设为首页 加入收藏 期刊导航 网站地图

Advances in Clinical Medicine
Vol. 14  No. 02 ( 2024 ), Article ID: 81271 , 7 pages
10.12677/ACM.2024.142494

一例误诊为“脑炎”的晚发型甲基丙二酸血症cbIC型的临床特点、家系基因学分析

韩蕾1，张正军2，刘瑞花3，郑钦亮3，寇睿3，李秋波3*

1济宁医学院临床医学院，山东 济宁

2济宁医学院附属医院内分泌遗传代谢科，山东 济宁

3济宁医学院附属医院儿科，山东 济宁

收稿日期：2024年1月23日；录用日期：2024年2月16日；发布日期：2024年2月26日

摘要

目的：探讨1例误诊为“脑炎”的晚发型甲基丙二酸血症(MMA) cbIC型患儿的临床特点、家系MMA基因突变分析，旨在进一步提高临床医师对晚发型MMA的认识和重视，从而为提高对该病的早期诊治能力。方法：收集1例反复误诊为“脑炎”的cbIC型MMA患儿的临床表现、诊断及治疗过程，并对其家系共4名成员进行MMACHC基因突变检测。结果：患儿为青春期男性，起病隐匿，表现为反应迟钝、认知功能下降、视幻。患儿自8岁后反复患“脑炎”，每年1~2次，均在当地诊所输液后缓解。头颅MRI显示无异常。实验室检查：血清同型半胱氨酸(Hcy)明显增高，尿有机酸分析亦显示尿甘油酸-3,3羟基丙酸-2、甲基丙二酸均明显升高，诊断为cbIC型MMA合并高同型半胱氨酸血症。经维生素B12、左卡尼汀、甜菜碱治疗后症状迅速改善。患儿及其哥哥甲基丙二酸尿症cbIC型的致病基因(MMACHC基因)测序均发现了两个突变C.394C > T和C.482G > A，前者来源于患儿父亲，后者来自母亲，C.394C > T突变发生在第3外显子上，C.482G > A突变发生在第4外显子上，均为杂合子。结论：合并高同型半胱氨酸血症的晚发型甲基丙二酸血症cbIC型临床表现复杂、多样，缺乏特异性，许多患者首次就诊时经常被漏诊或误诊，延误最佳治疗时机。当遇到临床中无法用脑炎等疾病解释的神经系统损害的患儿，需要考虑MMA等遗传代谢病可能，应该及时完善有机酸检测以及相关基因检测协助诊断。

关键词

晚发型甲基丙二酸血症cbIC型，临床特点，家系基因学分析

Clinical Characteristics and Family Genetic Analysis of a Case of cbIC Type of Late-Onset Methylmalonic Acidemia Misdiagnosed as Encephalitis

Lei Han1, Zhengjun Zhang2, Ruihua Liu3, Qinliang Zheng3, Rui Kou3, Qiubo Li3*

1Clinical Medicine School of Jining Medical University, Jining Shandong

2Department of Endocrinology, Genetics, and Metabolism, Affiliated Hospital of Jining Medical University, Jining Shandong

3Department of Pediatrics, Affiliated Hospital of Jining Medical University, Jining Shandong

