Phenylketonuria Due to a Deficiency of Dihydropteridine Reductase

The onset of neurologic symptoms in a child who had markedly elevated blood phenylalanine levels during the first two weeks of life and who was promptly treated with a low phenylalanine diet, with excellent control of serum phenylalanine levels, suggested that this child had an unusual form of phenylketonuria. In assays of the components of the phenylalanine hydroxylating system (open liver biopsy at 14 months), the activity of phenylalanine hydroxylase was 20 per cent of the average normal adult value. By contrast, no dihydropteridine reductase activity was detected in the patient's liver, brain or cultured skin fibroblasts. Since dihydropteridine reductase is also essential for the biosynthesis of dopamine, norepinephrine, and serotonin, disturbed neurotransmitter function may be responsible for the patient's neurologic deterioration. On the basis of these results, assay of reductase in cultured skin fibroblasts may be advisable in the initial diagnosis of phenylketonuria. (N Engl J Med 293:785–790, 1975). PHENYLKETONURIA is caused by a genetic defect in the enzyme system that catalyzes the conversion of phenylalanine to tyrosine.¹The hydroxylase system is a complex one composed of at least two essential enzymes, phenylalanine hydroxylase (catalyzing reaction 1 ) and dihydropteridine reductase (catalyzing reaction 2), and an essential, nonprotein coenzyme, tetrahydrobiopterin²: Quinonoid dihydrobiopterin, an extremely unstable compound, undergoes tautomerization to 7,8-dihydrobiopterin, an isomer of the quinonoid compound.³The 7,8-dihydrobiopterin is not a substrate for dihydropteridine reductase, but is a substrate for another enzyme, dihydrofolate reductase, which catalyzes reaction 3⁴: In addition to serving a role in the reduction.