精氨酸血症的临床与分子遗传学研究进展

吴桐菲; 杨艳玲

doi:10.7499/j.issn.1008-8830.2013.11.007

PDF(1309 KB)

中国当代儿科杂志 ›› 2013, Vol. 15 ›› Issue (11) : 954-959. DOI: 10.7499/j.issn.1008-8830.2013.11.007

遗传性疾病专题

精氨酸血症的临床与分子遗传学研究进展

吴桐菲，杨艳玲

作者信息 +

Advances in clinical and molecular genetics studies on argininemia

WU Tong-Fei, YANG Yan-Ling

Author information +

文章历史 +

摘要

精氨酸血症是一种罕见的尿素循环障碍性疾病，属常染色体隐性遗传，由于ARG1基因缺陷导致肝脏精氨酸酶缺乏，精氨酸降解障碍，鸟氨酸与尿素生成减少。本文就近年来精氨酸血症的临床表现、诊断、治疗、产前诊断与遗传学研究进展进行了综述。精氨酸血症患者临床表现复杂，缺乏特异性，诊断困难，常表现为痉挛性瘫痪、癫癎及小脑萎缩，早期常常被误诊为脑性瘫痪，生存质量极差，预后不良。血液氨基酸分析、精氨酸酶活性测定及基因分析是确诊精氨酸血症的重要方法。随着液相串联质谱技术在新生儿筛查和高危筛查中的应用，越来越多的精氨酸血症患者在无症状期或疾病早期获得诊断，通过低蛋白饮食、瓜氨酸与苯甲酸等药物治疗可改善预后。

Abstract

Argininemia is a rare, autosomal recessive, metabolic disorder caused by an hereditary deficiency of hepatocytes arginase due to ARG1 gene defect. Arginase is the final enzyme in the urea cycle, catalyzing the hydrolysis of arginine to ornithine and urea. Research advances in the clinical manifestations, diagnosis, treatment, prenatal diagnosis and genetics of argininemia were reviewed in this paper. The clinical manifestations of patients with argininemia are complicated and nonspecific so that clinical diagnosis is usually difficult and delayed. Progressive spastic tetraplegia, seizures and cerebella atrophy are common clinical features of the disease. Blood amino acids analysis, arginase assay and ARG1 gene analysis are important to the diagnosis of argininemia. Early diagnosis and a protein-restricted diet with citrulline and benzoate supplements can contribute a lot to improve patient prognosis. With the application of liquid chromatography-tandem mass spectrometry in selective screening and newborn screening for inborn errors of metabolism, an ever-increasing number of patients with argininemia are detected at the asymptomatic or early stages.

Key words

Arginiemia / Arginase / ARG1 gene / Spastic tetraplegia

引用本文

EndNote

Ris (Procite)

Bibtex

导出引用

吴桐菲，杨艳玲. 精氨酸血症的临床与分子遗传学研究进展[J]. 中国当代儿科杂志. 2013, 15(11): 954-959 https://doi.org/10.7499/j.issn.1008-8830.2013.11.007

WU Tong-Fei, YANG Yan-Ling. Advances in clinical and molecular genetics studies on argininemia[J]. Chinese Journal of Contemporary Pediatrics. 2013, 15(11): 954-959 https://doi.org/10.7499/j.issn.1008-8830.2013.11.007

参考文献

[1] Terheggen HG, Lowenthal A, Lavinha F, Colombo JP. Familial hyperargininaemia[J]. Arch Dis Child, 1975, 50(1): 57-62.

[2] Cederbaum SD, Yu H, Grody WW, Kern RM, Yoo P, Iyer RK. Arginases I and II: do their functions overlap?[J]. Mol Genet Metab, 2004, 81(Suppl 1): S38-S44.

[3] Lee BH, Jin HY, Kim GH, Choi JH, Yoo HW. Argininemia presenting with progressive spastic diplegia[J]. Pediatr Neurol, 2011, 44(3): 218-220.

