甲基丙二酸尿症合并亚甲基四氢叶酸还原酶缺陷1例报道并文献复习
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摘要
目的报道1例疑诊急性播散性脑脊髓炎(ADEM)的晚发型甲基丙二酸尿症合并亚甲基四氢叶酸还原酶(MTHFR)缺陷的临床特点及诊疗过程。方法就患者的临床、实验室资料进行分析。结果患儿,男,12岁半时感冒后出现体倦乏力、精神差、记忆力差、学习成绩下降、双下肢无力、行走困难;发病1个月后头颅及全脊髓MRI提示大脑皮质、左侧侧脑室后部、T_(8～9)水平脊髓内异常信号。脑脊液常规、生化、病原学及免疫性脑炎相关抗体检测均未见异常,临床诊断为急性播散性脑脊髓炎,治疗后好转。13岁半时无诱因症状加重,行走困难,双下肢无力,复查头颅MRI提示轻度脑萎缩;间断康复治疗,效果不明显,下肢肌张力进行性增高。检测尿甲基丙二酸29.63 mmol/mol肌酐(参考值0.2～3.6 mmol/mol肌酐)、3-羟基丙酸6.68 mmol/mol肌酐(参考值0.0～1.1 mmol/mol肌酐),血液游离肉碱16.17μmol/L(参考值20.0～60.0μmol/L),丙酰肉碱2.35μmol/L(参考值1.00～5.00μmol/L),血清同型半胱氨酸水平明显增高49μmon/L(参考值0.0～15.0μmol/L),MMACHA基因存在C.482G>A和c.626dupT两处杂合突变,MTHFR基因存在c.665C>T一处纯合突变。最终确诊为晚发型甲基丙二酸尿症合并高同型半胱氨酸血症,亚甲基四氢叶酸还原酶缺陷。经羟钴铵肌内注射、左卡尼汀、甜菜碱、叶酸口服,配合康复治疗半年后明显好转。结论报道我国首例以ADEM起病的MMA患者,同时该患儿共患甲基丙二酸血症合并高同型半胱氨酸血症与MTHFR缺陷两种遗传代谢病,对于临床症状不典型的神经系统疾病,代谢筛查是非常必要的。
Objective To report the clinical features and the process of diagnosis and treatment of late-onset methylmalonic aciduria complicated with methylenetetrahydrofolate reductase(MTHFR) deficiency in one case, which was suspected to be acute disseminated encephalomyelitis(ADEM).Methods The clinical and laboratory data of the patient was analyzed.Results The patient was a boy. When he was 12, he caught a cold, after which he had tiredness, poor spirit and memory, reduced school performance, weakness in lower limbs and memory, reduced school performance, weakness in lower limbs and difficulty in walking. One month later, he received an MRI of head and the whole spinal cord, which showed there was abnormal signal in cerebral cortex, posterior part of left paracele and T_(8-9) level spinal cord. Routine test of cerebrospinal fluid(CSF), biochemical and etiological test, and antibody detection related to immune encephalitis revealed nothing abnormal, and it was clinically diagnosed as ADEM, which was improved after treatment. When he was 13.5 years old, the symptoms aggravated without any cause. The body had difficulty in walking and felt weak in lower limbs. Reexamination by head MRI indicated slight encephalatrophy. The effect of intermittent treatment was not significant, and the muscular tension of lower limbs was increasing progressively. The detection results were as follows: urinary methylmalonic acid 29.63 mmol/mol creatinine(reference value 0.2-3.6 mmol/mol creatinine), 3-hydroxypropionic acid 6.68 mmol/mol creatinine(reference value 0.0-1.1 mmol/mol creatinine), serum free carnitine 16.17 μmol/L(reference value 20.0-60.0 μmol/L), propionyl carnitine 2.35 μmol/L(reference value 1.00-5.00 μmol/L); the level of serum homocysteine increased significantly(49 μmol/L)(reference value 0.0-15.0 μmol/L); there was heterozygous mutation of C.482 G> A and c.626 dupT in MMACHA gene, and heterozygous mutation of c. 665 C > T in MTHFR gene. Finally, the boy was diagnosed with late-onset methylmalonic aciduria complicated with hyperhomocysteinemia and MTHFR deficiency. He was treated by intramuscular injection of hydroxycobalamin and taking levocarnitine, betaine and folic acid orally, as well as rehabilitation treatment, and got significantly improved after six months.Conclusion It is the first MMA case with the onset of ADEM, which is complicated with methylmalonic aciduria combined with two inheritary metabolic diseases: hyperhomocysteinemia and MTHFR. Metabolic screening is really necessary for the neuvous system diseases with atypical clinical symptoms.
