Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism
Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism
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DOI：
10.1093/jn/134.10.2775s
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发表时间：
2004-10-01
影响因子：
4.2
通讯作者：
Lee, B
中科院分区：
文献类型：
--
作者：
Scaglia, F;Brunetti-Pierri, N;Lee, B
尿素循环障碍 (UCD) 是由氨氮到尿素的氮转移失调引起的人类疾病。这些疾病的生物化学和遗传学已得到很好的阐明。早期诊断和改进治疗导致出现了一批寿命更长的患者。其中一些疾病的自然史开始指向可能与急性发病和死亡的主要原因（即高氨血症）无关的病理生理过程。氨甲酰磷酸合成酶 I 单核苷酸多态性可能与血管阻力的改变有关，当存在特定的环境应激源时，血管阻力的改变就会变得具有临床意义。由于精氨酸琥珀酸裂解酶缺乏而导致精氨酸琥珀酸尿症的患者特别容易患慢性肝炎，并可能导致肝硬化。此外，我们最近的观察表明，原发性高血压的患病率可能有所增加。相比之下，精氨酸酶 1 缺乏症患者中发现的高精氨酸血症与锥体束表现和痉挛有关，但没有明显的高氨血症。一个有趣的潜在病理生理学联系是细胞内精氨酸可用性的失调及其对一氧化氮（NO）代谢的潜在影响。通过将详细的自然史研究与尿素循环酶的组织特异性无效小鼠模型的开发以及LICID患者中尿素和NO的循环氮通量的测量相结合，我们可以开始剖析不同来源的精氨酸对NO产生的贡献以及对罕见遗传和常见多因素疾病的影响。
Urea cycle disorders (UCD) are human conditions caused by the dysregulation of nitrogen transfer from ammonia nitrogen into urea. The biochemistry and the genetics of these disorders were well elucidated. Earlier diagnosis and improved treatments led to an emerging, longer-lived cohort of patients. The natural history of some of these disorders began to point to pathophysiological processes that may be unrelated to the primary cause of acute morbidity and mortality, i.e., hyperammonemia. Carbamyl phosphate synthetase I single nucleotide polymorphisms may be associated with altered vascular resistance that becomes clinically relevant when specific environmental stressors are present. Patients with argininosuccinic aciduria due to a deficiency of argininosuccillic acid lyase are uniquely prone to chronic hepatitis, potentially leading to cirrhosis. Moreover, our recent observations suggest that there may be an increased prevalence of essential hypertension. In contrast, hyperargininemia found in patients with arginase 1 deficiency is associated with pyramidal tract findings and spasticity, without significant hyperammonemia. An intriguing potential pathophysiological link is the dysregulation of intracellular arginine availability and its potential effect on nitric oxide (NO) metabolism. By combining detailed natural history studies with the development of tissue-specific null mouse models for urea cycle enzymes and measurement of nitrogen flux through the cycle to urea and NO in LICID patients, we may begin to dissect the contribution of different sources of arginine to NO production and the consequences on both rare genetic and common multifactorial diseases.