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J Zhejiang Univ (Med Sci)  2020, Vol. 49 Issue (5): 539-547    DOI: 10.3785/j.issn.1008-9292.2020.04.11
    
Consensus on diagnosis and treatment of ornithine trans-carbamylase deficiency
Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health ()
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Abstract  

Ornithine transcarbamylase deficiency(OTCD)is a most common ornithine cycle (urea cycle) disorder. It is a X-link inherited disorder caused by OTC gene mutation that in turn leads to reduction or loss of OTC enzyme activity. Its onset time is related to the lack of enzyme activity. Patients with neonatal onset usually have complete absence of OTC enzyme activity, which is mainly associated with male semi-zygotic mutations; and the disease progresses rapidly with high mortality rates. Patients with late onset vary in onset age and clinical manifestations, and the course of disease can be progressive or intermittent. The acute attack mainly manifests neuropsychiatric symptoms accompanied by digestive symptoms like liver function damage or even acute liver failure. Elevated blood ammonia is the main biochemical indicator of OTCD patients. Increased glutamine, decreased citrulline in blood, and increased orotic acid in urine are typical clinical manifestations for OTCD patients. Genetic testing of OTC gene is important for OTCD diagnosis. The goal of treatment is to minimize the neurological damage caused by hyperammonemia while ensuring the nutritional needs for patient development. For patients with poor response to medication and diet, liver transplantation is recommended under the condition of stable metabolic state and absence of severe neurological damage. During long-term treatment, physical growth indicators, nutrition status, liver function, blood ammonia and amino acids should be regularly monitored. This consensus aims to standardize the diagnosis and treatment of OTCD, improve the prognosis, reduce the mortality and disability of patients.



Key wordsOrnithine transcarbamylase deficiency      Hyperammonemia      Diagnosis      Treatment      Experts consensus     
Received: 19 December 2019      Published: 29 May 2020
CLC:  R596  
Corresponding Authors: Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health      E-mail: 6305022@zju.edu.cn
Cite this article:

Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health . Consensus on diagnosis and treatment of ornithine trans-carbamylase deficiency. J Zhejiang Univ (Med Sci), 2020, 49(5): 539-547.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2020.04.11     OR     http://www.zjujournals.com/med/Y2020/V49/I5/539


鸟氨酸氨甲酰转移酶缺乏症诊治专家共识

鸟氨酸氨甲酰转移酶(OTC)缺乏症(OTCD)是由OTC基因突变引起OTC酶活性降低或缺失导致的常见鸟氨酸循环障碍疾病,为X连锁遗传病。OTCD的发病时间与酶活性缺乏程度有关,新生儿期起病型患者通常为OTC酶活性完全丧失,多为男性半合子突变,起病急且进展迅速,病死率高;迟发型患者发病年龄及临床表现个体差异较大,病程可为渐进性或间歇性,急性发作以神经精神症状为主要表现,同时可伴有肝功能损害甚至急性肝衰竭等消化系统症状。血氨升高是OTCD患者的主要血生化异常指标,OTCD患者的典型表现是血液谷氨酰胺增加伴瓜氨酸减少,尿乳清酸增加,OTC基因突变是OTCD确诊的重要依据。治疗目标是尽可能减少高氨血症造成的神经系统损害,同时保证患者发育所需的营养。对于药物和饮食治疗效果不佳的患者,建议在代谢状态稳定且没有严重神经系统损伤的条件下进行肝移植。在长期治疗过程中,应定期监测患者体格生长指标、营养摄入情况和血氨、血脂、肝功能及血氨基酸等生化指标。本共识有助于规范OTCD的诊治,以改善患者预后、减少死亡及残障。


关键词: 鸟氨酸氨甲酰转移酶缺乏症,  高氨血症,  诊断,  治疗,  专家共识 
血氨水平(μmol/L) 治疗措施
*口服给药剂量见表 2, 静脉给药选用10%葡萄糖溶液配制,负荷量250 mg/kg,于90~120 min内泵入,维持剂量为每日250 mg/kg,如进行血液净化治疗,维持剂量增加至每日350 mg/kg;#口服给药剂量见表 2,静脉给药选用10%葡萄糖溶液配制,负荷量250 mg/kg,于90~120 min内泵入,体质量≤20 kg时维持剂量为每日250~500 mg/kg,体质量>20 kg时维持剂量为每日5.5 g/m2,如进行血液透析或血浆置换,维持剂量增加至每日350 mg/kg;口服给药剂量见表 2,静脉给药配置同精氨酸.
高于正常值但低于100 减少蛋白质摄入;静脉输注10%葡萄糖溶液
100~250
(新生儿:150~250)
停止蛋白质摄入;开始抗高血氨药治疗;精氨酸口服或静脉给药*,促进鸟氨酸循环实现氨排泄最大化;苯甲酸钠口服或静脉给药#(可同时苯乙酸钠或苯丁酸钠口服或静脉给药),促进鸟氨酸循环旁路快速降血氨
>250~500
静脉点滴抗高血氨药;如患者出现明显脑病征象和/或血氨急骤升高(起病1~2 d血氨达250~500 μmol/L),准备血液透析或血浆置换;经3~6 h治疗血氨仍无快速下降趋势,即刻开始血液透析或血浆置换
>500~1000 即刻开始血液透析或血浆置换
>1000 评估是否需要积极治疗(抢救)
Tab 1 Emergency treatment for hyperammonemia in patients with ornithine transcarbamylase deficiency
药物 每日推荐剂量 每日最大剂量(g)
*苯丁酸甘油酯(Ravicti®)在临床试验中表现出比苯丁酸钠更好的稳定代谢作用; #可替代精氨酸,疗效可能略优于精氨酸,两者不宜同时应用.
苯甲酸钠 100~250 mg/kg 12
苯丁酸钠或苯丁酸甘油酯* 体质量≤20 kg时,100~250 mg/kg;
体质量>20 kg时,2~5.5 g/m2
12
精氨酸 体质量≤20 kg时,100~200 mg/kg;
体质量>20 kg时,2~6 g/m2
6
瓜氨酸# 100~200mg/kg 6
Tab 2 Recommended oral dosage of antihyperammonemics for patients with ornithine transcarbamylase deficiency
年龄 安全摄入量(g/kg)
1~2月 1.50~1.77
3~5月 1.31~1.36
6~12月 1.14~1.31
1~3岁 0.90~1.14
4~10岁 0.87~0.92
11~18岁 0.82~0.90
18岁以上 0.83
Tab 3 Safe daily intake of protein for people[36]
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