Pathology of Retinitis Pigmentosa

Eyes from patients with retinitis pigmentosa were obtained at autopsy. They were processed in celloidin and examined by light microscopy. The earliest evidence of retinal degeneration occurred in the equatorial zone and then extended peripherally and centrally. In the eyes with the earliest involvement, a sequence could be demonstrated in the zone of transition from the less involved macula to the more degenerated retina at the equator. The probable order for the development of degenerative changes in our material appeared to be as follows: (1) migration of nuclei from the outer nuclear layer to the rod and cone layer and the outer plexiform layer; (2) degeneration and loss of photoreceptors and their nuclei in the outer nuclear layer; (3) loss of connecting fibers in the outer plexiform layer; (4) migration of the retinal pigment epithelium (RPE) into the retina, mainly around the blood vessels, but also as isolated balls and spots (this prominent feature, which characterizes the disease, is secondary and only follows the loss of the photoreceptors and their nuclei); (5) adhesion of the retinal to the retinal pigment epithelium or Bruch’s membrane in spots or broad areas and; (6) possible transneuronal degeneration of some cells in the inner nuclear and ganglion cell layers. Gliosis of the disc was universal as was the presence of glial membranes from the disc extending over the posterior retina, especially prominent in the macular region. As the material was obtained from 16 to 35 years ago, we lack electrophysiologic and familial data and electron microscopy was not possible     

Central Visual Function and Genotype–Phenotype Correlations in PDE6A-Associated Retinitis Pigmentosa

PurposeAutosomal recessive retinitis pigmentosa (arRP) can be caused by mutations in the phosphodiesterase 6A (PDE6A) gene. Here, we describe the natural course of disease progression with respect to central retinal function (i.e., visual acuity, contrast sensitivity, and color vision) and establish a detailed genotype-–phenotype correlation.MethodsForty-four patients (26 females; mean age ± SD, 43 ± 13 years) with a confirmed genetic diagnosis of PDE6A-associated arRP underwent comprehensive ophthalmological examinations including best-corrected visual acuity (BCVA) with Early Treatment Diabetic Retinopathy Study charts, contrast sensitivity (CS) with Pelli–Robson charts at distances of 3 m and 1 m, and color vision testing using Roth 28-Hue and Panel D-15 saturated color cups.ResultsThe most frequently observed variants were c.998+1G>A/p.?, c.304C>A/p.R102S, and c.2053G>A/p.V685M. Central retinal function in patients homozygous for variant c.304C>A/p.R102S was better when compared to patients homozygous for variant c.998+1G>A/p.?, although the former were older at baseline. Central retinal function was similar in patients homozygous for variant c.304C>A/p.R102S and patients heterozygous for variants c.304C>A/p.R102S and c.2053G>A/p.V685M, although the latter were younger at baseline. Annual decline rates in central retinal function were small.ConclusionsWe conclude that the severity of the different disease-causing PDE6A mutations in humans with respect to central visual function may be ranked as follows: c.2053G>A/p.V685M in homozygous state (most severe) > c.998+1G>A/p.? in homozygous state > c.304C>A/p.R102S and c.2053G>A/p.V685M in compound-heterozygous state > c.304C>A/p.R102S in homozygous state (mildest). The assessment of treatment efficacy in interventional trials will remain challenging due to small annual decline rates in central retinal function.     

Unique Characteristics of Two Types of Retinitis Pigmentosa Patients with Different Rod Sensitivities

Purpose To determine the psychophysical differences between two types of retinitis pigmentosa (RP) patients with different rod sensitivities.Methods Thirty-five RP patients with a visual acuity of 0.7 or better were classified by cone–rod perimetry into type 1, those with undetectable rod sensitivity, and type 2, those with measurable rod sensitivity. Their symptoms, age at onset of symptoms, cone and rod sensitivity, and full-field electroretinograms (ERGs) were compared.Results The age when the symptoms of night blindness were first noticed was 13.1 ± 3.3 years (mean ± SD) for type 1 and 34.5 ± 14.4 years for type 2 patients (P = 0.0001). One of nine type 1 patients (11%) and 10 of 26 type 2 patients (38%) did not have any symptoms of night blindness. The average rod sensitivity within the central 10° was 43.7 ± 12.0dB for type 2 patients with night blindness, and 54.8 ± 6.4dB for type 2 patients without night blindness (P = 0.014). One of nine (11%) type 1 patients and 9 of 23 (39%) type 2 patients had recordable ERGs (P = 0.13).Conclusions These findings indicate that the two types of RP patients, distinguished by their rod sensitivity, have different psychophysical characteristics of the visual system. The course of the disease process and the long-term prognosis for these two types of patients are different. Jpn J Ophthalmol 2005;49:114–120 © Japanese Ophthalmological Society 2005     

