Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA
Moorfields Eye Hospital NHS Foundation Trust, London, UK.
Br J Ophthalmol. 2019 Dec;103(12):1789-1796. doi: 10.1136/bjophthalmol-2018-313580. Epub 2019 Apr 12.
Defects in retinol dehydrogenase 12 () account for 3.4%-10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of -associated retinal degeneration.
A retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in .
57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects.
This study includes the largest collection of phenotypic data from children with -associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with -associated retinal degeneration and will inform future design of therapeutic trials.
视黄醇脱氢酶 12 基因（）缺陷占莱伯先天性黑矇和早发性严重视网膜营养不良（EOSRD）的 3.4%-10.5%，是基因治疗的潜在靶点。遗传性视网膜疾病的临床试验具有独特的挑战，自然病史研究对于成功的试验设计至关重要。本研究旨在描述与相关的视网膜变性的自然病史。
对 57 名患有视网膜变性和两种可能致病的基因变异的个体进行回顾性图表审查。
来自 9 个国家的 57 名受试者被纳入研究。其中 33 名受试者有来自儿童时期的临床记录。数据显示，EOSRD 的平均发病年龄为 4.1 岁。所有受试者均出现黄斑萎缩，最早可在 2 岁时发现。所有受试者的暗适应和明适应视网膜电图（ERG）反应均明显降低，最早可在 1 岁时记录到无法记录的 ERG。对视力、视野和光学相干断层扫描的评估显示，大多数受试者在 10 岁后功能和结构严重丧失。23 名受试者的广角成像显示，13 名受试者出现独特的、斑驳的水彩样萎缩模式，18 名受试者的视盘周围区域未受累。
本研究包括了患有与相关的 EOSRD 的儿童中最大的表型数据集合，并全面描述了这种严重的早发性疾病中视力丧失的时间进程。这些发现将有助于识别与相关的视网膜变性患者，并为未来的治疗试验设计提供信息。
