PKU is an autosomal recessive trait caused by the absence of phenylalanine hydroxylase. Phenylalanine hydroxylase is an enzyme involved in the metabolism of phenylalanine (Phe). When phenylalanine hydroxylase is absent or defective, Phe levels rise and toxic Phe metabolites accumulate, causing central nervous system injury. PKU is a treatable disease. Affected individuals must adhere to a diet low in Phe during childhood. Women with PKU should also adhere to a low Phe diet before and during pregnancy to avoid fetal damage. The offspring of women with untreated maternal hyperphenylalaninemia (HPA) usually exhibit mental retardation, microcephaly, growth retardation, and other congenital anomalies. This study will examine the effect of a restricted Phe diet on reproductive outcome in women with maternal HPA.

Participants in this study will be women with HPA whose blood Phe values are persistently greater than 4 mg/dl. Those women with blood Phe values consistently greater than 8 mg/dl will be placed on a Phe restricted diet to maintain plasma Phe concentrations between 2 and 8 mg/dl. This level of control is practical and achievable. Due to a gradient of increasing Phe level from mother to fetus, levels in the latter would vary from 3.5 to 12 mg/dl; these levels are usually associated with normal outcomes. Women will be monitored throughout their pregnancy on obstetric, biochemical, and nutritional parameters. Women on the Phe restricted diet will be given enough Phe-limited protein, calories, vitamins, and minerals to maintain adequate nutritional status. Folate supplementation will be provided. If indicated clinically, tyrosine (Tyr) and supplemental trace metals will be prescribed.

A matching control sample of women and their offspring will be developed in collaboration with associated coordinating and collaborating centers. The offspring of both groups of mothers will be followed as long as the project permits. Those offspring born to mothers admitted to the project during the first 2 to 3 years of the study will be assessed on their intellectual ability and physical health, as well as academic achievement in school. Those admitted during the last 3 to 4 years of the study will be assessed on their intellectual ability and physical health, recognizing that limited data will be available for these offspring.