Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Feb 15;97(4):1010–1019. doi: 10.1172/JCI118492

Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.

J W Lenders 1, G Eisenhofer 1, N G Abeling 1, W Berger 1, D L Murphy 1, C H Konings 1, L M Wagemakers 1, I J Kopin 1, F Karoum 1, A H van Gennip 1, H G Brunner 1
PMCID: PMC507147  PMID: 8613523

Abstract

Monoamine oxidase (MAO) exists as two isoenzymes and plays a central role in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subjects with genetically determined selective lack of MAO-A or a lack of both MAO-A and MAO-B with those of two subjects with a previously described X chromosome microdeletion in whom we now demonstrate selective MAO-B deficiency. Mapping of the distal deletion breakpoint demonstrates its location in intron 5 of the MAO-B gene, with the deletion extending proximally into the Norrie disease gene. In contrast to the borderline mental retardation and abnormal behavioral phenotype in subjects with selective MAO-A deficiency and the severe mental retardation in patients with combined MAO-A/MAO-B deficiency and Norrie disease, the MAO-B-deficient subjects exhibit neither abnormal behavior nor mental retardation. Distinct neurochemical profiles characterize the three groups of MAO-deficient patients. In MAO-A-deficient subjects, there is a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites. These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. In contrast, the only biochemical abnormalities detected in subjects with the MAO-B gene deletion are a complete absence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate that, under normal conditions, MAO-A is considerably more important than MAO-B in the metabolism of biogenic amines, a factor likely to contribute to the different clinical phenotypes.

