We have determined the in vivo flux through the urea cycle pathway by measuring the conversion of intravenously infused [15N-amide]glutamine to [15N]urea in both urea cycle patients and normal subjects. The patient population included neonatal onset citrullinemia and ornithine transcarbamylase deficiency (OTC) patients, symptomatic OTC heterozygotes, and asymptomatic OTC heterozygotes. Subjects were studied after maintenance on set protein and drug intake for 48 hrs. To evaluate the effects of protein intake, alternative route medications, and supplementary arginine or citrulline, patients and subjects were each studied twice. They were assigned to one of three groups:a) study on low and higher protein intake, b) study with and without Ucephan, or c) study with and without arginine. Enrichments of [15N] and 18O in plasma and urinary glutamine and urea were used to determine endogenous (urea cycle specific) and total urea synthesis. Neonatal onset patients exhibited zero [15N] enrichment consistent with an absence of endogenous urea synthesis, while OTC heterozygous females exhibited [15N] enrichment intermediate between normal controls and the citrullinemic patients. However, urea synthesis was markedly affected by either ucephan and arginine administration. We, therefore, derived an index of the proportion of endogenous to total urea synthesis as measured by the ratio of [15N]urea/[15N]glutamine. This index was found to be independent of diet, nutritional status, and alternative route medications. Moreover, the index correlated with severity of the clinical phenotype and exhibited little variability between serial studies. This index in combination with absolute measurements of urea synthetic rates will be useful for evaluating gene therapeutic interventions and for guiding the clinical management of urea cycle patients. These sutdies are now being extended to patients with other urea cycle defects.
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