晚发型钴胺素C缺陷病临床及分子遗传学特点分析

Characteristics of clinical manifestations and molecular genetics of late-onset cobalamin C deficiency

目的探讨晚发型钴胺素C（cblC）缺陷病，即甲基丙二酸血症伴高同型半胱氨酸血症cblC型的临床及分子遗传学特点。方法搜集山东大学齐鲁医院神经内科自2012—2017年诊断的26例晚发型cblC缺陷病患者的临床、生化、神经影像、治疗随访情况以及MMACHC基因检测结果，并汇总分析。结果26例患者中男女比为11∶15,诊断年龄4-39岁，有4个家系同胞共患病；其主要神经系统表现为痉挛性截瘫、精神行为异常、智能减退、癫痫发作、共济失调、肌张力障碍和周围神经病；4例在疾病初期表现为蛋白尿。初诊时血总同型半胱氨酸为61.4-193.4 μmol/L，尿甲基丙二酸均显著升高。26例患者的神经影像学检查显示：脑萎缩11例，胸髓萎缩变性10例，脑实质损伤5例，长节段脊髓病变3例，脊髓空洞1例，多发脑动脉狭窄1例。所有患者急性发作期经胃肠外补充钴胺素，口服叶酸、甜菜碱、左卡尼汀、维生素B6后急性脑病症状痊愈，但痉挛性截瘫改善不理想；慢性维持期肌肉注射羟钴胺和口服甜菜碱，在减少用药次数的同时可有效改善各项指标。经基因测序，26例患者均携带MMACHC基因复合杂合（22/26）或纯合突变（4/26），其中已知致病突变11种，以c.482G〉A（15/52）和c.609G〉A（13/52）错义突变最为常见，其次为c.656_658del（4/52）和c.452A〉G（4/52）。结论同型半胱氨酸是cblC缺陷病重要的血清学标志物；该病若及时诊治预后良好，但需终身胃肠外补充羟钴胺和甜菜碱；该组病例中检测的MMACHC基因突变以c.482G〉A及c.609G〉A最为常见。

ObjectiveTo investigate the characteristics of clinical manifestations and genetics of late-onset cobalamin （cbl） C deficiency, also named as combined methylmalonic acidemia and homocystinemia, cblC type.MethodsWe reviewed 26 late-onset cblC deficiency patients diagnosed in Qilu Hospital, Shandong University from 2012 to 2017 and analysed the clinical, biochemistry, neuroimaging, follow-up and MMACHC gene data.ResultsAmong the 26 patients, male∶female ratio is 11∶15, with the age of diagnosis from 4 to 39 years and sibling comorbidity in 4 families. The clinical manifestaions of nervous system included spastic paraplegia, mental and behavior disorder, intelectual decline, epilepsy, ataxia, dystonia and peripheral neuropathy. There were four cases with proteinuria at onset. At first visit, the levels of serum total homocystinuria of all patients were elevated, from 61.4 to 193.4 μmol/L with methylmalonic acidemia. The neuroimaging data of the 26 cases showed 11 with cerebral atrophy, 10 with thoracic spinal cord atrophy, five with brain parenchymal lesions, three with longitudinal myelopathy which were reversible in follow-up, one with syringomyelia, one with multiple cerebral artery stenosis. In all the cases, cobalamins were supplied parenterally and folate, betaine, L-carnitine, vitamin B6 were supplied orally during acute metabolic crisis, and the symptoms of acute encephalopathy disappeared but symptoms of spastic paraplegia had little improvement. In chronic stage, frequency of intramuscular injection of hydroxocobalamine could be decreased while the index can still be improved. All the 26 cases had definite mutations in MMACHC gene, the most common mutations of which were found to be c.482G〉A（15/52） and c.609G〉A（13/52）.ConclusionsHomocystine is the important biomarker for cblC deficiency. Once diagnosed, parenteral hydroxocobalamin and oral betaine should be supplied for a lifetime with good prognosis. The most common mutations of MMACHC gene in our cases are c.482G〉A and c.609G〉A missense mutations.