以急性脑干脑炎及脊髓炎起病的单纯型甲基丙二酸尿症1例
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摘要
MUT基因突变引起的甲基丙二酰辅酶A变位酶缺陷是我国单纯型甲基丙二酸尿症的主要病因。该文报道我国首例以急性脑干脑炎和脊髓炎样形式起病的MUT型患者,探讨甲基丙二酸尿症的复杂临床表型。患儿,女,3岁2个月时因发热伴肢体进行性无力3 d,呼吸困难伴意识障碍1 d就诊。头颅MRI扫描提示双侧苍白球及脑干背侧对称片状高信号,脊髓MRI扫描提示急性脊髓炎样改变。临床诊断为"病毒性脑炎、中枢型呼吸衰竭?",血液丙酰肉碱(6.83μmol/L,参考值1.0~5.0μmol/L)增高,尿甲基丙二酸(133.2 mmol/mol肌酐,参考值0.2~3.6 mmol/mol肌酐)显著增高,血清总同型半胱氨酸正常。MUT基因存在c.1663C>T和c.1630_1631GG>TA突变,其中c.1663C>T(p.A555T)为新突变,确诊为MUT型甲基丙二酸尿症。经特殊饮食、维生素B12、左卡尼汀治疗后,患儿病情逐渐好转。甲基丙二酸尿症临床表现复杂,早期的代谢筛查及基因诊断是鉴别病型、指导治疗的关键技术。
Methylmalonyl Co A mutase deficiency due to MUT gene defect has been known as the main cause of isolated methylmalonic acidemia in Mainland China. This study reported a patient with isolated methylmalonic aciduria(MUT type) characterized as acute brainstem encephalitis and myelitis. The previously healthy girl presented with fever, lethargy and progressive weakness in her extremities at the age of 3 years and 2 months. Three day later, she had respiratory distress and consciousness. Cranial MRI revealed bilateral symmetrical lesion of pallidum, brain stem and spinal cord, indicating acute brainstem encephalitis and myelitis. Her blood propionylcarnitine(6.83 μmol/L vs normal range 1.0 to 5.0 μmol/L) and urinary methylmalonic acid(133.22 mmol/mol creatinine vs normal range 0.2 to 3.6 mmol/mol creatinine) increased significantly. Plasma total homocysteine was normal. On her MUT gene, a reported mutation(c.1630_1631GG>TA) and a novel mutation(c.1663C>T, p.A555T) were identified, which confirmed the diagnosis of methylmalonic aciduria(MUT type). After cobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine, progressive improvement has been observed. The clinical manifestation of patients with methylmalonic aciduria is complex. Metabolic study and gene analysis are keys for the diagnosis and treatment of the disorder.
Methylmalonyl Co A mutase deficiency due to MUT gene defect has been known as the main cause of isolated methylmalonic acidemia in Mainland China. This study reported a patient with isolated methylmalonic aciduria(MUT type) characterized as acute brainstem encephalitis and myelitis. The previously healthy girl presented with fever, lethargy and progressive weakness in her extremities at the age of 3 years and 2 months. Three day later, she had respiratory distress and consciousness. Cranial MRI revealed bilateral symmetrical lesion of pallidum, brain stem and spinal cord, indicating acute brainstem encephalitis and myelitis. Her blood propionylcarnitine(6.83 μmol/L vs normal range 1.0 to 5.0 μmol/L) and urinary methylmalonic acid(133.22 mmol/mol creatinine vs normal range 0.2 to 3.6 mmol/mol creatinine) increased significantly. Plasma total homocysteine was normal. On her MUT gene, a reported mutation(c.1630_1631GG>TA) and a novel mutation(c.1663C>T, p.A555T) were identified, which confirmed the diagnosis of methylmalonic aciduria(MUT type). After cobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine, progressive improvement has been observed. The clinical manifestation of patients with methylmalonic aciduria is complex. Metabolic study and gene analysis are keys for the diagnosis and treatment of the disorder.
引文
[1]刘玉鹏,马艳艳,吴桐菲,等.早发型甲基丙二酸尿症160例新生儿期异常表现[J].中华儿科杂志,2012,50(6):410-414.
