Michaelides Michel, Jenkins Sharon A, Brantley Milam A, Andrews Richard M, Waseem Naushin, Luong Vy, Gregory-Evans Kevin, Bhattacharya Shomi S, Fitzke Fred W, Webster Andrew R
Moorfields Eye Hospital, City Road, and Instiute of Ophthalmology, University College London, United Kingdom.
Invest Ophthalmol Vis Sci. 2006 Jul;47(7):3085-97. doi: 10.1167/iovs.05-1600.
To determine (1) clinical features that distinguish maculopathy due to the R345W substitution in fibulin-3 from other forms of inherited or early-onset drusen, (2) the phenotypic variability, and (3) the extent of retinal disease in those with a positive molecular diagnosis.
Affected individuals underwent ophthalmic examination, digital color fundus photography, fundus autofluorescence (AF) imaging, and psychophysical testing with automated photopic and dark-adapted perimetry and fine matrix mapping. Blood samples were taken for DNA extraction and screening for the R345W mutation in fibulin-3. Patients were subsequently divided into mutation-positive and -negative groups, to compare the identified phenotypic findings in these two sets of subjects.
Twenty-nine subjects from 19 families were ascertained with inherited or early-onset drusen. Twenty-four (83%) subjects from 15 families were found to harbor the R345W fibulin-3 mutation. Peripapillary deposition and a radial distribution of macular drusen were consistent, distinguishing signs in the mutation-positive group. Subretinal neovascular membrane (SRNVM) was a rare occurrence, affecting only 1 of 48 eyes, whereas hyperpigmentation and atrophy of the retinal pigment epithelium (RPE) were common in older mutation-positive patients. Increased AF corresponding to the drusen was detected in both the mutation-positive and -negative groups. The phenotype in the group of patients positive for the R345W mutation was extremely variable, with evidence of interocular, intrafamilial, and interfamilial variability in visual loss, natural history, ophthalmoscopic findings, autofluorescence imaging, and psychophysical data. The novel finding of nonpenetrance was observed in a 62-year-old asymptomatic, mutation-positive man. The findings from detailed perimetry performed on a subset of subjects were consistent with the presence of widespread retinal dysfunction not isolated to the macula.
Marked inter- and intrafamilial variation associated with the fibulin-3 R345W mutation in terms of retinal appearance, severity, progression, and nonpenetrance were identified. It was noted that SRNVM is a rare occurrence in R345W fibulin-3 maculopathy. These findings are helpful for advice regarding prognosis and for genetic counseling. The findings established that the presence of peripapillary deposit is highly likely to indicate that a patient carries the R345W mutation.
确定（1）因纤连蛋白-3中R345W替代导致的黄斑病变与其他形式的遗传性或早发性玻璃膜疣相区别的临床特征，（2）表型变异性，以及（3）分子诊断呈阳性者的视网膜疾病程度。
受影响个体接受眼科检查、数字彩色眼底照相、眼底自发荧光（AF）成像，以及使用自动明视和暗适应视野计及精细矩阵映射进行的心理物理学测试。采集血样用于DNA提取和筛查纤连蛋白-3中的R345W突变。随后将患者分为突变阳性和阴性组，以比较这两组受试者中确定的表型发现。
确定了来自19个家庭的29名患有遗传性或早发性玻璃膜疣的受试者。发现来自15个家庭的24名（83%）受试者携带纤连蛋白-3的R345W突变。视乳头周围沉积物和黄斑玻璃膜疣的放射状分布是突变阳性组一致的鉴别体征。视网膜下新生血管膜（SRNVM）罕见，仅48只眼中有1只眼受影响，而色素沉着过度和视网膜色素上皮（RPE）萎缩在年龄较大的突变阳性患者中常见。在突变阳性和阴性组中均检测到与玻璃膜疣相对应的AF增加。R345W突变阳性患者组的表型极具变异性，在视力丧失、自然病程、检眼镜检查结果、自发荧光成像和心理物理学数据方面存在眼间差异、家族内差异和家族间差异。在一名62岁无症状的突变阳性男性中观察到了新的外显不全现象。对一部分受试者进行的详细视野检查结果与广泛的视网膜功能障碍（并非局限于黄斑）的存在一致。
确定了与纤连蛋白-3 R345W突变相关的显著家族间和家族内变异体现在视网膜外观、严重程度、进展和外显不全方面。注意到SRNVM在R345W纤连蛋白-3黄斑病变中罕见。这些发现有助于提供预后建议和遗传咨询。这些发现证实视乳头周围沉积物的存在极有可能表明患者携带R345W突变。
