Tetrahydrobiopterin deficiency

Blau N, Barnes I, Dhondt JL (1996) International database of tetrahydrobiopterin deficiencies. J Inherit Metab Dis 19 8-14... 

Shintaku H, Niederwieser A, leimbacher W, Curtius HC (1988) Tetrahydrobiopterin deficiency assay for 6-pyruvoyl-tetrahydropterin synthase activity in erythrocytes, and detection of patients and heterozygous carriers. Eur J Pediatr 147 15-19... 

Blau N, Bonafe L, Thony (2001) Tetrahydrobiopterin deficiencies without hyperphenyl-alaninemia diagnosis and genetics of Dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab 74 172-185... 

Dhondt JL Screening of tetrahydrobiopterin deficiency among hyperphenylalanenic patients. Ann Biol Clin Paris 60 165-71,2002. 

Heales S, Crawley F, Rudge P. Reversible parkinsonism following heroin pyrolysate inhalation is associated with tetrahydrobiopterin deficiency. Mov Disord 2004 19(10) 1248-51. 

C-7) Phenylketonuria (deficiency of phenylalanine hydroxylase). Occasionally, the defect is not in the enzyme but in the ability to regenerate tetrahydrobiop-terin, which is also necessary for the reaction. There is a buildup and excretion of phenylpyruvate in the urine, giving it a mousy odor. Mental retardation is a prominent feature. Diagnosis can be made by routine urine testing for phenylpyruvate or serum testing for elevated phenylalanine levels. The condition is treated with a diet low in phenylalanine. Sometimes, tetrahydrobiopterin deficiency may be treated by supplying biopterin,... 

There is clear biochemical and clinical heterogeneity between these conditions, but the small number of reported cases precludes an accurate ascertainment of intra-disease heterogeneity. Lack of TH leads to a specific deficit of the catecholamines (dopamine, norepinephrine and adrenaline). AADC is required for the synthesis of the catecholamines and serotonin. Lack of this enzyme therefore causes a global deficiency of all of these neurotransmitters as is found in the abnormalities of tetrahydrobiopterin metabolism (Chap. 1). The clinical symptoms are also similar, including developmental delay, central and peripheral hypotonia, temperature instability, chorea, ptosis and oculogyric crises. The two conditions are in general distinguishable as hyperphenylalaninemia is not present in AADC deficiency. However, certain forms of tetrahydrobiopterin deficiency also do not present with hyperphenylalaninemia. 

Tauri disease Tay-Sachs disease Testicular feminization syndrome Tetrahydrobiopterin deficiency Thiopurine methyltransferase deficiency Thymidine phosphorylase deficiency Transcobalamin II deficiency Tricho-hepato-enteric syndrome Trimethylaminuria Tripeptidyl peptidase I deficiency Tryptophan-2,3-dioxygenase deficiency Tryptophanuria... 

Cosentino F, Barker JE, Brand MP, Heales SJ, Werner ER, Tippins JR, West N, Chaimon KM, Volpe M, Luscher TF. Reactive oxygen species mediate endotheliiun-dependent relaxations in tetrahydrobiopterin-deficient mice. Arterioscler Thromb Vase Biol 2001 ... 

Curtius, H.-Ch., Niederwieser, A., Viscontini, M., Otten, A., Schaub, J., Scheibenreiter, S. and Schmidt, H. (1979), Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin, and sepiapterin. Clin. Ckim. Acta, 93,251. 

Folic acid deficiency is also related to megaloblastic anemia. Tetrahydrobiopterin is a co-factor for phenylalanine, tyrosine, and tryptophane hydroxilases — enzymes... 

FIGURE 40-2 The phenylalanine hydroxylase (PAH) pathway. Phenylketonuria usually is caused by a congenital deficiency of PAH (reaction 1), but it also can result from defects in the metabolism of biopterin, which is a cofactor for the hydroxylase. Enzymes (1) Phenylalanine hydroxylase (2) Dihydropteridine reductase (3) GTP cyclohydrolase (4) 6-pyruvoyltetrahydrobiopterin synthase. BH4, tetrahydrobiopterin DEDT, o-erythro-dihydroneopterin triphosphate QH2, dihydrobiopterin. 

