Four unrelated children, 2 girls and 2 boys, are found to have a complex syndrome which included seizures, ataxia, developmental delay, recurrent infections, severe language deficit and abnormal behavior with impulsivity, perseveration, attention deficit and aggressiveness. Biochemical analysis revealed increased activity of the cytosolic 5′-nucleotidase to 5-20-fold in the skin fibroblasts of all 4 patients, along with decreased incorporation of pyrimidine, but not purine precursors into nucleotides. To test the hypothesis that pyrimidine supplement may be beneficial to these patients, a double-blind placebo trial of a uridine prodrug, PN-401, was conducted. After the initial evaluation, each patient received blindly PN401/placebo at 0.1 g/kg/d for 1 month, followed by open-label PN401 for 1 month, followed by a crossover to PN401/placebo for another month. Subsequently, the daily dose of PN401 was escalated by 0.05 g/kg/d every 2-3 months. So far, the dose has been escalated to 0.3 g/kg/d at one year. The treatment was well tolerated without toxicity, as reflected by normal monthly CBC, chemistry panel and urinalysis. Pharmacokinetic study showed that the bioavailability of PN401 is 3.6 fold greater than uridine. At the completion of the initial blinded study, analysis of the data showed clear improvement in two of the four patients while on PN401, and deterioration while on placebo. The other two patients exhibited a questionable response pattern due to infectious complications. During the dose escalation phase of the study, all four patients continued to improve in all aspects of the syndrome. The results of neuropsychological and speech evaluation at prestudy and one year are summarized below: Table

Table 1
Full size table

These findings suggest that PN401 is safe and effective in the treatment of this complex disorder.