Journal of Autism and Developmental Disorders

, Volume 22, Issue 2, pp 295–308

Plasma and urinary levels of biopterin, neopterin, and related pterins and plasma levels of folate in infantile autism

  • Isao Eto
  • Mattie D. Bandy
  • C. E. ButterworthJr.


Tetrahydrobiopterin is essential for brain cells to make monoamine neurotransmitters. It has been reported that the concentrations of tetrahydrobiopterin in plasma and urine are low in certain mental disorders and that oral supplements are beneficial. A group of Japanese investigators have been conducting clinical trials of the effect of administration of tetrahydrobiopterin to autistic children and reported that it is beneficial with no significant side effects. We, therefore, initiated a study to assess plasma and urinary levels of tetrahydrobiopterin in infantile autism to see if they are reduced. Besides tetrahydrobiopterin, we also determined plasma and urinary levels of neopterin and monapterin in these individuals in order to evaluate the status of dihydroneopterin triphosphate, a key biosynthetic precursor of tetrahydrobiopterin. Sixteen autistic children and 12 healthy controls were included in this study. Results indicated that the plasma and urinary levels of tetrahydrobiopterin are not statistically different between the two groups and, therefore, no simple explanation for the beneficial effects of administration of tetrahydrobiopterin on autistic children can be offered at the present time. In contrast, plasma and urinary levels of neopterin were depressed (.01<p<.05) and plasma monapterin was also significantly depressed (p<.01) in autistic subjects compared with controls. Levels of other pterins, including folate, were not statistically different between the two groups. The basis for this depression in neopterin and monapterin is unknown. It does not seem likely that this depression could be attributed to a difference in age or T-lymphocyte/macrophage activity. However, further studies are needed to investigate these possibilities.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Blair, J. A., Morar, C., Hamon, C. G. B., Al-Salihi, J., Barford, P. A., Pheasant, A. E., Whitburn, S. B., Leeming, R. J., & Coppen, A. (1984). Tetrahydrobiopterin in depression.Lancet, 1, 163.Google Scholar
  2. Campbell, M., Small, A. M., Palij, M., Perry, R., Polonsky, B. B., Lukashok, D., & Anderson, L. T. (1987). The efficacy and safety of fenfluramine in autistic children: preliminary analysis of a double-blind study.Psychopharmacological Bulletin, 23, 123–127.Google Scholar
  3. Curtius, H. C., Muldner, H., & Niederwieser, A. (1982a). Endogenous depression and Parkinson's disease. Therapeutic trials with tetrahydrobiopterin. In H. Wachter, H. C. Curtius, & W. Pfleiderer (Eds.),Biochemical and clinical aspects of pteridines (Vol. 1, pp. 285–292). New York: Walter de Gruyter.Google Scholar
  4. Curtius, H. C., Muldner, H., & Niederwieser, A. (1982b). Tetrahydrobiopterin: efficacy in endogenous depression and Parkinson's disease.Journal of Neural Transmission, 55, 301–308.Google Scholar
  5. Curtius, H. C., Niederwieser, A., Levine, R., & Muldner, H. (1984). Therapeutic efficacy of tetrahydrobiopterin in Parkinson's disease.Advances in Neurology, 50, 463.Google Scholar
  6. Duch, D. S., Woolf, J. H., Nichol, C. A., Davidson, J. R. & Garbutt, J. C. (1984). Urinary excretion of biopterin and neopterin in psychiatric disorders.Psychiatry Research, 11, 83–89.Google Scholar
  7. Duch, D. S., Bowers, S. W., Woolf, J. H., Davisson, M. T., Maltais, L. J., & Nichol, C. A. (1986). Differences in the metabolism of the aromatic amino acid hydroxylase cofactor, tetrahydrobiopterin, in mutant mice with neurological and immunological defects.Biochemical Genetics, 24, 657–668.Google Scholar
  8. Eto, I., Fukushima, K. & Shiota, T. (1976). Enzymatic synthesis of biopterin from D-erythrodihydroneopterin triphosphate by extracts of kidneys from Syrian golden hamsters.Journal of Biological Chemistry 251, 6505–6512.Google Scholar
  9. Fukushima, T., & Nixon, J. C. (198). Analysis of reduced forms of biopterin in biological tissues and fluids.Analytical Biochemistry, 102, 176–188.Google Scholar