Other causes of PKU secondary to defective tetrahydrobiopterin synthesis include GTP cyclohydrolase deficiency and 6-pyravoyltetrahydrobiopterin synthase deficiency. Patients with either defect have psychomotor retardation, truncal hypotonia with limb hypertonia, seizures and a tendency to hyperthermia. The intravenous administration of BH4 may lower blood phenylalanine levels but this cofactor may not readily cross the blood-brain barrier. Treatment with synthetic pterin analogs or supplementation with tryptophan and carbidopa may prove more efficacious, particularly if treatment is started early in life. 

P. D., Loftus, M., Stuehr, D. J., Expression of human inducible nitric oxide synthase in a tetrahydrobiopterin (H4B)-deficient cell line H4B promotes assembly of enzyme subunits into an active dimmer, Proc. Natl. Acad. Sci. USA 92 (1995), p. 11771-11775... 

A Fig. 6.1.7a- HPLC of pterins using a column-switching system a standard mixture b control urine c urine guanosine triphosphate cyclohydrolase I (GTPCH) deficiency d urine 6-pyru-voyl-tetrahydropterin synthase (PTPS) deficiency e urine pterin-4a-carbinolamine dehydratase (PCD) deficiency f urine dihydropteridine reductase (DHPR) deficiency g urine phenylketonuria 4-8 h after tetrahydrobiopterin (BH4) administration h-k see next page... 

Rembold H (1983) Pteridine catabolism. In Curtius HC, Pfleidere W, Wachter H (eds) Biochemical and Clinical Aspects of Pteridines. Walter de Gruyter, Berlin, pp 107-122 Blau N, de Klerk JBC, Thony B, Heizmann CW, Kierat L, Smeitink JAM, Duran M (1996) Tetrahydrobiopterin loading test in xanthine dehydrogenase and molybdenum cofactor deficiencies. Biochem Mol Med 58 199-203... 

Bonafe L, Thony B, Penzien JM, Czarnecki B, Blau N (2001) Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet 69 269-277... 

Hyland K, Heales SJ. (1993) Tetrahydrobiopterin and quinonoid dihydrobiopterin concentrations in CSF from patients with dihydropteridine reductase deficiency. J Inherit Metab Dis 16 608-610... 

Blau N, Erlandsen H The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol. Genet. Metab. 82 101-111,2004. 

The first enzyme activity (dihydrobiopterin reductase) catalyzes the transfer of hydrogen to dihydrobiopterin, which is thus reduced to tetrahydrobiopterin. The second enzyme activity is a hydroxylase containing two Fe3+ atoms, and this catalyzes the reduction of Oz such that one oxygen atom is incorporated into phenylalanine to form tyrosine and the second into water. At the same time tetrahydrobiopterin is oxidized to dihydrobiopterin. Phenylalanine hydroxylase is an example of a mixed-function oxidase. An inherited deficiency of phenylalanine hydroxylase results in the accumulation of phenylalanine that is not converted to tyrosine but is excreted as phenylpyruvate. This condition, which affects young infants, is known as phenylketonuria and is associated with severe mental retardation. 

Phenylketonuria is perhaps the best known of the diseases of amino acid metabolism. Phenylketonuria is caused by an absence or deficiency of phenylalanine hydroxylase or, more rarely, of its tetrahydrobiopterin cofactor. Phenylalanine accumulates in all body fluids because it cannot be converted into tyrosine. Normally, three-quarters of the phenylalanine is converted into tyrosine, and the other quarter becomes incorporated into proteins. Because the major outflow pathway is blocked in phenylketonuria, the blood level of phenylalanine is typically at least 20-fold as high as in normal people. Minor fates of phenylalanine in normal people, such as the formation of phenylpyruvate, become major fates in phenylketonurics. 

