This project centers around examination of genetic deficiencies and polymorphisms of catecholamine metabolizing enzymes and association of these deficiencies and polymorphisms with normal and abnormal variations in neurochemical variables and behavior. Studies of patients with chromosomal deletions affecting monoamine oxidase (MAO) isoenzymes A and B -the two isoenzymes responsible for the deamination of biogenic amines -showed that deletions of either or both isoenzymes led to three phenotypes characterized by distinct neurochemical, behavioral and neurological disturbances. Deletion of both MAO isoenzymes was associated with severe mental retardation and profound changes in monoamine metabolites. Nearly as profound changes in monoamine metabolites were found in patients with selective deletions affecting the MAO-A isoenzyme. These patients suffered mild mental retardation, impaired impulse control and increased tendency towards aggression. In contrast, patients with selective deficiency of MAO-B isoenzymes showed a near normal neurochemical profile and no evidence of mental retardation or abnormal behavior. The results show that only the MAO-A isoenzyme is important for metabolism of catecholamines and serotonin and provide insight into how abnormalities of the enzyme may lead to developmental abnormalities in the expression of behavior. A follow-up study designed to screen for the presence of deficiencies of MAO-A in certain patient groups with impaired impulse control showed, however, that the presence of such deficiencies is extremely rare and unlikely to be an important determinant of variations in behavior in either the normal population or subjects with impaired impulse control (e.g., obsessive compulsive disorder). Another ongoing study focuses on normal genetic variations in catechol- O-methyltransferase, the other principal enzyme responsible for catecholamine metabolism. A common polymorphism is responsible for a low activity form of the enzyme. Subjects are being genotyped for the presence of heterozygous and homozygous low activity and high activity forms of the enzyme and association of these polymorphisms with differences in neurochemical metabolic profiles, red blood cell COMT activity, and variations in behavior and psychological profile.
