Abstract
A fourteen month-old boy with atypical phenylketonuria was treated with 5-hydroxytryptophan, L-dopa and peripheral aromatic amino acid decarboxylase inhibitor (Ro 4-4602:benserazide). Despite the good control of plasma phenylalanine on a low phenylalanine diet, he had shown no improvement in his development but progressive neurological symptoms, such asiirritability, convulsions and decrease voluntary movement. After beginning neurotransmitter therapy, his irritability disappeared promptly and the other symptoms diminished. He gradually reached his developmental milestones. At two and a half years of age, he had recovered sufficiently to be able to walk freely on treatment with 13 mg/kg/day of 5-hydroxytryptophan, 11 mg/kg/day of L-dopa and 2.7 mg/kg/day of benserazide in combination with slight restriction of phenylalanine intake (100 mg/kg/day).
Levels of serotonin and 5-hydroxyindoleacetic acid were low in the patient's CSF. His urinary biopterin (Crithidia factor) excretion was low. An increase in serum biopterin following L-phenylalanine loading was not found. Dihydropteridine reductase activity in his skin fibroblasts was normal. He excreated large amounts of erythro- and threo-neopterins (but only a trace of biopterin) in his urine. After loading with phenylalanine the urinary excretion of neopterins was even more enhanced, but biopterin remained at low levels. These findings indicated that the patient has a dihydrobiopterin synthetase deficiency.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Barbeau A (1973) Treatment of Parkinson's disease with L-dopa and Ro 4-4602; Review and present status. Advan Neurol 2:173–198
Bartholomé K, Byrd DJ (1975) L-dopa and 5-hydroxytryptophan therapy in phenylketonuria with normal phenylalanine-hydroxylase activity. Lancet 1:1042–1043
Bartholomé K, Byrd DJ, Kaufman S, Milstien S (1977) Atypical phenylketonuria with normal phenylalanine hydroxylase and dihydropteridine reductase activity in vitro. Pediatrics 59:757–761
Brewster TG, Moskowitz MA, Kaufman S, Breslow JL, Milstien S, Abroms F (1979) Dihydropteridine reductase deficiency associated with severe neurologic disease and mild hyperphenylalaninemia. Pediatrics 63:94–99
Butler IJ, Koslow SH, Krumholz A, Holtzman NA, Kaufman S (1978) A disorder of biogenic amines in dihydropteridine reductase deficiency. Ann Neurol 3:224–230
Chang CC (1964) A sensitive method for spectrophotometric assay of catecholamines. Int J Neuropharmacol 3:643–649
Curtius HCh, Niederwieser A, Viscontini M, Otten A, Schaub J, Scheibenreiter S, Schmidt H (1979) Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiapterin. Clin Chim Acta 93:251–262
Curzon G, Green AR (1970) Rapid method for the determination of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in small regions of rat brain. Brit J Pharmacol 39:653–655
Danks DM, Bartholomé K, Clayton BE, Curtius H, Gröbe H, Kaufman S, Leeming R, Pfleiderer W, Rembold H, Rey F (1978) Malignant hyperphenylalaninaemia — Current status (June, 1977). J Inher Metab Dis 1:49–53
Danks DM, Cotton RGH (1979) Variant forms of phenylketonuria. Lancet 1:982
Danks DM, Cotton RGH, Schlesinger P (1975) Tetrahydrobiopterin treatment of variant form of phenylketonuria. Lancet 1:1043
Danks DM, Schlesinger P, Firgaira F, Cotton RGH, Watson BM, Rembold H, Hennings G (1979) Malignant hyperphenylalaninemia — clinical features, biochemical findings and experience with administration of biopterins. Pediat Res 13: 1150–1155
Friedman PA, Kappelman AH, Kaufman S (1972) Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain. J Biol Chem 247:4165–4173
Gröbe H, Bartholomé K, Milstien S, Kaufman S (1978) Hyperphenylalaninemia due to dihydropteridine reductase deficiency. Eur J Pediatr 129:93–98
Iwai K, Kohashi M, Fujisawa H (1970) Occurrence of Crithidia factors and folic acid in various bacteria. J Bacterol 104:197–201
Kaufman S, Berlow S, Summer GK, Milstien S, Schulman JD, Orloff S, Spielberg S, Pueschel S (1978) Hyperphenylalaninemia due to a deficiency of biopterin. A variant form of phenylketonuria. New Engl J Med 299:673–679
Kaufman S, Neil D, Holtzman A, Milstien S, Butler IJ, Krumholz A (1975) Phenylketonuria due to a deficiency of dihydropteridine reductase. New Engl J Med 293:785–790
Kawaguchi M, Nagai B, Nagano S, Koshi K, Arashima S (1979) The 7th Annual Meeting of Japanese Society of Screening of Inborn Errors of Metabolism (Kurume, Japan)
Klettler R, Bartholini G, Pletscher A (1974) In vivo enhancement of tyrosine hydroxylation in rat striatum by tetrahydrobiopterin. Nature 249:476–478
Kohashi M, Tomita K, Iwai K (1980) Analysis of unconjugated pterins in food resources and human urine. Agric Biol Chem 44:2089–2094
Kondo T, Matsuo N, Seki T, Tsuchiya Y, Fukashima O, Kumagaya M (1979) The 82th Annual Meeting of Japanese Pediatric Society (Tokyo, Japan)
Leeming RJ, Blair JA, Green A, Raine KN (1976) Biopterin derivatives in normal and phenylketonuric patients after oral load of L-phenylalanine, L-tyrosine and L-tryptophan. Arch Dis Child 51:771–777
Maickel RP, Cox RH, Saillant J, Miller FP (1968) A method for the determination of serotonin and norepinephrine in discrete areas of rat brain. Int J Neuropharmacol 7:275–281
Milstien S, Holtzman NA, O'Flynn ME, Thomas GH, Butler IJ, Kaufman S (1976) Hyperphenylalaninemia due to dihydropteridine reductase deficiency. J Pediatr 89:763–766
Narisawa K, Arai N, Ishizawa S, Ogasawara Y, Onuma A, Iinuma K, Tada K (1980) Dihydropteridine reductase deficiency: Leukocyte enzyme assay for the diagnosis. Clin Chim Acta 105:335–342
Oura T (personal communication)
Rembold H (1965) Biologically active substances in royal zelly. Vitamins and Hormones 23:359–382
Rembold H (1978) metabolism and metabolic roles of 6-polyhydroxyalkylpterins. J Inher Metab Dis 1:61–62
Schaub J, Däumling S, Curtius HCh, Niederwieser A, Bartholomé K, Viscontini M, Schircks B, Bieri JH (1978) Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis. Arch Dis Child 53:674–683
Shiman R, Akino M, Kaufman S (1971) Solubilization and partial purification of tyrosine hydroxylase from bovine adrenal medulla. J Biol Chem 246:1330–1340
Smith I, Clayton BE, Wolff OH (1975) New variant of phenylketonuria with progressive neurological illness unresponsive to phenylalanine restriction. Lancet 1:1108–1111
Tada K, Narisawa K, Arai N, Ogasawara Y, Ishizawa S (1980) A sibling case of hyperphenylalaninemia due to a deficiency of dihydropteridine reductase; Biochemical and pathologic findings. Tohoku J Exp Med 132:123–131
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tanaka, T., Aihara, K., Iwai, K. et al. Hyperphenylalaninemia due to impaired dihydrobiopterin biosynthesis. Eur J Pediatr 136, 275–280 (1981). https://doi.org/10.1007/BF00442994
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00442994