Departments of Ophthalmology (NJN), Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia, IRCCS Istituto Delle Scienze Neurologiche di Bologna (VC), UOC Clinica Neurologica, Bologna, Italy, Department of Biomedical and Neuromotor Sciences (DIBINEM) (VC), Unit of Neurology, University of Bologna, Bologna, Italy, GenSight Biologics (MT), Paris, France, Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit (PY-W-M), Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom, Cambridge Eye Unit (PY-W-M), Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom, Moorfields Eye Hospital (PY-W-M), London, United Kingdom, and UCL Institute of Ophthalmology (PY-W-M), University College London, London, United Kingdom.
J Neuroophthalmol. 2020 Dec;40(4):547-557. doi: 10.1097/WNO.0000000000001045.
Leber hereditary optic neuropathy (LHON) is a maternally inherited bilaterally blinding optic neuropathy, predominantly affecting otherwise healthy young individuals, mostly men. The visual prognosis is generally poor, with most patients worsening to at least 20/200 visual acuity. The m.11778G>A (MTND4) mitochondrial DNA mutation is the most common cause of LHON and is associated with poor outcomes and limited potential for meaningful visual recovery. Treatments for LHON are limited, and clinical trials are hampered by inadequate data regarding the natural history of visual loss and recovery. In this article, we review the current literature specifically related to visual function of LHON patients with the m.11778G>A mutation.
Literature review was performed using MEDLINE through PubMed, Cochrane Reviews Library, and Orpha.net with search terms of "Leber hereditary optic neuropathy," "LHON," "ND4," "G11778A," "visual acuity," "nadir," "natural history," and "registry." All English-language, peer-reviewed publications with study cohorts of at least 5 LHON patients with the molecularly confirmed m.11778G>A mutation were included.
Meta-analysis of 12 retrospective and 3 prospective studies provided visual function information on 695 LHON patients with the m.11778G>A mutation, 100 (14.4%) of whom were reported to have "recovered" some vision, although definitions of "recovery" varied among studies and idebenone use could not always be excluded. When incorporating age at onset of visual loss into the analyses, and specifically addressing those patients aged 15 years or older, meaningful visual recovery occurred in 23 of 204 (11.3%) patients. A younger age at onset, especially less than 12 years, portends a better visual prognosis and a different natural history of visual loss progression and recovery than in adults.
The classic presentation of LHON patients with the m.11778G>A mutation of severe visual loss with rare or poor recovery from nadir still holds true for most affected individuals. Among patients 15 years and older, recovery of meaningful vision likely occurs in less than 20% of patients, irrespective of how recovery is defined, and ultimate visual acuities of better than 20/200 are rare. Adequate prospective studies with sufficient sample sizes of genotypically homogeneous untreated LHON patients stratified by age, immediately enrolled when symptomatic, followed regularly for adequate periods of time with consistent measures of visual function, and analyzed with a standard definition of visual improvement are unfortunately lacking. Future clinical trials for LHON will require more standardized reporting of the natural history of this disorder.
Leber 遗传性视神经病变（LHON）是一种母系遗传的双侧致盲视神经病变，主要影响其他健康的年轻个体，大多数为男性。视力预后通常较差，大多数患者的视力恶化至少达到 20/200 的视力。m.11778G>A（MTND4）线粒体 DNA 突变是 LHON 的最常见原因，与不良结局和有限的有意义的视力恢复潜力相关。LHON 的治疗方法有限，临床试验受到关于视力丧失和恢复的自然史的充分数据的限制。在本文中，我们回顾了与携带 m.11778G>A 突变的 LHON 患者的视觉功能相关的当前文献。
通过 MEDLINE 在 PubMed、Cochrane Reviews Library 和 Orpha.net 上使用搜索词“Leber hereditary optic neuropathy”、“LHON”、“ND4”、“G11778A”、“visual acuity”、“nadir”、“natural history”和“registry”进行文献复习。纳入了至少有 5 名携带分子证实的 m.11778G>A 突变的 LHON 患者的研究队列的所有英文同行评审出版物。
12 项回顾性研究和 3 项前瞻性研究的荟萃分析提供了 695 名携带 m.11778G>A 突变的 LHON 患者的视觉功能信息，其中 100 名（14.4%）报告说“恢复”了一些视力，尽管研究之间的“恢复”定义有所不同，并且无法始终排除依达拉奉的使用。当将发病年龄纳入分析中，特别是针对 15 岁或以上的患者时，204 名患者中有 23 名（11.3%）出现有意义的视力恢复。发病年龄较小，尤其是 12 岁以下，预示着更好的视力预后，以及与成年人不同的视觉丧失进展和恢复的自然史。
携带 m.11778G>A 突变的 LHON 患者的典型表现为严重的视力丧失，很少或没有从视力丧失的最低点恢复，这对大多数受影响的个体仍然适用。在 15 岁及以上的患者中，有意义的视力恢复可能发生在不到 20%的患者中，无论如何定义恢复，视力优于 20/200 的情况都很少见。遗憾的是，缺乏足够的、针对按年龄分层的、未经治疗的、基因型同质的 LHON 患者的前瞻性研究，这些患者应在出现症状时立即纳入，定期进行足够时间的随访，并使用视觉功能的标准定义进行分析。LHON 的未来临床试验将需要更标准化地报告这种疾病的自然史。
