PKU is transmitted by an autosomal recessive gene. Patients with this disorder have insufficient hepatic phenylalanine
hydroxylase, an enzyme that acts as a catalyst in the conversion of phenylalanine to tyrosine. As a result, phenylalanine and its metabolites accumulate in the blood, eventually causing mental retardation if left untreated. The exact biochemical mechanism that causes this retardation is unclear.

An infant with undiagnosed and untreated PKU appears normal at birth but by 4 months begins to show signs of arrested brain development, including mental retardation and, later, personality disturbances (schizoid and antisocial personality patterns and uncontrollable temper). Such a child may have a lighter complexion than unaffected siblings and commonly has blue eyes. He may also have microcephaly; eczematous skin lesions or dry, rough skin; and a musty (mousy) odor due to skin and urinary excretion of phenylacetic acid. Approximately 80% of these children have abnormal EEG patterns, and about one-third have seizures, usually beginning between ages 6 and 12 months.

Children with PKU show a precipitous decrease in IQ in their first year, are usually hyperactive and irritable, and exhibit purposeless, repetitive motions. They have increased muscle tone and an awkward gait.