成人晚发型丙酸血症分子病理学分析：附一例报告并文献复习

doi:10.3969/j.issn.1672-6731.2021.04.010

摘要/Abstract

摘要：

目的首次报道1例国内PCCB基因突变致成人晚发型丙酸血症患者，总结其临床和分子病理学特点。方法与结果 男性患者，18岁，临床主要表现为急性发病的双侧基底节区对称性损伤导致的代谢性脑病伴不自主运动。干血斑串联质谱（MS/MS）法显示丙酰肉碱（C3）为10.37 μmol/L，丙酰肉碱/乙酰肉碱（C3/C2）比值为0.69；尿液气相色谱-质谱（GC/MS）法显示尿液3-羟基丙酸为18 μmol/L，甲基枸橼酸为12.70 μmol/L。基因检测显示，患者存在PCCB基因外显子10 c.1087T > C（p.Ser363Pro）纯合突变，其父母存在PCCB基因外显子10 c.1087T > C（p.Ser363Pro）杂合突变，符合家系共分离现象，该突变位点符合疑似致病性变异。最终分子病理诊断为晚发型丙酸血症。经限制蛋白饮食、大剂量左卡尼汀、降氨治疗后症状明显改善，复查干血斑（MS/MS法）和尿液（GC/MS法）有机酸测定，丙酸和尿液3-羟基丙酸显著下降。结论 PCCB基因外显子10 c.1087T > C（p.Ser363Pro）为罕见的疑似致病性变异，干血斑（MS/MS法）和尿液（GC/MS法）有机酸检测联合全外显子组测序在晚发型丙酸血症的诊断中具有重要应用价值。

关键词: 丙酸血症, 基因, 突变, 质谱分析法, 病理学, 分子

Abstract:

Objective To report the first case of adult late-onset propionic acidemia (PA) caused by PCCB gene mutation in China, and summary the clinical and molecular pathological characteristics of patients with late-onset propionic acidemia. Methods and Results The clinical manisfestions of an eighteen-year-old male patient were acute onset of symmetrical injury at bilateral basal ganglia which induced metabolic encephalopathy with involuntury movement. Tandem mass spectrometry (MS/MS) test results of dried blood spots indicated that propionyl carnitine (C3) was 10.37 μmol/L, and the ratio of propionyl carnitine to acetyl carnitine (C3/C2) was 0.69. Gas chromatography-mass spectrometry (GC/MS) test results indicated urine 3-hydroxypropionic acid was 18 μmol/L, methyl citrate level was 12.70 μmol/L. The gene results detected a homozygous pathogenic mutation (exon 10: c. 1087T > C, p. Ser363Pro) in the PCCB gene. His parents had a heterozygous mutation in PCCB gene exon 10 c.1087T > C (p.Ser363Pro), which was consistent with the phenomenon of family co-segregation, and the mutation site was consistent with a suspected pathogenic variant. The final molecular pathological diagnosis was late-onset propionic acidemia. Following the protein restriction diet, high-dose L-carnitine injection, and ammonia-lowering treatment, the dried blood spots propionic acid level and the urine 3-hydroxypropionic acid level decreased significantly. Conclusions The mutation exon c.1087T > C (p.Ser363Pro) is a rare and highly suspected pathogenic mutation of PCCB gene. MS/MS and GC/MS detection combined with whole exome sequencing technology is very important in the diagnosis of late-onset propionic acidemia.

Key words: Propionic acidemia, Genes, Mutation, Mass spectrometry, Pathology, molecular

薛秀云, 董亚茹, 王珺, 由凤秋, 狄政莉, 刘志勤. 成人晚发型丙酸血症分子病理学分析：附一例报告并文献复习[J]. 中国现代神经疾病杂志, 2021, 21(4): 289-295.

XUE Xiu-yun, DONG Ya-ru, WANG Jun, YOU Feng-qiu, DI Zheng-li, LIU Zhi-qin. Molecular pathology report of late-onset propionic acidemia in adults: one case report and literature review[J]. Chinese Journal of Contemporary Neurology and Neurosurgery, 2021, 21(4): 289-295.

