Nitrogen Metabolism in Ornithine Transcarbamylase Deficiency

We developed a new technique that monitors metabolic competency in female heterozygotes for ornithine transcarbamylase deficiency (OTCD). The method uses mass spectrometry to measure conversion of 15 NH 4 Cl to [ 15 N]urea and [515 N]glutamine following an oral load of 15 NH 4 Cl. We found that heterozygotes converted significantly less NH 3 nitrogen to urea, with this difference being particularly obvious for symptomatic carriers, in whom the blood [ 15 N]urea concentration (mM) was significantly less than control values at most time points. The blood concentration of [515 N]glutamine ( m M) was significantly higher in both asymptomatic and symptomatic heterozygotes than it was in the control subjects. The administration of a test dose of sodium phenylbutyrate to the control group did not affect the rate of [ 15 N]urea formation. We conclude: ( a ) This test effectively monitors in vivo N metabolism and might obviate the need for liver biopsy to measure enzyme activity in OTCD; ( b ) Asymptomatic OTCD carriers form urea at a normal rate, indicating that ureagenesis can be competent even though enzyme activity is below normal; ( c ) Although ostensibly asymptomatic OTCD carriers form urea at a normal rate, their nitrogen metabolism is still abnormal, as reflected in their increased production of [515 N]glutamine; and ( d ) This new test may be important for monitoring the efficacy of novel treatments for OTCD, e.g., liver transplantation and gene therapy. ( J. Clin. Invest. 1996. 98:2167–2173.)