PKU babies typically appear normal at birth and in the neonatal period. Infants may later exhibit irritability, posturing, increased deep tendon reflexes, a peculiar “mousy” odor, and vomiting. Pale pigmentation develops in hair and skin, and seizures are sometimes present. Phenylalanine accumulates within the first days of life and tyrosine levels tend to be low. Although various phenylalanine metabolites are present, phenylalanine itself appears to be the toxic molecule in PKU. High phenylalanine levels prevent transport of other amino acids across the blood-brain barrier, inhibiting synthesis of key neurotransmitters and disrupting protein synthesis in the brain. This produces severe intellectual disability and white matter disease.
Women with untreated PKU who become pregnant are at high risk for having newborns with neurological damage. This is caused by the high phenylalanine levels in the untreated mother that cross the placenta during pregnancy and are toxic to the developing fetus. Mothers affected with PKU need to be on dietary control prior to conception to avoid the toxic effects of phenylalanine on their baby.