Maculopathy due to the R345W substitution in fibulin-3: Distinct clinical features, disease variability, and extent of retinal dysfunction
Maculopathy due to the R345W substitution in fibulin-3: Distinct clinical features, disease variability, and extent of retinal dysfunction
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DOI：
10.1167/iovs.05-1600
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发表时间：
2006-07-01
影响因子：
4.4
通讯作者：
Webster, Andrew R.
中科院分区：
文献类型：
--
作者：
Michaelides, Michel;Jenkins, Sharon A.;Webster, Andrew R.
目的.为了确定（1）区分由fibulin- 3中的R345 W取代引起的黄斑病变与其他形式的遗传性或早发性玻璃疣的临床特征，（2）表型变异性，和（3）具有阳性分子诊断的那些中视网膜疾病的程度。受影响的个体接受眼科检查、数字彩色眼底摄影、眼底自发荧光（AF）成像和使用自动明视和暗适应视野检查和精细矩阵映射的心理物理测试。采集血样用于DNA提取和筛选纤蛋白-3中的R345 W突变。随后将患者分为突变阳性组和突变阴性组，以比较这两组受试者中鉴定的表型结果。来自19个家庭的29名受试者被确定为遗传性或早发性玻璃疣。来自15个家系的24名（83%）受试者被发现具有R345 W fibulin- 3突变。在突变阳性组中，黄斑玻璃疣的视乳头周围沉积和放射状分布是一致的，是区别性的标志。视网膜下新生血管膜（SRNVM）是一种罕见的发生，仅影响48只眼睛中的1只，而色素沉着过度和视网膜色素上皮（RPE）萎缩是常见的老年突变阳性患者。在突变阳性组和突变阴性组中均检测到与玻璃疣相应的AF增加。R345 W突变阳性患者组的表型变化非常大，在视力丧失、自然史、检眼镜检查结果、自体荧光成像和心理物理学数据方面存在眼间、家族内和家族间变异的证据。在一名62岁无症状、突变阳性的男性中观察到非视网膜变性的新发现。对一部分受试者进行的详细视野检查的结果与广泛的视网膜功能障碍的存在一致，而不是孤立于黄斑。在视网膜外观、严重程度、进展和非视网膜变性方面，确定了与fibulin- 3 R345 W突变相关的显著的家族间和家族内变异。值得注意的是，SRNVM在R345 W fibulin- 3黄斑病变中罕见。这些发现有助于预后和遗传咨询方面的建议。研究结果表明，视乳头周围存款的存在很可能表明患者携带R345 W突变。
PURPOSE. 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.METHODS. 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.RESULTS. 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 mutationpositive 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.CONCLUSIONS. 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.