摘要：

目的 总结晚发型甲基丙二酸尿症 cblC 型两家系 4 例患儿临床表型、治疗原则及预后，探讨其病理生理学机制。方法与结果 采用外显子组测序技术快速诊断晚发型甲基丙二酸尿症cblC 型两家系。家系 1 姊妹存在 MMACHC 基因外显子 4 c.482G > A（p.Arg161Gln）和 c.615C > A（p.Tyr205X）复合杂合突变，分别来自其父母。先证者主要表现为智力减退、下肢痉挛性运动障碍伴癫痫发作；其妹则呈现以轴索损害为主的四肢周围神经病变和视神经萎缩，而智力减退症状相对较轻。家系 2 兄妹存在MMACHC 基因外显子 4 c.440_441del （p.Gly147fs）和c.482G > A（p.Arg161Gln）复合杂合突变，分别来自其父母。先证者表现为智力减退、精神行为异常和双下肢无力伴锥体束征，呈髓鞘和轴索混合性损害的周围神经病变；其妹症状相似但发病年龄较早。采用维生素 B₁₂、叶酸、左卡尼汀等药物联合治疗 6 个月患儿智力水平明显提高、癫痫发作得以控制，但均遗留不同程度双下肢运动障碍。结论 晚发型甲基丙二酸尿症 cblC 型临床表现复杂多样，可广泛累及大脑皮质、锥体束、锥体外系、周围神经等，目标区域捕获联合第二代测序技术可以快速明确诊断，早期诊断、积极治疗对改善患者预后至关重要。

关键词: 甲基丙二酸, 高胱氨酸尿, MMACHC基因（非 MeSH 词）, 突变, 系谱

Abstract:

Objective  To summarize phenotype, treatment principles and prognosis of 4 patients from 2 pedigrees with late-onset methylmalonic aciduria (MMA) and homocystinuria cobalamin C (cblC) type, so as to explore the pathophysiological mechanism of this disease. Methods and Results Exome sequencing was applied to rapidly diagnose 2 pedigrees of late-onset MMA and homocystinuria cblC type. The MMACHC gene mutations of the sisters in pedigree 1 were exon 4 c.482G > A (p.Arg161Gln) and c.615C > A (p.Tyr205X). Their parents carried the gene mutation respectively. The proband presented intelligence deterioration, spastic motor dysfunction of lower limbs and epilepsy. The younger sister presented axonal peripheral neuropathy and optic nerve atrophy, while the mental retardation was mild. For the brother and sister in pedigree 2, c.440_441del (p.Gly147fs) and c.482G > A (p.Arg161Gln) in exon 4 of MMACHC gene were identified which came from their parents respectively. The proband presented mental retardation and behavior disorder, weakness of lower limbs with pyramidal sign, and myelinated and axonal mixed peripheral neuropathy. His younger sister had similar symptoms and suffered earlier. After treated by vitamin B₁₂, folic acid and levocarnitine for 6 months, all patients showed intelligence improved and seizures controlled, while still suffered from different degrees of dyskinesia of lower limbs. Conclusions The clinical symptoms of late-onset MMA and homocystinuria cblC type are complex and variable. Cerebral cortex, pyramidal system, extrapyramidal system and peripheral nerve could be widely involved. Target region gene capture combined with next-generation sequencing technology can be used to diagnose the disease rapidly, and early diagnosis and treatment are crucial to improve the prognosis.

Key words: Methylmalonic acid, Homocystinuria, MMACHC (not in MeSH), Mutation, Pedigree