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)