Dihydropteridine reductase deficiency

Milstien S, Holtzman NA, Flynn ME, Thomas GH, Butler IJ, Kaufman S (1976) Hyper-phenylalaninemia due to dihydropteridine reductase deficiency. Assay of the enzyme in fibroblasts from affected infants, heterozygotes, and in normal amniotic fluid cells. J Pediatr 89 763-766... 

Arai N, Narisawa K, Hayakawa H, Tada (1982) Hyperphenylalaninemia due to dihydropteridine reductase deficiency diagnosis by enzyme assays on dried blood spots. Pediatrics 70 426-430... 

Narisawa K, Arai N, Hayakawa H, Tada (1981) Diagnosis of dihydropteridine reductase deficiency by erythrocyte enzyme assay. Pediatrics 68 591-592... 

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... 

Woody RC, Brewster MA. Adverse effects of trimethoprim-sulfamethoxazole in a child with dihydropteridine reductase deficiency. Dev Med Child Neurol 1990 32(7) 639 2. 

Extrapyramidal symptoms developed with co-trimox-azole in a girl with dihydropteridine reductase deficiency and rapidly disappeared after withdrawal. This variant of phenylketonuria should be considered in all infants found to have raised phenylalanine concentrations during the neonatal period (46). 

Genetic disorders (not included above) tyrosine hydroxylase deficiency dopa-responsive dystonia dihydropteridine reductase deficiency aromatic L-amino acid decarboxylase deficiency Menkes disease monoamine oxidase deficiency. 

Regarding the dihydropteridine reductase deficiency (DHPR) and defect in biosynthesis of biopterin, further studies may be in order in most hyperphenyla-laninemic infants. 

Several patients have now been described with this variant of hyperphenylalaninemia. Neurological symptoms, particularly hypotonia and delay in motor development, are recognized earlier than in classical PKU. In spite of adequate control of serum phenylalanine levels, deterioration continues unabated. Seizures have not been encountered in these patients, as there is a coexistence of dihydropteridine reductase deficiency. Since both tetrahydrobiopterin and dihydropteridine reductase are essential to the hydroxylases that synthesize serotonin and norepinephrine, it is not surprising that neurological symptoms are prominent in... 

Brewster, T.G., Moskowitz, M.A., Kaufman, S., Breslow, J.L., Milstien, S. and Abroms, I.F. (1979), Dihydropteridine reductase deficiency associated with severe neurologic disease and mild hyperphenylalaninemia. Pediatrics, 63,94. 

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. 

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... 

CFD is further associated with the following inherited metabolic disorders 5,10-methylen-tetrahydrofolate reductase (MTHFR) deficiency [7], 3-phos-phoglycerate dehydrogenase (PGDH) deficiency [8], dihydropteridine reductase (DHPR) deficiency [9], as well as with Rett syndrome [10], and Aicardi-Gou res Syndrome [11]. Furthermore, folate deficiency may be associated with congenital folate malabsorption, severe malnutrition, and formiminotransferase deficiency. 

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... 

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... 

A. The patient, despite being put on a low-Phe diet, exhibits neurologic problems resulting from an inability to synthesize catecholamine and indoleamine neurotransmitters. This is caused by a deficiency in dihydropteridine reductase (DHPR). DHPR regenerates tetrahydro-biopterin (BH ), which is oxidized to dihydrobiopterin by phenylalanine hydroxylase, as well as tyrosine hydroxylase and tryptophan hydroxylase (tryptophan 5-monooxygenase). If phenylalanine hydroxylase were deficient, a diet low in Phe would alleviate the effects. Since the urinary biopterin concentration is elevated, a deficiency in GTP cyclohydrolase I is eliminated because that is an enzyme in the biosynthetic pathway of BH. Phe hydroxylase, Tyr hydroxylase, and Tip hydroxylase activities are low because of a lack of BH. ... 

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. 

Phenylalanine hydroxylase uses teirahydrobioptcrin (BH4) as a cofactor. Defective BH4 supply or regeneration, due to deficiency of dihydropteridine reductase, have been identified as rare cau.ses of hyperphenylalaninaemia. a... 

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.

Assay of phenylalanine hydroxylase in a liver biopsy from one patient showed 20% of normal adult control values, but dihydropteridine reductase activity (Fig. 20.2) was less than 1% of normal in the liver, brain, and other tissues. This latter deficiency presents regeneration of tetrahydrobiopterin, the cofactor for the hydroxylase reaction. Since the reductase enzyme reaction regenerates the cofactor for tyrosine and tryptophan hydroxylase, catecholamine and serotonin synthesis are compromised as well. Patient studies are scanty, but in one patient dopamine and serotonin were decreased in the cerebrospinal fluid, brain, and various other tissues, while norepinephrine metabolites were normal. While phenylalanine hydroxylase activity was lower than that of adult controls, it was not determined whether this value represented significantly decreased activity in children. 

Dihydropteridine reductase (DHPR) deficiency all tissues 4pl5.3 261630... 

---