MONITORING UREAGENESIS IN PATIENTS WITH OTC DEFICIENCY

我们已经开发了一种新的技术来监测新陈代谢能力 女性鸟氨酸转氨酶缺乏症杂合子。我们的 一种用质谱学方法测量15NH4Cl到 口服后4小时内摄入(15N)尿素和(5-15N)谷氨酰胺 15NH_4C_1负荷(25.9 mmol)。我们发现形成了无症状的杂合子 (15N)尿素在控制率，但有症状的杂合子 将NH3-N转化为尿素的量显著减少。因此，(15N)尿素 症状性杂合子的血液浓度(Mm)是 在大多数时间点明显小于控制值。鲜血 两者的(5-15N)谷氨酰胺(MM)浓度均显著升高 与对照组相比，无症状和有症状的杂合子 研究对象。给药试验剂量的苯丁酸钠 对照组对(15N)尿素生成率无影响。 我们的结论是：a)这项测试提供了一个强大的工具，可以用来在 OTCD体内氮代谢的研究在许多情况下，它甚至可能不需要 进行肝脏活检，以测量酶活性；b) 无症状OTCD携带者以正常速率形成尿素，表明 尿失禁可以胜任，即使酶的活性是明显的 低于正常水平。这一发现对推定的 基因治疗的有效性；c)尽管表面上没有OTCD症状 携带者以正常的速度形成尿素，他们的氮代谢仍然 异常，反映在它们的(5-15N)谷氨酰胺的产生增加； D)这种新的测试可能不仅在诊断方面很重要，而且 监测OTCD的新治疗方法的疗效，例如肝脏 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.