Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency
Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency
复制标题
DOI：
10.1007/s10545-016-9928-y
复制
发表时间：
2016-05-01
影响因子：
4.2
通讯作者：
Karall, Daniela
中科院分区：
文献类型：
--
作者：
Huemer, Martina;Carvalho, Daniel R.;Karall, Daniela
精氨酸酶1（ARG 1）缺乏症是一种罕见的尿素循环障碍（UCD）。本研究探讨了ARG1缺乏的儿童和成人队列的临床表型、代谢特征、分子遗传学和治疗方法，以增加我们对潜在病理生理学的理解。血浆氨基酸，胍乙酸（GAA），氧化应激和一氧化氮（NO）的合成，以及不对称二甲基精氨酸（ADMA）的参数进行了测定在一个单一的研究site.Nineteen人ARG1缺乏症和19个匹配的对照组被纳入本研究。在患者中，轻瘫、认知障碍和癫痫发作显著相关，提示共同的潜在病理生理学。患者血浆GAA超过正常范围，血浆ADMA显著升高。与对照组相比，硝酸盐显着更高，亚硝酸盐：硝酸盐的比例显着降低与ARG1缺乏症的主题表明诱导型NO合酶（iNOS）的NO合成的优势超过内皮型NOS（eNOS）。Logistic回归分析显示，任何生化指标（包括精氨酸、硝酸盐、ADMA、GAA、氧化应激）或蛋白质限制对长期预后均无显著影响，本研究提出了三个主要假设：1）ARG 1缺乏症的临床表现与精氨酸、蛋白质摄入、ADMA、硝酸盐或氧化应激无关。2)GAA升高，可能是ARG 1缺乏症的病理生理学的标志物或活性部分。3)NO代谢的紊乱值得在ARG1缺乏症中进一步关注。
Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology.Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site.Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome.Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.