Please wait a minute...
浙江大学学报（医学版）
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 ()
Download: HTML( 40 )   PDF(1097KB)
Export: BibTeX | EndNote (RIS)      

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 words： Ornithine 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
Service
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
RSS
Articles by authors
Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health
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]
[1]   顾学范 . 临床遗传代谢病[M]. 北京: 人民卫生出版社, 2015.
GU Xuefan . Clinical genetic and metabolic diseases[M]. Beijing: People's Medical Publishing House, 2015.
[2]   LICHTER-KONECKI U, CALDOVIC L, MORIZONO H, et al. Ornithine transcarbamylase deficiency[A]//ADAM M P, ARDINGER H H, PAGON R A, et al. Gene reviews. Seattle (WA): University of Washington, 1993.
[3]   WILCKEN B . Problems in the management of urea cycle disorders[J]. Mol Genet Metab, 2004, 81 (Suppl 1): S86- S91
doi: 10.1016/j.ymgme.2003.10.016
[4]   SUMMAR M L , KOELKER S , FREEDENBERG D et al. The incidence of urea cycle disorders[J]. Mol Genet Metab, 2013, 110 (1-2): 179- 180
doi: 10.1016/j.ymgme.2013.07.008
[5]   DIONISI-VICI C , RIZZO C , BURLINA A B et al. Inborn errors of metabolism in the Italian pediatric population:a national retrospective survey[J]. J Pediatr, 2002, 140 (3): 321- 327
doi: 10.1067/mpd.2002.122394
[6]   KIDO J , NAKAMURA K , MITSUBUCHI H et al. Long-term outcome and intervention of urea cycle disorders in Japan[J]. J Inherit Metab Dis, 2012, 35 (5): 777- 785
doi: 10.1007/s10545-011-9427-0
[7]   杨艳玲, 孙芳, 钱宁 et al. 尿素循环障碍的临床和实验室筛查研究[J]. 中华儿科杂志, 2005, 43 (5): 331- 334
YANG Yanling , SUN Fang , QIAN Ning et al. Clinical and laboratory screening studies on urea cycle defects[J]. Chinese Journal of Pediatrics, 2005, 43 (5): 331- 334
doi: 10.3760/j.issn:0578-1310.2005.05.003
[8]   H?BERLE J , BURLINA A , CHAKRAPANI A et al. Suggested guidelines for the diagnosis and management of urea cycle disorders:first revision[J]. J Inherit Metab Dis, 2019, 42 (6): 1192- 1230
doi: 10.1002/jimd.12100
[9]   TUCHMAN M , LEE B , LICHTER-KONECKI U et al. Cross-sectional multicenter study of patients with urea cycle disorders in the United States[J]. Mol Genet Metab, 2008, 94 (4): 397- 402
doi: 10.1016/j.ymgme.2008.05.004
[10]   SINGH R H . Nutritional management of patients with urea cycle disorders[J]. J Inherit Metab Dis, 2007, 30 (6): 880- 887
doi: 10.1007/s10545-007-0718-4
[11]   BONEH A . Dietary protein in urea cycle defects:How much? Which? How?[J]. Mol Genet Metab, 2014, 113 (1-2): 109- 112
doi: 10.1016/j.ymgme.2014.04.009
[12]   NAKAMURA K , KIDO J , MITSUBUCHI H et al. Diagnosis and treatment of urea cycle disorder in Japan[J]. Pediatr Int, 2014, 56 (4): 506- 509
doi: 10.1111/ped.12439
[13]   H?BERLE J , BODDAERT N , BURLINA A et al. Suggested guidelines for the diagnosis and management of urea cycle disorders[J]. Orphanet J Rare Dis, 2012, 7 32
doi: 10.1186/1750-1172-7-32
[14]   MORRIS S M J R . Regulation of enzymes of the urea cycle and arginine metabolism[J]. Annu Rev Nutr, 2002, 22 87- 105
