Molecular genetics and outcome in PKU

Phenylketonuria (PKU) is a recessive trait that usually produces a clear-cu t Mendelian pattern in individual families. However, the distribution of ph enotypes among families is heterogeneous in severity and response to dietar y treatment, spanning from "classic" PKU to mild hyperphenylalaninemia (MHP ). A series of scientific achievements and technical advances during the la st 15 years have greatly improved our understanding of the molecular basis for the phenotypic heterogeneity in PKU. In 1984, the gene encoding the liv er-specific enzyme phenylalanine hydroxylase (PAH) was cloned. Progress in identifying the precise genetic alterations underlying PKU and MHP in indiv idual patients has led to our present recognition of PAH deficiency as a di sorder of extensive allelic complexity. To date, more than 325 different PA H gene mutations have been recorded worldwide. Each mutation has its own ef fect on PAH activity, and the plethora of possible mutation combinations (g enotypes) 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 m ajority of PKU cases, there is a simple relation between the two inherited mutations and the phenylalanine tolerance. Hence, mutation analysis in a ne wborn with hyperphenylalaninemia may provide, at a very early stage, valuab le information, which may be useful for dietary management and for counseli ng of the patient's family. (C) 1999 Wiley-Liss, Inc.