Management of Cystoid Macular Edema in Retinitis Pigmentosa

ABSTRACT

Retinitis pigmentosa is a genetically heterogeneous disorder with an estimated prevalence of one in 4,000 that is classically characterized by the progressive constriction of peripheral vision and a later deterioration of visual acuity. Central vision can be compromised earlier in disease, however, in the approximately 25% of patients that have cystoid macular edema. This poorly understood problem can thus significantly impair patient quality of life, particularly as available treatments have limited efficacy. We will review clinical features of retinitis pigmentosa-associated cystoid macular edema, potential causative mechanisms, and finally, evidence supporting currently employed therapies with emphasis upon which management strategies require further evidence-based evaluation.     

Retinitis Pigmentosa: A Review of the Tapeto-Retinal Dystrophies

ABSTRACT: The signs and symptoms, clinical course, underlying pathology, hereditary characteristics and management of retinitis pigmentosa are reviewed. Aberrant forms of retinitis pigmentosa are discussed and those syndromes in which retinitis pigmentosa feature are listed.     

Mutational Analysis of the Rhodopsin Gene in Sector Retinitis Pigmentosa

Background: To determine the role of rhodopsin (RHO) gene mutations in patients with sector retinitis pigmentosa (RP) from Northern Ireland.

Design: A case series of sector RP in a tertiary ocular genetics clinic.

Participants: Four patients with sector RP were recruited from the Royal Victoria Hospital (Belfast, Northern Ireland) and Altnagelvin Hospital (Londonderry, Northern Ireland) following informed consent.

Methods: The diagnosis of sector RP was based on clinical examination, International Society for Clinical Electrophysiology of Vision (ISCEV) standard electrophysiology, and visual field analysis. DNA was extracted from peripheral blood leucocytes and the coding regions and adjacent flanking intronic sequences of the RHO gene were polymerase chain reaction (PCR) amplified and cycle sequenced.

Main Outcome Measure: Rhodopsin mutational status.

Results: A heterozygous missense mutation in RHO (c.173C?>?T) resulting in a non-conservative substitution of threonine to methionine (p. Thr58Met) was identified in one patient and was absent from 360 control individuals. This non-conservative substitution (p.Thr58Met) replaces a highly evolutionary conserved polar hydrophilic threonine residue with a non-polar hydrophobic methionine residue at position 58 near the cytoplasmic border of helix A of RHO.

Conclusions: The study identified a RHO gene mutation (p.Thr58Met) not previously reported in RP in a patient with sector RP. These findings outline the phenotypic variability associated with RHO mutations. It has been proposed that the regional effects of RHO mutations are likely to result from interplay between mutant alleles and other genetic, epigenetic and environmental factors.     

Retinitis Pigmentosa: A Symposium on Terminology and Methods of Examination

This report represents a summary of opinions expressed at a meeting of specialists interested in retinitis pigmentosa (RP) and allied diseases, at which an attempt was made to define some minimum guidelines for ocular evaluation of these disorders. The term RP would be reserved for a group of hereditary disorders that diffusely involve photoreceptor and pigment epithelial function, and should not be used when a secondary cause is suspected. RP may be classified by genetic type (single cases without known affected relatives should be termed isolated or simplex), by the topography of retinal involvement, and by the severity of disease (to identify subtypes with mild or localized disease). Patients should have at least one comprehensive examination that conforms to basic standards, preferable early in the course of the disease. The visual field examination should use both a small and a large test light. Electroretinographic testing should (1) use a full-field stimulus, and (2) routinely document three independent responses (cone, rod, and mixed conerod). Patients should be identifiable for future study or therapeutic trials. They should be counseled about the disease and followed regularly. No specific therapy exists at present for most of these diseases, but optical and night vision aids are available. Sunglasses for outdoor use are recommended until more is known about whether long-term exposure to bright sunlight alters the course of these diseases.     

