Abstract
Six hundred and seventy-three children (483 newborns and 190 older selected children) were screened for tetrahydrobiopterin (BH4) deficiency by HPLC of urine pterins and BH4 load test. One patient with GTP cyclohydrolase I deficiency, 36 patients with dihydrobiopterin synthetase (DHBS) deficiency (of which six were in the newborn and 30 in the older children) and 14 with dihydropteridine reductase deficiency (DHPR) were found. All 37 patients with defective BH4 biosynthesis responded to a BH4 load by lowering of the elevated serum phenylalanine concentration but four of 14 patients with DHPR deficiency did not. Measurement of DHPR activity in blood spots on Guthrie cards is recommended. Since subvariants of patients with BH4 deficiency exist, homovanillic acid, 5-hydroxyindole acetic acid, pterins, phenylalanine, and tyrosine in cerebrospinal fluid should be measured for diagnosis and the control of therapy. The activity of the phosphate-eliminating enzyme (a key enzyme in BH4 biosynthesis and part of “DHBS”) was measured in human liver and activities of approx. 1 n U (mg protein)−1 were found. In the liver biopsy of a patient with DHBS deficiency no activity (less than 3% of controls) was demonstrated.
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Arai, N., Narisawa, K., Hayakawa, H. and Tada, K. Hyperphenylalaninaemia due to dihydropteridine reductase deficiency: Diagnosis by enzyme assay on dried blood spots.Pediatrics 98 (1982) 426–430
Bartholomé, K. A new molecular defect in phenylketonuria.Lancet II (1974) 1980
Bartholomé, K. and Byrd, D. J.l-Dopa and 5-hydroxytryptophan therapy in phenylketonuria with normal phenylalanine hydroxylase activity.Lancet II (1975) 1042
Blau, N., Joller, P., Atares, M., Cardesa-Garcia, J. and Niederwieser, A. Increase of GTP cyclohydrolase I activity in mononuclear blood cells by stimulation: Detection of heterozygotes of GTP cyclohydrolase I deficiency.Clin. Chim. Acta (In press) (1985)
Blau, N. and Niederwieser, A. GTP-cyclohydrolase I assay in human and rat liver using high-performance liquid chromatography of neopterin phosphates and guanine nucleotides.Analyt. Biochem. 128 (1983) 446–452
Bräutigam, M., Dreesen, R. and Herken, H. Tetrahydrobiopterin and total biopterin content of neuroblastoma (N1E-115, N2A) and pheochromocytoma (PC-12) clones and the dependence of catecholamine synthesis on tetrahydrobiopterin concentration in PC-12 cells.J. Neurochem. 42 (1984) 390–395
Curtius, H.-Ch., Heintel, D., Ghisla, S., Kuster, Th., Leimbacher, W. and Niederwieser, A. Biosynthesis of tetrahydrobiopterin in man.J. Inher. Metab. Dis. 8 Suppl. 1 (1985) 28–33
Danks, D. M., Bartholomé, K., Clayton, B. E., Curtius, H.-Ch., Gröbe, H., Kaufman, S.et al. Malignant hyperphenylalaninaemia—Current status (June 1977).J. Inher. Metab. Dis. 1 (1978) 49–53
Danks, D. M., Cotton, R. G. and Schlesinger, P. Tetrahydrobiopterin treatment of variant forms of phenylketonuria.Lancet II (1975) 1043
Dhondt, J. L., Ardouin, P., Hayte, J.-M. and Farriaux, J.-P. Developmental aspects of pteridine metabolism and relationships with phenylalanine metabolism.Clin. Chim. Acta 116 (1981) 143–152.
Dhondt, J. L., Leroux, B., Farriaux, J. P., Largilliere, C. and Leeming, R. J. Dihydrobiopterin biosynthesis deficiency.Eur. J. Pediatr. 141 (1983) 92–95
Fukushima, T. and Nixon, J. C. Analysis of reduced forms of biopterin in biological tissues and fluids.Analyt. Biochem. 102 (1980) 176–188
Gál, E. M., Nelson, J. M. and Sherman, A. D. Biopterin III. Purification and characterization of enzymes involved in the cerebral synthesis of 7,8-dihydrobiopterin.Neurochem. Res. 3 (1978) 69–88
Güttler, F., Lou, H., Lykkelund, C. and Niederwieser, A. Combined tetrahydrobiopterin-phenylalanine loading test in the detection of partially defective biopterin biosynthesis.Eur. J. Pediatr. 142 (1984) 126–129
Hreidarsson, S., Valle, D., Kapatos, N. and Kaufman, S. A peripheral defect in biopterin synthesis: A new mutant?Pediatr. Res. 16 (1982) 192A
Kaufman, S. Biopterin and metabolic disease. In Kisliuk, R. L. and Brown, G. M. (eds.)Chemistry and Biology of Pteridines, Elsevier-North Holland, New York, 1979, pp. 117–124
Kaufman, S., Holtzman, N. A., Milstien, S., Butler, I. J. and Krumholz, A. Phenylketonuria due to a deficiency of dihydropteridine reductase.N. Engl. J. Med. 293 (1975) 785–790
Kaufman, S., Kapatos, G., Rizzo, W. B., Schulman, J. D., Tamarkin, L. and van Loon, G. R. Tetrahydropterin therapy for hyperphenylalaninaemia caused by defective synthesis of tetrahydrobiopterin.Ann. Neurol. 14 (1983) 308–315
Leeming, R. J., Barford, P. A., Blair, J. A. and Smith, I. Blood spots on Guthrie cards can be used for inherited tetrahydrobiopterin deficiency screening in hyperphenylalaninaemic infants.Arch. Dis. Child. 59 (1984) 58–61
