The effect of administration of several pterins on serum phenylalanine concentration (Phe) and urinary pterin excretion was investigated in two patients with atypical phenylketonuria (PKU) due to L-erythro-7,8-dihydrobiopterin (BH₂) deficiency, one patient with atypical PKU caused by dihydropteridine reductase (DHPR, EC 1.6.99.7) deficiency, 5 patients with classical PKU (defective phenylalanine-4-hydroxylase, EC 1.14.16.1) and two adult controls.

A drastic and comparable decrease of serum Phe, lasting for about 48 h, was observed in the 2 patients with BH₂ deficiency after oral administration of L-erythro-5,6,7,8-tetrahydrobiopterin (BH₄), BH₂ (both 8μmol/kg body weight) and L-sepiapterin (2.8 and 4.2 μmol/kg in the 2 patients, respectively). BH₄ and partially even BH₂ decreased serum Phe also in the patient with DHPR deficiency. BH₄, intravenously, had no effect on serum Phe of the classical PKU patients and of the controls. d-erythro-5,6,7,8-Tetrahydroneopterin (NeH₄) had no effect on serum Phe in one patient with BH₂-deficiency.

The patients with BH₂ deficiency excreted large amounts of neopterin, some dihydroneopterin and dihydroxanthopterin (XH₂), but no trace of biopterins, indicating a BH₂ synthetase deficiency in both patients. The patient with DHPR deficiency excreted remarkable amounts of BH₂ and XH₂ and traces of biopterin and neopterin. After BH₄ administration, excessive amounts of BH₂ and XH₂ were excreted. Untreated PKU patients excreted more pterins than did patients under PKU diet or normal controls; after BH₄ administration, PKU patients and controls excreted large amounts of BH₄, BH₂, biopterin.

The results demonstrate that BH₄, BH₂, L-sepiapterin and NeH₄, in admixture with ascorbic acid (10 mg/kg body weight) can be absorbed easily upon oral administration. The PKU diet of patients with BH₄-deficiency can be replaced by oral BH₄ supplementation. The two patients with BH₂ synthetase deficiency need about 4μmol BH₄ kg⁻¹ d⁻¹ (1.25 mg BH₄ · 2 HC1 kg^-1 d⁻¹), and the patient with DHPR deficiency needs about 8 μmol BH₄ kg^-1 d^-1. Substitution of neurotransmitter precursors (dopa, 5-hydroxytryptophan and carbidopa) cannot be discontinued.

Screening of all newborn hyperphenylalaninemics for BH₄ deficiency is suggested by a single oral administration of BH₄ · 2 HCl, 8 μmol kg⁻¹, 1 h before a meal, and measurement of serum Phe before and 4 or 6 h after loading.