Developmental disorder associated with increased cellular nucleotidase activity

Abstract

Four unrelated patients are described with a syndrome that included developmental delay, seizures, ataxia, recurrent infections, severe language deficit, and an unusual behavioral phenotype characterized by hyperactivity, short attention span, and poor social interaction. These manifestations appeared within the first few years of life. Each patient displayed abnormalities on EEG. No unusual metabolites were found in plasma or urine, and metabolic testing was normal except for persistent hypouricosuria. Investigation of purine and pyrimidine metabolism in cultured fibroblasts derived from these patients showed normal incorporation of purine bases into nucleotides but decreased incorporation of uridine. De novo synthesis of purines and cellular phosphoribosyl pyrophosphate content also were moderately decreased. The distribution of incorporated purines and pyrimidines did not reveal a pattern suggestive of a deficient enzyme activity. Assay of individual enzymes in fibroblast lysates showed no deficiencies. However, the activity of cytosolic 5 -nucleotidase was elevated 6-to 10-fold. Based on the possibility that the observed increased catabolic activity and decreased pyrimidine salvage might be causing a deficiency of pyrimidine nucleotides, the patients were treated with oral pyrimidine nucleoside or nucleotide compounds. All patients showed remarkable improvement in speech and behavior as well as decreased seizure activity and frequency of infections. A double-blind placebo trial was undertaken to ascertain the efficacy of this supplementation regimen. Upon replacement of the supplements with placebo, all patients showed rapid regression to their pretreatment states. These observations suggest that increased nucleotide catabolism is related to the symptoms of these patients, and that the effects of this increased catabolism are reversed by administration of uridine.

The rs11191580 variant of the NT5C2 gene is associated with schizophrenia and symptom severity in a South Chinese Han population: evidence from GWAS

“…14 This gene encodes cytosolic 5 0 -nucleotidase II (cN-II), a ubiquitous nucleotide-hydrolyzing enzyme involved in purine metabolism. 6,15 Page et al 16 demonstrated that purine dysmetabolisms were often related to various degrees of neuromotor dysfunctions, mental retardation, or both. b adj = adjusted partial regression coefficient.…”

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

“…A polymorphism in the adenosine deaminase gene, that gives rise to a lower activity enzyme, is over-represented in autism. 67,68 Adenosine is formed by the action of 5 0 -nucleotidase on AMP, and Page et al 69 found eight-to 10-fold higher 5 0 -nucleotidase activity in association with an 'autismlike' developmental disorder. Each of these autismassociated metabolic abnormalities could synergize with reduced MS activity to impair methylation.…”

The Antiepileptic Potential of Nucleosides

“…However, UTP was ineffective in 4-aminopyridine (4-AP)-induced epileptiform activity [140]. Uridine has already been tested in human studies [360][361][362][363][364], and a decrease in seizure activity in response to Urd has been demonstrated in humans [363][364][365]. Uridine is also found in mother's milk and may be useful as a nutritional supplement during early postnatal development [366,367]; consequently, Urd is a well tolerable drug, which showed low toxicity [63,64,360,361].…”