Leupold, D., Wang, M. and Niederwieser, A. Tetrahydrobiopterin monotherapy in two siblings with dihydrobiopterin deficiency. In Wachter, H., Curtius, H.-Ch. and Pfleiderer, W. (eds.)Biochemical and Clinical Aspects of Pteridines, Vol. 1, De Gruyter, Berlin, 1982, pp. 307–317
Lunte, C. E., and Kissinger, P. T. The determination of pterins in biological samples by liquid-chromatography/electrochemistry.Analyt. Biochem. 129 (1983) 377–386
McInnes, R. R., Kaufman, S., Warsh, J. J., Van Loon, G. R., Milstien, S., Kapatos, G.et al. Biopterin synthesis defect. Treatment withl-Dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.J. Clin. Invest. 37 (1984) 458–469
Matalon, R. Current status of biopterin screening.J. Pediatr. 104 (1984) 579–580
Muenzer, J., Milstien, S., Sidbury, J., Berlow, S. and Kaufman, S. Treatment of phenylalaninaemia secondary to a deficiency of biopterin with reduced pterins.Pediatr. Res. 18 (1984) 297A
Niederwieser, A., Blau, N., Wang, M., Joller, P., Atarés, M. and Cardesa-Garcia, J. GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninaemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia.Eur. J. Pediatr. 141 (1984a) 208–214
Niederwieser, A., Curtius, H.-Ch., Bettoni, O., Bieri, J., Schircks, B., Viscontini, M. and Schaub, J. Atypical phenylketonuria caused by 7,8-dihydrobiopterin synthetase deficiency.Lancet I (1979) 131–133
Niederwieser, A., Curtius, H.-Ch., Gitzelmann, R., Otten, A., Baerlocher, K., Blehová, B.et al. Excretion of pterins in phenylketonuria and phenylketonuria variants.Helv. Paediatr. Acta 35 (1980a) 335–342
Niederwieser, A., Curtius, H.-Ch., Wang, M. and Leupold, D. Atypical phenylketonuria with defective biopterin metabolism. Monotherapy with tetrahydrobiopterin or sepiapterin, screening and study of biosynthesis in man.Eur. J. Pediatr. 138 (1982a) 110–112
Niederwieser, A., Matasović, A., Curtius, H.-Ch., Endres, W. and Schaub, J. 3′-Hydroxysepiapterin in patients with dihydrobiopterin deficiency.FEBS Lett. 118 (1980b) 299–302
Niederwieser, A., Matasović, A., Staudenmann, W., Wang, M. and Curtius, H.-Ch. Screening for tetrahydrobiopterin deficiency. In Wachter, H., Curtius, H.-Ch. and Pfleiderer, W. (eds.)Biochemical and Clinical Aspects of Pteridines, Vol. 1, De Gruyter, Berlin, 1982b, pp. 293–306
Niederwieser, A., Staudenmann, W., Wang, M., Curtius, H.-Ch., Atares, M. and Cardesa-Garcia, J. Hyperphenylalaninaemia with neopterin deficiency. A new enzyme defect presumably of GTP cyclohydrolase.Eur. J. Pediatr. 138 (1982c) 97
Niederwieser, A., Staudenmann, W. and Wetzel, E. Automatic HPLC of pterins with or without column switching. In Wachter, H., Curtius, H.-Ch. and Pfleiderer, W. (eds.)Biochemical and Clinical Aspects of Pteridines, Vol. 1, De Gruyter, Berlin, 1982d, pp. 81–102
Niederwieser, A., Staudenmann, W. and Wetzel, E. High-performance liquid chromatography with column switching for the analysis of biogenic amine metabolites and pterins.J. Chromatogr. 290 (1984b) 237–246
Rey, F., Harpey, J. P. and Leeming, R. J. Les hyperphénylalaninémies avec activité normale de la phenylalanine hydroxylase: Le déficit en tetrahydrobioptérine et la déficit en dihydropteridine reductase.Arch. Fr. Pédiatr. 34 (1977) 109–120
Rey, F., Leeming, R. J., Blair, J. A. and Rey, J. Biopterin defect in a normal appearing child affected by a transient phenylketonuria.Arch. Dis. Child. 55 (1980) 637–639
Rey, F., Saudubray, J. M., Leeming, R. J., Niederwieser, A., Curtius, H.-Ch. and Rey, J. Les déficits partiel en tétrahydrobioptérine.Arch Fr. Pédiatr. 40 (1983) 237–241
Smith, I. Atypical phenylketonuria accompanied by severe progressive neurological illness unresponsive to dietary treatment.Arch. Dis. Child. 49 (1974) 245
Smith, I., Clayton, B. E. and Wolff, O. H. New variant of phenylketonuria with progressive neurological illness unresponsive to phenylalanine restriction.Lancet 1 (1975) 1108
Wachter, H.et al. In Curtius, H.-Ch., Pfeiderer, W. and Wachter, H. (eds.)Biochemical and Clinical Aspects of Pteridines, Vols 2 and 3, De Gruyter, Berlin, 1983, 1984
Yoshioka, S., Masada, M., Yoshida, T., Mizokami, T., Akino, M. and Matsuo, N. Atypical phenylketonuria due to biopterin deficiency: Diagnosis by assay of an enzyme involved in the synthesis of sepiapterin from dihydroneopterin triphosphate.Zool. Sci. 1 (1984) 74–81
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Niederwieser, A., Ponzone, A. & Curtius, H.C. Differential diagnosis of tetrahydrobiopterin deficiency. J Inherit Metab Dis 8 (Suppl 1), 34–38 (1985). https://doi.org/10.1007/BF01800657
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DOI: https://doi.org/10.1007/BF01800657