ATYPICAL PHENYLKETONURIA DUE TO TETRAHYDROBIOPTERIN DEFICIENCY - DIAGNOSIS AND TREATMENT WITH TETRAHYDROBIOPTERIN, DIHYDROBIOPTERIN AND SEPIAPTERIN

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. © 1979.