Received: Jan. 23rd, 2024; accepted: Feb. 16th, 2024; published: Feb. 26th, 2024

ABSTRACT

Objective: To explore the clinical characteristics and genetic mutation analysis of MMA in a patient with late onset methylmalonic acidemia (MMA) cbIC type misdiagnosed as “encephalitis”, in order to further improve the understanding and attention of clinicians to late onset MMA, so as to improve the ability of early diagnosis and treatment of this disease. Methods: The clinical manifestations, diagnosis and treatment process of 1 child with cbIC MMA repeatedly misdiagnosed as “encephalitis” were collected, and MMACHC gene mutation was detected in 4 members of the family. Results: The children were adolescent males with insidious onset. The symptoms were slow reaction, cognitive decline and visual hallucination. The children suffered from “encephalitis” repeatedly since the age of 8, 1~2 times a year, all of which were alleviated after infusion at the local clinic. MRI of the head showed no abnormality. Laboratory tests showed that serum homocysteine (Hcy) was significantly increased, and urine organic acid analysis also showed that urinate-3, 3-hydroxypropionic acid-2 and methylmalonic acid were significantly increased, which was diagnosed as cbIC MMA with hyperhomocysteinemia. After treatment with vitamin B12, levocarnitine and betaine, symptoms improved rapidly. The sequencing of MMACHC gene of the children and their elder brother with methylmaloniduria cbIC type found two mutations C.394C > T and C.482G > A. The former was from the father of the child, while the latter was from the mother. C.394C > T mutation occurred on the third exon; C.482G > A mutation occurred on exon 4, all of which were heterozygous. Conclusion: The clinical manifestations of cbIC type of late onset methylmalonic acidemia complicated with hyperhomocysteinemia are complex, diverse and lack of specificity. Many patients are often missed or misdiagnosed at the first visit, which delays the best treatment opportunity. When children with neurological damage that cannot be clinically explained by diseases such as encephalitis need to consider the possibility of genetic metabolic diseases such as MMA, organic acid detection and related gene detection should be timely improved to assist diagnosis.

Keywords:Late-Onset Methylmalonic Acidemia: cbIC Type, Clinical Characteristics, Family Genetics Analysis

Copyright © 2024 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

甲基丙二酸血症(methylmalonic academia, MMA)是一种常见的有机酸血症，为常染色体隐性遗传性疾病，该疾病是由于甲基丙二酰辅酶A变位酶或其辅酶5’脱氧腺苷钻胺素合成障碍所致。根据酶缺陷的类型分为甲基丙二酰辅酶A变位酶缺陷及cbI缺陷两大类，后者分为cbIA、cbIB、cbIC、cbID、cbIF 5个亚型 [1] ，cbIC型常见 [2] [3] 。其编码基因MMACHC，基因突变已发现40余种 [4] 。MMA依据其发病年龄可以分为早发型(发病年龄 ≤ 1岁)和晚发型(发病年龄 ≥ 4岁) [5] ，患者多在新生儿期和婴儿期起病，晚发型少见。部分晚发型患儿可在几岁甚至十几岁才表现出症状，该疾病临床表现缺乏特异性 [6] [7] ，多数患者首次就诊时经常被漏诊或误诊，临床症状广泛多变，是一种容易被误诊、误治的疾病 [8] [9] 。本文报告1例学龄期起病、误诊为“脑炎”、青春期诊断的晚发型MMA合并高同型半胱氨酸血症患儿的诊治过程、家系基因学分析，并复习相关文献进行分析，以提高儿科医生对MMA的认识。

2. 病例资料

病史：男，12岁，因“反应迟钝10天，记忆力减退、视幻5天”入院。10天前患儿无明显诱因出现反应迟钝，表现为自主语言减少，有应答，问答迟钝、颠三倒四，计算能力明显减低，不能计算10以内加减法，动作迟钝，精神欠佳，多睡，有性格改变，易烦躁。5天前患儿出现记忆力减退，记忆模糊，自诉视幻。既往史：患儿自8岁后多次因“发热、精神差”在外院诊断为“脑炎”，每年1~2次，均在当地诊所给予静滴“抗病毒以及维生素类药物”后好转。来我院就诊前2月语言欠清晰。家族史：患儿父母体健、其哥哥自小学后逐渐表现为轻微智力低下，目前生活基本可以自理。父母非近亲婚配、否认家族史。查体：神志清，精神欠佳，反应迟钝，话少，易烦躁，心肺腹查体无异常。指鼻试验、指指试验、跟膝胫试验均不能配合，轮替动作缓慢不协调。余无异常。辅助检查：血常规、血糖、血脂、血乳酸、血氨、肝功、肾功、心肌酶、血生化、血钙镁磷、脑脊液(常规、生化、特定蛋白、寡克隆区带、nmda脑炎抗体)均正常。脑电图为界线性视频脑电图，背景节律慢，视频显示患儿表情怪异、多为惊恐，脑电图可见尖波、少许纺锤波。脑部MRI平扫未见异常。尿有机酸筛查，发现甘油酸-3,3羟基丙酸-2、甲基丙二酸大量增高。血同型半胱氨酸326.2 umoL/L (参考值：≤15 umol/L)，提示甲基丙二酸血症伴同型半胱氨酸血症。同时，检查该患儿哥哥同型半胱氨酸为175.1 umoL/L。

