IMMUNOSUPPRESSIVE EFFECTS OF ORGANIC-ACIDS ACCUMULATING IN PATIENTS WITH MAPLE-SYRUP-URINE-DISEASE

Maple syrup urine disease (MSUD) is an inherited metabolic disorder ca used by deficiency of the activity of the multienzyme branched-chain a -ketoacid dehydrogenase complex (BCKD; EC 1.2.4.4, McKusick 248600). I t is biochemically characterized by tissue elevations of the branched- chain amino acids (BCAA) valine, leucine and isoleucine, as well as by their organic acid derivatives (Danner and Elsas 1989). A common feat ure of a considerable number of patients with this disorder is recurre nt infection. Low resistance to infection reflects immunosuppression a nd can be attributed to a variety of factors present in metabolic dise ases such as malnutrition, acidosis and hypotonia. On the other hand, immunosuppressive activities have been found in a wide range of substa nces present in serum of patients suffering from various pathologies ( Nelson and Gatti 1976). Therefore, it is possible that the BCAA and/or their ketoacids (BCKA), whose concentrations are increased in patient s affected by MSUD, may act as immunosuppressants. We previously demon strated that valine, leucine and isoleucine in concentrations up to 8 mmol/L do not interfere with in vitro human lymphocyte blastogenesis ( Sommer et al 1992, 1994). In the present study we investigated the act ions of the principal acidic metabolites that accumulate in tissues of MSUD patients (alpha-ketoisocaproic (KIC), DL-alpha-keto-beta-methyl- n-valeric (KMV), and alpha-ketoisovaleric (KIV) acids, and also the hy droxyderivative alpha-hydroxyisovaleric (HIV) acid), on the in vitro p roliferation of lymphocytes stimulated with the mitogen phytohaemagglu tinin (PHA), a well-recognized test of cellular immunocompetence, in o rder to identify the possible immunoregulatory activities in these com pounds.