An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency.
An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency.
复制标题
部分鸟氨酸转氨甲酰酶缺乏症的诊断和前瞻性管理的综合方法。
作者：
F. Scaglia;Qiping Zheng;W. O'Brien;Joseph F. Henry;J. Rosenberger;P. Reeds;Brendan H. Lee
鸟氨酸转氨甲酰酶缺乏症（OTCD）是最常见的遗传性尿素循环障碍，并且作为X连锁性状传递。女性OTCD杂合子表现出广泛的临床严重性，从明显无症状到具有在受影响的男性中观察到的严重神经功能缺损。然而，在无症状期间部分OTCD的临床和实验室诊断是困难的，并且表型严重程度与DNA突变和/或体外酶活性的相关性是不精确的。包括用于诊断OTCD女性的蛋白质负荷和别嘌呤醇激发在内的激发性测试并非没有风险，并且会出现假阳性和假阴性。虽然成功时是确定的，但基于DNA的诊断无法在所有病例中检测到突变。我们以前曾使用[（15）N]尿素/[（15）N]谷氨酰胺（（15）N-U/G）的同位素富集比作为体内尿素循环活性的敏感指标，该比值来自通过稳定同位素输注进行的尿素生成的生理测量。我们现在已经将该方法与传统的生化测试相结合，以帮助诊断一名有症状的OTCD女性，在该患者中没有发现鸟氨酸转氨甲酰酶（OTC）基因突变。该患者的（15）N-U/G比率表明，她与受影响的男性受试者一样，体内尿素循环活性严重降低。这与她的肝脏中部分缺乏OTC活性、乳清酸尿程度和3岁前疑似复发性高氨血症发作史相关。体内尿素循环活性的测量结合传统的生化指标优化了对处于风险中的部分OTCD患者的诊断方法，特别是在分子测试无效的那些患者中。它们共同促成了关于追求药物治疗与手术治疗（即原位肝移植（奥尔特）治疗）的风险与获益考虑。在部分OTC活性的女性中采取奥尔特的决定是有争议的，需要考虑表型严重程度、药物治疗失败、进入三级护理中心治疗急性高氨血症的经验以及社会因素。在这个病人中，使用体内和体外尿素循环活性的措施，结合她的临床病史和医疗社会情况的考虑，导致决定奥尔特。
Ornithine transcarbamylase deficiency (OTCD) is the most common inherited urea cycle disorder, and is transmitted as an X-linked trait. Female OTCD heterozygotes exhibit wide clinical severities, ranging from being apparently asymptomatic to having the profound neurologic impairment observed in affected males. However, clinical and laboratory diagnosis of partial OTCD during asymptomatic periods is difficult, and correlation of phenotypic severity with either DNA mutation and/or in vitro enzyme activity is imprecise. Provocative testing, including protein load and allopurinol challenge used in the diagnosis of OTCD females, is not without risk and subject to both false positives and negatives. Although definitive when successful, DNA-based diagnosis is unable to detect mutations in all cases. We have previously used the ratio of isotopic enrichments of [(15)N]urea/[(15)N]glutamine ((15)N-U/G) derived from physiologic measurements of ureagenesis by stable isotope infusion as a sensitive index of in vivo urea cycle activity. We have now applied this method in combination with traditional biochemical testing to aid in the diagnosis of a symptomatic OTCD female in whom mutation in the ornithine transcarbamylase (OTC) gene was not found. The (15)N-U/G ratio in this patient showed that she had severe reduction of in vivo urea cycle activity on par with affected male subjects. This was correlated with partially deficient OTC activity in her liver, degree of orotic aciduria, and history of suspected recurrent hyperammonemic episodes before age 3. The measurement of in vivo urea cycle activity in combination with traditional biochemical indices optimizes a diagnostic approach to the at-risk partial OTCD patient, especially in those in whom molecular testing is unproductive. Together they contribute to the risk versus benefit considerations regarding the pursuit of medical therapy versus surgical, ie, orthotopic liver transplantation (OLT) therapy. The decision to resort to OLT in females with partial OTC activity is controversial, requiring consideration of phenotypic severity, failure of medical therapy, access to tertiary care centers experienced in the management of acute hyperammonemia, and social factors. In this patient, the use of in vivo and in vitro measures of urea cycle activity in conjunction with a consideration of her clinical history and medical-social situation led to a decision for OLT.