Genetic dissection of non-syndromic retinitis pigmentosa

Retinitis pigmentosa (RP) belongs to a group of pigmentary retinopathies. It is the most common form of inherited retinal dystrophy, characterized by progressive degradation of photoreceptors that leads to nyctalopia, and ultimately, complete vision loss. RP is distinguished by the continuous retinal degeneration that progresses from the mid-periphery to the central and peripheral retina. RP was first described and named by Franciscus Cornelius Donders in the year 1857. It is one of the leading causes of bilateral blindness in adults, with an incidence of 1 in 3000 people worldwide. In this review, we are going to focus on the genetic heterogeneity of this disease, which is provided by various inheritance patterns, numerosity of variations and inter-/intra-familial variations based upon penetrance and expressivity. Although over 90 genes have been identified in RP patients, the genetic cause of approximately 50% of RP cases remains unknown. Heterogeneity of RP makes it an extremely complicated ocular impairment. It is so complicated that it is known as “fever of unknown origin”. For prognosis and proper management of the disease, it is necessary to understand its genetic heterogeneity so that each phenotype related to the various genetic variations could be treated.     

视网膜色素变性发病机制及治疗进展

视网膜色素变性（retintis pigmentosa,RP）是指以进行性感光细胞及色素上皮功能丧失为共同表现的遗传性、退行性的疾病,RP是主要的致盲性眼病。其遗传方式包括X连锁遗传、常染色体隐性或者显性遗传,也有散发。临床表现为典型的三联征:骨细胞样色素沉着、视网膜血管缩窄和视盘蜡样苍白。RP具有高度的基因异质性(多个突变位点引起同一疾病）及表型异质性。本文对RP的发病机制和治疗方法进行简要综述。     

Flicker electroretinogram in retinitis pigmentosa

Electroretinograms (ERGs) were recorded as a function of flicker frequency from 5 to 50Hz for 14 retinitis pigmentosa (RP) patients, 12 normal subjects and 1 rod monochromat. Data were analyzed by measuring the angular position of the response maximum, i.e. the phase, as a function of pulse-train frequency. Flicker ERGs obtained from the RP patients showed non-linear, frequency-dependent phase shifts when compared to the normal data. These phase shifts were simulated in a normal observer by attenuating the stimulus luminance by 1 log unit. However, the shape of the waveforms recorded from the normal differed markedly from those recorded from the RP patients. The differences, but not the ratios of the times-to-peak of the positive and negative ERG wavelets were longer in the RP patients than in the normal. These data suggest that the temporal anomalies in the RP flicker ERG are most likely due to changes in the amplitudes and time constants of the ERG components, and not simply to a reduced quantum catch or photoreceptor loss.Supported by research and core facility grants from the National Institutes of Health (EY-01791 and EY-01765)     

视网膜色素变性1基因在常染色体显性遗传视网膜色素变性家系中的突变分析

目的:研究常染色体显性遗传视网膜色素变性(autosomal dominant retinitis pigmentosa,ADRP)家系中视网膜色素变性1(retinitis pigmentosa-1,RP1)基因的突变特征及其在RP发病机制中的作用。方法:运用聚合酶链反应和直接测序方法,对6个ADRP家系的47例成员和50例对照者进行了RP1基因全编码区和邻近剪切位点的内含子区域序列突变的筛选与检测。运用单因素分析、多因素Logistic回归分析研究RP1基因点突变在RP发病中的作用。结果:ADRP家系成员和对照组RP1基因第4外显子上检测出2个变异位点。在1691和1725密码子存在杂合的两种类型的密码子(S1691P,Ser-Pro,TCT→CCT;Q1725Q,Gln-Gln,CAA→CAG)。ADRP家系成员中Ser-1691-Pro及Gln-1725-Gln位点突变率显著高于正常对照组(χ2=11.202,P<0.05)。结论:RP1基因Ser-1691-Pro及Gln-1725-Gln位点多态性可增高RP的危险性,具有潜在的致病性,考虑为ADRP家系的易感基因。     

视网膜色素变性的研究进展

视网膜色素变性(retinitis pigmentosa,RP)是常见的与遗传相关的致盲性眼病之一,随着人类基因图谱的成功建立,它成为近几年国内外基础医学和临床医学共同的研究热点。本文回顾十余年来国内外特别是国外相关文献,对视网膜色素变性的发病机制、治疗方法的研究进展作一综述。     

