Hyperphenylalaninaemia due to impaired dihydrobiopterin biosynthesis: Leukocyte function and effect of tetrahydrobiopterin therapy

Abstract

We have described the clinical and biochemical status of two patients with tetrahydrobiopterin (BH4) deficiency due to impaired dihydrobiopterin biosynthesis. BH4 administration appeared to improve the mental and psychological status more than did neurotransmitter replacement therapy alone. This enhancement of activities of daily life was seen with a dose of BH4 as low as 1.25 mg kg-1 day-1. Granulocyte adherence capacity was below normal and recovered after BH4 therapy in both patients. B-cell differentiation capacity was altered either before or after therapy.

Sepiapterin Treatment in Atherosclerosis

“…In addition to its role in the biosynthesis of monoamine neurotransmitters, BH 4 serves as an essential cofactor in all isoforms of nitric oxide synthases (NOS), with the Km for BH 4 for NOS several orders of magnitude lower than for the aromatic amino acid hydroxylases: NOS, Ϸ0.3 mol/L vs Ϸ3 mol/L for phenylalanine hydroxylase, Ϸ30 mol/L for tyrosine hydroxylase and tryptophan hydroxylase, suggesting tight coupling of the cofactor with enzyme. 8 However, the precise function(s) of BH 4 in NOS enzymatic activity is not as well defined as in the aromatic amino acid hydroxylase enzymes and may vary according to enzyme isoform.…”

“…12,14 This NADPH-dependent formation of superoxide anion in the absence of NO production has been referred to as uncoupling of NOS activity. 15 Superoxide formation from eNOS is critically controlled by BH 4 , with increasing production of superoxide occurring at low levels of reduced pterin, even in the presence of L-arginine. 12,14 More recently, partially oxidized analogues of BH 4 have been shown to also enhance rates of superoxide formation from purified eNOS in the presence of saturating L-arginine concentrations, suggesting that the ratio of reduced and oxidized biopterin may be physiologically important in determining rates of NO production versus uncoupled superoxide formation from eNOS.…”

“…15 Superoxide formation from eNOS is critically controlled by BH 4 , with increasing production of superoxide occurring at low levels of reduced pterin, even in the presence of L-arginine. 12,14 More recently, partially oxidized analogues of BH 4 have been shown to also enhance rates of superoxide formation from purified eNOS in the presence of saturating L-arginine concentrations, suggesting that the ratio of reduced and oxidized biopterin may be physiologically important in determining rates of NO production versus uncoupled superoxide formation from eNOS. 16 The increase in oxidant formation that appears to accompany most, if not all, disease processes associated with endothelial-dependent vascular dysfunction may potentially be a result of inadequate BH 4 concentrations within the vasculature, with ensuing uncoupling of eNOS, increased superoxide formation and diminished NO formation.…”

“…[5][6][7] Mutations in either de novo biosynthetic or regeneration (salvage) pathways result in BH 4 deficiency associated with diminished levels of seratonin and dopamine with progressive neurologic symptoms. 8,9 The phenotypic presentation of these synthetic mutations can be predicted in large part by the role of BH 4 as an obligatory cofactor in phenylalanine, tryptophan, and tyrosine hydroxylases (the rate-limiting enzymes for catecholamine and seratonin synthesis). The function of BH 4 in these aromatic amino acid hydroxylases involves redox-active donation of electrons and reductive enzyme activation and is associated with a tightly coupled system for regeneration of BH 4 from the oxidized dihydrobiopterin.…”

“…T etrahydrobiopterin (BH 4 ) plays an important role in functional and metabolic cellular homeostasis, with additional effects on proliferation., 1,2 immune responsiveness, 3,4 and neuronal activity. [5][6][7] Mutations in either de novo biosynthetic or regeneration (salvage) pathways result in BH 4 deficiency associated with diminished levels of seratonin and dopamine with progressive neurologic symptoms.…”