Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Am J Hum Genet. 2012 May 4;90(5):836-46. doi: 10.1016/j.ajhg.2012.03.018. Epub 2012 Apr 26.
Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition.
精氨酸琥珀酸裂解酶（ASL）是合成和定向 L-精氨酸向一氧化氮合酶（NOS）以供产生一氧化氮（NO）所必需的。先天性 ASL 缺乏会导致精氨酸琥珀酸尿症（ASA），这是第二常见的尿素循环障碍，导致尿素生成和 NO 生成均不足。尽管早期开始治疗且无记录的高氨血症，但患有 ASA 的患者已被报道会发展出长期并发症，如高血压和神经认知缺陷。为了区分肝尿素循环缺陷和 NO 缺乏对表型的相对贡献，我们在 ASA 小鼠模型中进行了肝定向基因治疗。虽然基因治疗纠正了尿素生成缺陷，但通过使用外源性 NO 源治疗可以纠正小鼠的系统性高血压。在一名患有严重高血压且对降压药物耐药的 ASA 患者中，NO 补充剂的单一疗法可长期控制高血压并减少心脏肥大。此外，NO 治疗与与言语记忆和非言语解决问题等一些神经心理学参数的改善相关。我们的数据表明，ASA 除了是一种经典的尿素循环障碍外，还是先天性人类 NO 缺乏的模型，ASA 患者可能受益于 NO 补充。因此，应研究 NO 补充剂用于该疾病的长期治疗。
