
Physical
Clinical manifestations of phenylketonuria (PKU) are largely of historical interest, because the damaging features of the disease are usually prevented through early diagnosis and treatment.- Skin
- Fair skin and hair (most characteristic skin manifestation resulting from impairment of melanin synthesis; striking in black and Japanese persons [see Media File 1])
- Eczema (including atopic dermatitis)
- Light sensitivity
- Increased incidence of pyogenic infections
- Increased incidence of keratosis pilaris
- Decreased number of pigmented nevi
- Sclerodermalike plaques
- Hair loss6
- Other manifestations
- Mental retardation
- Musty odor
- Epilepsy (50%)7
- Extrapyramidal manifestations (eg, parkinsonism)
- Eye abnormalities (eg, hypopigmentation)
Causes
Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the PAH gene, which is located on band 12q23.2, spans about 171 kb, and contains 13 exons. More than 500 different mutations in the PAH gene have been identified. The PAH gene shows great allelic variation, and pathogenic mutations have been described in all 13 exons of the PAH gene and its flanking region. The mutations can be of various types, including missense mutations (62% of PAH alleles), small or large deletions (13%), splicing defects (11%), silent polymorphisms (6%), nonsense mutations (5%), and insertions (2%).5
Other causes of PKU include BH4 deficiency and DHPR deficiency. The former is caused by mutated alleles at 3 other loci (bands 11q22.3-23.3, 10q22, and 2p13). The latter involves abnormalities localized to bands 4p15.1-16.1. Additionally, PKU displays a marked genotypic heterogeneity, both within populations and between different populations.
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| References |
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References
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Santos LL, Castro-Magalhaes M, Fonseca CG, et al. PKU in Minas Gerais State, Brazil: mutation analysis. Ann Hum Genet. Nov 2008;72:774-9. [Medline].
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Waisbren SE, Noel K, Fahrbach K, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. Sep-Oct 2007;92(1-2):63-70. [Medline].
Bosch AM, Tybout W, van Spronsen FJ, et al. The course of life and quality of life of early and continuously treated Dutch patients with phenylketonuria. J Inherit Metab Dis. Feb 2007;30(1):29-34. [Medline].
Macdonald A, Davies P, Daly A, et al. Does maternal knowledge and parent education affect blood phenylalanine control in phenylketonuria?. J Hum Nutr Diet. Aug 2008;21(4):351-8. [Medline].
Lee PJ, Ridout D, Walter JH, Cockburn F. Maternal phenylketonuria: report from the United Kingdom Registry 1978-97. Arch Dis Child. Feb 2005;90(2):143-6. [Medline].
Maillot F, Lilburn M, Baudin J, Morley DW, Lee PJ. Factors influencing outcomes in the offspring of mothers with phenylketonuria during pregnancy: the importance of variation in maternal blood phenylalanine. Am J Clin Nutr. Sep 2008;88(3):700-5. [Medline].
Further Reading
Keywords
phenylketonuria, PKU, phenylalanine hydroxylase, PAH, phenylalanine, phenylpyruvic acid, phenylacetic acid, hyperphenylalaninemia type I, Folling disease, Folling's disease, phenylpyruvic oligophrenia, tetrahydrobiopterin
