Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
Ophthalmic Genet. 2021 Aug;42(4):440-445. doi: 10.1080/13816810.2021.1913611. Epub 2021 Apr 16.
Leber hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease. The majority (>90%) is related to three primary mitochondrial DNA (mtDNA) variants: m.3460G>A, m.11778G>A and m.14484T>C. The remaining 10% is associated with >40 secondary variants with variable penetrance and incidence between different ethnic backgrounds.
Five sisters underwent an extensive ophthalmic workup including psychophysical, electrophysiological, multimodal brain imaging, biochemical testing and molecular screening. MT-ND6 protein modelling was performed.
A 23-year-old woman presented with acute central visual loss to counting fingers in the right eye. She developed a central visual field scotoma, severe color vision deficiencies and impaired pattern visual evoked responses. Progressive optic atrophy ensued. The left eye was unremarkable, except for borderline thinning of the temporal retinal nerve fiber layer. Alcohol use and passive smoking were noted. MtDNA analysis revealed a rare variant, m.14502T>C in , exclusively known to cause optic neuropathy in an Asian population. Three sisters of the proband, two of whom reported tobacco and alcohol abuse, had bilateral temporal optic disc pallor without functional impact. A fourth non-smoker sister had a completely normal eye exam.
The rare Asian m.14502T>C variant in the gene was linked to a mild LHON phenotype in a Western European family. Penetrance in this family was likely triggered by alcohol and tobacco abuse. A full mtDNA sequencing is warranted in the case of high clinical suspicion of LHON when mutation analysis for the three common pathogenic variants is negative.
Leber 遗传性视神经病变（LHON）是一种线粒体神经退行性疾病。大多数（>90%）与三种主要的线粒体 DNA（mtDNA）变异有关：m.3460G>A、m.11778G>A 和 m.14484T>C。其余 10%与>40 种次要变异有关，不同种族背景之间的外显率和发病率存在差异。
五位姐妹接受了广泛的眼科检查，包括心理物理学、电生理学、多模态脑成像、生化测试和分子筛查。进行了 MT-ND6 蛋白建模。
一位 23 岁的女性因右眼视力急剧下降至指数而就诊。她出现了中心视野暗点、严重的色觉缺陷和模式视觉诱发电位受损。随后出现进行性视神经萎缩。左眼无明显异常，仅颞侧视网膜神经纤维层稍薄。注意到饮酒和被动吸烟。mtDNA 分析显示一种罕见的变异 m.14502T>C，仅在亚洲人群中引起视神经病变。先证者的三位姐妹，其中两位报告有烟草和酒精滥用，双眼颞侧视盘苍白，但无功能影响。第四位非吸烟者的眼睛检查完全正常。
该基因中的罕见亚洲 m.14502T>C 变异与一个西欧家族中的轻度 LHON 表型相关。该家族的外显率可能是由酒精和烟草滥用引发的。当三种常见致病性变异的突变分析为阴性时，如果高度怀疑 LHON，应进行完整的 mtDNA 测序。
