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Key Points

  • Disease summary:

    • Phenylketonuria (PKU) is a genetic inborn error of metabolism characterized by the presence of a nonfunctional hepatic (and to a lesser extent renal) enzyme phenylalanine hydroxylase (PAH) that converts the amino acid phenylalanine (PHE) into tyrosine. When there is loss of PAH activity, phenylalanine accumulates leading to brain toxicity and is also secondarily metabolized into phenylketones that are excreted in urine giving the disease its name. PKU is divided into classic PKU with PHE levels greater than 1200 μmol/L and variant PKU with hyperphenylalaninemia lower than 1200 μmol/L. In 1% to 2% of the cases elevated PHE is caused by a deficiency in the PAH cofactor tetrahydrobiopterin (BH4) due to reduced synthesis or deficient recycling.

    • The prevalence of PKU varies worldwide and ranges from 1/2600 (in Turkey) to 1/200,000 (in Thailand) live births. In the United States prevalence is estimated at 1/15000. PKU affects all ethnic groups and both sexes equally.

    • Untreated PKU can result in developmental delay, progressive intellectual disability, seizures, eczema, behavioral and psychiatric issues. In countries with established newborn screening, most affected patients are detected and treated at birth. Adolescents and adults with PKU who have been partially treated, treated for only a short period or noncompliant with their treatment might exhibit a wide array of clinical symptoms ranging from cognitive reduction to intellectual disability; some might present with neuropsychiatric decline.

    • Teratogenicity in maternal PKU occurs when the fetus is exposed to high PHE; only rarely does the fetus have PKU. Teratogenicity results from PHE actively crossing the placenta producing a 1.3 to 2-fold increase in the fetus causing multiple fetal abnormalities.

    • Early diagnosis and prompt dietary treatment with tight control and monitoring of the PHE level will prevent the complications of this disease in the person with PKU and, when begun before or early in pregnancy will prevent teratogenicity from maternal PKU.

  • Hereditary basis:

    • PKU is a monogenic disorder with an autosomal recessive pattern of inheritance.

  • Differential diagnosis:

    • Secondary PAH dysfunction from deficient cofactor can occur from defects in the pathways of BH4 metabolism:

      • Impaired synthesis of BH4 usually due to deficiency of guanosine triphosphate cyclohydrolase (GTPCH) or 6-pyruvoyl tetrahydropterin synthase (PTPS).

      • Impaired recycling of BH4 due to deficiency of dihydropteridine reductase (DHPR) or deficient pterin-4 acarbinolamine dehydratase (PCD).

  • These are autosomal recessive conditions resulting in hyperphenylalaninemia ranging from slightly abnormal (>120 μmol/L) to as high as 2500 μmol/L. Clinical manifestations overlap with PKU and include microcephaly, intellectual disability, seizures, gait instability, drowsiness, irritability, abnormal movements, recurrent hyperthermia without infections, hypersalivation, and swallowing difficulties.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

Patients with hyperphenylalaninemia have a consistently elevated PHE levels above 120 μmol/L (>2 mg/dL). PKU is diagnosed when BH4 cofactor is normal and can be divided as in Table 97-1.

Table 97-1Classification of Hyperphenylalaninemia

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