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. "... 

Deficiencies of tyrosine hydroxylase or of enzymes involved in production of tetrahydrobiopterin cofactor (e.g., dopa-responsive dystonia) usually result in presentation of severe neurological abnormalities in early childhood. Depending on the exact mutation, deficiencies of tyrosine hydroxylase can involve moderate to severe loss of enzyme activity, most accurately diagnosed by low cerebrospinal fluid levels of catecholamine metabolites, such as MHPG and HVA, but normal levels of In the autosomal... 

NADH exhibits a lower and higher V ,ax for the reductase than NADPH. Thus, the pterin coenzyme functions stoichiometrically (in the hydroxylase reaction) and catalytically (in the reductase reaction). Deficiency of dihydropteridine reductase causes a substantial decrease in the rate of phenylalanine hy-droxylation. Dihydropteridine reductase and tetrahydrobiopterin are involved in hydroxylation of tyrosine and of tryptophan to yield neurotransmitters and hormones (dopamine, norepinephrine, epinephrine, and serotonin). Unlike phenylalanine hydroxylase, dihydropteridine... 

Tetrahydrobiopterin is synthesized starting from GTP and requires at least three enzymes. The first committed step is GTP-cyclohydrolase, which converts GTP to dihy-droneopterin triphosphate. 6-Pyruvoyltetrahydrobiopterin synthase transforms dihydroneopterin triphosphate into 6-pyruvoyltetrahydrobiopterin. The latter is reduced to tetrahydrobiopterin by NADPH-dependent sepi-apterin reductase. Deficiency of GTP-cyclohydrolase and... 

Deficiency of phenylalanine hydroxylase, tetrahydrobiopterin, or dihydropteridine reductase results in phenylketonuria (PKU), an autosomal recessive trait. Because phenylalanine accumulates in tissues and plasma (hyperphenylalaninemia), it is metabolized by alternative pathways and abnormal amounts of phenylpyruvate appear in urine (Figure 17-22). Phenylalanine hydroxylase deficiency may be complete (classic PKU, type 1) or partial... 

Phenylalanine hydroxylase The enzyme that converts the essential amino acid phenylalanine to the amino acid tyrosine using tetrahydrobiopterin and molecnlar oxygen. A genetic deficiency in this enzyme gives rise to the disease phenylketonuria. 

PKU Phenylketonuria the pathologic condition of increased excretion of phenylketones in the urine because of impaired conversion of phenylalanine to tyrosine. Classical PKU is because of a genetic deficiency of phenylalanine hydroxylase however, other causes are deficiencies in dihydropteridine reductase or in the biosynthesis of tetrahydrobiopterin. 

PKU can be caused by deficiencies in phenylalanine hydroxylase and by enzymes catalyzing the formation and regeneration of 5,6,7,8-tetrahydrobiopterin. How can this second defect cause the symptoms of PKU ... 

Fig. 39.18. Hydroxylation of phenylalanine. Phenylalanine hydroxylase (PAH) is a mixed-function oxidase i.e., molecular oxygen (Oj) donates one atom to water and one to the product, tyrosine. The cofactor, tetrahydrobiopterin (BH4), is oxidized to dihydrobiopterin (BHj), and must be reduced back to BH4 for the phenylalanine to continue forming tyrosine. BH4 is synthesized in the body from GTP. PKU results from deficiencies of PAH (the classic form), dihydropteridine reductase, or enzymes in the biosynthetic pathway for BH4.

Answers (b), (c), and (e) are correct. Phenylketonuria is a metabolic disorder arising from an absence or deficiency in the enzyme phenylalanine hydroxylase or (more rarely) its cofactor tetrahydrobiopterin. It results in the build-up of phenylalanine in the body and is treated -with a diet low in phenylalanine. 

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