  10. Fukushima, T., Kobayashi, K., Eto, I., & Shiota, T. (1978). A differential microdetermination for the various forms of biopterin.Analytical Biochemistry, 89, 71–79.Google Scholar
  11. Garbutt, J. C., Duch, D. S., Nichol, C. A. & Woolf, J. H. (1985). Urinary biopterin and neopterin excretion and pituitary-adrenal activity in psychiatric patients.Psychiatry Research, 16, 181–187.Google Scholar
  12. Gillberg, C. & Svennerholm, L. (1987). CSF monoamines in autistic syndromes and other pervasive developmental disorders of early childhood.British Journal of Psychiatry, 151, 89–94.Google Scholar
  13. Gillberg, C., Svennerholm, L. & Hamilton-Hillberg, C. (1983). Childhood psychosis and monoamine metabolites in spinal fluid.Journal of Autism and Developmental Disorders, 13, 383–396.Google Scholar
  14. Hannonen, P., Tikanoja, S., Hakola, M., Mottonen, T., Viinikka, L. & Oka, M. (1986). Urinary neopterin index as a measure of rheumatoid activity.Scandinavian Journal of Rheumatology 15, 148–152.Google Scholar
  15. Hausen, A. D., Fuchs, D., Reibnegger, G., Wachter, H., Egg, D., & Gunther, R. (1983). Neopterin as index for activity of disease in patients with rheumatoid arthritis. In H. C. Curtius, W. Pfleiderer, & H. Wachter (Eds.),Biochemical and clinical aspects of pteridines (Vol. 2, pp. 245–254). New York: Walter de Gruyter.Google Scholar
  16. Heintel, D., Ghisla, H., Curtius, H.-C., Niederwieser, A., & Levine, R. A. (1984). Biosynthesis of tetrahydrobiopterin: possible involvement of tetrahydropterin intermediates.Neurochemistry International, 6, 141–155.Google Scholar
  17. Heintel, D., Leimbacher, W., Redweik, U., Zagalak, B., & Curtius, H.-C. (1985). Purification and properties of the phosphate eliminating enzyme involved in the biosynthesis of BH4 in man.Biochemical Biophysical Research Communications, 127, 213–219.Google Scholar
  18. Kellner, C. H., Rakita, R. M., Rubinow, D. A., Gold, P. W., Ballenger, J. C., & Post, R. M. (1983). Tetrahydrobiopterin levels in cerebrospinal fluid of affectively ill patients.Lancet, 2, 55–56.Google Scholar
  19. Knapp, S., & Irwin, M. (1989). Plasma levels of tetrahydrobiopterin and folate in major depression.Biological Psychiatry, 26, 156–162.Google Scholar
  20. Lake, C. R., Ziegler, M. G., & Murphy, D. L. (1977). Increased norepinephrine levels and decreased dopamine-β-hydroxylase activity in primary autism.Archives of General Psychiatry, 34, 553–556.Google Scholar
  21. Leventhal, B. L., Cook, E. H., Morford, M., & Ravitz, A. (1990). Relationship of whole blood serotonin and plasma norepinephrine within families.Journal of Autism and Developmental Disorders, 20, 499–511.Google Scholar
  22. LeWitt, P., Newman, R., Miller, L., Lovenberg, W. & Eldridge, R. (1983). Treatment of dystonia with tetrahydrobiopterin.New England Journal of Medicine, 308, 157–158.Google Scholar
  23. LeWitt, P., Miller, L., Newman, R., Burns, R., Insel, T., Levine, R., Lovenberg, W., & Calne, D. (1984). Tyrosine hydroxylase cofactor (tetrahydrobiopterin) in Parkinsonism.Advances in Neurology, 50, 459–462.Google Scholar
  24. Lovenberg, W., Levine, R., Robinson, D., Ebert, M., Williams, A., & Calne, D. (1979). Hydroxylase cofactor activity in cerebrospinal fluid of normal subjects and patients with Parkinson's disease.Science, 204, 624–626.Google Scholar
  25. McInnes, R., Kaufman, S., Warsh, J., Van Loon, G., Milstein, S., Kapatos, G., Soldin, S., Walsh, P., MacGregor, D., & Hanley, W. (1984). Biopterin synthesis defect: Treatment with leuor-dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.Journal of Clinical Investigation, 73, 458–469.Google Scholar
  26. Minderaa, R. B., Anderson, G. M., Volkmar, F. R., Akkerhuis, G. W., & Cohen, D. J. (1987). Urinary 5-hydroxyindolacetic acid and whole blood serotonin and tryptophan in autistic and normal subjects.Biological Psychiatry, 22, 933–940.Google Scholar
  27. Morar, C., Whitburn, S., & Blair, J. (1983). Tetrahydrobiopterin metabolism in senile dementia of the Alzheimer type.Journal of Neurology, Neurosurgery, and Psychiatry, 46, 582.Google Scholar
  28. Narabayashi, H., Kondo, T., Nagatsu, T., Sugimoto, T., & Matsuura, S. (1982). Tetrahydrobiopterin administration for Parkinsonian symptoms.Proceedings of Japan Academy, 58, 283–287.Google Scholar