doi: 10.1146/annurev.nutr.22.110801.140547
[15]   CALDOVIC L , ABDIKARIM I , NARAIN S et al. Genotype-phenotype correlations in ornithine transcarbamylase deficiency:a mutation update[J]. J Genet Genomics, 2015, 42 (5): 181- 194
doi: 10.1016/j.jgg.2015.04.003
[16]   BRAISSANT O . Current concepts in the pathogenesis of urea cycle disorders[J]. Mol Genet Metab, 2010, 100 (Suppl 1): S3- S12
doi: 10.1016/j.ymgme.2010.02.010
[17]   POSSET R , GARBADE S F , BOY N et al. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-A successful strategy for clinical research of rare diseases[J]. J Inherit Metab Dis, 2019, 42 (1): 93- 106
doi: 10.1002/jimd.12031
[18]   BURGARD P , K?LKER S , HAEGE G et al. Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders-review and meta-analysis of observational studies published over more than 35 years[J]. J Inherit Metab Dis, 2016, 39 (2): 219- 229
doi: 10.1007/s10545-015-9901-1
[19]   GORDON N . Ornithine transcarbamylase deficiency:a urea cycle defect[J]. Eur J Paediatr Neurol, 2003, 7 (3): 115- 121
doi: 10.1016/s1090-3798(03)00040-0
[20]   NASSOGNE M C , HéRON B , TOUATI G et al. Urea cycle defects:management and outcome[J]. J Inherit Metab Dis, 2005, 28 (3): 407- 414
doi: 10.1007/s10545-005-0303-7
[21]   王海军, 李东晓, 王琪 et al. 一家系3例鸟氨酸氨甲酰基转移酶缺乏症的临床特征及基因分析[J]. 中华实用儿科临床杂志, 2018, 33 (13): 1028- 1029
WANG Haijun , LI Dongxiao , WANG Qi et al. Clinical features of 3 patients from 1 family affected by ornithine aminotransferase deficiency and gene analysis[J]. Chinese Journal of Applied Clinical Pediatrics, 2018, 33 (13): 1028- 1029
doi: 10.3760/cma.j.issn.2095-428X.2018.13.015
[22]   MARTíN-HERNáNDEZ E , ALDáMIZ-ECHEVARRíA L , CASTEJóN-PONCE E et al. Urea cycle disorders in Spain:an observational, cross-sectional and multicentric study of 104 cases[J]. Orphanet J Rare Dis, 2014, 9 187
doi: 10.1186/s13023-014-0187-4
[23]   GALLAGHER R C , LAM C , WONG D et al. Significant hepatic involvement in patients with ornithine transcarbamylase deficiency[J]. J Pediatr, 2014, 164 (4): 720- 725.e6
doi: 10.1016/j.jpeds.2013.12.024
[24]   LEONARD J V , MORRIS A A . Urea cycle disorders[J]. Semin Neonatol, 2002, 7 (1): 27- 35
doi: 10.1053/siny.2001.0085
[25]   BRASSIER A , GOBIN S , ARNOUX J B et al. Long-term outcomes in ornithine transcarbamylase deficiency:a series of 90 patients[J]. Orphanet J Rare Dis, 2015, 10 58
doi: 10.1186/s13023-015-0266-1
[26]   SHAO Y , JIANG M , LIN Y et al. Clinical and mutation analysis of 24 Chinese patients with ornithine transcarbamylase deficiency[J]. Clin Genet, 2017, 92 (3): 318- 322
doi: 10.1111/cge.13004
[27]   CAVICCHI C , MALVAGIA S , LA MARCA G et al. Hypocitrullinemia in expanded newborn screening by LC-MS/MS is not a reliable marker for ornithine transcarbamylase deficiency[J]. J Pharm Biomed Anal, 2009, 49 (5): 1292- 1295
doi: 10.1016/j.jpba.2009.03.001
[28]   周平, 宋元宗, 肖昕 et al. 鸟氨酸氨甲酰基转移酶缺陷病1例[J]. 实用儿科临床杂志, 2006, 21 (8): 459, 462
ZHOU Ping , SONG Yuanzong , XIAO Xin et al. A case of ornithine transcarbamylase deficiency[J]. Journal of Applied Clinical Pediatrics, 2006, 21 (8): 459, 462
doi: 10.3969/j.issn.1003-515X.2006.08.029
[29]   龚珠文, 韩连书, 叶军 et al. 多重连接探针扩增技术诊断鸟氨酸氨甲酰转移酶缺乏症五例[J]. 中华儿科杂志, 2016, 54 (6): 437- 440
GONG Zhuwen , HAN Lianshu , YE Jun et al. Applying multiple probe amplification in the diagnosis of 5 cases with ornithine transcarbamylase deficiency[J]. Chinese Journal of Pediatrics, 2016, 54 (6): 437- 440
doi: 10.3760/cma.j.issn.0578-1310.2016.06.010
[30]   SHCHELOCHKOV O A , LI F Y , GERAGHTY M T et al. High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH[J]. Mol Genet Metab, 2009, 96 (3): 97- 105
doi: 10.1016/j.ymgme.2008.11.167
[31]   ENGEL K , NUOFFER J M , MVHLHAUSEN C et al. Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency[J]. Mol Genet Metab, 2008, 94 (3): 292- 297
doi: 10.1016/j.ymgme.2008.03.009
[32]   TAKANASHI J , BARKOVICH A J , CHENG S F et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders[J]. AJNR Am J Neuroradiol, 2003, 24 (6): 1184- 1187
[33]   PACHECO-COLóN I , FRICKE S , VANMETER J et al. Advances in urea cycle neuroimaging:Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013[J]. Mol Genet Metab, 2014, 113 (1-2): 118- 126
doi: 10.1016/j.ymgme.2014.05.005
[34]   BACHMANN C . Outcome and survival of 88 patients with urea cycle disorders:a retrospective evaluation[J]. Eur J Pediatr, 2003, 162 (6): 410- 416
doi: 10.1007/s00431-003-1188-9
[35]   ADAM S , ALMEIDA M F , ASSOUN M et al. Dietary management of urea cycle disorders:European practice[J]. Mol Genet Metab, 2013, 110 (4): 439- 445
doi: 10.1016/j.ymgme.2013.09.003
[36]   World Health Organization, Food and Agriculture Organization of the United Nations, United Nations University. Protein and amino acid requirements in human nutrition. Report of a joint FAO/WHO/UNU expert consultation (WHO Technical Report Series 935)[R]. Geneva: WHO, 2007.
[37]   KIM I K , NIEMI A K , KRUEGER C et al. Liver transplantation for urea cycle disorders in pediatric patients:a single-center experience[J]. Pediatr Transplant, 2013, 17 (2): 158- 167
doi: 10.1111/petr.12041
[38]   MORIOKA D , KASAHARA M , TAKADA Y et al. Current role of liver transplantation for the treatment of urea cycle disorders:a review of the worldwide English literature and 13 cases at Kyoto University[J]. Liver Transpl, 2005, 11 (11): 1332- 1342
doi: 10.1002/lt.20587
[39]   孙丽莹, 朱志军, 魏林 et al. 肝移植治疗儿童遗传代谢性疾病42例[J]. 中华器官移植杂志, 2017, 38 (6): 337- 342
SUN Liying , ZHU Zhijun , WEI Lin et al. Pediatric liver transplantation for metabolic liver diseases report of 42 children[J]. Chinese Journal of Organ Transplantation, 2017, 38 (6): 337- 342
doi: 10.3760/cma.j.issn.0254-1785.2017.06.004
[40]   BUSUTTIL A A , GOSS J A , SEU P et al. The role of orthotopic liver transplantation in the treatment of ornithine transcarbamylase deficiency[J]. Liver Transpl Surg, 1998, 4 (5): 350- 354
doi: 10.1002/lt.500040504
[1] JIN Xiaoxiao, JIN Pengzhen, YAN Kai, QIAN Yeqing, DONG Minyue. Genetic analysis of a mosaic case with low proportion mutation of TSC2 gene[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 586-590.
[2] DUAN Runping, XU Yesheng, ZHENG Libin, YAO Yufeng. Research progress on etiologic diagnosis of ocular viral diseases[J]. J Zhejiang Univ (Med Sci), 2020, 49(5): 644-650.
[3] XU Jiahui,JIN Bo,ZHANG Lisan,WANG Shuang. Advances in sleep-related hypermotor epilepsy[J]. J Zhejiang Univ (Med Sci), 2020, 49(4): 425-430.
[4] KONG Yuanmei,CHEN Hong,LIANG Li,ZHENG Maoni,FANG Yanlan,WANG Chunlin. Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 283-290.
[5] WANG Chunlin,LIANG Li. Reconsideration of the third-generation non-steroidal aromatase inhibitors in pediatrics[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 275-282.
[6] XU De,LU Wenli,WANG Xueqing,WANG Junqi,XIE Yiwen,DONG Zhiya,WANG Wei. Efficacy and safety of letrozole in treatment of McCune-Albright syndrome girls with peripheral precocious puberty[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 291-296.
[7] WANG Qian,ZHANG Shule,MA Xue,LI Guimei,WANG Zengmin,WANG Fengxue. Efficacy of letrozole in treatment of children with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 302-307.
[8] SUN Jinhong,QIU Chenyang,WU Ziheng,ZHANG Hongkun. Preliminary result of stents implantation for spontaneous isolated dissection of the superior mesenteric artery: a prospective single-arm study[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 383-388.
[9] LI Yanhong,DU Minlian,MA Huamei,CHEN Qiuli,CHEN Hongshan,ZHANG Jun. Efficacy of letrozole in treatment of male adolescents with idiopathic short stature[J]. J Zhejiang Univ (Med Sci), 2020, 49(3): 308-314.
[10] CHEN Jun,LIU Danping,LIU Li,LIU Ping,XU Qingnian,XIA Lu,LING Yun,HUANG Dan,SONG Shuli,ZHANG Dandan,QIAN Zhiping,LI Tao,SHEN Yinzhong,LU Hongzhou. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 215-219.
[11] CHEN Zhimin,FU Junfen,SHU Qiang,WANG Wei,CHEN Yinghu,HUA Chunzhen,LI Fubang,LIN Ru,TANG Lanfang,WANG Tianlin,WANG Yingshuo,XU Weize,YANG Zihao,YE Sheng,YUAN Tianming,ZHANG Chenmei,ZHANG Yuanyuan. Diagnosis and treatment recommendation for pediatric COVID-19 (the second edition)[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 139-146.
[12] YE Ziqi,HONG Yun,WU Xiuhua,HONG Dongsheng,ZHANG Yanfang,DONG Xihao,RAO Yuefeng,LU Xiaoyang. Management of a colon cancer patient complicated with COVID-19[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 245-248.
[13] DING Shubo,YU Shi'an,CHEN Haijun,ZHANG Dehe,XU Yejin,ZHU Dan,CHENG Kun. Roles of multidisciplinary team in diagnosis and treatment of suspected cases of COVID-19[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 209-214.
[14] FAN Tiantian,CHEN Yongcan,BAI Yu,MA Fengqi,WANG Hengcang,YANG Yiping,CHEN Jinxu,LIN Yuqi. Analysis of medication characteristics of traditional Chinese medicine in treating COVID-19 based on data mining[J]. J Zhejiang Univ (Med Sci), 2020, 49(2): 260-269.
[15] GAO Mingxuan,NIE Dejun,CHANG Yanfeng,XIE Weiqiang,WANG Yue,PU Xingyu,ZHANG Wei,LUO Wenyuan. Internal fixation of lateral and medial borders for displaced scapular body fractures via minimally invasive approach: results of 23 cases[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 651-656.