经医院医学伦理委员会批准，患儿家长知情同意后，取患儿以及父母、哥哥静脉血各2 mL，使用Qiagen FlexiGene DNA Kit的方法提取样本DNA。随后采用聚合酶链反应(PCR)进行文库构建，并对扩增后的产物进行纯化和定量。接下来使用illumina公司的NextSeq500测序仪进行测序，获得下机原始数据，并用CASAVA (1.8.2)软件将原始数据转化为可识别的碱基序列，再经生物信息分析系统进行分析注释获得突变位点，并筛选出符合患者临床的位点，用Sanger测序进行一代验证和家系验证。

患者MMACHC基因编码区发现2个突变位点：C.394C > T (无义突变)和C.482G > A (错义突变) (见图1)。其哥哥MMACHC基因测序亦为上述杂合变异，患者及其哥哥均遗传了父母的MMACHC致病基因(见图2)。其中，来自于父亲的C.394C > T基因突变发生在第3外显子上，由CGA变成TGA，氨基酸由精氨酸变成终止密码子，为无义突变。来自于母亲的C.482G > A基因突变发生在第4外显子上，CGA变成CAA，氨基酸由精氨酸变成谷氨酰胺，为错义突变(见表1)。

该患儿应用VitB12 1 mg/d肌注，维生素B6 0.2/d静滴、左卡尼汀3 g/d静推、叶酸10 mg/d口服，应用3天后，症状明显改善，精神、反应、记忆力、语言均明显进步，复查同型半胱氨酸浓度下降至185.7 umoL/L。证实为VitB12有效型MMA合并高同型半胱氨酸血症。患儿出院后继续给予每周肌注2次VitB121 mg，同时给予叶酸、甜菜碱及左卡尼汀口服，辅以低蛋白、高热量饮食。出院1个月后，该患儿出现双下肢无力，行走姿势异常，再次就诊于我院，复查同型半胱氨酸浓度为70.5 umoL/L，肌电图检查示左胫前肌、右腓肠肌内侧头可见纤颤，正向电位轻收缩右腓肠肌内侧头、双股内侧肌波幅增高，左胫前肌轻、重收缩均未募集到运动单位电位。再次给予VitB121 mg/d肌注应用1周，双下肢无力无明显改善，自动出院回家。经随访，该患儿目前精神良好、智力较前明显提高，已继续求学，仍行走无力。

Figure 1. Gene sequencing map of the patient, C.394C > T on the left, CGA turned into TGA, and C.482G > A on the right, CGA turned into CAA

图1. 患者基因测序图，左侧为C.394C > T，CGA变成TGA，右侧为C.482G > A，CGA变成CAA

Figure 2. Pedigree of a patient with late-onset methylmalonic aciduria cbIC type. II1 and II2 inherited the MMACHC gene C.394C > T from their father (I1) and the MMACHC gene C.482G > A from their mother (I2)

图2. 晚发型甲基丙二酸尿症cbIC型患者家系系谱图。II1､II2遗传了来自父亲(I1)的MMACHC致病基因C.394C > T和母亲(I2)的MMACHC致病基因C.482G > A

Table 1. Summary chart of genetic testing of the patient and his family (From Molecular genetics report)

表1. 患儿及其家系基因检测归纳图表(引自分子遗传学检验报告)

