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At a glance

Inborn error of phenylalanine metabolism. Results in severe irreversible mental retardation at infancy.

Synonym

Phenylpyruvic Oligophrenia.

Incidence

1:10,000 to 12,000 live births in North America with considerable geographic variability. Heterozygous carriers 1:50 in general population.

Genetic inheritance

Autosomal recessive.

Pathophysiology

Phenylketonuria is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) located on chromosome 12q22-24.1. More than 950 mutations (mostly missense) in the gene encoding PAH are described resulting in protein misfolding or impairment of catalytic functions of PAH. Phenylalanine is hydroxylated by PAH, requiring tetrahydrobiopterin (BH4) as a cofactor. During the hydroxylation of phenylalanine, BH4 is oxidized to a 4a-hydroxy intermediate and regenerated to BH4 by carbinolamie-4a-dehydratase and dihydropteridine reductase.

Diagnosis

Neonatal screening programs for phenylketonuria (PKU) are established in many countries (Guthrie test). Elevated plasma levels of phenylalanine are seen in affected infants after protein feeding.

Clinical aspects

Affected infants are normal at birth. Untreated children develop severe mental retardation with movement disorders. They typically have pale, dry skin, and blue eyes. Severe vomiting, mimicking infantile pyloric stenosis, may be the presenting feature. Typical mousy pungent odor caused by the excretion of phenylacetic acid. Perirectal eczema-like or scleroderma-like skin rash. Treatment consists of a diet low in phenylalanine with untreated blood phenylalanine concentrations determining management: No intervention is required if the blood phenylalanine concentration is less than 360 µmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 µmol/L and 600 µmol/L, and lifelong treatment is recommended if the concentration is more than 600 µmol/L.

Precautions before anesthesia

Ensure patient is receiving appropriate diet. Avoid prolonged fasting in order to reduce protein catabolism.

Anesthetic considerations

There should be no difficulties with anesthetic management of children who are receiving appropriate dietary manipulation. However, if there is a risk of poor diet supplementation it is prudent to avoid nitrous oxide due to the risk of vitamin B12 deficiency.

Pharmacological implications

Aspartame and gelatin containing (oral) drug preparations are to be avoided. The composition of these drugs needs to be verified using local pharmaceutical data sheets.

Other condition to be considered

  • Tetrahydrobiopterin (BH4) Deficiency: Of children with phenylketonuria, 1 to 2% have a defect in the gene coding for that cofactor of phenylalanine hydroxylase instead of a deficiency in the enzyme itself. BH4 deficiency also causes decreased synthesis of L-dopa, 5 hydroxytryptophan, and nitric oxide (NO). Without treatment, the most severe form leads to microcephaly, developmental delay, and progressive neurological deterioration with parkinsonian ...

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