Objective To report the clinical features and the process of diagnosis and treatment of late-onset methylmalonic aciduria complicated with methylenetetrahydrofolate reductase(MTHFR) deficiency in one case, which was suspected to be acute disseminated encephalomyelitis(ADEM).Methods The clinical and laboratory data of the patient was analyzed.Results The patient was a boy. When he was 12, he caught a cold, after which he had tiredness, poor spirit and memory, reduced school performance, weakness in lower limbs and memory, reduced school performance, weakness in lower limbs and difficulty in walking. One month later, he received an MRI of head and the whole spinal cord, which showed there was abnormal signal in cerebral cortex, posterior part of left paracele and T_(8-9) level spinal cord. Routine test of cerebrospinal fluid(CSF), biochemical and etiological test, and antibody detection related to immune encephalitis revealed nothing abnormal, and it was clinically diagnosed as ADEM, which was improved after treatment. When he was 13.5 years old, the symptoms aggravated without any cause. The body had difficulty in walking and felt weak in lower limbs. Reexamination by head MRI indicated slight encephalatrophy. The effect of intermittent treatment was not significant, and the muscular tension of lower limbs was increasing progressively. The detection results were as follows: urinary methylmalonic acid 29.63 mmol/mol creatinine(reference value 0.2-3.6 mmol/mol creatinine), 3-hydroxypropionic acid 6.68 mmol/mol creatinine(reference value 0.0-1.1 mmol/mol creatinine), serum free carnitine 16.17 μmol/L(reference value 20.0-60.0 μmol/L), propionyl carnitine 2.35 μmol/L(reference value 1.00-5.00 μmol/L); the level of serum homocysteine increased significantly(49 μmol/L)(reference value 0.0-15.0 μmol/L); there was heterozygous mutation of C.482 G> A and c.626 dupT in MMACHA gene, and heterozygous mutation of c. 665 C > T in MTHFR gene. Finally, the boy was diagnosed with late-onset methylmalonic aciduria complicated with hyperhomocysteinemia and MTHFR deficiency. He was treated by intramuscular injection of hydroxycobalamin and taking levocarnitine, betaine and folic acid orally, as well as rehabilitation treatment, and got significantly improved after six months.Conclusion It is the first MMA case with the onset of ADEM, which is complicated with methylmalonic aciduria combined with two inheritary metabolic diseases: hyperhomocysteinemia and MTHFR. Metabolic screening is really necessary for the neuvous system diseases with atypical clinical symptoms.
引文
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[4] 杨坤芳,陈育才.儿童多发性硬化和其他中枢神经系统脱髓鞘疾病诊断标准共识(2012版)解读[J].中国当代儿科杂志,2016,18(12):1199-1204.
[5] Keyfi F,Talebi S,Varasteh AR.Methylmalonic Acidemia Diagnosis by Laboratory Methods[J].Rep Biochem Mol Biol,2016,5(1):1-14.
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[7] 闫振文.急性播散性脑脊髓炎头颅MRI表现分析[A].//中华医学会第十八次全国神经病学学术会议论文集[C].中山大学附属第二医院,2015:535-536.
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[9] Han L,Han F,Ye J,et al.Spectrum analysis of common inherited metabolic diseases in Chinese patients screened and diagnosed by tandem mass spectrometry[J].J Clin Lab Anal,2015,29(2):162-168.
[10] 吴家顺,周婧.脑脊髓炎样起病的成人型甲基丙二酸血症1例临床分析及文献复习[J].中风与神经疾病杂志,2018,35(7):646-647.
[11] 魏妍平,彭斌,王琳,等.疑似脑炎的晚发型甲基丙二酸尿症伴高同型半胱氨酸血症8例临床分析[J].中国实用内科杂志,2017,37(3):259-261.
[12] Iida S,Nakamura M,Asayama S,et al.Rapidly progressive psychotic symptoms triggered by infection in a patient with methylenetetrahydrofolate reductase deficiency:a case report[J].BMC Neurol,2017,17(1):47.
[13] 王年臻,余丹.同型半胱氨酸及其代谢酶基因多态性与缺血性脑卒中的相关性研究进展[J].中华临床医师杂志(电子版),2016,10(1):105-109.
[14] 徐琳,张永青,产芳晓,等.高同型半胱氨酸血症的研究进展[J].中华保健医学杂志,2017,19(6):540-542.
[15] 张国领,张林,刘桂萍.高同型半胱氨酸血症的临床研究进展[J].中国医药导报,2018,15(20):29-32.
[16] 刘怡,刘玉鹏,张尧,等.中国1 003例甲基丙二酸血症的复杂临床表型、基因型及防治情况分析[J].中华儿科杂志,2018,56(6):414-420.
[17] 葛娟,乔凌燕,李堂.甲基丙二酸血症发病和诊治及预后的研究进展[J].中国儿童保健杂志,2017,25(3):258-260.
[18] 梁志刚,杨绍婉,李敏,等.表现为“脑炎”的甲基丙二酸血症合并肉碱增多症病例报告及文献回顾[J].中国临床神经科学,2017,25(3):279-284.