3. 讨论

cbIC型是最常见的甲基丙二酸血症，同时伴有同型半胱氨酸血症，又称为cbIC病。在哺乳动物细胞内，外源性钴胺素(VitB12)参与两种辅酶的形成：腺苷钴胺素(AdoCbI)和甲基钴胺素(MeCbI)。AdoCbI对于位于线粒体中的甲基丙二酰辅酶a突变酶(MUT)的活性至关重要，它催化甲基丙二酰辅酶a转化为琥珀酰辅酶a。MeCbI对细胞质中蛋氨酸合酶(MTR)的活性至关重要，它能催化同型半胱氨酸转化为蛋氨酸。cbIC患者中AdoCbI和MecbI合成受损，导致上述两个步骤的代谢异常，进而导致甲基丙二酸血症合并高胱氨酸血症 [10] 。cbIC病的致病基因为MMACHC基因，目前已知的致病性的基因突变约有100种 [10] [11] [12] [13] 。MMACHC基因定位在lp34.1，包括5个外显子，外显子14为编码区，eDNA全长1518 bp，有846 bp的开放阅读框共编码282个氨基酸，分子量为31,700 [4] 。基因突变的位置与cbIC病临床表型相关，文献报道C.609G > A纯和突变最常见，约占27％，与中国人早发型CbIC有关 [14] 。而c.482G > A和c.394C > T则与晚发型有关 [15] 。C.482G > A基因突变导致cbIC蛋白161位氨基酸由精氨酸变为谷氨酰胺，推测该位点可能对蛋白质的功能影响较小，因此患者发病较晚。此外有研究发现，c.394C > T位点的突变可使mRNA转录提前终止而产生截短的cbIC蛋白，截短的突变体还具有野生型蛋白的部分功能，因此携带该突变的患者发病较晚 [7] 。本病例中，先证者母亲携带C.482G > A杂合突变，CGA变成CAA，氨基酸由精氨酸变成谷氨酰胺，为错义突变。先证者父亲则携带C.394C > T杂合突变，CGA变成TGA，氨基酸由精氨酸变成终止密码子，为无义突变。2名子女均为复合杂合突变，均在学龄期起病，进一步证实了C.482G > A基因突变与C.394C > T基因突变与迟发型cbIC病的相关性。

cbIC的临床表现多种多样，不典型，严重程度不一，常累及多个系统。该病最常见的表现为癫痫、生长迟缓、营养不良、贫血、代谢异常、血小板减少症、小头症、痴呆和眼部异常。超过90%的cbIC患儿是严重的早发性婴儿病例 [11] [16] 。最严重的病例通常在出生后出现临床表型，甚至可能导致死亡。4岁以后发病的晚发型于1970年首次被描述 [17] ，临床表现通常较轻，多以神经系统症状表现为主，有些以神经系统受累为唯一表现，无其他系统损害以及代谢危象的特征性表现，有些患者甚至可能永久不发病 [18] ，临床诊断相对困难，很容易漏诊、误诊。在统计的所有已报道的晚发型患者中，神经系统症状可表现为发作性意识障碍、进行性痴呆、感觉障碍(包括深感觉障碍)、运动障碍、病理征阳性、共济失调等。还可表现为反应迟钝、记忆力减退、行为怪异、注意力不集中、执行功能障碍等症状 [19] 。分析本病例患儿临床特点，① 学龄期发病，自8岁后每年均因“发热、精神差”在外院诊断为“脑炎”，每次均给予静滴“抗病毒、维生素类药物”好转，故误诊为病毒性脑炎。但患儿脑脊液检查正常，病情每年发作1~2次，不符合病毒性脑炎特点。每次发作时均有发热表现，推测感染可能为本病发作的诱因。② 本次急性起病，以“反应迟钝，记忆力减退、视幻”为主要临床特点，入院后查血Hcy明显增高，患儿哥哥自小学后表现为轻度智力障碍，完善血Hcy检查，亦明显增高。尿有机酸筛查，发现甘油酸-3,3羟基丙酸-2、甲基丙二酸大量增高，我们对患儿以及其父母、哥哥均进行基因检测，明确了患儿的诊断为甲基丙二酸血症cbIC型，同时明确了患儿父母、哥哥携带的突变，为家族下一代的产前诊断提供了依据。故临床上出现智力障碍、共济失调、癫痫、周围神经损害等神经系统症状表现突出的学龄期以上儿童，应想到本病的可能，早期进行血、尿有机酸分析、同型半胱氨酸测定及神经影像学、肌电图、脑电图等检查，并及时完善基因学检测，有助于早诊断、早治疗。根据Yang等和Rosenblatt等的观察，晚发型甲基丙二酸血症cbIC型患者死亡风险低，其原因可能是由于部分酶活性缺失，治疗反应较好。应用维生素B12、左卡尼汀、甜菜碱等药物及时治疗，其中维生素B12可使突变的酶蛋白活性最大化，有助于增加辅酶的合成，左卡尼汀预防肉碱缺乏，并促进有毒代谢物的排泄，甜菜碱作为甲基供体，激活同型半胱氨酸重甲基化的旁路途径 [20] [21] ，以上药物配合限制蛋白质摄入等饮食调节，可有效改善急性期症状，减慢病程进展，部分病例甚至可完全逆转神经系统的损害，有助于降低该病的进展及死亡率 [14] [22] 。

