Phenotype and Progression of Retinal Degeneration Associated With Nullizigosity of ABCA4
Phenotype and Progression of Retinal Degeneration Associated With Nullizigosity of ABCA4
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DOI：
10.1167/iovs.16-19829
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发表时间：
2016-09-01
影响因子：
4.4
通讯作者：
Webster, Andrew R.
中科院分区：
文献类型：
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作者：
Fakin, Ana;Robson, Anthony G.;Webster, Andrew R.
目的。我们描述了与 ABCA4 基因中的无效性和九个剪接突变相关的表型。该研究包括 19 名双等位基因无效突变患者（A 组，无效合子）、27 名具有纯合状态或反式剪接突变的无效突变患者（B 组），以及 20 名 p 组患者。反式 G1961E 具有无效突变（C 组，对照）。根据病史确定发病年龄和视力。使用区域查找器测量 30 度 x 30 度眼底自发荧光 (FAF) 图像内自发荧光减少的区域 (N = 58)。全视野视网膜电图 (ERG) 是根据国际临床视觉电生理学会 (ISCEV) 标准进行的 (N = 40)。 结果。 A 至 C 组的中位发病年龄分别为 6 岁、8 岁和 17 岁。 Kaplan Meier 生存分析估计，50% 的患者分别在 29 岁、48 岁和 66 岁时视力低于 20/400。 FAF 减少的面积估计每年分别增加 1.5、1.2 和 0.03 mm(2)，并且锥杆营养不良分别出现在 10/12、13/15 和 0/13 的病例中。剪接突变 C.与所有参数无效的患者相比，5714+5G>A 与显着较轻的表型相关。结论。 ABCA4 的无效合子与早发的视锥杆功能障碍相关，并伴有快速进展，表现为 FAF 中央萎缩扩大、ERG 振幅随年龄增长而下降，以及到 40 岁时达到法定失明的高风险。大多数研究的剪接突变都与类似的严重表型相关。估计的进展率可能有助于进一步的基因型-表型相关性并为治疗试验的设计提供信息。
PURPOSE. We describe the phenotypes associated with nullizigosity and nine splicing mutations in the ABCA4 gene.METHODS. The study included 19 patients with biallelic null mutations (Group A, nullizygous), 27 with splicing mutations in the homozygous state or in trans with a null mutation (Group B), and 20 with p. G1961E in trans with a null mutation (Group C, control). Ages at onset and visual acuities were determined from medical histories. Area of decreased autofluorescence within a 30 degrees x 30 degrees fundus autofluorescence (FAF) image was measured with the Region Finder (N = 58). Full-field electroretinography (ERG) was performed incorporating the International Society for Clinical Electrophysiology of Vision (ISCEV) standard (N = 40).RESULTS. For groups A to C, the median ages of onset were 6, 8, and 17, respectively. Kaplan Meier survival analysis estimated that 50% of patients reached visual acuity below 20/400 at the ages of 29, 48, and 66 years, respectively. The area of reduced FAF was estimated to increase by 1.5, 1.2, and 0.03 mm(2) per year, respectively, and cone-rod dystrophy was present in 10/12, 13/15, and 0/13 of cases, respectively. Splicing mutation c. 5714+5G>A was associated with a significantly milder phenotype in comparison with nullizygous patients for all parameters.CONCLUSIONS. Nullizygosity for ABCA4 is associated with early onset cone-rod dysfunction with rapid progression shown by enlargement of central atrophy on FAF, decline of ERG amplitudes with age, and a high risk of reaching legal blindness by the fourth decade. Most studied splicing mutations were associated with a similarly severe phenotype. Estimated rates of progression may facilitate further genotype-phenotype correlations and inform the design of treatment trials.