视网膜色素变性的多焦视诱发电位及其与视野的比较

目的:探讨视网膜色素变性(retinitispigmentosa,RP)的多焦视诱发电位(multifocalvisualevokedpotential,mfVEP)特性及评价mfVEP作为RP客观视野检测方法的可能性。方法:检测12例(19只眼)RP患者和15例(30只眼)正常人的mfVEP,刺激野为带图形的含60个小块的飞镖盘,单侧对应视角为26°。比较RP患者与正常人mfVEP的二阶函数核第一片的P1波的振幅。对RP患者还进行30°阈值视野检测,检验对应区域mfVEP的P1波振幅总和与视野光敏感度总和的相关性。结果:与正常人相比,RP患者各环的mfVEP的P1振幅总和的降低均有显著意义(P<0.05)。除了下1环和下2环外,其余各环mfVEP的P1振幅总和与视野光敏感度总和均有显著相关(P<0.05)。结论:mfVEP与视野间存在着一定的相关性,mfVEP可作为评价RP患者视功能的客观方法。     

New COL6A6 Variant Causes Autosomal Dominant Retinitis Pigmentosa in a Four-Generation Family

PurposeTo report that variants in the gene for a large lamina basal component protein, COL6A6 (collagen type VI alpha 6 chain, Col6α6), linked to chromosome 3p22.1 causes retinitis pigmentosa (RP) in patients with autosomal dominant transmission (adRP).MethodsA positional-cloning approach, whole exome sequencing, and modeling were used. The proband and several affected family members have been phenotyped and followed for over 12 years.ResultsA heterozygous missense variant, c.509C>G (p. Ser170Cys) in exon 2 of COL6A6 (comprised of 36 exons and 2236 amino acids), was observed in a four- generation family and is likely to cause the adRP phenotype. It was identified in 10 affected members. All affected family members had a distinct phenotype: late-onset rod cone dystrophy, with good retained visual acuity, until their late 70s. Immunohistochemistry of human retina showed a dot-like signal at the base of the inner segments of photoreceptors and outer plexiform layer (OPL). The structural modeling of the N7 domain of Col6α6 suggests that the mutant might result in the abnormal cellular localization of collagen VI or malformation of collagen fibers resulting in the loss of its unique filament structure.Conclusions COL6A6 is widely expressed in human tissues and evolutionary conserved. It is thought to interact with a range of extracellular matrix components. Our findings suggest that this form of RP has long-term useful central visual acuity and a mild progression, which are important considerations for patient counseling.     

The Saccade Main Sequence in Patients With Retinitis Pigmentosa and Advanced Age-Related Macular Degeneration

PurposeMost eye-movement studies in patients with visual field defects have examined the strategies that patients use while exploring a visual scene, but they have not investigated saccade kinematics. In healthy vision, saccade trajectories follow the remarkably stereotyped “main sequence”: saccade duration increases linearly with saccade amplitude; peak velocity also increases linearly for small amplitudes, but approaches a saturation limit for large amplitudes. Recent theories propose that these relationships reflect the brain''s attempt to optimize vision when planning eye movements. Therefore, in patients with bilateral retinal damage, saccadic behavior might differ to optimize vision under the constraints imposed by the visual field defects.MethodsWe compared saccadic behavior of patients with central vision loss, due to age-related macular degeneration (AMD), and patients with peripheral vision loss, due to retinitis pigmentosa (RP), to that of controls with normal vision (NV) using a horizontal saccade task.ResultsBoth patient groups demonstrated deficits in saccade reaction times and target localization behavior, as well as altered saccade kinematics. Saccades were generally slower and the shape of the velocity profiles were often atypical, especially in the patients with RP. In the patients with AMD, the changes were far less dramatic. For both groups, saccade kinematics were affected most when the target was in the subjects’ blind field.ConclusionsWe conclude that defects of the central and peripheral retina have distinct effects on the saccade main sequence, and that visual inputs play an important role in planning the kinematics of a saccade.     

Visual Outcomes in Japanese Patients with Retinitis Pigmentosa and Usher Syndrome Caused by USH2A Mutations

Purpose: EYS and USH2A are the most common causative genes for retinitis pigmentosa (RP) in Japan. We determined the clinical outcomes for USH2A-related non-syndromic RP or Usher syndrome type II (USH2). Methods: Two non-syndromic RP and 11 USH2 patients with previously identified USH2A mutations were included. Their complete history and medical records were collected using standard procedures. Visual fields and acuity were compared with those of patients with EYS mutations. Clinical analyses were based on ophthalmic and otolaryngologic examinations. Results: In all patients, the fundus displayed changes typical of RP. Most patients showed relatively well-preserved visual acuity in their thirties or forties, with rapid deterioration in their fifties. Concentric constriction started in the twenties or thirties, and no effective residual visual field was observed after the fifties. Conclusions: The visual outcome for non-syndromic RP or USH2 patients with USH2A mutations is consistent with that for RP patients with EYS mutations.     

