Screening for biopterin defects in newborns with phenylketonuria and other hyperphenylalaninemias

The newborn screening for phenylketonuria (PKU) has become a common practice in many countries. The success of this type of mass screening is the result of the reliability of the Guthrie test in the identification of high blood phenylalanine levels. Recently, new syndromes other than PKU have been recognized that give high blood phenylalanine levels. These syndromes are referred to as 'atypical' PKU. While in classical PKU phenylalanine hydroxylase is the deficient enzyme, in the atypical forms of PKU the deficiency is in the enzymes affecting the production of tetrahydrobiopterin, the cofactor required for the activity of phenylalanine hydroxylase. Two types of atypical forms of PKU are now known. One is caused by a deficiency of dihydropteridine reductase, and the other is caused by defects in the synthetic pathways of biopterin, termed as 'biopterin synthetase deficiency'. In addition, a transient form of biopterin synthetase deficiency occurs in the newborn period which has to be distinguished from the permanent defect in biopterin synthesis. Analysis of oxidized pterins in urine by high performance liquid chromatography identifies classical PKU, dihydropteridine reductase deficiency, and biopterin synthetase defects. The early recognition of these cofactor defects is essential for the successful treatment of patients with the atypical forms of hyperphenylalaninemias.