Unsolved problems in diagnosis and therapy of hyperphenylalaninemia caused by defects in tetrahydrobiopterin metabolism

Abstract

Phenylketonuria is caused by a defect in the phenylalanine hydroxylating system. This complex system consists of two enzymes, phenylalanine hydroxylase and dihydropteridine reductase, and the essential coenzyme tetrahydrobiopterin. DHPR and BH4 are also essential for tyrosine hydroxylase and tryptophan hydroxylase. The way in which BH4 and DHPR function in all of these hydroxylating systems is shown in the Figure, which also outlines the pathway for the de novo synthesis of BH4 from guanosine triphosphate. It should be noted that the DHPR-catalyzed reaction (reaction 6) is necessary for BH4 to function catalytically. The classic form of PKU is caused by a lack of phenylalanine hydroxylase, 1 the enzyme that catalyzes reaction 5. In addition to this most prevalent form of the disease, variants of PKU have been discovered during the last 10 years that are caused by a defect in either the regeneration of BH4 (caused by a lack of DHPR, the enzyme that catalyzes reaction 6) or a defect in the de novo biosynthesis of BH4 2 (caused by a lack of an enzyme catalyzing reactions 1 or 2). Although methods of differential diagnosis and therapy of these diseases have been developed, there are still challenging and urgent problems.