[2]Yang Y,Sun F,Song J,et al.Clinical and biochemical studies on Chinese patients with methylmalonic aciduria[J].J Child Neurol,2006,21(12):1020-1024.
[3]Lerner-Ellis JP,Tirone JC,Pawelek PD,et al.Identification of the gene responsible for methylmalonic aciduria and homocystinuria,cbl C type[J].Nat Genet,2005,38(1):93-100.
[4]Lerner-Ellis JP,Dobson CM,Wai T,et al.Mutations in the MMAA gene in patients with the cbl A disorder of vitamin B12metabolism[J].Hum Mutat,2004,24(6):509-516.
[5]Liu MY,Liu TT,Yang YL,et al.Mutation profile of the MUT gene in chinese methylmalonic aciduria patient[J].JIMD Rep,2012,6:55-64.
[6]刘玉鹏,王海军,吴桐菲,等.甲基丙二酸尿症cbl B型1例及其MMAB基因新突变[J].中国当代儿科杂志,2015,17(2):172-175.
[7]Merinero B,Pérez B,Pérez-CerdáC,et al.Methylmalonic acidaemia:examination of genotype and biochemical data in 32patients belonging to mut,cbl A or cbl B complementation group[J].J Inherit Metab Dis,2008,31(1):55-66.
[8]Worgan LC,Niles K,Tirone JC,et al.Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype[J].Hum Mutat,2006,27(1):31-43.
[9]Yi Q,Lv J,Tian F,et al.Clinical characteristics and gene mutation analysis of methylmalonic aciduria[J].J Huazhong Univ Sci Technol Med Sci,2011,31(3):384-389.
[10]罗小平,王慕逖,魏虹,等.尿滤纸片法气相色谱—质谱分析技术在遗传性代谢病高危筛查诊断中的应用[J].中华儿科杂志,2003,41(4):245-248.
[11]杨艳玲,宋金青,孙芳,等.气相色谱-质谱联用分析在有机酸尿症筛查与诊断中的应用[J].中国医刊,2006,41(2):38-40.
[12]顾学范,韩连书,高晓岚,等.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.
[13]Sujan S,张尧,杨艳玲,等.血浆总同型半胱氨酸测定在智力低下等神经精神异常病因调查中的应用[J].临床儿科杂志,2008,26(12):1013-1014.
[14]王斐,韩连书.甲基丙二酸血症诊治研究进展[J].临床儿科杂志,2008,26(8):724-727.
[15]韩连书,毋盛楠,叶军,等.单纯型甲基丙二酸血症患者诊治分析[J].中华医学遗传学杂,2013,30(5):589-593.
[16]Fowler B,Leonard JV,Baumgartner MR,et al.Causes of and diagnostic approach to methylmalonic acidurias[J].J Inherit Metab Dis,2008,31(3):350-360.
[17]Vatanavicharn N,Champattanachai V,Liammongkolkul S,et al.Clinical and molecular findings in Thai patients with isolated methylmalonic acidemia[J].Mol Genet Metab,2012,106(4):424-429.
[18]H?rster F,Baumgartner MR,Viardot C,et al.Long-term outcome in methylmalonic acidurias is influenced by the underlying defect(mut0,mut-,cbl A,cbl B)[J].Pediatr Res,2007,62(2):225-230.
[19]Dündar H,?zgül RK,Güzel-Ozantürk A,et al.Microarray based mutational analysis of patients with methylmalonic acidemia:identification of 10 novel mutations[J].Mol Genet Metab,2012,106(4):419-423.
[20]徐三清,刘艳,方峰,等.儿童基底节对称性病变28例临床分析[J].中国小儿急救医学,2009,16(6):553-555.
[21]侯新琳,钱宁,杨艳玲.甲基丙二酸尿症研究进展[J].中国当代儿科杂志,2005,7(2):183-185.
[22]Sakamoto O,Ohura T,Matsubara Y,et al.Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia[J].J Hum Genet,2006,52(1):48-55.
[23]刘玉鹏,吴桐菲,王海军,等.因预防接种诱发急性脑病的甲基丙二酸尿症cbl A型一例[J].中华儿科杂志,2015,1(53):62-65.
