DEVELOPMENTAL DISORDER ASSOCIATED WITH INCREASED CELLULAR NUCLEOTIDASE ACTIVITY

Four unrelated patients are described with a syndrome that included de velopmental delay, seizures, ataxia, recurrent infections, severe lang uage deficit, and an unusual behavioral phenotype characterized by hyp eractivity, short attention span, and poor social interaction, These m anifestations appeared within the first few years of life, Each patien t displayed abnormalities on EEG. No unusual metabolites were found in plasma or urine, and metabolic testing was normal except for persiste nt hypouricosuria. Investigation of purine and pyrimidine metabolism i n cultured fibroblasts derived from these patients showed normal incor poration of purine bases into nucleotides but decreased incorporation of uridine, De novo synthesis of purines and cellular phosphoribosyl p yrophosphate content also were moderately decreased, The distribution of incorporated purines and pyrimidines did not reveal a pattern sugge stive of a deficient enzyme activity, Assay of individual enzymes in f ibroblast lysates showed no deficiencies, However, the activity of cyt osolic 5'-nucleotidase was elevated 6- to 10-fold, Based on the possib ility that the observed increased catabolic activity and decreased pyr imidine salvage might be causing a deficiency of pyrimidine nucleotide s, the patients were treated with oral pyrimidine nucleoside or nucleo tide compounds, All patients showed remarkable improvement in speech a nd behavior as well as decreased seizure activity and frequency of inf ections, A double-blind placebo trial was undertaken to ascertain the efficacy of this supplementation regimen, Upon replacement of the supp lements with placebo, all patients showed rapid regression to their pr etreatment states, These observations suggest that increased nucleotid e catabolism is related to the symptoms of these patients, and that th e effects of this increased catabolism are reversed by administration of uridine.