视网膜色素变性伴发高度近视的临床特征和诊治研究进展

视网膜色素变性（RP）是全球最常见的致盲性眼病之一,它具有高度遗传异质性。患者因感光细胞和色素上皮细胞功能逐渐丧失,表现出夜盲、管状视野,甚至失明。但研究表明,有些RP患者还会伴发其他眼病如白内障、高度近视,其中,RP伴发高度近视因对视力损害严重而不断被关注。笔者回顾了近年来RP伴发高度近视病例的相关报道,通过总结该类患者的临床特征和诊治研究进展,旨在了解该病的基因型-表型关系,为该病的诊断和遗传咨询提供一定的理论依据。     

Factors associated with visual acuity in patients with cystoid macular oedema and Retinitis Pigmentosa

Purpose: Retinitis pigmentosa is the most common inherited retinal dystrophy. The factors associated with visual acuity in patients with other retinal diseases are well known, but are poorly understood in patients with retinitis pigmentosa. This knowledge is useful for prognosis and to support secondary endpoints in clinical trials.

Methods: We conducted a cross-sectional study of consecutive patients recruited from the inherited retinal disease service from January 2012 to December 2012. Central macular thickness (CMT) was measured using spectral domain optical coherence tomography.

Results: Data were available for 81 patients and 162 eyes. After multivariable analyses, older age, earlier age of onset of symptoms, and thicker CMT were associated with lower visual acuity. Gender and inheritance pattern were not associated with visual acuity. Each decade older age, younger age of onset, and thicker CMT was associated with 0.12, 0.10, and 0.11 worse logarithm of the minimal angle of resolution units of visual acuity, respectively (p < 0.05 for all).

Conclusions: Age, age of onset, and CMT are associated with visual acuity and important factors to measure in studies of retinitis pigmentosa.     

Non-viral retinal gene therapy: a review

In the developed world, diseases of the retina are common causes of untreatable blindness. In many cases, a genetic component to the aetiology has been identified, making the development of gene-based treatments a logical long-term goal. The clinical strategy for retinal gene therapy broadly encompasses two distinct advantages over systemic drug delivery. First is that gene delivery can limit expression of a therapeutic protein to a specific target cell, which is rarely possible even with local drug delivery methods. Second, by delivering DNA that remains stable and non-degraded, gene expression and hence protein production could in theory be indefinite, obviating the need for repeated tablets or injections. Viruses have evolved distinct mechanisms, such as receptor mediated uptake and genomic integration, which efficiently encompass these two properties. For non-viral gene therapy approaches, however, nuclear localization and stable long-term transgene expression remain significant hurdles that need to be overcome. The challenge of non-viral gene therapy is therefore to harness current laboratory and molecular-based techniques to develop a man-made system that can approach the efficiency of a natural biological process. In the unique environment of the retina, this goal may not be insurmountable and would overcome the major limiting factor of adeno-associated viral vectors, which is the size of gene that can be delivered.     

基因组编辑技术在遗传性视网膜营养不良基因治疗和细胞治疗中的应用

遗传性视网膜营养不良(inherited retinal dystrophies,IRDs)是发展中国家青年人群视力障碍的主要原因,这些疾病呈现不可逆的视觉功能障碍和(或)神经视网膜细胞的丢失,显著影响患者生活质量。由于眼睛的解剖学可及性和免疫赦免特性,眼科研究一直处于创新的基因治疗和细胞治疗的前沿,这两种疗法均具有作为IRDs患者治疗方法的巨大潜力。群集规则间隔短回文重复序列(CRISPR)和CRISP相关蛋白(Cas)等基因组编辑技术为编辑人类基因组提供了准确和有效的方法,成为治疗IRDs的一个极具前景的替代方案。目前,基因组编辑和干细胞技术领域迅猛发展,可以联合为患者提供精确和个性化的治疗,但尚存在缺陷和不足,需进一步研究。     

Peripheral Visual Fields in Children and Young Adults Using Semi-automated Kinetic Perimetry: Feasibility of Testing,Normative Data,and Repeatability

Normative visual field area, feasibility and repeatability using (Octopus) semi-automated kinetic perimetry are reported in 221 healthy volunteers aged 5–22 years. I4e and I2e stimuli assessed the visual field at 5°/second (°/s) or 3°/s. Blind spot was assessed with I2e at 2°/s. Reliable visual fields were plotted in 23% of participants <10 years, 64% of 10–12-year-olds, and 98% aged 13–22 years. Visual field areas were unchanged with age using 5°/s, but increased using 3°/s for I2e (p = 0.028). Blind spot area was unchanged with age. Reaction times reduced with age (p < 0.004). There was no learning effect. A test speed of 5°/s is recommended.     

