Tetrahydrobiopterin-responsive phenylketonuria

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

Figure 19-4. Differences between the frequency of phenylketonuria (PKU) and hyper-phenylalaninemia (HPA) caused by problems in tetrahydrobiopterin (BH4) metabolism and reports of positive therapeutic responses to BH4 therapy. (A) Frequency of PKU and HPA cases documented to be caused by defects in BH4 metabolism. D, Clinical cases documented to be caused by defects in BH4 D, clinical cases presumable due to a defect in the phenylalanine hydroxylase enzyme. (II) Frequency of PKU and HPA cases that have been reported to respond positively to BH4 therapy. , Positive response to BH4 therapy 0, no response to BH4 therapy. Different reports in the literature varied with respect to the numbers of individuals responding to BH4 therapy. The differences in reported numbers of BH4 responders are indicated by the boxes with cross-hatching.

Fiege B, Bonafe L, Ballhausen D, et al. Extended tetrahydrobiopterin loading test in the diagnosis of cofactor-responsive phenylketonuria A pilot study. Mol Genet Metab 86 s91-s95,... 

Matalon R, Michals-Matalon K, Koch R, et al. Response of patients with phenylketonuria in the U.S. to tetrahydrobiopterin. Mol Genet Metab 86 sl7-s21, 2005. 

Both tyrosine and tryptophan hydroxylases belong to a small family of monooxygenases, that also includes phenylalanine hydroxylase all three enzymes require tetrahydro-biopterin as a substrate to drive the hydroxylation reaction." Deficiencies in the enzymes responsible for formation and recycling of tetrahydrobiopterin result in variant forms of phenylketonuria and hyperphenylalaninemia characterized by low levels of monoamine neurotransmitters and severe neurological abnormalities. "... 

Phenylketonuria, an inborn error of phenylalanine metabolism, occurs with a frequency of about 1 in 10,000 births and is treated with a strict dietary regimen. Recently, some patients with PKU have been found to show increased tolerance towards phenylalanine intake, while receiving tetrahydrobiopterin (BH ) supplementation. We have treated two infants with BH -responsive PKU with BH for more than 2 years. No additional dietary control was required to maintain blood phenylalanine concentrations in the desired range. Both children have shown normal development. Generally, these results suggest that BH treatment might be an option for some patients with mild PKU, as it frees them from dietary restriction and thus improves their quality of life. 

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