In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle

Urea cycle disorders are a group of inborn errors of hepatic metabolism tha t result in often life-threatening hyperammonemia and hyperglutaminemia, Cl inical and laboratory diagnosis of partial deficiencies during asymptomatic periods is difficult, and correlation of phenotypic severity with either g enotype and/or in vitro enzyme activity is often imprecise. We hypothesized that stable isotopically determined in vivo rates of total body urea synth esis and urea cycle-specific nitrogen flux would correlate with both phenot ypic severity and carrier status in patients with a variety of different en zymatic deficiencies of the urea cycle, We studied control subjects, patien ts, and their relatives with different enzymatic deficiencies affecting the urea cycle while consuming a low protein diet, On a separate occasion the subjects either received a higher protein intake or were treated with an al ternative route medication sodium phenylacetate/benzoate (Ucephan), or oral arginine supplementation. Total urea synthesis from all nitrogen sources w as determined from [O-18]urea labeling, and the utilization of peripheral n itrogen was estimated from the relative isotopic enrichments of [N-15]urea and [N-15]glutamine during i.v. co-infusions of [5-(amide)N-15]glutamine an d [O-18]urea, The ratio of the isotopic enrichments of N-15-urea/N-15-gluta mine distinguished normal control subjects (ratio = 0.42 +/- 0.06) from ure a cycle patients with late (0.17 +/- 0.03) and neonatal (0.003 +/- 0.007) p resentations irrespective of enzymatic deficiency. This index of urea cycle activity also distinguished asymptomatic heterozygous carriers of arginino succinate synthetase deficiency (0.22 +/- 0.03), argininosuccinate lyase de ficiency (0.35 +/- 0.11), and partial ornithine transcarbamylase deficiency (0.26 +/- 0.06) from normal controls. Administration of Ucephan lowered, a nd arginine increased, urea synthesis to the degree predicted from their re spective rates of metabolism. The N-15-urea/N-15-glutamine ratio is a sensi tive index of in vivo urea cycle activity and correlates with clinical seve rity, Urea synthesis is altered by alternative route medications and argini ne supplementation to the degree that is to be expected from theory. This s table isotope protocol provides a sensitive tool for evaluating the efficac y of therapeutic modalities and acts as an aid to the diagnosis and managem ent of urea cycle patients.