线粒体脑肌病伴高乳酸血症和脑卒中样发作综合征的临床、影像学特征及线粒体基因A3243G位点点突变异质性分析(附1家系报告)

Clinical and imaging characteristics and mitochondrial gene A3243G mutation heterogeneity analysis of mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes syndrome(report of one family)

目的探讨线粒体脑肌病伴高乳酸血症和脑卒中样发作(MELAS)综合征的临床、影像学特征及线粒体基因突变异质性。方法通过对1例以头痛及卒中样发作起病的MELAS患者及其家系成员的临床诊治,结合病史、实验室检查、影像学检查、病理学检查及基因学检查及已有的文献报道,分析其家系患者临床表型是否与致病基因异质性相关。结果先证者存在典型的MELAS临床症状,其生化指标、肌肉活检和影像学资料均符合MELAS诊断标准,但血液标本线粒体基因一代测序结果显示突变比例未高于其突变阈值。因先证者小女儿发病,取其尿液标本行基因检测,测序结果提示先证者小女儿线粒体基因组存在chrM:3243A>G(tRNA Leu1)突变,尿液标本突变负荷为97%。随后对先证者的血液及尿液行二代深度测序,结果显示血液及尿液突变负荷分别为5.0%、51%。结论MELAS综合征患者临床表现复杂多样,拟诊MELAS的患者应行基因检测。当线粒体病患者血液中突变率较低,或对于突变较低的仅有单一症状和无症状的患者,需要取材多种组织行基因检测,避免漏诊的发生。

Objective To observe the clinical and imaging features,and mitochondrial gene mutation heterogeneity of mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes syndrome(MELAS).Methods Combined with the medical history,laboratory tests,imaging examination,pathology,genetic analysis and literature reports,the clinical phenotype of the MELAS patient was analyzed whether the heterogeneity of the pathogenic gene was related to the family,based on the clinical diagnosis,treatment of a MELAS patient with headache and stroke-like onset and his family members.Results The proband had typical clinical symptoms of MELAS,and the biochemical indicators,muscle biopsy and imaging data of the her all met the diagnostic criteria of MELAS.However,the first-generation sequencing results of the mitochondrial gene showed that the mutational loads were not higher than the mutation threshold.Later,due to the onset of the younger daughter of her,urine samples were taken for gene testing.The sequencing results indicated that the mutation of mitochondrial genome of the younger daughter of her was chrM:3243A>G(tRNA Leu1),and the mutation of the urine sample was 97%.Then,the blood and urine of the proband were deeply sequenced for the second generation,and the results showed that the mutation load of blood and urine was 5.0%and 51%,respectively.Conclusions The clinical manifestations of MELAS syndrome patients are complex and diverse.MELAS patients should undergo genetic testing.When the blood mutation rate of patients with mitochondrial disease is low,or for patients with only one symptom or none of symptom with low mutation,multiple tissues should be taken for genetic testing to avoid the occurrence of missed diagnosis.