Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
Ophthalmology. 2015 May;122(5):997-1007. doi: 10.1016/j.ophtha.2014.11.025. Epub 2015 Jan 21.
Achromatopsia (ACHM) is a congenital, autosomal recessive retinal disease that manifests cone dysfunction, reduced visual acuity and color vision, nystagmus, and photoaversion. Five genes are known causes of ACHM. The present study took steps toward performing a trial of gene therapy in ACHM by characterizing the genetics of ACHM in Israel and the Palestinian Territories and analyzing retinal function and structure in CNGA3 ACHM patients from the Israeli-Palestinian population and US patients with other origins.
Case series study.
Patients with clinically suspected ACHM, cone dysfunction phenotypes, and unaffected family members were included. The protocol was approved by the local institutional review board and informed consent was obtained from all participants.
Genetic analyses included homozygosity mapping and exome sequencing. Phenotype was assessed with electroretinography (ERG), optical coherence tomography, psychophysics, and photoaversion testing.
Single nucleotide polymorphism microarray, exome analysis, DNA sequence analysis, visual function testing including ERG, and photoaversion.
We identified 148 ACHM patients from 57 Israeli and Palestinian families; there were 16 CNGA3 mutations (5 novel) in 41 families and 5 CNGB3 mutations (1 novel) in 8 families. Two CNGA3 founder mutations underlie >50% of cases. These mutations lead to a high ACHM prevalence of ∼1:5000 among Arab-Muslims residing in Jerusalem. Rod ERG abnormalities (in addition to cone dysfunction) were detected in 59% of patients. Retinal structure in CNGA3 ACHM patients revealed persistent but abnormal foveal cones. Under dark- and light-adapted conditions, patients use rod-mediated pathways. Photoaversion was readily demonstrated with transition from the dark to a dim light background.
Among Israeli and Palestinian patients, CNGA3 mutations are the leading cause of ACHM. Retinal structural results support the candidacy of CNGA3 ACHM for clinical trials for therapy of cone photoreceptors. Efficacy outcome measures would include chromatic light-adapted psychophysics, with attention to the photoreceptor basis of the response, and quantitation of photoaversion.
色盲（ACHM）是一种先天性、常染色体隐性视网膜疾病，表现为 cones 功能障碍、视力和色觉下降、眼球震颤和畏光。已知有五个基因是 ACHM 的致病原因。本研究通过对以色列和巴勒斯坦地区 ACHM 的遗传学进行特征描述，并对来自以色列-巴勒斯坦人群和其他起源的 US 患者的 CNGA3 ACHM 患者的视网膜功能和结构进行分析，朝着在 ACHM 中进行基因治疗试验迈出了一步。
病例系列研究。
纳入临床疑似 ACHM、cones 功能障碍表型和未受影响的家庭成员。该方案获得了当地机构审查委员会的批准，并获得了所有参与者的知情同意。
遗传分析包括 homozygosity mapping 和 exome sequencing。表型评估包括视网膜电图（ERG）、光学相干断层扫描、心理物理学和畏光测试。
单核苷酸多态性微阵列、外显子分析、DNA 序列分析、包括 ERG 在内的视觉功能测试和畏光测试。
我们从 57 个以色列和巴勒斯坦家庭中确定了 148 名 ACHM 患者；在 41 个家庭中发现了 16 个 CNGA3 突变（5 个新突变）和 8 个家庭中的 5 个 CNGB3 突变（1 个新突变）。两个 CNGA3 启动子突变导致超过 50%的病例。这些突变导致居住在耶路撒冷的阿拉伯穆斯林中的 ACHM 患病率高达约 1:5000。在 59%的患者中检测到 rod ERG 异常（除了 cones 功能障碍之外）。CNGA3 ACHM 患者的视网膜结构显示出持续但异常的中央凹 cones。在暗适应和明适应条件下，患者使用 rod 介导的途径。从暗适应过渡到昏暗的背景时，很容易出现畏光现象。
在以色列和巴勒斯坦患者中，CNGA3 突变是 ACHM 的主要原因。视网膜结构结果支持 CNGA3 ACHM 作为 cone 光感受器治疗的临床试验候选药物。疗效评估指标将包括色觉明适应心理物理学，注意反应的光感受器基础，并定量畏光。
