Differences in Purine Metabolism in Patients with Down Syndrome

Marie A. Peeters, André Megarbane, Fabio Cattaneo, Marie-Odile Réthoré, Jérôme Lejeune, Institute de Progenèse, Paris, France.


In order to gain better understanding of purine synthesis anomalies, we investigated 38 uncomplicated patients with Down syndrome (DS) (21 males, 17 females; mean age: 15.5 ± 1.8) and 19 DS patients with psychotic complications (13 males, 6 females; mean age: 9.3 ± 3.6). Using a standard 72 hours lymphocyte culture assay we added on initiation of the culture differents metabolites. The ones who showed significant results were: inosine (125mg/L), adenosine (16mg/L), guanosine (3.1mg/L) as well as rt3 (5mg/L) added 12 to 16 hours prior to termination of the cultures. Results were analysed by comparing the mitotic index of each experiment to the patient's own control culture and expressed as the percentage increment or decrease in mitotic index. 135 normal adults were used as controls. In uncomplicated DS patients severe cytotoxicity was noted in the presence of exogenous inosine (P<.0001). A significant decrease of the mitotic index in the presence of adenosine (0.02<p<0.01) and of guanosine (0.02<p<001) was also noted. These findings are in keeping with the metabolic repercussions of genes mapped to chromosome 21: three de novo purine synthesis genes and cystathionine-B synthetase (CBS). When patients receiving folic acid therapy were studied with this assay, normalisation of the in vitro response to inosine was noted but adenosine toxicity was aggravated. This indicates that some modulation of the gene dosage effect is possible for de novo purine synthesis but that the gene dosage effect for CBS remained uncompensated for. In DS patients with psychotic complications the in vitro response was quite different. A highly significant increase in mitotic index was noted in the presence of inosine (p=0.001) and of adenosine (0.02<p<0.01) but the response to guanosine did not differ from that observed in normal controls. When patients receiving either folic acide or folinic acide were studied the increase of mitotic index in the presence of inosine persisted. This finding was unexpected and suggests that patients with DS and psychotic complications are, in spite of the gene dosage effect, unable to complete de novo purine synthesis. In conclusion: uncomplicated and psychotic DS patients, in spite of the common gene dosage effect, show different in vitro purine metabolism.