Mobility performance with retinitis pigmentosa

Purpose : Reduced mobility can have a serious impact on quality of life. Though previous studies have demonstrated that some vision measures relate to the mobility of subjects with simulated and true low vision, the relationship between residual vision and mobility is not clear. We investigated the relationship between clinical vision measures and mobility performance under different illumination levels for subjects with retinitis pigmentosa (RP). Methods : Binocular visual acuities, letter contrast sensitivities and static central threshold visual fields were measured on 10 subjects with RP and nine age-matched control subjects. Mobility performance was measured on an indoor mobility course at high and low illuminances and was assessed by percentage preferred walking speed (PPWS) and number of errors. Results : The RP group showed significantly reduced PPWS and greater numbers of errors than the control group. The reduction in illumination resulted in significantly worse error and PPWS scores. Unlike the control group, the presence of a glare source did not reduce the PPWS of the RP group under high illumination. Multiple regression analyses showed that the average visual field extent was the most significant predictor of mobility; letter contrast sensitivity and visual acuity added to the regression models for the low illumination measures to account for up to 75 per cent of the variation in mobility performance. Conclusions : People with RP have worse mobility than people with normal vision, more so under reduced illumination levels. Visual field extent was the strongest predictor of mobility performance. (Clin Exp Optom 1996; 80: 1: 1–12)     

视网膜色素变性的实验研究进展

视网膜色素变性是一种遗传性眼病,遗传方式包括常染色体显性遗传、常染色体隐性遗传及性连锁隐性遗传等,目前已知的突变位点超过3 000个,造成本病临床治疗困难。眼科学者致力于探索视网膜色素变性的治疗方式,进行了大量实验研究,主要有药物治疗、细胞移植、基因治疗等治疗方式。药物治疗包括中药、抗氧化剂、抗凋亡剂、神经营养因子等,与其它治疗方式相比,无侵入性,且方便价廉,但其作用机制尚需更深入的研究。细胞移植被认为是治疗视网膜色素变性的有效方法,但有可能引起视网膜前膜及黄斑皱褶。基因治疗虽然存在一定的局限性,但随着基因编辑技术和新型基因递送载体的发展,未来会成为视网膜色素变性最有希望的治疗方式之一。本文对近年来视网膜色素变性的实验研究进行了综述与展望。     

Properties of electroretinographic intensity-response functions in retinitis pigmentosa

Dark-adapted electroretinogram (ERG) b-wave amplitudes and implicit times were recorded as a function of stimulus luminance for 15 retinitis pigmentosa (RP) patients and 15 normal subjects. B-wave amplitude as a function of log stimulus luminance was fit by non-linear regression with the Naka-Rushton equation, which has 3 independent parameters: The maximum response (R_max), slope (n) and half-saturation constant (K). B-wave implicit-time as a function of log stimulus luminance was fit by linear regression. Compared to normal, the RP R_max values were markedly reduced, suggesting response compression; the RP K values were elevated by an average of 0.76 log unit, suggesting relatively small losses in retinal sensitivity. There was no correspondence between R_max and visual field area for the RP patients (coefficient of correlation = -0.02). All but 2 of the 15 RP patients had normal or shallower-than-normal implicit-time intensity-response functions, indicating that over most of the dynamic range of the ERG, the implicit-times were either normal or faster-than-normal. These results are discussed in terms of possible RP disease mechanisms.Presented at the annual meeting of the Association for Research in Vision and Ophthalmology, Sarasota, Florida, 1981.Supported by research and core facility grants from the National Eye Institute (EY-01791 and EY-01765).Research to Prevent Blindness, Foreign Scholar Fellowship recipient; from Capital Hospital, Chinese Academy of Medical Sciences, Beijing, Peoples Republic of China.     

视网膜色素变性治疗最新进展

视网膜色素变性(retinitis pigmentosa,RP)是视网膜感光细胞和色素上皮细胞变性导致的最常见遗传性致盲眼病,预后不佳,目前尚无有效的预防和治愈方法。近年来,随着基因治疗、视网膜移植等技术在动物实验中的广泛开展,给人类RP的治疗带来了新的希望。本文对RP的各种最新治疗进展进行综述。     

Accumulation of tissue inhibitor of metalloproteinases-3 in human eyes with Sorsby's fundus dystrophy or retinitis pigmentosa

BACKGROUND/AIMS—Tissue inhibitor of metalloproteinases-3 (TIMP-3) is normally synthesised by the retinal pigment epithelium (RPE) and deposited in Bruch's membrane. Mutations in the TIMP3 gene cause Sorsby's fundus dystrophy (SFD), which is characterised by thickening of Bruch's membrane, choroidal neovascularisation, and photoreceptor degeneration. To elucidate the role of TIMP-3 in human retinal degenerative diseases, we immunolocalised TIMP-3 in eyes with SFD caused by the Ser-181-Cys TIMP3 gene mutation or retinitis pigmentosa (RP; not caused by TIMP3 mutations).
METHODS—Standard light microscopic immunocytochemistry, including antigen retrieval, was used to localise TIMP-3 in paraffin sections of human eyes: two with SFD, three with different genetic forms of RP, and two normal.
RESULTS—In the SFD eyes, the thickened Bruch's membrane was strongly TIMP-3 positive except where RPE cells had degenerated. Similarly, in the RP eyes, Bruch's membrane was TIMP-3 positive except where RPE cells were lost, consistent with ongoing RPE mediated turnover of TIMP-3 in this region. In areas of total photoreceptor loss, migrated RPE cells formed cuffs around blood vessels in the RP retinas. Thick, TIMP-3 positive extracellular matrix (ECM) deposits associated with the migrated RPE cells occluded some vascular lumina, correlating with the observed loss of inner retinal neurons in RP.
CONCLUSIONS—TIMP-3 is a component of the increased ECM sequestered in Bruch's membrane in SFD. Further information is needed on normal TIMP-3/ECM interactions in Bruch's membrane and the effect of mutant TIMP-3 on this process. The finding of TIMP-3 accumulations in retinas with RP not caused by TIMP-3 mutations emphasises the importance of ECM remodelling in normal and diseased human eyes.