Full Text

The Full Text of this article is available as a PDF (225.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abeling N. G., van Gennip A. H., Overmars H., Voûte P. A. Simultaneous determination of catecholamines and metanephrines in urine by HPLC with fluorometric detection. Clin Chim Acta. 1984 Feb 28;137(2):211–226. doi: 10.1016/0009-8981(84)90181-5. [DOI] [PubMed] [Google Scholar]
  2. Berger W., Meindl A., van de Pol T. J., Cremers F. P., Ropers H. H., Döerner C., Monaco A., Bergen A. A., Lebo R., Warburg M. Isolation of a candidate gene for Norrie disease by positional cloning. Nat Genet. 1992 Jun;1(3):199–203. doi: 10.1038/ng0692-199. [DOI] [PubMed] [Google Scholar]
  3. Berry M. D., Juorio A. V., Paterson I. A. The functional role of monoamine oxidases A and B in the mammalian central nervous system. Prog Neurobiol. 1994 Feb;42(3):375–391. doi: 10.1016/0301-0082(94)90081-7. [DOI] [PubMed] [Google Scholar]
  4. Bleeker-Wagemakers E. M., Zweije-Hofman I., Gal A. Norrie disease as part of a complex syndrome explained by a submicroscopic deletion of the X chromosome. Ophthalmic Paediatr Genet. 1988 Nov;9(3):137–142. doi: 10.3109/13816818809031489. [DOI] [PubMed] [Google Scholar]
  5. Brunner H. G., Nelen M. R., van Zandvoort P., Abeling N. G., van Gennip A. H., Wolters E. C., Kuiper M. A., Ropers H. H., van Oost B. A. X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am J Hum Genet. 1993 Jun;52(6):1032–1039. [PMC free article] [PubMed] [Google Scholar]
  6. Brunner H. G., Nelen M., Breakefield X. O., Ropers H. H., van Oost B. A. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science. 1993 Oct 22;262(5133):578–580. doi: 10.1126/science.8211186. [DOI] [PubMed] [Google Scholar]
  7. Buchsbaum M. S., Coursey R. D., Murphy D. L. The biochemical high-risk paradigm: behavioral and familial correlates of low platelet monoamine oxidase activity. Science. 1976 Oct 15;194(4262):339–341. doi: 10.1126/science.968488. [DOI] [PubMed] [Google Scholar]
  8. Buffoni F. Histaminase and related amine oxidases. Pharmacol Rev. 1966 Dec;18(4):1163–1199. [PubMed] [Google Scholar]
  9. Campbell I. C., Robinson D. S., Lovenberg W., Murphy D. L. The effects of chronic regimens of clorgyline and pargyline on monoamine metabolism in the rat brain. J Neurochem. 1979 Jan;32(1):49–55. doi: 10.1111/j.1471-4159.1979.tb04508.x. [DOI] [PubMed] [Google Scholar]
  10. Cases O., Seif I., Grimsby J., Gaspar P., Chen K., Pournin S., Müller U., Aguet M., Babinet C., Shih J. C. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science. 1995 Jun 23;268(5218):1763–1766. doi: 10.1126/science.7792602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen K., Wu H. F., Shih J. C. The deduced amino acid sequences of human platelet and frontal cortex monoamine oxidase B are identical. J Neurochem. 1993 Jul;61(1):187–190. doi: 10.1111/j.1471-4159.1993.tb03554.x. [DOI] [PubMed] [Google Scholar]
  12. Collins F. A., Murphy D. L., Reiss A. L., Sims K. B., Lewis J. G., Freund L., Karoum F., Zhu D., Maumenee I. H., Antonarakis S. E. Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes. Am J Med Genet. 1992 Jan 1;42(1):127–134. doi: 10.1002/ajmg.1320420126. [DOI] [PubMed] [Google Scholar]
  13. Devor E. J., Cloninger C. R., Hoffman P. L., Tabakoff B. Association of monoamine oxidase (MAO) activity with alcoholism and alcoholic subtypes. Am J Med Genet. 1993 Dec 15;48(4):209–213. doi: 10.1002/ajmg.1320480407. [DOI] [PubMed] [Google Scholar]
  14. Donnai D., Mountford R. C., Read A. P. Norrie disease resulting from a gene deletion: clinical features and DNA studies. J Med Genet. 1988 Feb;25(2):73–78. doi: 10.1136/jmg.25.2.73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Donnelly C. H., Murphy D. L. Substrate- and inhibitor-related characteristics of human platelet monoamine oxidase. Biochem Pharmacol. 1977 May 1;26(9):853–858. doi: 10.1016/0006-2952(77)90398-7. [DOI] [PubMed] [Google Scholar]
  16. Eisenhofer G., Finberg J. P. Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats. J Pharmacol Exp Ther. 1994 Mar;268(3):1242–1251. [PubMed] [Google Scholar]
  17. Eisenhofer G., Friberg P., Pacak K., Goldstein D. S., Murphy D. L., Tsigos C., Quyyumi A. A., Brunner H. G., Lenders J. W. Plasma metadrenalines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism? Clin Sci (Lond) 1995 May;88(5):533–542. doi: 10.1042/cs0880533. [DOI] [PubMed] [Google Scholar]
  18. Eisenhofer G., Goldstein D. S., Ropchak T. G., Kopin I. J. Source and physiological significance of plasma 3,4-dihydroxyphenylalanine in the rat. J Neurochem. 1988 Oct;51(4):1204–1213. doi: 10.1111/j.1471-4159.1988.tb03088.x. [DOI] [PubMed] [Google Scholar]
  19. Eisenhofer G., Goldstein D. S., Stull R., Keiser H. R., Sunderland T., Murphy D. L., Kopin I. J. Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. Clin Chem. 1986 Nov;32(11):2030–2033. [PubMed] [Google Scholar]
  20. Eisenhofer G., Pecorella W., Pacak K., Hooper D., Kopin I. J., Goldstein D. S. The neuronal and extraneuronal origins of plasma 3-methoxy-4-hydroxyphenylglycol in rats. J Auton Nerv Syst. 1994 Dec 1;50(1):93–107. doi: 10.1016/0165-1838(94)90127-9. [DOI] [PubMed] [Google Scholar]