[4] Seminara J, Tuchman M, Krivitzky L, Krischer J, Lee HS, Lemons C. Establishing a Consortium for the Study of Rare Diseases: The Urea Cycle Disorders Consortium[J]. Mol Genet Metab, 2010, 100(Suppl 1): S97-105.

[5] Deignan JL, Cederbaum SD, Grody WW. Contrasting features of urea cycle disorders in human patients and knockout mouse models[J]. Mol Genet Metab, 2008, 93(1): 7-14.

[6] Nagata N, Matsuda I, Oyanagi K. Estimated frequency of urea cycle enzymopathies in Japan[J]. Am J Med Genet, 1991, 39(2): 228-229.

[7] Burke W, Tarini B, Press NA, Evans JP. Genetic screening[J]. Epidemiol Rev, 2011, 33(1): 148-164.

[8] Segawa Y, Matsufuji M, Itokazu N, Utsunomiya H, Watanabe Y, Yoshino M, et al. Long-term survival case of arginase deficiency with severe multicystic white matter and compound mutations[J]. Brain Dev, 2011, 33(1): 45-48.

[9] Hertecant JL, Al-Gazali LI, Karuvantevida NS, Ali BR. A novel mutation in ARG1 gene is responsible for arginase deficiency in an Asian family[J]. Saudi Med J, 2009, 30(12): 1601-1603.

[10]    顾学范, 韩连书, 高晓岚, 杨艳玲, 叶军, 邱文娟. 串联质谱技术在遗传性代谢病高危儿童筛查中的初步应用[J]. 中华儿科杂志, 2004, 42 (6): 401-404..

[11] Zytkovicz TH, Fitzgerald EF, Marsden D, Larson CA, Shih VE, Johnson DM, et al. Tandem mass spectrometric analysis for amino, organic, and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program[J] . Clin Chem, 2001, 47(11): 1945-1955.

[12] Marsden D. Expanded newborn screening by tandem mass spectrometry: the Massachusetts and New England experience[J]. Southeast Asian J Trop Med Public Health, 2003, 34(Suppl 3): 111-114.

[13] 娄燕, 尹娜, 陈凤琴, 程亚颖, 徐丽瑾, 戴方, 等. 串联质谱技术选择性筛查遗传代谢病高危患儿552例初步分析[J]. 中国当代儿科杂志, 2011, 13(4): 296-299.

[14] 韩连书, 叶军, 邱文娟, 高晓岚, 王瑜, 金晶, 等. 串联质谱联合气相色谱-质谱检测遗传性代谢病[J]. 中华医学杂志，2008, 88(30): 2122-2126.

[15] 杨艳玲, 孙芳, 钱宁, 宋金青, 王爽, 常杏芝, 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.

[16] Carvalho DR, Brum JM, Speck-Martins CE, Ventura FD, Navarro MM, Coelho KE, et al. Clinical features and neurologic progression of hyperargininemia[J]. Pediatr Neurol, 2012, 46(6): 369-374.

[17] Scholl-Burgi S, Baumgartner Sigl S, Haberle J, Haberlandt E, Rostásy K, Ertl C, et al. Amino acids in CSF and plasma in hyperammonaemic coma due to arginase1 deficiency [J]. J Inherit Metab Dis, 2008, 31(Suppl 2): S323-328.

[18] 罗小平, 王慕逖. 遗传性代谢病的治疗[J]. 中华儿科杂志, 2003, 41 (4): 264-268.

[19] Cohen YH, Bargal R, Zeigler M, Markus-Eidlitz T, Zuri V, Zeharia A. Hyperargininemia: a family with a novel mutation in an unexpected site[J]. JIMD Rep, 2012, 5: 83-88.

[20] Gomes Martins E, Santos Silva E, Vilarinho S, Saudubray JM, Vilarinho L. Neonatal cholestasis: an uncommon presentation of hyperargininemia [J]. J Inhert Metab Dis, 2010, 33(Suppl 3): S503-S506.

[21] Scaglia F, Lee B. Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency [J]. Am J Med Genet Part C, 2006, 142C (2): 113-120.

