New Developments in Hyperphenylalaninemia

Abstract

In recent years it has become apparent that hyperphenylalaninemia in newborn infants may be caused by a variety of defects in the enzyme phenylalanine hydroxylase or by an abnormality in either the enzyme dihydropteridine reductase (DHPR) or the synthesis of dihydrobiopterin (BH2) (Figure). Despite the rarity of the latter conditions1 there are important implications for management in making this diagnosis. It has been suggested that all new cases of hyperphenylalaninemia now be screened for these variants.2 The purpose of the Task Force was to define the feasibility of this course at the present time. BACKGROUND The hepatic system for conversion of phenylalanine to tyrosine is complex and consists of at least two essential enzymes, phenylalanine hydroxylase (catalyzing reaction 1) and dihydropteridine reductase (catalyzing reaction 2), and an essential, nonprotein cofactor, tetrahydrobiopterin3: (1) Phenylalanine + O2 + tetrahydrobiopterin → tyrosine + H2O + quinonoid dihydrobiopterin; (2) nicotinamide adenine dinucleotide (reduced form) + H+ + quinonoid dihydrobiopterin → nicotinamide adenine dinucleotide (oxidized form) + tetrahydrobiopterin. Most cases of hyperphenylalaninemia detected by newborn infant screening programs are caused by deficiencies of phenylalanine hydroxylase ranging from the severe "classic phenylketonuria (PKU)" to the more benign "hyperphenylalaninemic variant." The patients with classic PKU usually respond to a diet low in phenylalanine. However, of the estimated 400 cases of classic PKU detected annually in the United States, up to 3% may show progressive neurologic deterioration despite adequate dietary treatment. The elevated phenylalanine in these infants may be caused by either DHPR deficiency or a deficient synthesis of BH2 or to other still unidentified causes.