http://journal11.magtechjournal.com/cjcnn/CN/Y2021/V21/I4/289

参考文献

[1] Huang CS, Sadre-Bazzaz K, Shen Y, Deng B, Zhou ZH, Tong L. Crystal structure of the alpha(6)beta(6) holoenzyme of propionyl-coenzyme A carboxylase[J]. Nature, 2010, 466:1001-1005.
[2] Campeau E, Desviat LR, Leclerc D, Wu X, Pérez B, Ugarte M, Gravel RA. Structure of the PCCA gene and distribution of mutations causing propionic academia[J]. Mol Genet Metab, 2001, 74:238-247.
[3] Childs B, Nyhan WL, Borden M, Bard L, Cooke RE. Idiopathic hyperglycinemia and hyperglycinuria:a new disorder of amino acid metabolism. Ⅰ[J]. Pediatrics, 1961, 27:522-538.
[4] Nyhan WL, Borden M, Childs B. Idiopathic hyperglycinemia:a new disorder of amino acid metabolism. Ⅱ. The concentrations of other amino acids in the plasma and their modification by the administration of leucine[J]. Pediatrics, 1961, 27:539-550.
[5] Hsia YE, Scully KJ, Rosenberg LE. Defective propionate carboxylation in ketotic hyperglycinaemia[J]. Lancet, 1969, 1:757-758.
[6] Gompertz D, Storrs CN, Bau DC, Peters TJ, Hughes EA. Localisation of enzymic defect in propionicacidaemia[J]. Lancet, 1970, 1:1140-1143.
[7] Hsia YE, Scully KJ, Rosenberg LE. Inherited propionyl-Coa carboxylase deficiency in "ketotic hyperglycinemia"[J]. J Clin Invest, 1971, 50:127-130.
[8] Brandt IK, Hsia YE, Clement DH, Provence SA. Propionicacidemia (ketotic hyperglycinemia):dietary treatment resulting in normal growth and development[J]. Pediatrics, 1974, 53:391-395.
[9] Pérez B, Desviat LR, Rodríguez-Pombo P, Clavero S, Navarrete R, Perez-Cerdá C, Ugarte M. Propionic academia:identification of twenty-four novel mutations in Europe and North America[J]. Mol Genet Metab, 2003, 78:59-67.
[10] Haberlandt E, Canestrini C, Brunner-Krainz M, Möslinger D, Mussner K, Plecko B, Scholl-Bürgi S, Sperl W, Rostásy K, Karall D. Epilepsy in patients with propionic academia[J]. Neuropediatrics, 2009, 40:120-125.
[11] Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17:405-424.
[12] Fenton W, Gravel RA, Rosenblatt DS. Disorders of propionate and methylmalonate metabolism[M/OL]//Scriver C, Beaudet AL, Sly WS, Valle D. The Metabolic and Molecular Bases of Inherited Disease. New York:McGraw-Hill, 2001:2165-2194.
[13] Sass JO, Hofmann M, Skladal D, Mayatepek E, Schwahn B, Sperl W. Propionic acidemia revisited:a workshop report[J]. Clin Pediatr (Phila), 2004, 43:837-843.
[14] Lücke T, Pérez-Cerdá C, Baumgartner M, Fowler B, Sander S, Sasse M, Scholl S, Ugarte M, Das AM. Propionic academia:unusual course with late onset and fatal outcome[J]. Metabolism, 2004, 53:809-810.
[15] Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grünert SC, Grünewald S, Honzik T, Merinero B, Pérez-Cerdá C, Scholl-Bürgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A. Proposed guidelines for the diagnosis and management of methylmalonic and propionic academia[J]. Orphanet J Rare Dis, 2014, 9:130.
[16] Coude FX, Sweetman L, Nyhan WL. Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria:a possible explanation for hyperammonemia in propionic and methylmalonic academia[J]. J Clin Invest, 1979, 64:1544-1551.
[17] Filipowicz HR, Ernst SL, Ashurst CL, Pasquali M, Longo N. Metabolic changes associated with hyperammonemia in patients with propionic academia[J]. Mol Genet Metab, 2006, 88:123-130.
[18] Bergman AJ, Van der Knaap MS, Smeitink JA, Duran M, Dorland L, Valk J, Poll-The BT. Magnetic resonance imaging and spectroscopy of the brain in propionic academia:clinical and biochemical considerations[J]. Pediatr Res, 1996, 40:404-409.
[19] Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism[J]. AJNR Am J Neuroradiol, 1994, 15:1459-1473.
[20] North KN, Korson MS, Gopal YR, Rohr FJ, Brazelton TB, Waisbren SE, Warman ML. Neonatal-onset propionic academia:neurologic and developmental profiles, and implications for management[J]. J Pediatr, 1995, 126:916-922.
[21] Chemelli AP, Schocke M, Sperl W, Trieb T, Aichner F, Felber S. Magnetic resonance spectroscopy (MRS) in five patients with treated propionic academia[J]. J Magn Reson Imaging, 2000, 11:596-600.
[22] Haas RH, Marsden DL, Capistrano-Estrada S, Hamilton R, Grafe MR, Wong W, Nyhan WL. Acute basal ganglia infarction in propionic academia[J]. J Child Neurol, 1995, 10:18-22.