[22] Hewson S, Clarke JT, Cederbaum S. Prenatal diagnosis for arginase deficiency: a case study [J]. J Inherit Metab Dis, 2003, 26(6): 607-610.

[23] Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A. Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported?[J]. Mol Genet Metab, 2011, 104(1-2): 107-111.

[24] Oldham MS, VanMeter JW, Shattuck KF, Cederbaum SD, Gropman AL. Diffusion tensor imaging in arginase deficiency reveals damage to corticospinal tracts[J]. Pediatr Neurol, 2010, 42(1): 49-52.

[25] Deignan JL, De Deyn PP, Cederbaum SD, Fuchshuber A, Roth B, Gsell W, et al. Guanidino compound levels in blood, cerebrospinal fluid, and post-mortem brain material of patients with argininemia[J]. Mol Genet Metab, 2010, 100(Suppl 1): S31-36.

[26] Gungor S, Akinci A, Firat AK, Tabel Y, Alkan A. Neuroimaging findings in hyperargininemia[J]. J Neuroimaging, 2008, 18(4): 457-462.

[27] Jay A, Seeterlin M, Stanley E, Grier R. Case report of argininemia: the utility of the arginine/ornithine ratio for newborn screening (NBS)[J]. JIMD Rep, 2013, 9: 121-124.

[28] Kuhara T, Inoue Y, Ohse M, Krasnikov BF, Cooper AJ. Urinary 2-hydroxy-5-oxoproline, the lactam form of α-ketoglutaramate, is markedly increased in urea cycle disorders[J]. Anal Bioanal Chem, 2011, 400(7): 1843-1851.

[29] Kanda H, Sumi D, Endo A, Toyama T, Chen CL, Kikushima M, et al. Reduction of arginase I activity and manganese levels in the liver during exposure of rats to methylmercury: a possible mechanism[J]. Arch Toxicol, 2008, 82(11): 803-808.

[30] 陈红, 王德芬, 李立群. 高精氨酸血症的酶学诊断 [J]. 上海医学检验杂志, 1989, 4 (4): 215-216.

[31] Korman SH, Gutman A, Stemmer E, Kay BS, Ben-Neriah Z, Zeigler M. Prenatal diagnosis for arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysis[J]. Prenat Diagn, 2004, 24(11): 857-860.

[32] 包美珍. 尿素循环障碍疾病 [J]. 国外医学内分泌学分册，2002, 22 (5): 276-279.

[33]   Carvalho DR, Brand GD, Brum JM, Takata RI, Speck-Martins CE, Pratesi R. Analysis of novel ARG1 mutations causing hyperargininemia and correlation with arginase I activity in erythrocytes[J].Gene, 2012, 509(1): 124-130.

[34] Vockley JG, Goodman BK, Tabor DE, Kern RM, Jenkinson CP, Grody WW, et al. Loss of function mutations in conserved regions of the human arginase I gene [J]. Biochem Mol Med, 1996, 59(1): 44-51.

[35] Haraguchi Y, Aparicio JM, Takiguchi M, Akaboshi I, Yoshino M, Mori M, et al. Molecular basis of argininemia. Identification of two discrete frame-shift deletions in the liver-type arginase gene[J]. J Clin Invest, 1990, 86(1): 347-350.

[36] Grody WW, Klein D, Dodson A E, Kern RM, Wissmann PB, Goodman BK, et al. Molecular genetic study of human arginase deficiency[J]. Am J Hum Genet, 1992, 50(6): 1281-1290.

[37] Uchino T, Haraguchi Y, Aparicio JM, Mizutani N, Higashikawa M, Naitoh H, et al. Three novel mutations in the liver-type arginase gene in three unrelated Japanese patients with argininemia[J]. Am J Hum Genet, 1992, 51(6): 1406-1412.

[38] Haberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects[J]. Prenat Diagn, 2004, 24(5): 378-383.

[39] Uchino T, Snyderman SE, Lambert M, Qureshi IA, Shapira SK, Sansaricq C, et al. Molecular basis of phenotypic variation in patients with argininemia[J]. Hum Genet, 1995, 96(3): 255-260.