[19] 刘玉鹏,丁圆,李溪远,等.甲基丙二酸尿症合并先天性肾上腺皮质增生症1例报告[J].临床儿科杂志,2016,34(3):208-211.
[20] Nogueira C,Meschini MC,Nesti C,et al.A novel SUCLA2 mutation in a Portuguese child associated with "mild" methylmalonic aciduria[J].J Child Neurol,2015,30(2):228-232.
[21] 刘喆,王文红,张碧丽.表现为溶血尿毒综合征的cblC+cblD型甲基丙二酸血症1例[J].中华实用儿科临床杂志,2017,32(8):625-626.
[22] Ku CA,Ng JK,Karr DJ,et al.Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonicacidemia[J].Ophthalmic Genet,2016,37(4):404-414.
[2] Fraser JL,Venditti CP.Methylmalonic and propionic acidemias:clinical management update[J].Curr Opin Pediatr,2016,28(6):682-693.
[3] Han L,Han F,Ye J,et al.Spectrum analysis of common inherited metabolic diseases in Chinese patients screened and diagnosed by tandem mass spectrometry[J].J Clin Lab Anal,2015,29(2):162-168.
[4] 杨坤芳,陈育才.儿童多发性硬化和其他中枢神经系统脱髓鞘疾病诊断标准共识(2012版)解读[J].中国当代儿科杂志,2016,18(12):1199-1204.
[5] Keyfi F,Talebi S,Varasteh AR.Methylmalonic Acidemia Diagnosis by Laboratory Methods[J].Rep Biochem Mol Biol,2016,5(1):1-14.
[6] Trindade RAR,Klaes AINM,Duarte J.The many faces of demyelinating diseases: acute disseminated encephalomyelitis and Guillain-Barré syndrome in the same patient[J].Arq Neuropsiquiatr,2017,75(5):324-325.
[7] 闫振文.急性播散性脑脊髓炎头颅MRI表现分析[A].//中华医学会第十八次全国神经病学学术会议论文集[C].中山大学附属第二医院,2015:535-536.
[8] Krupp LB,Tardieu M,Amato MP,et al.International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders:revisions to the 2007 definitions[J].Mult Scler,2013,19(10):1261-1267.
[9] Han L,Han F,Ye J,et al.Spectrum analysis of common inherited metabolic diseases in Chinese patients screened and diagnosed by tandem mass spectrometry[J].J Clin Lab Anal,2015,29(2):162-168.
[10] 吴家顺,周婧.脑脊髓炎样起病的成人型甲基丙二酸血症1例临床分析及文献复习[J].中风与神经疾病杂志,2018,35(7):646-647.
[11] 魏妍平,彭斌,王琳,等.疑似脑炎的晚发型甲基丙二酸尿症伴高同型半胱氨酸血症8例临床分析[J].中国实用内科杂志,2017,37(3):259-261.
[12] Iida S,Nakamura M,Asayama S,et al.Rapidly progressive psychotic symptoms triggered by infection in a patient with methylenetetrahydrofolate reductase deficiency:a case report[J].BMC Neurol,2017,17(1):47.
[13] 王年臻,余丹.同型半胱氨酸及其代谢酶基因多态性与缺血性脑卒中的相关性研究进展[J].中华临床医师杂志(电子版),2016,10(1):105-109.
[14] 徐琳,张永青,产芳晓,等.高同型半胱氨酸血症的研究进展[J].中华保健医学杂志,2017,19(6):540-542.
[15] 张国领,张林,刘桂萍.高同型半胱氨酸血症的临床研究进展[J].中国医药导报,2018,15(20):29-32.
[16] 刘怡,刘玉鹏,张尧,等.中国1 003例甲基丙二酸血症的复杂临床表型、基因型及防治情况分析[J].中华儿科杂志,2018,56(6):414-420.
[17] 葛娟,乔凌燕,李堂.甲基丙二酸血症发病和诊治及预后的研究进展[J].中国儿童保健杂志,2017,25(3):258-260.
[18] 梁志刚,杨绍婉,李敏,等.表现为“脑炎”的甲基丙二酸血症合并肉碱增多症病例报告及文献回顾[J].中国临床神经科学,2017,25(3):279-284.
[19] 刘玉鹏,丁圆,李溪远,等.甲基丙二酸尿症合并先天性肾上腺皮质增生症1例报告[J].临床儿科杂志,2016,34(3):208-211.
[20] Nogueira C,Meschini MC,Nesti C,et al.A novel SUCLA2 mutation in a Portuguese child associated with "mild" methylmalonic aciduria[J].J Child Neurol,2015,30(2):228-232.
[21] 刘喆,王文红,张碧丽.表现为溶血尿毒综合征的cblC+cblD型甲基丙二酸血症1例[J].中华实用儿科临床杂志,2017,32(8):625-626.
[22] Ku CA,Ng JK,Karr DJ,et al.Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonicacidemia[J].Ophthalmic Genet,2016,37(4):404-414.