Atypical phenylketonuria with defective biopterin metabolism. Monotherapy with tetrahydrobiopterin or sepiapterin, screening und study of biosynthesis in man

Abstract

Administration of a single dose of tetrahydrobiopterin dihydrochloride, 10--20 mg/kg orally, to a patient with dihydrobiopterin deficiency led to disappearance of clinical symptoms for 4 days, normalization of urinary phenylalanine and serotonin and decrease of elevated neopterin for 2--3 days. A dose-dependent stimulation of serotonin production was observed. A similar effect was noted with even lower doses of L-sepiapterin. The patient is now under monotherapy with tetrahydrobiopterin . 2 HCl, 2.5 mg/kg daily. Other patients with this disease may not respond as well. Results of screening for tetrahydrobiopterin deficiency in 228 cases with hyperphenylalaninemia, including 140 newborns, are reported. There is evidence that biopterin biosynthesis in human kidney and liver proceeds via a dioxo compound and L-sepiapterin.

Biopterin synthesis defect. Treatment with L-dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.

“…However, clinical trials using high doses of BH4 or 6MPH4 must be monitored with great care, since virtually nothing is known about the toxicity of the tetrahydropterins. The results presented in this paper and others (14,16) indicate that certain patients will not be neurologically responsive to high dose pterin treatment; as we have shown, such patients may still respond, at least partially, to L-dopa and 5-HTP (8,9,13,16). The limited response of our patient may be related to the premature removal of maternally derived BH4 due to the 35-wk-gestation, the late age at which treatment was begun (7 mo), and/or to the severity ofher defect.…”

“…Our preliminary data (18,42) and those of Niederwieser et al (14) show that therapy with a tetrahydropterin may be effective in treating the defect in monoamine synthesis in some patients with BH4-deficiency. These findings imply that in all newly diagnosed hyperphenylalaninemic patients who have a defect in brain monoamine synthesis, a trial of high dose BH4 should be given.…”

Tetrahydrobiopterin Uptake in Supplemental Administration: Elevation of Tissue Tetrahydrobiopterin in Mice Following Uptake of the Exogenously Oxidized Product 7,8-Dihydrobiopterin and Subsequent Reduction by an Anti-folate-Sensitive Process

“…Sepiapterin and 7,8BH 2 were proven to be the intermediate precursors of BH 4 in a vertebrate system using bull frog (23). Actually, patients of BH 4 -deficiency were reported to have been relieved from abnormal urinary excretion of high phenylalanine and low serotonin by a single administration of sepiapterin (9,10). In the early 1980s, on the other hand, it was feared that since this pathway included dihydrofolate reductase as an immediate to BH 4 production, an MTX supplement might possibly deplete tissues of BH 4 (32).…”

Dihydropteridine reductase deficiency in man: From biology to treatment

“…Increased purity and availability of synthetic cofactor allowed the introduction of an oral test, 64,65 which was standardized at the dose of 7.5 mg/kg b.w. 66 However, it was soon ascertained that this procedure could miss the diagnosis of some DHPR deficient patients who failed to respond to this test. 11,60,67 Non-responders were identified among patients sharing high plasma Phe levels or belonging to the CRMþ type.…”