Liver or liver cell transplantation for phenylketonuria

Phenylketonuria (PKU) is an inherited autosomal reces- sive disorder (OMIM 261600). The causes of PKU include mutations in the gene encoding phenylalanine hydroxylase (PAH) enzyme or less frequently defect in the metabolism of tetrahydrobiopterin, the cofactor of PAH. PAH is expressed mainly in the liver. It catalyzes the hydroxylation of phenylalanine to tyrosine. Alter- ation of PAH activity causes an increase in phenylala- nine concentrations in blood and tissues, and reduced tyrosine concentrations. Although there is a considerable variation in genotype and phenotype, the great majority of PKU patients are at risk of intellectual and neurolog- ical impairements and severe disability. Phenylalanine itself is probably the neurotoxic agent but the exact pathophysiological mechanisms are still unknown. Pathogenesis of PKU can be considered from three viewpoints : a putative deficiency of tyrosine in the brain ; the effect of hyperphenylalaninemia on transport and distribution of metabolites in the brain and an effect on neurochemical processes, such as defective brain myelination or perturbed protein synthesis. Risk of brain dysfunction due to transient or chronic hyperphenylala- ninemia persists throughout life, although risk in adult- hood is apparently smaller than in childhood, during brain development.