IN-VIVO NITROGEN-METABOLISM IN ORNITHINE TRANSCARBAMYLASE DEFICIENCY

We developed a new technique that monitors metabolic competency in fem ale heterozygotes for ornithine transcarbamylase deficiency (OTCD). Th e method uses mass spectrometry to measure conversion of (NH4Cl)-N-15 to [N-15]urea and [5-N-15]glutamine following an oral load of (NH4Cl)- N-15. We found that heterozygotes converted significantly less NH3 nit rogen to urea, with this difference being particularly obvious for sym ptomatic carriers, in whom the blood [N-15]urea concentration (mM) was significantly less than control values at most time points. The blood concentration of [5-N-15]glutamine (mu M) was significantly higher in both asymptomatic and symptomatic heterozygotes than it was in the co ntrol subjects. The administration of a test dose of sodium phenylbuty rate to the control group did not affect the rate of [N-15]urea format ion, We conclude: (a) This test effectively monitors in vivo N metabol ism and might obviate the need for liver biopsy to measure enzyme acti vity in OTCD; (b) Asymptomatic OTCD carriers form urea at a normal rat e, indicating that ureagenesis can be competent even though enzyme act ivity is below normal; (c) Although ostensibly asymptomatic OTCD carri ers form urea at a normal rate, their nitrogen metabolism is still abn ormal, as reflected in their increased production of [5-N-15]glutamine ; and (d) This new test may be important for monitoring the efficacy o f novel treatments for OTCD, e.g., liver transplantation and gene ther apy.