Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism

Objective: To investigate catecholamine phenotypes and the effects of a tyr osine hydroxylase inhibitor in individuals with the 22q11.2 deletion syndro me and low-activity catechol-O-methyltransferase (COMT). Background: Many p ersons with the 22q11.2 deletion syndrome suffer severe disability from a c haracteristic ultrarapid-cycling bipolar disorder and associated "affective storms." One etiologic hypothesis for this condition is that deletion of t he COMT gene from one chromosome 22 results in increased catecholamine neur otransmission, particularly if the undeleted chromosome 22 encodes a varian t of COMT with low activity. Methods: In a preliminary study, plasma, urine , and CSF catecholamines and catecholamine metabolites were measured in fou r teenage patients with a neuropsychiatric condition associated with 22q11. 2 deletion and the low-activity COMT polymorphism on the nondeleted chromos ome. In these four patients, and an additional institutionalized adult with the condition, an uncontrolled, open-label trial of metyrosine was adminis tered in an attempt to lower catecholamine production and to alleviate symp toms. Results: Mild elevations of baseline CSF homovanillic acid (HVA) were found in three of four patients and a moderate reduction in CSF HVA after metyrosine treatment in the patient with the highest pretreatment concentra tion. The course of the five patients during the clinical trial is describe d. Conclusions: In patients with the 22q11.2 deletion syndrome and low-acti vity COMT, controlled studies of pharmacologic agents that decrease catecho lamine production, block presynaptic catecholamine storage, or enhance S-ad enosylmethionine, the cosubstrate of COMT, are warranted.