Peripheral Visual Fields in Children and Young Adults Using Semi-automated Kinetic Perimetry: Feasibility of Testing,Normative Data,and Repeatability

Abstract

Normative visual field area, feasibility and repeatability using (Octopus) semi-automated kinetic perimetry are reported in 221 healthy volunteers aged 5–22 years. I4e and I2e stimuli assessed the visual field at 5°/second (°/s) or 3°/s. Blind spot was assessed with I2e at 2°/s. Reliable visual fields were plotted in 23% of participants <10 years, 64% of 10–12-year-olds, and 98% aged 13–22 years. Visual field areas were unchanged with age using 5°/s, but increased using 3°/s for I2e (p?=?0.028). Blind spot area was unchanged with age. Reaction times reduced with age (p?<?0.004). There was no learning effect. A test speed of 5°/s is recommended.     

A transgenic mouse model for gene therapy of rhodopsin-linked Retinitis Pigmentosa

Mutational heterogeneity in genes causative of dominantly inherited disorders represents a significant barrier for development of therapies directed towards correction of the primary genetic defect. To circumvent the mutational heterogeneity present in rhodopsin- (RHO-) linked autosomal dominant Retinitis Pigmentosa (adRP), a strategy involving suppression and replacement of RHO has been adopted. RNA interference- (RNAi-) mediated suppression of RHO has been explored as has the generation of an RNAi-resistant replacement gene using the degeneracy of the genetic code. Additionally, the functional equivalence of codon-modified replacement genes has been demonstrated in a transgenic animal (RHO-M). Suppression and replacement, while exemplified by adRP, may also be relevant to many other dominantly inherited diseases with the hallmark of mutational heterogeneity.     

Assessment of Functional Vision Score and Vision-Specific Quality of Life in Individuals With Retinitis Pigmentosa

Purpose

To determine the relationship between the American Medical Association''s (AMA) functional vision score (FVS) and vision-specific quality of life in retinitis pigmentosa (RP) patients using the National Eye Institute''s Visual Functioning Questionnaire (NEI-VFQ 25).

Methods

One hundred eight patients with RP participated in the study. We measured best-corrected visual acuity, conducted Goldmann perimetry, and collected the self-reported NEI-VFQ 25. The FVS was calculated using the functional field score (FFS) and the functional acuity score (FAS). The correlations of the VFQ composite scores to the FVS, FFS, and FAS were determined using correlation and regression analyses.

Results

FVS was highly correlated to the BCVA (r=0.69, p<0.001), the FFS (r=0.86, p<0.001) and the FAS (r=0.73, p<0.001). Significant correlations of the VFQ composite score to the BCVA (r=0.60, p<0.001), FFS (r=0.44, p<0.001), FAS (r=0.60, p<0.001), FVS (r=0.58, p<0.001) were also found. However, the correlation strengths of BCVA, FVS, FAS, and FFS to NEI-FVQ were not different.

Conclusions

In RP patients, the vision-specific quality of life was correlated with the AMA guidelines'' FVS, FFS, and FAS. Their correlation degrees to NEI-FVQ were not different. This result suggests that vision-specific quality of life can be explained by both visual acuity and visual field in RP patients.     

Histopathological Changes of Inner Retina,Optic Disc,and Optic Nerve in Rabbit with Advanced Retinitis Pigmentosa

We observed the histopathological changes of retinal ganglion cells (RGCs), optic disc, and optic nerve in rabbit with advanced retinitis pigmentosa (RP). Wild-type (WT) and rhodopsin transgenic (Tg) of RP rabbits were used at age 24 months. Light and electron microscopy were used to observe the retina, optic disc, and optic nerve. RGCs were also confirmed by immunofluorescent staining with a TUJ-1 monoclonal antibody. In addition to the rod and cone degeneration, we observed the astrocyte infiltration of the optic disc due to the damage of small RGCs and nerve fibres and atrophy of small optic nerve fibres. They subsequently lead to the optic disc excavation and atrophy of the optic nerve. Consequently, our histopathological study clarified that not only the outer retina but also the inner retina, the optic disc, and the optic nerve were also affected in the late stages of RP rabbit.