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

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。

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 “en-cephalitis” 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 reac-tion, cognitive decline and visual hallucination. The children suffered from “encephalitis” repeat-edly 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 diag-nosed 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.