Koilkonda Rajeshwari D, Guy John
Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
J Ophthalmol. 2011;2011:179412. doi: 10.1155/2011/179412. Epub 2010 Dec 26.
Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.
Leber遗传性视神经病变（LHON）是一种由线粒体DNA（mtDNA）点突变引起的母系遗传疾病。大多数病例是由于编码NADH-泛醌氧化还原酶亚基的基因突变所致，该酶是电子传递链（ETC）的复合体I。这些突变位于线粒体基因组的第3460、11778或14484位核苷酸处。该疾病的特征是突发性、双侧性和严重视力丧失。虽然突变的mtDNA会损害所有线粒体的ATP生成，但仅视网膜神经节细胞会选择性丧失，视神经轴突会发生退化。因此，失明通常是永久性的。携带致病性mtDNA突变的男性中有一半以及女性中有10%会实际出现该表型。这种不完全外显率和性别偏向尚未完全明确。其他线粒体和/或核遗传因素可能会调节LHON的表型表达。在一项基于人群的研究中，单倍群J的mtDNA背景与低ATP生成和活性氧（ROS）产生增加呈负相关。LHON的有效治疗方法一直难以捉摸。在本文中，我们描述了相关已发表研究的结果，并讨论了改善该疾病潜在策略的争议。