文章引用

韩 蕾,张正军,刘瑞花,郑钦亮,寇 睿,李秋波. 一例误诊为“脑炎”的晚发型甲基丙二酸血症cbIC型的临床特点、家系基因学分析
Clinical Characteristics and Family Genetic Analysis of a Case of cbIC Type of Late-Onset Methylmalonic Acidemia Misdiagnosed as Encephalitis[J]. 临床医学进展, 2024, 14(02): 3528-3534. https://doi.org/10.12677/ACM.2024.142494

参考文献

  1. 1. 毋盛楠, 韩连书, 叶军, 等. 甲基丙二酸血症患者血串联质谱及尿气相色谱质谱检测分析[J]. 中华医学杂志, 2013, 93(8): 561-565.

  2. 2. 宇亚芬, 黎芳, 麻宏伟. cbIC型甲基丙二酸血症基因型与临床表型及疗效的关系[J]. 中国当代儿科杂志, 2015(8): 769-774.

  3. 3. 刘怡, 刘玉鹏, 张尧, 等. 中国1003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.

  4. 4. Lerner-Ellis, J.P., Tirone, J.C., Pawelek, P.D., et al. (2006) Identification of the Gene Responsible for Methylmalonic Aciduria and Homocystinuria, cbIC Type. Nature Genetics, 38, 93-100. https://doi.org/10.1038/ng1683

  5. 5. Martinelli, D., Deodato, F. and Dionisi-Vici, C. (2011) Cobalamin C Defect: Natural History, Pathophysiology, and Treatment. Journal of Inherited Metabolic Disease, 34, 127-135. https://doi.org/10.1007/s10545-010-9161-z

  6. 6. 宇亚芬, 黎芳, 麻宏伟. cbIC型甲基丙二酸血症基因型与临床表型及疗效的关系[J]. 中国当代儿科杂志, 2015, 17(8): 769-774.

  7. 7. Huemer, M., Scholl-Bürgi, S., Hadaya, K., et al. (2014) Three New Cases of Late-Onset cbIC Defect and Review of the Literature Illustrating When to Consider Inborn Errors of Metabolism Beyond Infancy. Orphanet Journal of Rare Diseases, 9, 161. https://doi.org/10.1186/s13023-014-0161-1

  8. 8. Wang, X., Sun, W., Yang, Y., et al. (2012) A Clinical and Gene Analysis of Late-Onset Combined Methylmalonic Aciduria and Homocystinuria, cbIC Type, in China. Journal of the Neurological Sciences, 318, 155-159. https://doi.org/10.1016/j.jns.2012.04.012

  9. 9. 管贤伟, 孙云, 马定远, 王彦云, 蒋涛. 甲基丙二酸血症被误诊为血液系统疾病二例分析并文献复习[J]. 中华妇幼临床医学杂志(电子版), 2019, 15(1): 57-62.