[2]Yang Y,Sun F,Song J,et al.Clinical and biochemical studies on Chinese patients with methylmalonic aciduria[J].J Child Neurol,2006,21(12):1020-1024.
[3]Lerner-Ellis JP,Tirone JC,Pawelek PD,et al.Identification of the gene responsible for methylmalonic aciduria and homocystinuria,cbl C type[J].Nat Genet,2005,38(1):93-100.
[4]Lerner-Ellis JP,Dobson CM,Wai T,et al.Mutations in the MMAA gene in patients with the cbl A disorder of vitamin B12metabolism[J].Hum Mutat,2004,24(6):509-516.
[5]Liu MY,Liu TT,Yang YL,et al.Mutation profile of the MUT gene in chinese methylmalonic aciduria patient[J].JIMD Rep,2012,6:55-64.
[6]刘玉鹏,王海军,吴桐菲,等.甲基丙二酸尿症cbl B型1例及其MMAB基因新突变[J].中国当代儿科杂志,2015,17(2):172-175.
[7]Merinero B,Pérez B,Pérez-CerdáC,et al.Methylmalonic acidaemia:examination of genotype and biochemical data in 32patients belonging to mut,cbl A or cbl B complementation group[J].J Inherit Metab Dis,2008,31(1):55-66.
[8]Worgan LC,Niles K,Tirone JC,et al.Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype[J].Hum Mutat,2006,27(1):31-43.
[9]Yi Q,Lv J,Tian F,et al.Clinical characteristics and gene mutation analysis of methylmalonic aciduria[J].J Huazhong Univ Sci Technol Med Sci,2011,31(3):384-389.
[10]罗小平,王慕逖,魏虹,等.尿滤纸片法气相色谱—质谱分析技术在遗传性代谢病高危筛查诊断中的应用[J].中华儿科杂志,2003,41(4):245-248.
[11]杨艳玲,宋金青,孙芳,等.气相色谱-质谱联用分析在有机酸尿症筛查与诊断中的应用[J].中国医刊,2006,41(2):38-40.
[12]顾学范,韩连书,高晓岚,等.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.
[13]Sujan S,张尧,杨艳玲,等.血浆总同型半胱氨酸测定在智力低下等神经精神异常病因调查中的应用[J].临床儿科杂志,2008,26(12):1013-1014.
[14]王斐,韩连书.甲基丙二酸血症诊治研究进展[J].临床儿科杂志,2008,26(8):724-727.
[15]韩连书,毋盛楠,叶军,等.单纯型甲基丙二酸血症患者诊治分析[J].中华医学遗传学杂,2013,30(5):589-593.
[16]Fowler B,Leonard JV,Baumgartner MR,et al.Causes of and diagnostic approach to methylmalonic acidurias[J].J Inherit Metab Dis,2008,31(3):350-360.
[17]Vatanavicharn N,Champattanachai V,Liammongkolkul S,et al.Clinical and molecular findings in Thai patients with isolated methylmalonic acidemia[J].Mol Genet Metab,2012,106(4):424-429.
[18]H?rster F,Baumgartner MR,Viardot C,et al.Long-term outcome in methylmalonic acidurias is influenced by the underlying defect(mut0,mut-,cbl A,cbl B)[J].Pediatr Res,2007,62(2):225-230.
[19]Dündar H,?zgül RK,Güzel-Ozantürk A,et al.Microarray based mutational analysis of patients with methylmalonic acidemia:identification of 10 novel mutations[J].Mol Genet Metab,2012,106(4):419-423.
[20]徐三清,刘艳,方峰,等.儿童基底节对称性病变28例临床分析[J].中国小儿急救医学,2009,16(6):553-555.
[21]侯新琳,钱宁,杨艳玲.甲基丙二酸尿症研究进展[J].中国当代儿科杂志,2005,7(2):183-185.
[22]Sakamoto O,Ohura T,Matsubara Y,et al.Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia[J].J Hum Genet,2006,52(1):48-55.
[23]刘玉鹏,吴桐菲,王海军,等.因预防接种诱发急性脑病的甲基丙二酸尿症cbl A型一例[J].中华儿科杂志,2015,1(53):62-65.