Genetic Deficiencies of Monoamine Oxidase

Background

Monoamine oxidase (MAO), an enzyme that plays a crucial role in the metabolic degradation of biogenic amines, exists in two functional forms: MAO-A and MAO-B. The two isoenzymes have different substrate and inhibitor specificities and are encoded by two genes on the short arm of the X-chromosome.

Understanding the consequences of genetic deficiencies of MAO isoenzymes requires an understanding of the role of these enzymes in the metabolism of biogenic amines. In addition to inactivating catecholamines and their O-methylated metabolites, MAO deaminates other biogenic amines including 5-hydroxytryptamine and the trace amines phenylethylamine, m-tyramine and p-tyramine. The catecholamines and their deaminated metabolites are also subject to O-methylation by catechol-O-methyltransferase. MAO and catechol-O-methyltransferase, in combination with alcohol dehydrogenase, are responsible for the production of a wide range of catecholamine metabolites, that for the purpose of this study can be divided into two groups: deaminated metabolites and O-methylated amine metabolites (Figure 1).

This study compares the neurochemical and clinical phenotypes of subjects with genetically determined selective lack of MAO-A or MAO-B and lack of both MAO-A and MAO-B.

Findings

In contrast to the mild 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, 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 (Table 1). These neurochemical changes are only slightly exaggerated in patients with combined lack of MAO-A and MAO-B. 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 decreased plasma concentrations of deaminated metabolites and increased plasma concentrations of O-methylated metabolites results in a greatly elevated ratio of O-methylated to deaminated metabolites in patients with deficiencies of MAO (Figure 2).

Conclusions

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 observed in patients with deficiencies of either or both isoenzymes.
The functional differences in the two isoenzymes of MAO may help in understanding the basis for therapeutic interventions involving specific inhibition of one or other isoenzymes.
Use of ratios of plasma concentrations of O-methylated to deaminated metabolites (e.g. the NMN/DHPG ratios in figure 2) provides a sensitive method for the detection of subjects suspected of having reduced activity of MAO-A.

This work has been published in more detail in a number of papers, either published or in press. Reprint requests can be directed to Graeme Eisenhofer at ge@box-g.nih.gov

Eisenhofer G., P. Friberg, K. Pacak, D.S. Goldstein, D.L. Murphy, C. Tsigos, A.A. Quyyumi, H. G. Brunner and J.W.M. Lenders. Plasma metanephrines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism? Clinical Science 88: 533-542, 1995.

Lenders J.W.M., G. Eisenhofer, N.G.G.M. Abeling, W. Berger, D. Murphy, C.H. Konings, L.M.B. Wagemakers, I.J. Kopin, A.H. van Gennip, and H.G. Brunner. Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes. Journal of Clinical Investigation. 97: 1010-1019, 1996.

Eisenhofer G., J.W.M. Lenders, J. Harvey-White, M. Ernst, A. Zametkin, D.L. Murphy, I.J. Kopin. Differential inhibition of neuronal and extraneuronal monoamine oxidase. Neuropsychopharmacology. 'in press', 1996.

Back to Research Directions / CV