Phenylketonuria: screening, treatment and maternal PKU

Phenylketonuria (PKU) has become a paradigm of a disease that can be identified by screening in the newborn period and treated to prevent serious complications. After many years of experience treating PKU, new challenges have emerged. It has become apparent that defective activity of phenylalanine hydroxylase leads to a spectrum of clinical presentations that has led to subclassifications of PKU. Blood phenylalanine greater than 1200 μmol/L usually indicates severe deficiency of phenylalanine hydroxylase and is often called "classical PKU." Blood phenylalanine levels between 600 and 1200 μmol/L lead to "atypical PKU." Cases where blood phenylalanine remains between 120 and 480 μmol/L on a normal diet are termed "benign hyperphenylalaninemia." A deficiency of the cofactor tetrahydrobiopterin (BH₄), which is required for phenylalanine hydroxlyase activity, leads to hyperphenylalaninemia. This cofactor is also required for the enzymatic hydroxylation of tyrosine and tryptophan. Cofactor defects account for only 1-3% of hyperphenylalaninemia, which has been termed "malignant PKU", but they must be identified so that appropriate treatment can be established. Long-term treatment of PKU is currently advised because loss of IQ, poor school performance, and behavior problems occur when blood phenylalanine levels increase. Therefore, there is reason to continue the diet as patients become older. When blood phenylalanine levels are elevated during pregnancy a "maternal PKU syndrome" may result. Babies born to untreated mothers with PKU are at risk for being small for gestational age with microcephaly, mental retardation and congenital heart defects. A national collaborative study for the treatment of maternal PKU is underway. The characterization of the gene for phenylalanine hydroxylase has added a new exciting chapter to the study of PKU. Molecular biology has made it possible to determine the mutations in PKU, to detect carriers of the gene for PKU and to offer prenatal diagnosis.