Phenotypic correlation and diagnosis of urea cycle disorders with stable isotope infusions. B. Lee¹, H. Yu², F. Jahoor², W. O'Brien¹, A.L. Beaudet¹, P. Reeds². 1) Dept of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX; 2) Dept of Pediatrics and CNRC, Baylor College of Medicine, Houston, TX.

   Urea cycle disorders are a group of inborn errors of hepatic metabolism in which enzymatic deficiencies result in often life-threatening hyperammonemia. Clinical and laboratory diagnosis is often difficult during asymptomatic periods or in cases of partial deficiencies. Moreover, correlation of phenotypic severity with either genotype and/or in vitro enzyme activity is often imprecise or unavailable. We report here specific correlations of rates of total body urea synthesis, urea cycle-specific nitrogen flux, and glutamine flux, with phenotypic severity and carrier status in urea cycle patients, as well as with the effects of increased protein intake and pharmacotherapy aimed at activating alternative waste-nitrogen excretion. For controls, we studied 18 adult and pediatric subjects. In our urea cycle patient cohort, we studied a total of 32 patients and relatives with different enzymatic deficiencies. All subjects were studied twice, first on a low protein diet, and then again on either higher protein intake, on treatment with an alterative route medication (Ucephan), or arginine supplementation. After stabilization on the assigned protein intake, flux measurements were determined from ¹⁵N-urea, ¹⁸O-urea, and ¹⁵N-glutamine enrichments measured in blood during intravenous co-infusions of 5-¹⁵N-glutamine and ¹⁸O-urea. The ratio of ¹⁵N-urea/¹⁵N-glutamine distinguished: 1) normal control subjects, 2) late presenting urea cycle patients with partial urea cycle activity, and 3) patients who presented in the neonatal period (p<0.001). Moreover, this index distinguished heterozygous carrier parents of citrullinemia patients from normal controls. In subjects studied on medications, the absolute rate of total body urea production directly correlated with molar conversion of medications used to treat these patients. The ¹⁵N-urea/¹⁵N-glutamine ratio is a sensitive index of in vivo urea cycle activity, correlates with clinical everity and is a sensitive tool for evaluating efficacy of therapeutic modalities as well as for the diagnosis and management of urea cycle patients.