We have developed a novel technique for monitoring metabolic competency in female heterozygotes for ornithine transcarbamylase deficiency (OTC). Our method uses mass spectrometry to measure the conversion of 15NH4C1 to (15N) urea and (5-15N) glutamine during a 4 hour period following an oral 15NH4C1 load (25.9 mmol). We found that asymptomic heterozygotes formed (15N) urea at the control rate, but that sympotomatic heterozygotes converted significantly less NH3 nitrogen to urea. Thus, the (15N) urea concentration (mM) in the blood of symtomatic heterozygotes was signifacantly less than control values at most time points. The blood concentration of (5-15N) glutamine (mM) 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 (15N) urea formation. We conclude: a) This test affords a powerful tool with which to monitor in vivo N metabolism in OTCD. In many cases it even may obviate the need to perform a liver biopsy in order to measure enzyme activity; b) Asymptomatic OTCD carriers form urea at a normal rate, indicating that ureagenesis can be competent even though enzyme activity is appreciably below normal. This finding has important implications for the putative efficacy of gene therapy; 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 (5-15N) glutamine; d) This new test may be important not only in terms of diagnosis, but also to monitor the efficacy of novel treatments for OTCD, e.g., liver transplantation and gene therapy.
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