  10. 10. Lerner-Ellis, J.P., Anastasio, N., Liu, J., et al. (2009) Spectrum of Mutations in MMACHC, Allelic Expression, and Evidence for Genotype-Phenotype Correlations. Human Mutation, 30, 1072-1081. https://doi.org/10.1002/humu.21001

  11. 11. Fischer, S., Huemer, M., Baumgartner, M., et al. (2014) Clinical Presentation and Outcome in a Series of 88 Patients with the cbIC Defect. Journal of Inherited Metabolic Disease, 37, 831-840. https://doi.org/10.1007/s10545-014-9687-6

  12. 12. Hu, S., Mei, S., Liu, N., et al. (2018) Molecular Genetic Characterization of cbIC Defects in 126 Pedigrees and Prenatal Genetic Diagnosis of Pedigrees with Combined Methylmalonic Aciduria and Homocystinuria. BMC Medical Genetics, 19, 154. https://doi.org/10.1186/s12881-018-0666-x

  13. 13. Liu, M.Y., Yang, Y.L., Chang, Y.C., et al. (2010) Mutation Spectrum of MMACHC in Chinese Patients with Combined Methylmalonic Aciduria and Homocystinuria. Journal of Human Genetics, 55, 621-626. https://doi.org/10.1038/jhg.2010.81

  14. 14. Wang, F., Han, L., Yang, Y., et al. (2010) Clinical, Biochemical, and Molecular Analysis of Combined Methylmalonic Acidemia and Hyperhomocysteinemia (cbIC Type) in China. Journal of Inherited Metabolic Disease, 33, S435-S442. https://doi.org/10.1007/s10545-010-9217-0

  15. 15. Backe, P.H., Ytre-Arne, M., Røhr, A.K., et al. (2013) Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cbIC Type. JIMD Reports, 11, 79-85. https://doi.org/10.1007/8904_2013_225

  16. 16. Rosenblatt, D.S., Aspler, A.L., Shevell, M.I., et al. (1997) Clinical Heterogeneity and Prognosis in Combined Methylmalonic Aciduria and Homocystinuria (cbIC). Journal of Inherited Metabolic Disease, 20, 528-538. https://doi.org/10.1023/A:1005353530303

  17. 17. 雷如意, 刘艳茹, 籍炀飞, 等. 晚发型甲基丙二酸尿症cbIC型三例临床特点和基因分析[J]. 中华神经科杂志, 2014, 47(2): 101-106.

  18. 18. Han, L., Wu, S., Ye, J., et al. (2015) Biochemical, Molecular and Outcome Analysis of Eight Chinese Asymptomatic Individuals with Methyl Malonic Acidemia Detected through Newborn Screening. American Journal of Medical Genetics Part A, 167A, 2300-2305. https://doi.org/10.1002/ajmg.a.37147

  19. 19. 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.

  20. 20. 孟华夏, 张国强, 韩丽娜, 张立明. 溶血性贫血为主要表现甲基丙二酸血症1例[J]. 世界最新医学信息文摘(连续型电子期刊), 2019, 19(66): 306-307.

  21. 21. Fraser, J.L. and Venditti, C.P. (2016) Methylmalonic and Propionic Acidemias: Clinical Management Update. Current Opinion in Pediatrics, 28, 682-693. https://doi.org/10.1097/MOP.0000000000000422

  22. 22. Yang, Y., Sun, F., Song, J., et al. (2006) Clinical and Biochemical Studies on Chinese Patients with Methylmalonic Aciduria. Journal of Child Neurology, 21, 1020-1024. https://doi.org/10.1177/7010.2006.00231

    23. NOTES

    *通讯作者。

期刊菜单