M. Viscontini

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 (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.

Atypical phenylketonuria caused by 7,8-dihydrobiopterin synthetase deficiency

A patient with atypical phenylketonuria and normal liver dihydropteridine reductase and phenylalanine-4-hydroxylase activities excreted neopterin but not biopterin or dihydrobiopterin in urine. The oral administration of L-sepiapterin (1 mg/kg body weight) lowered serum-henylalanine from 17.1 to 1.1 mg/dl within 6 h. Comparable responses were observed after oral administration of L-erythro-7, 8-dihydrobiopterin or L-erythro-5, 6, 7, 8-tetrahydrobiopterin (each given in a dose of 2.5 mg/kg body weight). The results indicate a 7, 8-dihydrobiopterin synthetase deficiency in the patient.

Serotonin and dopamine synthesis in phenylketonuria.

Two regulation systems of the serotonin and dopamine biosynthesis in patients with classical and atypical PKU were investigated. In classical PKU, the serotonin and dopamine biosynthesis is inhibited by high L-phenylalanine in blood and tissues. The dopamine formation in vivo was inhibited by phenylalanine blood concentrations higher than 25 mg/dl: the serotonin formation was inhibited even at a phenylalanine blood concentration of only 8 mg/dl. In two patients with dihydrobiopterin synthetase deficiency, the dopamine, and even more pronounced the serotonin, excretions are considerably reduced. The dopamine excretion was reduced to about 50% and the serotonin excretion to only 10% compared to controls. Under BH4 therapy (16 mg daily), the dopamine values increased about twice, serotonin threefold and the phenylalanine blood concentration normalized to 1-1.5 mg/dl. On loading a patient with BH2 synthetase deficiency with 50 mg/kg deuterated tryptophan-d5 and 150 mg/kg deuterated tyrosine d2 (phenylalanine blood concentration of 16 mg/dl), deuterated dopamine d1 and serotonin d4 could only be formed in detectable amounts after BH4 administration. During BH4 therapy the amount of dopamine d1 and serotonin d4 formed was lower than but comparable to normal controls.

Molybdenum-pterin complexes: a functional and structural model for the binding site in the enzyme dimethyl sulfoxide reductase.

In addition to the nitrogenases there is a large group of molybdenum containing enzymes catalyzing oxidation and reduction of various substrates1.