  21. Eisenhofer G., Rundquist B., Aneman A., Friberg P., Dakak N., Kopin I. J., Jacobs M. C., Lenders J. W. Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines. J Clin Endocrinol Metab. 1995 Oct;80(10):3009–3017. doi: 10.1210/jcem.80.10.7559889. [DOI] [PubMed] [Google Scholar]
  22. Glover V., Sandler M., Owen F., Riley G. J. Dopamine is a monoamine oxidase B substrate in man. Nature. 1977 Jan 6;265(5589):80–81. doi: 10.1038/265080a0. [DOI] [PubMed] [Google Scholar]
  23. Grimsby J., Chen K., Wang L. J., Lan N. C., Shih J. C. Human monoamine oxidase A and B genes exhibit identical exon-intron organization. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3637–3641. doi: 10.1073/pnas.88.9.3637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Karoum F., Nasrallah H., Potkin S., Chuang L., Moyer-Schwing J., Phillips I., Wyatt R. J. Mass fragmentography of phenylethylamine, m- and p-tyramine and related amines in plasma, cerebrospinal fluid, urine, and brain. J Neurochem. 1979 Jul;33(1):201–212. doi: 10.1111/j.1471-4159.1979.tb11722.x. [DOI] [PubMed] [Google Scholar]
  25. Kochersperger L. M., Parker E. L., Siciliano M., Darlington G. J., Denney R. M. Assignment of genes for human monoamine oxidases A and B to the X chromosome. J Neurosci Res. 1986;16(4):601–616. doi: 10.1002/jnr.490160403. [DOI] [PubMed] [Google Scholar]
  26. Kopin I. J. Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev. 1985 Dec;37(4):333–364. [PubMed] [Google Scholar]
  27. Lenders J. W., Eisenhofer G., Armando I., Keiser H. R., Goldstein D. S., Kopin I. J. Determination of metanephrines in plasma by liquid chromatography with electrochemical detection. Clin Chem. 1993 Jan;39(1):97–103. [PubMed] [Google Scholar]
  28. McEwen C. M., Jr Human plasma monoamine oxidase. 1. Purification and identification. J Biol Chem. 1965 May;240(5):2003–2010. [PubMed] [Google Scholar]
  29. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Murphy D. L., Sims K. B., Karoum F., Garrick N. A., de la Chapelle A., Sankila E. M., Norio R., Breakefield X. O. Plasma amine oxidase activities in Norrie disease patients with an X-chromosomal deletion affecting monoamine oxidase. J Neural Transm Gen Sect. 1991;83(1-2):1–12. doi: 10.1007/BF01244447. [DOI] [PubMed] [Google Scholar]
  31. Murphy D. L., Sims K. B., Karoum F., de la Chapelle A., Norio R., Sankila E. M., Breakefield X. O. Marked amine and amine metabolite changes in Norrie disease patients with an X-chromosomal deletion affecting monoamine oxidase. J Neurochem. 1990 Jan;54(1):242–247. doi: 10.1111/j.1471-4159.1990.tb13307.x. [DOI] [PubMed] [Google Scholar]
  32. Paterson I. A., Juorio A. V., Boulton A. A. 2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system? J Neurochem. 1990 Dec;55(6):1827–1837. doi: 10.1111/j.1471-4159.1990.tb05764.x. [DOI] [PubMed] [Google Scholar]
  33. Pickar D., Cohen R. M., Jimerson D. C., Murphy D. L. Tyramine infusions and selective monoamine oxidase inhibitor treatment. I. Changes in pressor sensitivity. Psychopharmacology (Berl) 1981;74(1):4–7. doi: 10.1007/BF00431747. [DOI] [PubMed] [Google Scholar]
  34. Sims K. B., Lebo R. V., Benson G., Shalish C., Schuback D., Chen Z. Y., Bruns G., Craig I. W., Golbus M. S., Breakefield X. O. The Norrie disease gene maps to a 150 kb region on chromosome Xp11.3. Hum Mol Genet. 1992 May;1(2):83–89. doi: 10.1093/hmg/1.2.83. [DOI] [PubMed] [Google Scholar]
  35. Sims K. B., de la Chapelle A., Norio R., Sankila E. M., Hsu Y. P., Rinehart W. B., Corey T. J., Ozelius L., Powell J. F., Bruns G. Monoamine oxidase deficiency in males with an X chromosome deletion. Neuron. 1989 Jan;2(1):1069–1076. doi: 10.1016/0896-6273(89)90231-6. [DOI] [PubMed] [Google Scholar]
  36. Stroomer A. E., Overmars H., Abeling N. G., van Gennip A. H. Simultaneous determination of acidic 3,4-dihydroxyphenylalanine metabolites and 5-hydroxyindole-3-acetic acid in urine by high-performance liquid chromatography. Clin Chem. 1990 Oct;36(10):1834–1837. [PubMed] [Google Scholar]
  37. Sunderland T., Mueller E. A., Cohen R. M., Jimerson D. C., Pickar D., Murphy D. L. Tyramine pressor sensitivity changes during deprenyl treatment. Psychopharmacology (Berl) 1985;86(4):432–437. doi: 10.1007/BF00427904. [DOI] [PubMed] [Google Scholar]
  38. Weyler W., Hsu Y. P., Breakefield X. O. Biochemistry and genetics of monoamine oxidase. Pharmacol Ther. 1990;47(3):391–417. doi: 10.1016/0163-7258(90)90064-9. [DOI] [PubMed] [Google Scholar]
  39. Whitaker-Azmitia P. M., Zhang X., Clarke C. Effects of gestational exposure to monoamine oxidase inhibitors in rats: preliminary behavioral and neurochemical studies. Neuropsychopharmacology. 1994 Oct;11(2):125–132. doi: 10.1038/npp.1994.42. [DOI] [PubMed] [Google Scholar]
  40. Young W. F., Jr, Laws E. R., Jr, Sharbrough F. W., Weinshilboum R. M. Human monoamine oxidase. Lack of brain and platelet correlation. Arch Gen Psychiatry. 1986 Jun;43(6):604–609. doi: 10.1001/archpsyc.1986.01800060098012. [DOI] [PubMed] [Google Scholar]
  41. van Kempen G. M., van Brussel J. L., Pennings E. J. Assay of platelet monoamine oxidase in whole blood. Clin Chim Acta. 1985 Dec 31;153(3):197–202. doi: 10.1016/0009-8981(85)90352-3. [DOI] [PubMed] [Google Scholar]
  42. von Knorring L., Oreland L., Winblad B. Personality traits related to monoamine oxidase activity in platelets. Psychiatry Res. 1984 May;12(1):11–26. doi: 10.1016/0165-1781(84)90134-3. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES