迟发型鸟氨酸氨甲酰基转移酶缺乏症8例临床表现及OTC基因分析
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摘要
目的总结急性发病的迟发型鸟氨酸氨甲酰基转移酶缺乏症(ornithine transcarbamylase deficiency,OTCD)的临床及基因突变特点,提高快速识别与诊治的能力。方法对2014年1月至2017年12月在郑州大学附属儿童医院确诊为OTCD的8例患儿临床表现、实验室检查、血氨基酸、尿有机酸及基因突变进行回顾性分析,总结OTCD的诊疗要点。结果 8例患儿中男性3例,女性5例,于10个月至6岁10月龄时初诊,5例发病前健康,3例既往智力运动发育落后;主要临床表现为呕吐、食欲下降、意识障碍、惊厥等;检查发现肝损伤,血氨显著增高,血瓜氨酸降低,尿乳清酸、尿嘧啶增高,鸟氨酸氨甲酰基转移酶(OTC)基因各检出不同的致病突变,其中c.118C>T、c.482A>G、c.898del T、c.275G>A、c.803T>C为5种已知突变,c.67C>T、c.416T>G、c.898dup T为3种新突变。经血液净化等治疗后,4例患儿好转,4例放弃治疗后死亡。结论 OTCD是一种严重的尿素循环障碍疾病,临床表现缺乏特异性,个体差异显著。血氨检测是发现OTCD的关键,对不明原因的呕吐、意识障碍患儿应高度重视,代谢分析及基因分析是确诊的关键,及早诊疗可改善预后。
Objective To improve the ability of rapid identification and diagnosis of late-onset ornithine transcarbamylase(OTC)deficiency by summarizing the clinical and mutations features of eight cases. Methods The clinical manifestation,laboratory examination,blood amino acids,urinary organic acids and gene analysis of 8 patients with OTC deficiency treated in Children's Hospital Affiliated to Zhengzhou University from Jan.2014 to Dec.2017 were studied. The points of diagnosis and treatment for OTC deficiency were summarized. Results Eight children(3 boys and 5 girls)first visited the emergency department of our hospital at the age from 10 months to 6 years and 10 months due to vomiting,loss of appetite,conscious disturbance and convulsions. Liver dysfunction,significantly elevated blood ammonia,decreased blood citrulline,and elevated urine orotic acid and uracil were found by laboratory tests. Different mutations in their OTC gene were identified from these patients. Five mutations,c.118 C>T,c.482 A>G,c.898 del T,c.275 G>A and c.803 T>C,were reported. c.67 C>T,c.416 T>G and c.898 dup T were novel mutations. After hemofiltration and other active symptomatic treatment,4 patients were improved,while the other 4 patients who discontinued treatment died soon. Conclusion OTC deficiency is a severe urea cycle disorder with significant individual differences. The patients are usually lack of specific clinical manifestations. For the patients with vomiting of unknown reasons and disturbance of consciousness,blood ammonia test is the key to the diagnosis. Metabolic studies and genetic studies are important to confirm the diagnosis. Early treatment can improve the prognosis.
Objective To improve the ability of rapid identification and diagnosis of late-onset ornithine transcarbamylase(OTC)deficiency by summarizing the clinical and mutations features of eight cases. Methods The clinical manifestation,laboratory examination,blood amino acids,urinary organic acids and gene analysis of 8 patients with OTC deficiency treated in Children's Hospital Affiliated to Zhengzhou University from Jan.2014 to Dec.2017 were studied. The points of diagnosis and treatment for OTC deficiency were summarized. Results Eight children(3 boys and 5 girls)first visited the emergency department of our hospital at the age from 10 months to 6 years and 10 months due to vomiting,loss of appetite,conscious disturbance and convulsions. Liver dysfunction,significantly elevated blood ammonia,decreased blood citrulline,and elevated urine orotic acid and uracil were found by laboratory tests. Different mutations in their OTC gene were identified from these patients. Five mutations,c.118 C>T,c.482 A>G,c.898 del T,c.275 G>A and c.803 T>C,were reported. c.67 C>T,c.416 T>G and c.898 dup T were novel mutations. After hemofiltration and other active symptomatic treatment,4 patients were improved,while the other 4 patients who discontinued treatment died soon. Conclusion OTC deficiency is a severe urea cycle disorder with significant individual differences. The patients are usually lack of specific clinical manifestations. For the patients with vomiting of unknown reasons and disturbance of consciousness,blood ammonia test is the key to the diagnosis. Metabolic studies and genetic studies are important to confirm the diagnosis. Early treatment can improve the prognosis.
引文
[1]江载芳,申昆玲,沈颖,等.诸福棠实用儿科学[M].8版.北京:人民卫生出版社,2015:2276-2280.
[2]Caroline U,Anibn D,Vassili V,et al.Clinical course of 63 patients with neonatal onset urea cycle disorders in the years2001-2013[J].Orphanet J Rare Dis,2016,11(1):116-126.
[3]Gallagher RC,Lam C,Wong D,et al.Significant hepatic involvement in patients with ornithine transcarbamylase deficiency[J].J Pediatr,2014,164(4):720-725.
[4]Bergmann KR,Mc Cabe J,Smith TR,et al.Late-onset ornithine transcarbamylase deficiency:treatment and outcome of hyperammonemic crisis[J].J Pediatr,2014,133(4):1702-1706.
[5]Bijvoet GP,van der Sijs-Bos CJ,Wielders JP,et al.Fatal hyperammonaemia due to late-onset ornithine transcarbamylase deficiency[J].Neth J Med,2016,74(1):36-39.
[6]顾学范.临床遗传代谢病[M].北京:人民卫生出版社,2015:76-78.
[7]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.
[8]Gardeitchik T,Humphrey M,Nation J,et al.Early clinical manifestations and eating patterns in patients with urea cycle disorders[J].J Pediatr,2012,161(2):328-332.
[9]Burgard P,Kolker 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.
[10]Jamiolkowski D,K?lker S,Glahn EM,et al.Behavioural and emotional problems,intellectual impairment and health-related quality of life in patients with organic acidurias and urea cycle disorders[J].J Inherit Metab Dis,2016,39(2):231-241.
[11]Florence C,Thomas D,Leon E.X-chromosome inactivation in human liver:confirmation of X-linkage of ornithine transcarbamylase[J].Am J Hum Genet,1976,28(4):332-338.
[12]Jeanne D,Robert A,Ralph J,et al.X-chromosome inactivation in the liver of female heterozygous OTC-deficiency sparse_furash mice[J].Biochem Med Metab Biol,1991,45:333-343.
[13]Yorifuji T,Muroi J,Uematsu A,et al.X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase(OTC)deficiency[J].Clin Genet,1998,54:349-353.
[14]朱蔚云,谢天炽,李佩琼,等.人类X染色体失活与基因的剂量补偿效应[J].中国优生与遗传杂志,2017,25(11):61-63.
[15]周爽,谢平原,卢光琇,等.女性Duchenne/Becker型肌营养不良症携带者发病机理的研究进展[J].现代生物医学进展,2017,17(25):4986-4989.
[16]周芸,曾祥丽,黄子真,等.以头晕为首发表现的遗传性尿素循环障碍特点分析[J].中国耳鼻咽喉头颈外科杂志,2015,22(5):244-245.
[17]杨艳玲,孙芳,钱宁,等.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.
[18]杨艳玲.血氨检测有助于脑病、肝病的病因诊断[J].中国医刊,2006,41(3):18-21.
[19]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.
[20]Brassier A,Gobin S,Arnoux JB,et al.Long-term outcomes in ornithine transcarbamylase deficiency:a series of 90 patients[J].Orphanet J Rare Dis,2015,10(1):58-71.
[21]Kido J,Ohura T,Matsuo M,et al.Long-term outcome and intervention of urea cycle disorders in Japan[J].J Inherit Metab Dis,2012,35(5):777-785.
[22]Spinale JM,Laskin BL,Sondheimer N,et al.High-dose continuous renal replacement therapy for neonatal hyperammonemia[J].Pediatr Nephrol,2013,28(6):983-986.
[23]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(1):32.
[24]周光鹏,朱志军,孙丽莹,等.活体肝移植治疗鸟氨酸氨甲酰基转移酶缺乏症3例报告及文献复习[J].首都医科大学学报,2017,38(6):824-826.
[25]Yang Y,Wang L,Bell P,et al.A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice[J].Nat Biotechnol,2016,34(3):334-338.
[26]Wang L,Bell P,Morizono H,et al.AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice[J].Mol Genet Metab,2017,120(4):299-305.
[27]黄荷凤.当生殖医学遇上大数据[J].中国实用妇科与产科杂志,2018,34(1):5-9.
[2]Caroline U,Anibn D,Vassili V,et al.Clinical course of 63 patients with neonatal onset urea cycle disorders in the years2001-2013[J].Orphanet J Rare Dis,2016,11(1):116-126.
[3]Gallagher RC,Lam C,Wong D,et al.Significant hepatic involvement in patients with ornithine transcarbamylase deficiency[J].J Pediatr,2014,164(4):720-725.
[4]Bergmann KR,Mc Cabe J,Smith TR,et al.Late-onset ornithine transcarbamylase deficiency:treatment and outcome of hyperammonemic crisis[J].J Pediatr,2014,133(4):1702-1706.
[5]Bijvoet GP,van der Sijs-Bos CJ,Wielders JP,et al.Fatal hyperammonaemia due to late-onset ornithine transcarbamylase deficiency[J].Neth J Med,2016,74(1):36-39.
[6]顾学范.临床遗传代谢病[M].北京:人民卫生出版社,2015:76-78.
[7]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.
[8]Gardeitchik T,Humphrey M,Nation J,et al.Early clinical manifestations and eating patterns in patients with urea cycle disorders[J].J Pediatr,2012,161(2):328-332.
[9]Burgard P,Kolker 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.
[10]Jamiolkowski D,K?lker S,Glahn EM,et al.Behavioural and emotional problems,intellectual impairment and health-related quality of life in patients with organic acidurias and urea cycle disorders[J].J Inherit Metab Dis,2016,39(2):231-241.
[11]Florence C,Thomas D,Leon E.X-chromosome inactivation in human liver:confirmation of X-linkage of ornithine transcarbamylase[J].Am J Hum Genet,1976,28(4):332-338.
[12]Jeanne D,Robert A,Ralph J,et al.X-chromosome inactivation in the liver of female heterozygous OTC-deficiency sparse_furash mice[J].Biochem Med Metab Biol,1991,45:333-343.
[13]Yorifuji T,Muroi J,Uematsu A,et al.X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase(OTC)deficiency[J].Clin Genet,1998,54:349-353.
[14]朱蔚云,谢天炽,李佩琼,等.人类X染色体失活与基因的剂量补偿效应[J].中国优生与遗传杂志,2017,25(11):61-63.
[15]周爽,谢平原,卢光琇,等.女性Duchenne/Becker型肌营养不良症携带者发病机理的研究进展[J].现代生物医学进展,2017,17(25):4986-4989.
[16]周芸,曾祥丽,黄子真,等.以头晕为首发表现的遗传性尿素循环障碍特点分析[J].中国耳鼻咽喉头颈外科杂志,2015,22(5):244-245.
[17]杨艳玲,孙芳,钱宁,等.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.
[18]杨艳玲.血氨检测有助于脑病、肝病的病因诊断[J].中国医刊,2006,41(3):18-21.
[19]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.
[20]Brassier A,Gobin S,Arnoux JB,et al.Long-term outcomes in ornithine transcarbamylase deficiency:a series of 90 patients[J].Orphanet J Rare Dis,2015,10(1):58-71.
[21]Kido J,Ohura T,Matsuo M,et al.Long-term outcome and intervention of urea cycle disorders in Japan[J].J Inherit Metab Dis,2012,35(5):777-785.
[22]Spinale JM,Laskin BL,Sondheimer N,et al.High-dose continuous renal replacement therapy for neonatal hyperammonemia[J].Pediatr Nephrol,2013,28(6):983-986.
[23]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(1):32.
[24]周光鹏,朱志军,孙丽莹,等.活体肝移植治疗鸟氨酸氨甲酰基转移酶缺乏症3例报告及文献复习[J].首都医科大学学报,2017,38(6):824-826.
[25]Yang Y,Wang L,Bell P,et al.A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice[J].Nat Biotechnol,2016,34(3):334-338.
[26]Wang L,Bell P,Morizono H,et al.AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice[J].Mol Genet Metab,2017,120(4):299-305.
[27]黄荷凤.当生殖医学遇上大数据[J].中国实用妇科与产科杂志,2018,34(1):5-9.