  29. Naruse, H., Takesada, M., Hayaishi, O., & Watanabe, Y. (1986). Pharmaceuticals containing tetrahydrobiopterin or related compounds for treatment of autism.Japanese Kokai Tokyo Koho, JP 61, 277, 618 [86, 277, 618] (Cl. A61K31/505), 08 Dec. 1986, Appl. 85/121, 347,04 Jun. 1985; 10pp.Google Scholar
  30. Niederwieser, A., Curtius, H.-C., Gitzermann, R., Otten, A., Baerlocher, K., Blehova, B., Berlow, S., Groebe, H., Rey, F., Schaub, J., Scheibenreiter, S., Schmidt, H., & Viscontini, M. (1980). Excretion of pterins in phenylketonuria and phenylketonuria variants.Helvetica Paediatrica Acta 35, 335–342.Google Scholar
  31. Niederwieser, D., Fuchs, D., Hausen, A., Judmaier, G., Reibnegger, G., Wachter, H., & Huber, C. (1985). Neopterin as a new biochemical marker in the clinical assessment of ulcerative colitis.Immunobiology, 170, 320–326.Google Scholar
  32. Niederwieser, A., Joller, P., Seger, R., blau, N., Prader, A., Bettex, J. D., Luthy, R., Hirschel, B., Schaedelin, J., & Vetter, U. (1986). Neopterin in AIDS, other immunodeficiencies, and bacterial and viral infections.Klinische Wochenschrift, 64, 333–337.Google Scholar
  33. Prior, M. R. (1987). Biological and neurophysiological approaches to childhood autism.British Journal of Psychiatry, 150, 8–17.Google Scholar
  34. Santelli, G., Marfella, A., Abate, G., Comella, P., Nitsch, F., & Perna, M. (1986). Urinary neopterin levels in hematologic malignancies.Tumori, 72, 139–143.Google Scholar
  35. Sanua, V. D. (1986). The organic etiology of infantile autism: a critical review of the literature.International Journal of Neuroscience, 30, 195–225.Google Scholar
  36. Schoedon, G., Troppmair, J., Adolf, G., Huber, C., & Niederwieser, A. (1986). Interferon-gamma enhances biosynthesis of pterins in peripheral blood mononuclear cells by induction of GTP-cyclohydrolase I activity.Journal of Interferon Research 6, 697–703.Google Scholar
  37. Scott, J. M., Ghanta, V., & Herbert, V. (1974). Trouble-free microbiologic serum and red cell folate assays.American Journal of Medical Technology, 40, 125–134.Google Scholar
  38. Takesada, M., Nakane, A., Yamazaki, K., Noguchi, T., Watanabe, Y., & Hayaishi, O. (1987). Therapeutic effect of tetrahydrobiopterin in infantile autism.Proceedings of Japanese Academy Series B., 63, 231–239.Google Scholar
  39. Van Kammen, D., Levine, R., Sternberg, D., Ballinger, J., Marder, J., Post, R., & Bunney, W. (1978). Preliminary evaluation of hydroxylase cofactor in human spinal fluid: potential biochemical and clinical relevance in the study of psychiatric disease.Psychopharmacological Bulletin, 14, 51–52.Google Scholar
  40. Williams, A., Eldridge, R., Levine, R., Lovenberg, W., & Paulson, G. (1979). Low CSF hydroxylase co-factor (tetrahydrobiopterin) levels in inherited dystonia.Lancet, 2, 410–411.Google Scholar
  41. Williams, A., Levine, R., Chase, T., Lovenberg, W., & Calne, D. (1980). CSF hydroxylase cofactor levels in some neurological diseases.Journal of Neurology Neurosurgery and Psychiatry, 43, 735–738.Google Scholar
  42. Woggon, B., Angst, J., Curtius, H. C., Niederwieser, A., Levine, R., Borbely, A., & Tobler, I. (1985). Tetrahydrobiopterin (BH4) in endogenous depression.Pharmacopsychiatry 18, 98–99.Google Scholar
  43. Yamaguchi, T., Nagatsu, T., Sugimoto, T., Matsuura, S., Kondo, T., Iizuka, R., & Narabayashi, H. (1983). Effects of tyrosine administration on serum biopterin in normal controls and patients with Parkinson's disease.Science, 219, 75–77.Google Scholar
  44. Young, J. G., Kavanagh, M. E., Anderson, G. M., Shaywitz, B. A., & Cohan, D. J. (1982). Clinical neurochemistry of autism and associated disorders.Journal of Autism and Developmental Disorders, 12, 147–165.Google Scholar
  45. Zitko, M., Andrysek, O., Cernovska, I., & Vasickova, M. (1986). Renal excretion of neopterin and bioterin in patients with malignant melanoma and Hodgkin's disease.Neoplasma 33, 387–391.Google Scholar

Copyright information

© Plenum Publishing Corporation 1992

Authors and Affiliations

  • Isao Eto
    • 1
  • Mattie D. Bandy
    • 1
  • C. E. ButterworthJr.
    • 1
  1. 1.Department of Nutrition SciencesUniversity of Alabama at BirminghamBirmingham

Personalised recommendations