[23] Pérez-Cerdá C, Merinero B, Martí M, Cabrera JC, Peña L, García MJ, Gangoiti J, Sanz P, Rodríguez-Pombo P, Hoenicka J, Richard E, Muro S, Ugarte M. An unusual late-onset case of propionic acidaemia:biochemical investigations, neuroradiological findings and mutation analysis[J]. Eur J Pediatr, 1998, 157:50-52.
[24] Johnson JA, Le KL, Palacios E. Propionic academia:case report and review of neurologic sequelae[J]. Pediatr Neurol, 2009, 40:317-320.
[25] Hamilton RL, Haas RH, Nyhan WL, Powell HC, Grafe MR. Neuropathology of propionic academia:a report of two patients with basal ganglia lesions[J]. J Child Neurol, 1995, 10:25-30.
[26] Asconapé J, Challa VR, Angelo JN. Spongy degeneration of the nervous system associated with propionic academia[J]. Acta Neurol Latinoam, 1981, 27:91-98.
[27] Kim SN, Ryu KH, Lee EH, Kim JS, Hahn SH. Molecular analysis of PCCB gene in Korean patients with propionic academia[J]. Mol Genet Metab, 2002, 77:209-216.
[28] Yang X, Sakamoto O, Matsubara Y, Kure S, Suzuki Y, Aoki Y, Yamaguchi S, Takahashi Y, Nishikubo T, Kawaguchi C, Yoshioka A, Kimura T, Hayasaka K, Kohno Y, Iinuma K, Ohura T. Mutation spectrum of the PCCA and PCCB genes in Japanese patients with propionic academia[J]. Mol Genet Metab, 2004, 81:335-342.
[29] Rivera-Barahona A, Navarrete R, García-Rodríguez R, Richard E, Ugarte M, Pérez-Cerda C, Pérez B, Gámez A, Desviat LR. Identification of 34 novel mutations in propionic academia:functional characterization of missense variants and phenotype associations[J]. Mol Genet Metab, 2018, 125:266-275.
[30] Hu YH, Han LS, Ye J, Qiu WJ, Zhang YF, Yang YL, Liu L, Ma HW, Gao XL, Gu XF. Gene mutation analysis in patients with propionic acidemia[J]. Zhonghua Er Ke Za Zhi, 2008, 46:416-420.
[31] Ohura T, Narisawa K, Iinuma K. Mutation analysis of the propionyl-CoA carboxylase alpha-subunit gene in four Japanese patients with propionic acidaemia[J]. J Inherit Metab Dis, 1999, 22:851-852.
[32] Desviat LR, Clavero S, Perez-Cerdá C, Navarrete R, Ugarte M, Perez B. New splicing mutations in propionic academia[J]. J Hum Genet, 2006, 51:992-997.
[33] Gupta D, Bijarnia-Mahay S, Kohli S, Saxena R, Puri RD, Shigematsu Y, Yamaguchi S, Sakamoto O, Gupta N, Kabra M, Thakur S, Deb R, Verma IC. Seventeen novel mutations in PCCA and PCCB genes in Indian propionic acidemia patients, and their outcomes[J]. Genet Test Mol Biomarkers, 2016, 20:373-382.
[34] Wang H, Meng L, Li W, Du J, Tan Y, Gong F, Lu G, Lin G, Zhang Q. Combinations of exonic deletions and rare mutations lead to misdiagnosis of propionic acidemia[J]. Clin Chim Acta, 2020, 502:153-158.
[35] Yang Q, Xu H, Luo J, Li M, Yi S, Zhang Q, Geng G, Feng S, Fan X. Case reports:three novel variants in PCCA and PCCB genes in Chinese patients with propionic academia[J]. BMC Med Genet, 2020, 21:72.
[36] Ohura T, Narisawa K, Tada K. Propionic acidaemia:sequence analysis of mutant mRNAs from Japanese beta subunit-deficient patients[J]. J Inherit Metab Dis, 1993, 16:863-867.
[37] Tahara T, Kraus JP, Ohura T, Rosenberg LE, Fenton WA. Three independent mutations in the same exon of the PCCB gene:differences between Caucasian and Japanese propionic acidaemia[J]. J Inherit Metab Dis, 1993, 16:353-360.
[38] Lee TM, Addonizio LJ, Barshop BA, Chung WK. Unusual presentation of propionic acidaemia as isolated cardiomyopathy[J]. J Inherit Metab Dis, 2009, 32 Suppl 1:97-101.
[39] Yorifuji T, Kawai M, Muroi J, Mamada M, Kurokawa K, Shigematsu Y, Hirano S, Sakura N, Yoshida I, Kuhara T, Endo F, Mitsubuchi H, Nakahata T. Unexpectedly high prevalence of the mild form of propionic acidemia in Japan:presence of a common mutation and possible clinical implications[J]. Hum Genet, 2002, 111:161-165.
[40] Chen ZL, Wen PQ, Wang GB, Hu YH, Liu XH, Chen L, Chen SL, Wan LS, Cui D. Analysis of PCCA and PCCB gene mutations in patients with propionic academia[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2015, 32:26-30.[陈占玲, 温鹏强,王国兵, 胡宇慧, 刘晓红, 陈黎, 陈淑丽, 万力生, 崔冬. 丙酸血症患儿PCCA和PCCB基因突变分析[J]. 中华医学遗传学杂志, 2015, 32:26-30.]
[41] Kasahara M, Sakamoto S, Kanazawa H, Karaki C, Kakiuchi T, Shigeta T, Fukuda A, Kosaki R, Nakazawa A, Ishige M, Nagao M, Shigematsu Y, Yorifuji T, Naiki Y, Horikawa R. Living-donor liver transplantation for propionic academia[J]. Pediatr Transplant, 2012, 16:230-234.

