Pathophysiology

Phenylketonuria (PKU), an aminoaciduria, is characterized by an absence or severe deficiency of phenylalanine hydroxylase, the enzyme that hydroxylates phenylalanine to tyrosine. PKU is inherited as an autosomal recessive trait. Variant forms caused by other enzyme defects have been identified.

Normal diets typically contain more than twice the amount of phenylalanine (an essential amino acid) needed for protein synthesis. Excess phenylalanine is converted to tyrosine. In the absence of phenylalanine hydroxylase, plasma phenylalanine concentrations are elevated, and phenylalanine is excreted in the urine. Some excess phenylalanine is metabolized to phenylacetic acid, as well as other acids, and excreted in the urine and sweat.

Clinical presentation

Serum phenylalanine concentrations in infants with PKU are normal at birth but begin to rise within the first few weeks of life. Excessive phenylalanine is generally thought responsible for the brain damage that underlies the severe mental retardation and seizure disorder of PKU. In untreated infants, cognitive delay becomes evident within 6 months and is progressive. The majority of affected children are unable to talk, and a significant proportion never learns to walk.

Characteristic physical findings include:

  • light hair, eye, and skin pigmentation
  • an eczematous rash
  • hyperactive behavior
  • a musty or mousy odor (due to phenylacetic acid in the sweat)

Approximately 25% of patients have generalized or partial seizures. Infantile spasms and myoclonic seizures may occur.70 On the EEG, all patients have slowing, epileptiform discharges, or hypsarrhythmic patterns.71

Evaluation

Because newborns with PKU usually seem healthy, the diagnosis requires screening tests, which are mandated by law. Confirmatory tests are high plasma phenylalanine and normal or low plasma tyrosine concentrations.

Treatment

Treatment consists of dietary restriction of phenylalanine. The goal is to provide necessary but not excessive amounts of phenylalanine, typically 250 to 500 mg per day. The diet should be instituted immediately after birth and maintained throughout life to preserve cognitive and neuropsychologic function. Monitoring of plasma phenylalanine levels is required to gauge compliance and adequacy of the prescribed diet.

Antiepileptic drugs are given when necessary.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195–208.
With permission from Elsevier (www.elsevier.com). 

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Reviewed By: 
Steven C. Schachter, MD
on: 
Wednesday, March 31, 2004