Purpose

To investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children.

Design

Retrospective case series.

Participants

Patients with mutations in CEP290 identified at a single UK referral center.

Methods

Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing.

Main Outcome Measures

Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment.

Results

Forty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features.

Conclusions

Detailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches.

中文翻译：

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与CEP290，临床表型和自然病史突变相关的Leber先天性阿玛特病，为新疗法的试验做准备

目的

调查并详细描述了突变相关的人口统计数据，功能和解剖特点，莱伯先天性黑蒙（LCA）的临床病程CEP290基因（LCA- CEP290）在一大群的成年人和儿童。

设计

回顾案例系列。

参加者

在单个英国转诊中心鉴定出CEP290突变的患者。

方法

审查病例记录和视网膜成像结果（彩色眼底照相，眼底自发荧光[FAF]成像，OCT），电生理评估和分子遗传学检测。

主要观察指标

分子遗传学检测，包括视力和视网膜成像在内的临床发现以及电生理评估。

结果

鉴定了40名LCA- CEP290患者。深内含子突变c.2991 + 1655 A> G是最常见的致病变异（23/40例），在20例（50％）的复合杂合状态和2例（5％）的纯合中鉴定。视敏度（VA）从6/9到无光感知，并且在12例具有纵向VA数据的患者中，只有2例的视力随着时间的推移显示VA恶化。诊断较年轻的患者（平均年龄，1.9岁）的眼底正常，而老年患者显示白色斑点（平均年龄，5.9岁）或色素性视网膜病变（平均年龄，21.7岁）。OCT成像的12例患者中有11例（92％）保留了中央凹结构。FAF影像学检查的12例患者中有10例（83％）出现了小凹周围性自体荧光环。废话2CEP290突变与较差的最终VA和非眼功能的存在有关。

结论

对一个大型队列中的LCA- CEP290临床表型的详细分析证实，在相当大比例的患者中，基于中央锥体富含视网膜的相对结构保存，儿童期存在进行治疗干预的机会之窗深的内含子变异体可能会吸引到几种计划中的基因编辑方法。