Disorders of the Urea Cycle and Related Enzymes
Disorders of the Urea Cycle and Related Enzymes
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DOI：
10.1007/978-3-662-49771-5_19
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
J. Häberle;V. Rubio
中科院分区：
文献类型：
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作者：
J. Häberle;V. Rubio
尿素循环障碍（UCDs）是一种导致尿素循环（UC）酶(氨甲酰磷酸合成酶1 （CPS1）、鸟氨酸转氨基甲酰基酶（OTC）、精氨酸琥珀酸合成酶（ASS）、精氨酸琥珀酸裂解酶（ASL）和精氨酸酶（ARG1）功能丧失的遗传缺陷；线粒体鸟氨酸/瓜氨酸反转运蛋白（ORC1）；cps1激活酶n -乙酰谷氨酸合成酶（NAGS）。它们的总发生率约为1:35 000，至少有25%的病例出现新生儿症状。NAGS、CPS1和OTC是线粒体，它们的缺乏引起高氨血症。线粒体外酶ASS、ASL和ARG1以及ORC1反转运蛋白的缺乏也会引起氨基酸水平的特异性改变，从而影响疾病的发病机制。碳酸酐酶Va (CAVA)，肝脏线粒体柠檬酸天冬氨酸/谷氨酸反转运蛋白和Δ1-pyrroline-5-carboxylate合成酶（P5CS）的缺乏，可通过损害碳酸氢盐、天冬氨酸和新鸟氨酸对UC的供应而导致高氨血症。除了OTC缺陷（x连锁）和P5CS缺陷（显性或隐性）外，ucd的遗传均为常染色体隐性遗传。急性高氨血症是一种临床紧急情况，发生在大多数ucd和新生儿短暂性高氨血症（THAN）中，这是一种病因不明的罕见情况。其表现为易怒、拒食、呕吐、营养不稳定、张力低下、抽搐、嗜睡、嗜睡、昏迷和死亡，如不治疗则会出现神经系统后遗症。UCDs的治疗目标是通过以下方法快速降低氨水平：(1)通过限制蛋白质和防止分解代谢来减少氨的产生；(2)使用透析方法最大限度地去除氨，用苯甲酸酯和/或苯乙酸酯或苯丁酸酯激活交替的氨清除途径，并在适当的情况下用精氨酸或瓜氨酸增强残余UC功能。肝移植可以治愈或几乎治愈这些疾病，但对于ASL缺乏症可能不行。重要的是，柠檬酸缺乏症与其他ucd的显著不同之处在于，应该限制碳水化合物的摄入，并给予大量蛋白质。NAGS缺乏症实际上可以通过给予n -氨甲酰谷氨酸来代替缺失的n -乙酰谷氨酸来治愈。正在测试的新疗法包括基因添加和酶替代。
Urea cycle disorders (UCDs) are genetic defects causing loss of function of any of the urea cycle (UC) enzymes carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase (ARG1); the mitochondrial ornithine/citrulline antiporter (ORC1); and the CPS1-activating enzyme N-acetylglutamate synthase (NAGS). Their combined frequency is about 1:35,000 births, with newborn presentations in at least 25% of cases. NAGS, CPS1 and OTC are mitochondrial and their deficiencies cause hyperammonaemia. The deficiencies of the extramitochondrial enzymes ASS, ASL and ARG1, and of the ORC1 antiporter additionally cause specific alterations in amino acid levels with impact on disease pathogenesis. Deficiencies of carbonic anhydrase Va (CAVA), the liver mitochondrial citrin aspartate/glutamate antiporter and Δ1-pyrroline-5-carboxylate synthetase (P5CS), can cause hyperammonaemia by impairing supply to the UC of bicarbonate, aspartate andde novomade ornithine, respectively. Inheritance of UCDs is autosomal recessive except OTC deficiency, which is X-linked, and P5CS deficiency, which can be dominant or recessive. Acute hyperammonaemia is a clinical emergency occurring in most UCDs and in the transient hyperammonaemia of the newborn (THAN), a rarer condition of unclear etiology. It manifests as irritability, food refusal, vomiting, vegetative instability, hypotonia, convulsions, somnolence, lethargy, coma and death or neurological sequelae if untreated. Therapy of UCDs aims at rapid lowering of ammonia levels by (1) minimizing ammonia production via protein restriction and prevention of catabolism; (2) maximizing ammonia removal using dialytic measures, activation of alternate ammonia scavenging pathways with benzoate and/or phenylacetate or phenylbutyrate, and by enhancing residual UC function with arginine or citrulline where appropriate. Liver transplantation is curative or nearly so for most of these disorders but probably not for ASL deficiency. Importantly, citrin deficiency dramatically differs from other UCDs in that carbohydrates should be limited and high amounts of protein given. NAGS deficiency is virtually cured by giving N-carbamylglutamate to replace the missing N-acetylglutamate. Novel therapies being tested include gene addition and enzyme replacement.