Joumal of Intellectual Disability Research, 1993, 37, 491-505 Differences in purine metabolism in patients with Down's syndrome M. A. PEETERS, A. MEGARBANE, F. CATTANEO, M.-O. RETHORE & J. LEJEUNE Institut de Progenese, Paris, France ABSTRACT. Three enzymes intervening in de novo purine synthesis, as well as cystathionine B-synthetase, have been mapped to chromosome 21. In order to gain a better understanding of purine synthesis anomalies in Down's syndrome, the present authors studied the variations in mitodc index of lymphocyte cultures to which various inhibitors or metabolites of purine synthesis had been added. In spite of common gene dosage effects, unexpected and highly significant differences were noted between Dovm's syndrome patients without complications and those presenting with additional psychotic features. In Down's syndrome patients without complications, a highly significant decrease in mitotic index was noted in the presence of exogenous inosine. A significant decrease in the presence of adenosine and guanosine was also noted. These findings are in keeping with the expected metabolic repercussions of genes mapped to chromosome 21. In Down's syndrome patients with psychotic complications, the in vitro reactions were quite different. A paradoxal increase in mitotic index was noted in the presence of inosine and of adenosine, but the response to guanosine did not differ fi-om that observed in normal controls. These findings were unexpected and seem to indicate that, in spite of the gene dosage effect, psychotic Down's syndrome patients are unable to compensate abnormal purine synthesis and resulting imbalances. Furthermore, a marked difference in purine metabolic reactions was noted between Down's syndrome patients receiving supplemental folic/folinic acid and those on no therapy. This suggests that some modulation of the gene dosage effect may be possible. INTRODUCTION Much progress has been made in understanding not only, the molecular basis of the pathophysiology and phenotype of Down's syndrome but also some of the biochemical modifications resulting from the chromosomal imbalance (Cooper & Hall 1988; Lejeune 1983, 1990; Lejeune et al. 1992; Opitz & Gilbert-Bamess 1990; Peeters & Lejeune 1989). Despite the clinical importance of trisomy 21, little is known about the mechanisms by which chromosomal imbalance results in specific and often highly deleterious phenotypic effects. Correspondence: Marie A. Peeters, Institut de Progenese, 45 rue des Sainds Peres, 75006 Paris, France. 491