SPECIFIC GENETIC DEFICIENCIES OF THE A-ISOENZYME AND B-ISOENZYME OF MONOAMINE-OXIDASE ARE CHARACTERIZED BY DISTINCT NEUROCHEMICAL AND CLINICAL PHENOTYPES

Monoamine oxidase (MAO) exists as two isoenzymes and plays a central r ole in the metabolism of monoamine neurotransmitters. In this study we compared the neurochemical phenotypes of previously described subject s with genetically determined selective lack of MAO-A or a lack of bot h MAO-A and MAO-B with those of two subjects with a previously describ ed 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 extendin g proximally into the Norrie disease gene. In contrast to the borderli ne mental retardation and abnormal behavioral phenotype in subjects wi th selective MAO-A deficiency and the severe mental retardation in pat ients with combined MAO-A/MAO-B deficiency and Norrie disease. the MAO -B-deficient subjects exhibit neither abnormal behavior nor mental ret ardation. Distinct neurochemical profiles characterize the three group s of MAO-deficient patients. In MAO-A-deficient subjects, there is a m arked decrease in deaminated catecholamine metabolites and a concomita nt marked elevation of O-methylated amine metabolites. These neurochem ical changes are only slightly exaggerated in patients with combined l ack of MAO-A and MAO-B. In contrast. the only biochemical abnormalitie s detected in subjects with the MAO-B gene deletion are a complete abs ence of platelet MAO-B activity and an increased urinary excretion of phenylethylamine. The differences in neurochemical profiles indicate t hat, under normal conditions, MAO-A is considerably more important tha n MAO-B in the metabolism of biogenic amines, a factor likely to contr ibute to the different clinical phenotypes.