Leber hereditary optic neuropathy: bad habits, bad vision?
Leber hereditary optic neuropathy: bad habits, bad vision?
复制标题
莱伯遗传性视神经病：坏习惯，视力不好？
DOI：
10.1093/brain/awp195
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Newman,NancyJ
中科院分区：
文献类型：
--
作者：
Newman,NancyJ
尽管线粒体遗传学在近 20 年中取得了快速进展，但 Leber 遗传性视神经病 (LHON) 所代表的谜团在 250 多年来仍未得到彻底解决（Newman，2005；Yu-Wai-Man 等，2009）。尽管线粒体 DNA (mtDNA) 中大多数潜在的致病点突变已被识别，但我们仍然无法回答有关这种疾病的最基本问题 (Newman, 2002)。为什么携带 LHON 线粒体 DNA 点突变的人在一生中不会出现视力丧失？为什么男性比女性更容易受到影响？为什么视力丧失更容易发生在人生的第二个和第三个十年，而在 50 岁以后很少发生？是什么导致了几周到几个月内同时或相继发生的如此突然和灾难性的视力丧失？最后，当线粒体 DNA 存在于身体的每个细胞中时，视神经（可能还有视网膜神经节细胞）有何特别之处，使得这些结构对线粒体 DNA 异常如此敏感？研究人员提出了多种理论来解释 LHON 的这些不寻常特征，但其中只有极少数得到了证实。关于可能的遗传/表观遗传因素，主要线粒体 DNA 突变（主要是核苷酸位置 11778、14484 或 3460 处的突变）的存在对于该疾病的表型表达是必要的，但还不够（Yu-Wai-Man 等，2009）。异质性（可能存在于视网膜神经节细胞中）可能会减少视力丧失的机会，但即使是同质性本身也不能解释大多数 LHON 病例（Chinnery 等，2001）。某些 mtDNA 背景单倍型可能会影响表达（Hudson 等，2007），特别是 11778 和 14484 突变的单倍型 J 以及 3460 突变的单倍型 K；然而，大多数携带者在其一生中都不会出现视力丧失。此外，还提出了核遗传影响，其中最合乎逻辑的是将病理突变定位于 X 染色体，解释了 LHON 表达中男性显着的优势（Hudson 等，2005；Shankar 等，2008）。然而，具有 LHON 主要突变的男性同卵双胞胎组中的不一致（Johns 等，1993；Biousse 等，1997）进一步支持影响 LHON 表达的非遗传因素的作用。已提出的导致 LHON 视力丧失的因素包括内部和外部环境触发因素（Newman，2005；Yu-Wai-Man 等，2009）。前者包括全身性疾病，例如糖尿病、营养缺乏、心理压力、代谢紊乱或正常生理或荷尔蒙状态的变化。提出的外部环境因素包括头部外伤、工业毒素、药物（特别是抗逆转录病毒和抗分枝杆菌药物），当然还有烟草和酒精。尽管文献中充斥着有关吸烟和饮酒的报道，但这些因素均未被证明是因果关系（Cullom 等人，1993 年；Riordan-Eva 等人，1995 年；Chalmers 和 Harding，1996 年；Tsao 等人，1999 年；Kerrison 等人，2000 年；Sadun 等人，2003 年）。在本期《Brain》中，Kirkman 等人（2009）报告了迄今为止最大规模的流行病学研究的结果，该研究调查了吸烟和饮酒在 LHON 视力丧失中的作用。对来自 125 个 LHON 谱系的 196 名受影响和 206 名未受影响的携带者进行了结构化电话访谈，这些谱系由三种主要 mtDNA 突变之一定义。与之前除一项病例对照研究之外的所有研究不同……
The puzzle that Leber hereditary optic neuropathy (LHON) represents has not been completely solved for over 250 years, despite 20 recent years of rapid advances in mitochondrial genetics (Newman, 2005; Yu-Wai-Man et al., 2009). Although the majority of the underlying causative point mutations in mitochondrial DNA (mtDNA) have been identified, we still cannot answer the most fundamental questions about this disease (Newman, 2002). Why does not everyone who carries a LHON mitochondrial DNA point mutation have visual loss in their lifetime? Why are males affected more often than females? Why does visual loss occur so preferentially during the second and third decades of life, and so infrequently past the age of 50? What accounts for such an abrupt and catastrophic loss of vision, either simultaneously or sequentially, within weeks to months? And, finally, what is so special about the optic nerve, and presumably the retinal ganglion cells, that makes these structures so exclusively sensitive to an abnormality in mitochondrial DNA, when this is present in every cell of the body? Researchers have proposed multiple theories to account for these unusual features of LHON, only very few of which have been proven. Regarding possible genetic/epigenetic factors, the presence of a primary mitochondrial DNA mutation, primarily those at nucleotide positions 11778, 14484 or 3460, is necessary but not sufficient for the phenotypic expression of the disorder (Yu-Wai-Man et al., 2009). Heteroplasmy, presumably in the retinal ganglion cells, may diminish the chances of visual loss, but even homoplasmy cannot of itself account for most cases of LHON (Chinnery et al., 2001). Certain mtDNA background haplotypes may influence expression (Hudson et al., 2007), in particular haplotype J for the 11778 and 14484 mutations and haplotype K for the 3460 mutation; yet still, the majority of the carriers will not experience visual loss in their lifetime. Additionally, nuclear genetic influences have been proposed, the most logical of which would localize a pathological mutation to the X chromosome, explaining the striking male predominance in LHON expression (Hudson et al., 2005; Shankar et al., 2008). However, discordance in sets of male monozygotic twins with LHON primary mutations (Johns et al., 1993; Biousse et al., 1997) further supports a role for non-genetic factors influencing LHON expression.Factors that have been proposed as precipitating LHON visual loss include both internal and external environmental triggers (Newman, 2005; Yu-Wai-Man et al., 2009). Among the former are systemic illnesses such as diabetes mellitus, nutritional deficiencies, psychological stress, metabolic disturbances or variations in normal physiological or hormonal status. Proposed external environmental factors include head trauma, industrial toxins, medications (in particular, the anti-retroviral and antimycobacterial drugs) and of course tobacco and alcohol. None of these factors has been proven to be causal, although the literature is most replete with reports on smoking and drinking alcohol but with conflicting results (Cullom et al., 1993; Riordan-Eva et al., 1995; Chalmers and Harding, 1996; Tsao et al., 1999; Kerrison et al., 2000; Sadun et al., 2003). In this issue of Brain, Kirkman et al.(2009) report the results of the largest epidemiological study, to date, investigating the role of smoking and alcohol exposure in the expression of visual loss in LHON. A structured telephone interview was conducted on 196 affected and 206 unaffected carriers from 125 LHON pedigrees defined by one of the three primary mtDNA mutations. Unlike all but one of the previous case–control studies …
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通讯作者：
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DOI：
--
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期刊：
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