Molecular genetics and outcome in PKU

Phenylketonuria (PKU) is a recessive trait that usually produces a clear-cut Mendelian pattern in individual families. However, the distribution of phenotypes among families is heterogeneous in severity and response to dietary treatment, spanning from “classic” PKU to mild hyperphenylalaninemia (MHP). A series of scientific achievements and technical advances during the last 15 years have greatly improved our understanding of the molecular basis for the phenotypic heterogeneity in PKU. In 1984, the gene encoding the liver-specific enzyme phenylalanine hydroxylase (PAH) was cloned. Progress in identifying the precise genetic alterations underlying PKU and MHP in individual patients has led to our present recognition of PAH deficiency as a disorder of extensive allelic complexity. To date, more than 325 different PAH gene mutations have been recorded worldwide. Each mutation has its own effect on PAH activity, and the plethora of possible mutation combinations (genotypes) explains the quantitative distributions of PKU phenotypes. Recent large-scale compilations of patient data, including data on genotypes and a variety of clinical parameters, have greatly improved our knowledge about individual mutations and their contribution to the PKU phenotype. In the majority of PKU cases, there is a simple relation between the two inherited mutations and the phenylalanine tolerance. Hence, mutation analysis in a newborn with hyperphenylalaninemia may provide, at a very early stage, valuable information, which may be useful for dietary management and for counseling of the patient's family. MRDD Research Reviews 1999;5:113–116. © 1999 Wiley-Liss, Inc.