晚发型甲基丙二酸尿症cblC型三例临床特点和基因分析

Clinical features and gene analysis of three cases of late-onset methylmalonic aciduria, cblC type

目的 探讨晚发型甲基丙二酸尿症cblC型合并高同型半胱氨酸血症的临床表现、影像学特点、治疗方案、可能的病理生理机制及基因特点.方法 报道3例晚发型甲基丙二酸尿症合并高同型半胱氨酸血症患者（男性2例,女性1例）,分析其临床表现、实验室检查、影像学发现及基因突变特点.结果 例1甲基丙二酸尿症cblC型的致病基因（MMACHC基因）测序发现了c.482G〉A和c.609G〉A突变;例2 MMACHC基因测序发现c.482G〉A和c.658_660delAAG突变;例3 MMACHC基因测序发现c.482G〉A和IVS1,＋1G〉A突变.3例患者临床表现广泛多变,主要表现为精神异常、癫痫、认知功能损害、双下肢无力、共济失调、锥体束和周围神经损害的症状等.3例患者都存在对高蛋白食物（如肉、蛋、牛奶、豆腐等）的厌恶.头颅MRI检查均发现脑萎缩,其中例1患者MRIT2像发现双侧小脑半球皮质病变.3例患者在应用甲钴胺治疗之后智力显著提高,癫痫得以控制,精神行为恢复正常,但均遗留双下肢无力及步态异常.结论 合并高同型半胱氨酸血症的晚发型甲基丙二酸尿症cblC型在神经系统可广泛累及大脑皮质、锥体系、锥体外系、周围神经（运动神经、感觉神经及自主神经）.对于临床出现厌食高蛋白食物、步态异常、癫痫、短期内迅速出现的痴呆或精神异常的年轻患者要考虑该病的可能.MRI发现脑萎缩可帮助诊断.

Objective To investigate the gene mutations, clinical manifestations, imaging features, treatments and pathophysiologic mechanisms of the patients with late-onset methylmalonic aciduria, cblC type. Methods Two boys and one girl were diagnosed as late-onset combined methylmalonic aciduria and homocystinuria cblC type by MMCHC gene sequencing at their 13, 12 and 17 years old, respectively. Their clinical manifestations, imaging features, laboratory findings and responses of treatment were reviewed. Results The MMACHC gene mutations in case 1 were c. 482G 〉 A and c. 609G 〉 A. For case 2, they were c. 482G 〉 A and c. 658_660delAAG. And for case 3, they were c. 482G 〉 A and IVS1, ＋ 1G 〉 A. The three patients presented with heterogeneous clinical pictures, including mental disorder, cognitive impairment, epilepsy, ataxia and signs of pyramidal damage and peripheral nerve injuries. Personal histories of all these 3 patients showed dislike for high-protein foods, such as meat, eggs, milk and tofu. Cerebral atrophy was visible in magnetic resonance imaging （MRI） scans of three cases. In addition, bilateral cerebellar cortex abnormalities were also found in one patient. Conclusions The cerebral cortex, pyramidal system, extrapyramidal system, peripheral nerve （including motor nerve, sensory nerve and autonomic nerve） can be widely involved in this disease. This disease should be suspected when the young patients present with abnormal gait, epilepsy, rapidly progressive dementia or mental disorder and dislike for high-protein food, such as meat, eggs, tofu. Brain MRI showing encephalatrophy prompts the diagnosis.