Keywords: tissue inhibitor of metalloproteinases-3; Sorsby's fundus dystrophy; retinitis pigmentosa; inherited retinal diseases     

Retinal histopathology of a carrier of X-chromosome-linked retinitis pigmentosa

Autopsy eyes were examined from a 79-year-old female carrier of X-chromosome-linked retinitis pigmentosa. At age 78 years, she had no visual symptoms but had intraretinal bone spicule pigmentation in the nasal and inferior periphery of both eyes. Rods, cones, and pigment epithelium in the central retina appeared normal. In the midperiphery, patches with advanced photoreceptor cell degeneration were observed overlying pigment epithelium containing melanolysosomes. Within these patches, rods and cones were reduced in number or absent, and pigment epithelial cells abutted the external limiting membrane. A precipitous decline in rod nuclei was observed in transitional zones between areas of apparently normal photoreceptors and areas of absent photoreceptors. In the far periphery, large areas lacked photoreceptors and pigment epithelium. Histopathologic findings in this elderly carrier are compared with those previously described in a 24-year-old man with X-chromosome-linked retinitis pigmentosa.     

Posterior chamber intraocular lens implantation in patients with retinitis pigmentosa

20 eyes of 12 Retinitis Pigmentosa patients underwent extracapsular cataract extraction followed by I.O.L. implantation. No unusual intra or post operative complications were encountered. All pseudophakic eyes showed improvement in visual acuity whereas the V.F. remained unaltered. Subjectively all 12 patients reported a benefit from surgery despite the Visual Field impairment.     

视网膜色素变性晚期自发荧光与中心视力相关性分析(英文)

目的:探讨典型视网膜色素变性晚期自发荧光影像与中心视力关系。方法:晚期典型视网膜色素变性37例( 70眼),采用HRA-2共焦激光扫描系统获取眼底自发荧光影像,视野30°,像素1 536×1 536,瞳孔直径>6mm,部分患者进行FERG和Humphrey静态视野检查。结果:根据自发荧光影像表现将所有患者分为4种类型,即完整型、斑驳型、孤岛型和中心低荧光型。不同类型的自发荧光表现出不同的中心视力。结果证实,眼底自发荧光影像改变与中心视力高度相关,自发荧光面积与视力有显著差异(n=57,r=0.385,P<0.01),自发荧光面积与年龄有显著差异(n=57,r=-2.67,P<0.05)。结论:自发荧光影像对于中心视力的监测和预测具有实际价值。自发荧光变化与中心视力相关,不同的荧光类型视力改变程度不同。尽管视网膜色素变性仍无彻底治愈方法,但保护性治疗是必要的,如抑制细胞凋亡、改善供血以及营养神经元等。     

A novel missense variant in IDH3A causes autosomal recessive retinitis pigmentosa

Background: Inherited retinal degenerations (IRDs) encompass a wide spectrum of genetic ocular diseases characterized by considerable genetic and clinical heterogeneity.

Methods: Complete ophthalmic examination and next-generation sequencing.

Results: We describe a patient with no family history of vision loss, who at the age of 28 years developed visual impairment consistent with a severe form of retinitis pigmentosa. Genetic testing by means of whole exome sequencing identified a homozygous variant in the gene IDH3A. To date, only three papers have reported mutations in IDH3A, in families with early-onset retinal degeneration with or without the presence of macular pseudocoloboma.

Conclusion: This study highlights the importance of including this rarely-mutated gene in the molecular diagnostic set-ups for IRDs, and further delineates the phenotypic spectrum elicited by mutations in IDH3A.     

视网膜色素变性的治疗进展

视网膜色素变性(retinitis pigmentosa,RP)是一类以进行性感光细胞和色素上皮细胞功能障碍为特征的遗传性疾病,是世界范围内常见的致盲性眼病。其发病机制和确切病因尚不明了,至今缺乏有效治疗办法。我们回顾近年来国内外特别是国外相关文献,对视网膜色素变性的治疗方法的研究进展作一综述。