MONITORING UREAGENESIS IN PATIENTS WITH OTC DEFICIENCY

我们已经开发了一种新的技术，用于监测代谢能力， 鸟氨酸转氨甲酰酶缺乏症（OTC）的女性杂合子。我们 该方法使用质谱法测量15 NH 4C 1向 (15N)尿素和（5- 15 N）谷氨酰胺在口服后4小时内 15 NH 4Cl负载（25.9mmol）。我们发现， (15N)尿素在控制率，但共显性杂合子 将显著较少的NH3氮转化为尿素。因此，（15 N）尿素 浓度（mM）在血液中的symptoms杂合子是 在大多数时间点显著低于对照值。血液 （5- 15 N）谷氨酰胺浓度（mM）在两种中均显著较高 无症状和有症状的杂合子比对照组 科目给予试验剂量的苯丁酸钠， 对照组不影响（15 N）尿素形成速率。 我们的结论是：a）该测试提供了一个强大的工具，以监测 OTCD中的体内N代谢。在许多情况下，它甚至可能不需要 进行肝活组织检查以测量酶活性; B） 无症状OTCD携带者以正常速率形成尿素，这表明 即使酶活性明显降低， 低于正常水平。这一发现对假定的 c）虽然表面上无症状的OTCD 携带者以正常的速率形成尿素，他们的氮代谢仍然是 异常，如其（5- 15 N）谷氨酰胺的产生增加所反映的; d）这种新的测试可能不仅在诊断方面很重要，而且 监测OTCD的新治疗的功效，例如，肝 移植和基因治疗。

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.