DISORDERED METHIONINE HOMOCYSTEINE METABOLISM IN PREMATURE VASCULAR-DISEASE - ITS OCCURRENCE, COFACTOR THERAPY, AND ENZYMOLOGY

Mild homocysteinemia occurs surprisingly often in patients with premat ure vascular disease. We studied the possible enzymatic sources of thi s mild hyperhomocysteinemia and the control of homocysteine levels in plasma by treatment of patients with the cofactors and cosubstrates of homocysteine catabolism. We assessed homocysteine metabolism in 131 p atients who had premature disease in their coronary, peripheral, or ce rebrovascular circulation by using a standard oral methionine-load tes t. Impaired homocysteine metabolism occurred in 28 patients. We assaye d levels of the primary enzymes of homocysteine catabolism in cultured skin fibroblast extracts from 15 of these 28 patients. The patients' cystathionine beta-synthase levels (3.68+/-2.52 nmol/h per milligram o f cell protein, mean+/-SD) were markedly depressed compared with those from 31 healthy adult control subjects (7.61+/-4.49, P<.001). The pat ients' levels of 5-methyltetrahydrofolate:homocysteine methyltransfera se were normal. While betaine: homocysteine methyltransferase was not expressed in skin fibroblasts, 24-hour urinary betaine and N,N-dimethy lglycine measurements were consistent with normal or enhanced remethyl ation of homocysteine by betaine: homocysteine methyltransferase in th e 13 patients tested. When treated daily with choline and betaine, pyr idoxine, or folic acid, there was a normalization of the postmethionin e plasma homocysteine level in 16 of 19 patients. Our results indicate that mild homocysteinemia in premature vascular disease may be caused by either a folate deficiency or deficiencies in cystathionine beta-s ynthase activity. It does not necessarily involve deficiencies of eith er 5-methyltetrahydrofolate: homocysteine methyltransferase or betaine : homocysteine methyltransferase. Effective treatment regimens are als o defined.