Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes / myoclonus epilepsy with ragged-red fibers /Leigh overlap syndrome caused by mitochondrial DNA 8344A>G mutation
Received date: 2018-10-12
Online published: 2020-10-15
目的:线粒体DNA 8344 A>G(m.8344A>G)是肌阵挛性癫痫伴破碎红纤维(mitochondrial myoclonus epilepsy with ragged-red fibers,MERRF)综合征的常见致病突变,报道1例罕见的由m.8344A>G突变引起的线粒体脑肌病伴乳酸酸中毒和卒中样发作/肌阵挛性癫痫伴破碎红纤维/Leigh(mitochondrial encephalopathy, lactic acidosis and stroke-like episodes /MERRF/Leigh,MELAS/MERRF/Leigh)重叠综合征。方法:随访观察1例线粒体病患者,应用聚合酶链反应-限制性片段长度多态性(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)、高通量测序及Sanger测序对其线粒体基因进行分析。结果:患者男性,25岁,6岁后出现运动耐力差;10岁时因偏侧视野缺损行头颅磁共振成像(magnetic resonance imaging,MRI)示枕叶卒中样病灶,磁共振波谱分析(magnetic resonance spectroscopy,MRS)示病灶内乳酸峰升高;后患者认知功能逐渐减退;12岁出现行走不稳、意向性震颤,以及四肢肌阵挛发作;21岁因意识障碍入院,多次行头颅MRI示双侧壳核后部、丘脑及中脑对称性异常信号且范围逐渐扩大,并出现额叶多发卒中样病灶,经改善代谢、抗癫痫和物理康复治疗后症状逐渐好转;24岁时复查MRI示双侧基底节及丘脑异常信号范围缩小,中脑病灶消退。肌肉病理活检可见破碎红纤维(ragged-red fibers,RRF)。PCR-PFLP检测患者血液DNA发现存在m.8344A>G突变,二代测序显示其突变比例为90%,且未发现其他线粒体DNA位点致病突变。患者母亲的血液亦存在低比例m.8344A>G突变。结论:报道了m.8344A>G可导致MELAS/MERRF/Leigh重叠综合征,该例患者扩展了m.8344A>G的表型谱。
候越 , 赵旭彤 , 谢志颖 , 袁云 , 王朝霞 . 线粒体DNA 8344 A>G突变导致的MELAS/MERRF/Leigh重叠综合征[J]. 北京大学学报（医学版）, 2020 , 52(5) : 851 -855 . DOI: 10.19723/j.issn.1671-167X.2020.05.009
Objective: Mitochondrial deoxyribonucleic acid (mtDNA) 8344 A>G (m.8344A>G) mutation is the common mutation associated with mitochondrial myoclonus epilepsy with ragged-red fibers (MERRF) syndrome. Herein we report a rare case with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes/MERRF/Leigh (MELAS/MERRF/Leigh) overlap syndrome caused by m.8344A>G mutation. Methods: The clinical and imaging data of the patient were collected and an open muscle biopsy was carried out. We further employed molecular genetic analyses to detect mtDNA mutation in the proband and his mother. And then a clinical and neuroimaging follow-up was performed. Results: This patient was a 25-year-old male, who developed exercise intolerance since the age of 6. At age 10, he suffered from acute episodes of hemianopia, and cranial magnetic resonance imaging (MRI) showed occipital stroke-like lesions and cranial magnetic resonance spectroscopy (MRS) revealed a lactate peak corresponding to the lesion. After that the patient presented slowly progressive psychomotor decline. He had myoclonic seizures and cerebellar ataxia since the age of 12. At age 21, he was admitted to our hospital because of confusion and cranial MRI revealed symmetrical lesions in bilateral posterior putamen, thalami and midbrain. Then repeated MRI showed progression of original lesions and new frontal multiple stroke-like lesions. Symptomatic and rehabilitation treatment relieved his condition. Follow-up cranial MRI at age 24 showed the lesions in basal ganglia and thalami diminished, and the midbrain lesions even completely vanished. Muscle pathology indicated the presence of numerous scattered ragged-red fibers (RRF), suggestive of a mitochondrial disorder. Polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) detected the m.8344A>G mutation of the MT-TK gene encoding mitochondrial transfer RNA for lysine in the patient’s blood. Next generation sequencing (NGS) of the whole mitochondrial genome identified that the proportion of m.8344A>G was 90%, and no other mtDNA mutation was detected. Sanger sequencing further identified this mutation both in the proband and his mother’s blood, although the mutation load was much lower in his mother’s blood with approximately 10% heteroplasmy. Conclusion: The present study is the first to describe a patient with m.8344A>G mutation in association with the MELAS/MERRF/Leigh overlap syndrome, which expands the phenotypic spectrum of the m.8344A>G mutation.
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