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Abstract：
BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a systemic disorder in which multi-organ dysfunction may occur from mitochondrial metabolism failure. Maternally inherited mutations in the MT-TL1 gene are the most frequent causes for this disorder. Clinical manifestations may include stroke-like episodes, epilepsy, dementia, headache and myopathy. Among these, acute visual failure, usually in association with cortical blindness, can occur because of stroke-like episodes affecting the occipital cortex or the visual pathways. Vision loss due to optic neuropathy is otherwise considered a typical manifestation of other mitochondrial diseases such as Leber hereditary optic neuropathy (LHON).
METHODS: Here we describe a 55-year-old woman, sister of a previously described patient with MELAS harbouring the m.3243A > G (p.0, MT-TL1) mutation, with otherwise unremarkable medical history, that presented with subacute, painful visual impairment of one eye, accompanied by proximal muscular pain and headache. Over the next weeks, she developed severe and progressive vision loss limited to one eye. Ocular examination confirmed unilateral swelling of the optic nerve head; fluorescein angiography showed segmental perfusion delay in the optic disc and papillary leakage. Neuroimaging, blood and CSF examination and temporal artery biopsy ruled out neuroinflammatory disorders and giant cell arteritis (GCA). Mitochondrial sequencing analysis confirmed the m.3243A > G transition, and excluded the three most common LHON mutations, as well as the m.3376G > A LHON/MELAS overlap syndrome mutation. Based on the constellation of clinical symptoms and signs presented in our patient, including the muscular involvement, and the results of the investigations, the diagnosis of optic neuropathy as a stroke-like event affecting the optic disc was performed. L-arginine and ubidecarenone therapies were started with the aim to improve stroke-like episode symptoms and prevention. The visual defect remained stable with no further progression or outbreak of new symptoms.
CONCLUSIONS: Atypical clinical presentations must be always considered in mitochondrial disorders, even in well-described phenotypes and when mutational load in peripheral tissue is low. Mitotic segregation of mitochondrial DNA (mtDNA) does not allow to know the exact degree of heteroplasmy existent within different tissue, such as retina and optic nerve. Important therapeutic implications arise from a correct diagnosis of atypical presentation of mitochondrial disorders.
METHODS: Here we describe a 55-year-old woman, sister of a previously described patient with MELAS harbouring the m.3243A > G (p.0, MT-TL1) mutation, with otherwise unremarkable medical history, that presented with subacute, painful visual impairment of one eye, accompanied by proximal muscular pain and headache. Over the next weeks, she developed severe and progressive vision loss limited to one eye. Ocular examination confirmed unilateral swelling of the optic nerve head; fluorescein angiography showed segmental perfusion delay in the optic disc and papillary leakage. Neuroimaging, blood and CSF examination and temporal artery biopsy ruled out neuroinflammatory disorders and giant cell arteritis (GCA). Mitochondrial sequencing analysis confirmed the m.3243A > G transition, and excluded the three most common LHON mutations, as well as the m.3376G > A LHON/MELAS overlap syndrome mutation. Based on the constellation of clinical symptoms and signs presented in our patient, including the muscular involvement, and the results of the investigations, the diagnosis of optic neuropathy as a stroke-like event affecting the optic disc was performed. L-arginine and ubidecarenone therapies were started with the aim to improve stroke-like episode symptoms and prevention. The visual defect remained stable with no further progression or outbreak of new symptoms.
CONCLUSIONS: Atypical clinical presentations must be always considered in mitochondrial disorders, even in well-described phenotypes and when mutational load in peripheral tissue is low. Mitotic segregation of mitochondrial DNA (mtDNA) does not allow to know the exact degree of heteroplasmy existent within different tissue, such as retina and optic nerve. Important therapeutic implications arise from a correct diagnosis of atypical presentation of mitochondrial disorders.
摘要：
背景：线粒体脑肌病，乳酸性酸中毒,卒中样发作（MELAS）综合征是一种全身性疾病，其中线粒体代谢衰竭可能导致多器官功能障碍。MT-TL1基因的母体遗传突变是这种疾病的最常见原因。临床表现可能包括中风样发作，癫痫,痴呆症,头痛和肌病。其中,急性视觉障碍,通常与皮质盲有关，可能是由于影响枕骨皮质或视觉通路的中风样发作而发生的。视神经病变导致的视力丧失被认为是其他线粒体疾病的典型表现，例如Leber遗传性视神经病变（LHON）。
方法：这里我们描述一个55岁的女人，先前描述的MELAS患者的姐妹具有m.3243A>G（p.0，MT-TL1）突变，没有明显的病史，表现为亚急性，一只眼睛的视力损害疼痛，伴有近端肌肉疼痛和头痛。在接下来的几周里，她出现严重和进行性视力丧失，仅限于一只眼睛。眼部检查证实视神经头单侧肿胀；荧光素血管造影显示视盘节段性灌注延迟和乳头状渗漏。神经影像学,血液和脑脊液检查和颞动脉活检排除了神经炎性疾病和巨细胞动脉炎（GCA）。线粒体测序分析证实了m.3243A>G转变，并排除了三种最常见的LHON突变，以及m.3376G>LHON/MELAS重叠综合征突变。根据我们患者的临床症状和体征，包括肌肉的参与，以及调查结果,将视神经病变诊断为影响视盘的卒中样事件.开始使用L-精氨酸和ubidecarenone疗法，旨在改善中风样发作症状和预防。视觉缺陷保持稳定，没有进一步的进展或新症状的爆发。
结论：线粒体疾病必须始终考虑非典型临床表现，即使在良好描述的表型和外周组织中的突变负荷较低时。线粒体DNA（mtDNA）的有丝分裂分离不允许知道不同组织中存在的异质体的确切程度，如视网膜和视神经。重要的治疗意义来自线粒体疾病的非典型表现的正确诊断。
方法：这里我们描述一个55岁的女人，先前描述的MELAS患者的姐妹具有m.3243A>G（p.0，MT-TL1）突变，没有明显的病史，表现为亚急性，一只眼睛的视力损害疼痛，伴有近端肌肉疼痛和头痛。在接下来的几周里，她出现严重和进行性视力丧失，仅限于一只眼睛。眼部检查证实视神经头单侧肿胀；荧光素血管造影显示视盘节段性灌注延迟和乳头状渗漏。神经影像学,血液和脑脊液检查和颞动脉活检排除了神经炎性疾病和巨细胞动脉炎（GCA）。线粒体测序分析证实了m.3243A>G转变，并排除了三种最常见的LHON突变，以及m.3376G>LHON/MELAS重叠综合征突变。根据我们患者的临床症状和体征，包括肌肉的参与，以及调查结果,将视神经病变诊断为影响视盘的卒中样事件.开始使用L-精氨酸和ubidecarenone疗法，旨在改善中风样发作症状和预防。视觉缺陷保持稳定，没有进一步的进展或新症状的爆发。
结论：线粒体疾病必须始终考虑非典型临床表现，即使在良好描述的表型和外周组织中的突变负荷较低时。线粒体DNA（mtDNA）的有丝分裂分离不允许知道不同组织中存在的异质体的确切程度，如视网膜和视神经。重要的治疗意义来自线粒体疾病的非典型表现的正确诊断。