选择文件类型/文献管理软件名称

选择包含的内容

2 成人晚发型丙酸血症分子病理学分析：附一例报告并文献复习

Molecular pathology report of late-onset propionic acidemia in adults: one case report and literature review

RichHTML

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	任修德, 李涛, 范吉康, 王希森, 贾晓丹, 杨学军. 胶质母细胞瘤FGFR3-TACC3融合基因介导丙酮酸激酶M2入核促进DNA损伤修复基础研究[J]. 中国现代神经疾病杂志, 2023, 23(8): 745-757.
[2]	吴旭玲, 张安妮, 雷晓阳, 冯占辉, 王维, 贺电. 强直性肌营养不良症1型一例[J]. 中国现代神经疾病杂志, 2023, 23(8): 765-769.
[3]	马晓丽, 童家杰, 张秀智, 杜倩, 隋爱霞, 赵焕芬. 表现为垂体腺瘤卒中的黄色瘤性垂体炎[J]. 中国现代神经疾病杂志, 2023, 23(7): 599-603.
[4]	李跃文, 褚先舟, 李娟, 秦艳, 吴桐, 陈先文. BSCL2基因c.455A>G突变致远端型遗传性运动神经病V型一家系[J]. 中国现代神经疾病杂志, 2023, 23(7): 643-647.
[5]	杜倩, 邓素君, 邹姗, 金珺, 周青山. 宏基因组第二代测序技术在重症中枢神经系统感染中的应用[J]. 中国现代神经疾病杂志, 2023, 23(6): 479-484.
[6]	崔立立, 纪坤乾, 张正华, 张同霞, 赵玉英. 以排尿困难发病的SOD1基因变异致肌萎缩侧索硬化一例[J]. 中国现代神经疾病杂志, 2023, 23(5): 472-476.
[7]	蔡洪钱, 张安妮, 徐子茜, 龚慧蓝, 曾红梅, 贺电. 伴PSEN2基因V214L突变的早发型阿尔茨海默病一家系临床研究[J]. 中国现代神经疾病杂志, 2023, 23(4): 335-340.
[8]	徐蓉, 宁泽淑, 康庆云, 陈波, 廖红梅, 杨理明, 吴丽文. 钾离子通道基因变异相关婴儿癫痫性脑病临床表型与基因变异特点分析[J]. 中国现代神经疾病杂志, 2023, 23(3): 196-204.
[9]	唐薇婷, 肖波. N-甲基-D-天冬氨酸受体GRIN2A基因变异与癫痫研究进展[J]. 中国现代神经疾病杂志, 2023, 23(2): 89-93.
[10]	李字林, 胡文瀚, 张凯. 癫痫外科常见病理类型体细胞突变研究进展[J]. 中国现代神经疾病杂志, 2023, 23(2): 115-123.
[11]	王圆圆, 王鲁宁, 朱明伟. 病理性TDP-43蛋白在常见神经系统变性疾病患者杏仁核中的表达变化[J]. 中国现代神经疾病杂志, 2022, 22(9): 787-794.
[12]	姚盈盈, 王雷明, 滕梁红. 脑胶质瘤DNA甲基化临床意义及研究进展[J]. 中国现代神经疾病杂志, 2022, 22(9): 823-828.
[13]	菅凤增, 王兴文. 分子病理诊断时代脊柱脊髓肿瘤的诊断与治疗[J]. 中国现代神经疾病杂志, 2022, 22(8): 651-654.
[14]	姚庆宇, 马龙冰, 菅凤增. 脊髓空洞症大鼠模型长期稳定性评价[J]. 中国现代神经疾病杂志, 2022, 22(8): 662-668.
[15]	夏钰, 沙倩倩, 朱雯华, 乔凯, 都爱莲. SCN4A基因R672G位点突变致低钾性周期性瘫痪伴肌萎缩一家系分析并文献复习[J]. 中国现代神经疾病杂志, 2022, 22(8): 717-722.

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

2 成人晚发型丙酸血症分子病理学分析：附一例报告并文献复习

Molecular pathology report of late-onset propionic acidemia in adults: one case report and literature review

RichHTML

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价