Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiapterin

Abstract

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 (BH 2) 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 BH 2 deficiency after oral administration of L- erythro-5,6,7,8-tetrahydrobiopterin (BH 4), BH 2 (both 8μmol/kg body weight) and L-sepiapterin (2.8 and 4.2 μmol/kg in the 2 patients, respectively). BH 4 and partially even BH 2 decreased serum Phe also in the patient with DHPR deficiency. BH 4, intravenously, had no effect on serum Phe of the classical PKU patients and of the controls. d- erythro-5,6,7,8-Tetrahydroneopterin (NeH 4) had no effect on serum Phe in one patient with BH 2-deficiency. The patients with BH 2 deficiency excreted large amounts of neopterin, some dihydroneopterin and dihydroxanthopterin (XH 2), but no trace of biopterins, indicating a BH 2 synthetase deficiency in both patients. The patient with DHPR deficiency excreted remarkable amounts of BH 2 and XH 2 and traces of biopterin and neopterin. After BH 4 administration, excessive amounts of BH 2 and XH 2 were excreted. Untreated PKU patients excreted more pterins than did patients under PKU diet or normal controls; after BH 4 administration, PKU patients and controls excreted large amounts of BH 4, BH 2, biopterin. The results demonstrate that BH 4, BH 2, L-sepiapterin and NeH 4, in admixture with ascorbic acid (10 mg/kg body weight) can be absorbed easily upon oral administration. The PKU diet of patients with BH 4-deficiency can be replaced by oral BH 4 supplementation. The two patients with BH 2 synthetase deficiency need about 4μmol BH 4 kg −1 d −1 (1.25 mg BH 4 · 2 HC1 kg -1 d −1), and the patient with DHPR deficiency needs about 8 μmol BH 4 kg -1 d -1. Substitution of neurotransmitter precursors (dopa, 5-hydroxytryptophan and carbidopa) cannot be discontinued. Screening of all newborn hyperphenylalaninemics for BH 4 deficiency is suggested by a single oral administration of BH 4 · 2 HCl, 8 μmol kg −1, 1 h before a meal, and measurement of serum Phe before and 4 or 6 h after loading.