Phenylketonuria 

Phenylketonuria (PKU), the most common an inborn error of amino acid metabolism, results from an impaired ability to metabolize the essential amino acid phenylalanine. Deficiency of the enzyme phenylalanine hydroxylase (PAH) leads to accumulation of phenylalanine in body fluids. Phenylalanine has ketogenic and gluconeogenic intermediates that contribute to the glucose pool, which can play a role in normal brain development and function.

Classic phenylketonuria is present when plasma phenylalanine levels exceed 20 mg/dL (1200 µmol/L) without treatment. Lesser degrees of elevation of plasma phenylalanine are referred to as hyperphenylalaninemia. Elevated phenylalanine levels negatively impact cognitive function, and individuals with classic phenylketonuria almost always have intellectual disability unless levels are controlled through dietary or pharmacologic treatment.

In the United States and many other countries, phenylketonuria is detected by newborn screening, and individuals who are appropriately treated (eg, with a diet low in phenylalanine and/or tetrahydrobiopterin) can have normal intelligence and lead a normal life.

In most patients, the classic type of PKU involves a deficiency of PAH that leads to increased levels of phenylalanine 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. PAH catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the oxidative degradation of phenylalanine (see the image below).

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), the so-called defects of biopterin metabolism.

The mechanism by which elevated phenylalanine levels cause intellectual disability is not known, although restriction of dietary phenylalanine ameliorates this effect if initiated within a few weeks of birth. A strong relation between control of blood phenylalanine levels in childhood and intelligence quotient (IQ) is recognized.

Subtle neuropsychological deficits in children with treated phenylketonuria are under investigation. Some investigators have attributed these deficits to small residual neurotransmitter abnormalities (eg, reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membranes).

A small percentage of children with elevated phenylalanine levels exhibit normal PAH levels but have a deficiency in synthesis or recycling of BH₄ (see Tetrahydrobiopterin Deficiency). This condition is termed malignant phenylketonuria. The BH₄ cofactor is also required for hydroxylation of tyrosine (a precursor of dopamine) and tryptophan (a precursor of serotonin). Thus, individuals with BH₄ cofactor deficiency can have additional neurologic problems that are not fully corrected by dietary phenylalanine reduction alone, but often require additional treatments that may not be fully effective.

PKU is an autosomal recessive disorder caused by mutations in the PAH gene, which expresses PAH. This gene is located on 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%).^[1]

Other causes of PKU include BH₄ deficiency and DHPR deficiency. The former is caused by mutated alleles at 3 other loci (11q22.3-23.3, 10q22, and 2p13). The latter involves abnormalities localized to 4p15.1-16.1.

PKU displays a marked genotypic heterogeneity, both within populations and between different populations. Genotype and phenotype are broadly related (ie, reproducible mild versus severe mutations), but unrelated individuals with identical mutations have some degree of variability in phenylalanine tolerance.

United States statistics

Disease frequency varies by population. The prevalence in the general US 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 intellectual disability clinics are affected by PKU. A low incidence is reported in African Americans (1/50,000).

International statistics

A high incidence is reported in Turkey (approximately 1 case in 2600 births), the Yemenite Jewish population (1/5300), Scotland (1:5300), Estonia (1:8090),^[2] Hungary (1/11,000), Denmark (1/12,000), France (1/13,500), the 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),^[3] and the former Yugoslavia (1/25,042).^[4] A low incidence is reported in Finland (< 1/100,000)^[5] and Japan (1/125,000).^[1]

Age-, sex-, and race-related demographics

Phenylketonuria is most commonly diagnosed in neonates because of newborn screening programs. Consider phenylketonuria at any age in an individual with developmental delay or intellectual disability because infants are missed by newborn screening programs on rare occasions.

No sex predilection is known. Women with phenylketonuria must restrict their phenylalanine levels during pregnancy to avoid birth defects and intellectual disability in their infants. Untreated maternal PKU increases the risk for developmental problems in offspring.

In the United States, phenylketonuria is most common in whites. Worldwide, phenylketonuria is most common in whites and Asians.

The prognosis for normal intelligence is excellent when patients have been put on a diet low in phenylalanine in the first month of life, with careful monitoring. However, school functioning can be mildly impaired in some children, particularly when dietary control is poor.

A quantitative, proportional relation exists between blood phenylalanine levels and IQ for early-treated patients with PKU assessed either during the critical early childhood years (age 0-12 y) or by a lifetime Index of Dietary Control. A 100-μmol/L increase in phenylalanine has resulted in a 1.3- to 4.1-point reduction in IQ.^[6]

Patients with PKU who are treated early and continuously can have a normal health-related quality of life and course of life.^[7] Well-treated patients should have IQs within approximately 5-8 points of their siblings.

Most untreated individuals with phenylketonuria have profound intellectual disability. After the discovery of phenylketonuria, routine testing of institutionalized patients with intellectual disability identified a 1% incidence of phenylketonuria in this group.

Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment. Treated patients with phenylketonuria often experience subtle performance and attention and behavioral changes, especially when phenylalanine levels exceed 360 µmol/L.

Teach parents how to administer the diet at home, and involve all caregivers as well. Children should begin involvement in their dietary planning as soon as they are developmentally ready. Poor dietary control is often associated with increasing noncompliance by older children, but it could also be due to a more relaxed dietary approach by parents and increasing dietary errors.^[8]

Women with PKU should be educated about the risks of untreated pregnancy and the benefits of dietary and, in some cases, pharmacologic, treatment. Patients with PKU should avoid aspartame (an artificial sweetener). Aspartame is widely used in medicines, vitamins, beverages, and other substances.

The phenylalanine-restricted diet with semisynthetic supplementation is not without risk. PKU patients under dietary treatment can have low concentrations of trace elements and cholesterol and can have some disturbance to folate metabolism and distortion of their fatty acid profile.^[1] In addition, overtreatment resulting in insufficient phenylalanine intake can cause intellectual disability

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