[40] Cardoso ML, Martins E, Vasconcelos R, Vilarinho L, Rocha J. Identification of a novel R21X mutation in the liver-type arginase gene (ARG1) in four Portuguese patients with argininemia[J]. Hum Mutat, 1999, 14(4): 355-356.

[41] Vockley JG, Tabor DE, Kern RM, Goodman BK, Wissmann PB, Kang DS, et al. Identification of mutations (D128G, H141L) in the liver arginase gene of patients with hyperargininemia [J]. Hum Mutat, 1994, 4(2): 150-154.

[42]    Edwards RL, Moseley K, Watanabe Y, Wong LJ, Ottina J, Yano S. Long-term neurodevelopmental effects of early detection and treatment in a 6-year-old patient with argininaemia diagnosed by newborn screening[J]. J Inherit Metab Dis, 2009, 32(Suppl 1): S197-200.

[43]    Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, et al. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases[J]. Hum Mutat, 2009, 30(1): 56-60.

[44]    杨艳玲. 遗传代谢病的饮食与药物治疗[J]. 中国儿童保健杂志, 2011, 19(2): 102-103.

[45] Boles RG, Stone ML. A patient with arginase deficiency and episodic hyperammonemia successfully treated with menses cessation[J]. Mol Genet Metab, 2006, 89(4): 390-391.

[46] Romero PA, Stone E, Lamb C, Chantranupong L, Krause A, Miklos A, et al. SCHEMA designed variants of human arginase I & II reveal sequence elements important to stability and catalysis[J]. ACS Synth Biol, 2012, 1(6): 221-228.

[47] Glazer ES, Piccirillo M, Albino V, Di Giacomo R, Palaia R, Mastro AA, et al. Phase II study of pegylated arginine eiminase for nonresectable and metastatic hepatocellular carcinoma[J]. J Clin Oncol, 2010, 28 (13): 2220-2226.

[48] McKay TR, Rahim AA, Buckley SM, Ward NJ, Chan JK, Howe SJ, et al. Perinatal gene transfer to the liver[J]. Curr Pharm Des, 2011, 17(24): 2528-2541.

[49] Meyburg J, Das AM, Hoerster F, Lindner M, Kriegbaum H, Engelmann G, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects [J]. Transplantation, 2009, 87(5): 636-641.

[50] Hughes RD, Mitry RR, Dhawan A. Hepatocyte transplantation for metabolic liver disease: UK experience [J]. J R Soc Med, 2005, 98(8): 341-345.

[51] Pietrosi G, Vizzini GB, Gruttadauria S, Gridelli B. Clinical applications of hepatocyte transplantation [J]. World J Gastroenterol, 2009, 15 (17): 2074-2077.

[52] Meyburg J, Hoffmann GF. Liver, liver cell and stem cell transplantation for the treatment of urea cycle defects [J]. Mol Genet Metab, 2010, 100(Suppl 1): S77-S83.

[53] 唐湘凤, 栾佐. 造血干细胞移植治疗黏多糖病研究进展[J]. 实用儿科临床杂志, 2011, 26 (3): 162-165.

[54] Greenberg AJ, McCormick J, Tapia CJ, Windebank AJ. Translating gene transfer: a stalled effort [J]. Clin Transl Sci, 2011, 4(4): 279-281.

[55] Gau CL, Rosenblatt RA, Cerullo V, Lay FD, Dow AC, Livesay J, et al. Short-term correction of arginase deficiency in a neonatal murine model with a helper-dependent adenoviral vector [J]. Mol Ther, 2009, 17(7): 1155-1163.

[56] 孙振晓, 于相芬. 丙戊酸钠导致高氨血症及脑病的研究进展 [J]. 中华临床医师杂志(电子版), 2012, 6 (8): 2163-2164.

[57] 杨艳玲. 北京市可治疗性遗传性疾病的诊疗现状 [J]. 药品评价, 2011, 8(4): 4-8.