MUTATION ANALYSIS IN FAMILIES WITH DISCORDANT PHENOTYPES OF PHENYLALANINE-HYDROXYLASE DEFICIENCY - INHERITANCE AND EXPRESSION OF THE HYPERPHENYLALANINAEMIAS

Neonatal hyperphenylalaninaemia caused by mutations in the gene encodi ng phenylalanine hydroxylase (PAH) represents a wide spectrum of metab olic phenotypes, ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). The marked interindividual heterogeneity is due to the expression of multiple PAH mutations in genetic compoun ds. We have investigated four unusual families in which both PKU and M HP were present. In each family three different mutations in the PAH g ene were identified, including two associated with PKU and one associa ted with MHP. The unexpected outcome of discordant phenotypes within t he families described is explained by previously unrecognized parental MHP. By mutation analysis we have also predicted the phenotypical out come in a hyperphenylalaninaemic infant born to a mother who before pr egnancy had been diagnosed as having MHP. Our results demonstrate the utility of nucleic acid analysis in follow-up in PKU screening program mes.