James Tee

RPGR-associated retinopathy: clinical features, molecular genetics, animal models and therapeutic options

Retinitis pigmentosa GTPase regulator (RPGR) gene sequence variants account for the vast majority of X linked retinitis pigmentosa (RP), which is one of the most severe forms of RP. Symptoms of nyctalopia typically begin in childhood, with increasing loss of peripheral visual field during teenage years, and progressive central visual loss during the second to fourth decade of life. There is however marked intrafamilial and interfamilial phenotypic heterogeneity in affected males and carrier females. There is now a far greater understanding of the range of phenotypes associated with variants in this gene; including rod-cone dystrophy, cone-rod dystrophy, cone dystrophy, macular dystrophy and non-ocular phenotypes. There are also increasingly established genotype-phenotype associations and structure-function correlations. RPGR is involved in ciliary function, with ciliary dysfunction now recognised as the mechanism underlying a large proportion of inherited retinal disease. There has been significant progress in identifying naturally occurring animal models and developing novel models to define the underlying disease mechanisms and to test gene replacement therapy, in addition to advances in human retinal imaging, culminating in completed and planned clinical trials. These significant developments will be discussed.

The Effect of Multispot Laser Panretinal Photocoagulation on Retinal Sensitivity and Driving Eligibility in Patients With Diabetic Retinopathy

IMPORTANCE Panretinal photocoagulation (PRP) for proliferative diabetic retinopathy (PDR) may lead to peripheral field loss that prevents driving. Anti-vascular endothelial growth factor agents are proposed as treatments for PDR that spare peripheral vision. If multispot lasers cause less visual field loss, continuing to perform PRP may be justified. OBJECTIVE To assess the effect of bilateral multispot laser PRP on retinal sensitivity and driving visual fields in PDR. DESIGN, SETTING, AND PARTICIPANTS This prospective nonrandomized interventional cohort analysis performed at a tertiary referral center included 43 laser-naive patients with PDR that required bilateral PRP. Participants were recruited from June 27, 2012, to October 14, 2013. At baseline and 6-month follow-up, patients underwent detailed static and kinetic perimetry, microperimetry, optical coherence tomography, wide-field color fundus photography, and fluorescein angiography. Quantitative change in retinal sensitivity was assessed by comparing the mean global retinal sensitivity before and after laser treatment and by comparing the modeled hill of vision by deriving a volumetric measure. Final follow-up was completed on May 21, 2014. INTERVENTIONS Multispot laser treatment was applied using standard parameters, until neovascularization regressed or complete retinal coverage was achieved. MAIN OUTCOMES AND MEASURES Participants who passed the Esterman binocular visual field test for driving in the United Kingdom (at least 120° horizontal field with no significant defects within the central 20°) and full-field and macular retinal sensitivity. RESULTS Of the 43 patients (17 men; 26 women; mean [SD] age, 46.6 [13.3] years), 38 (88%) completed the study. Before treatment, 41 of 43 patients (95%) passed the Esterman visual field test for driving; after completion of laser treatment, 35 of 38 patients (92%) passed. The mean (SD) change in retinal sensitivity on static perimetry was -1.4 (3.7) (95% CI, -2.7 to -0.1) dB OD and -2.4 (2.9) (95% CI, -3.4 to -1.4) dB OS. Mean (SD) 4° macular sensitivity decreased by 3.0 (5.2) dB OD and 2.6 (5.4) dB OS. CONCLUSIONS AND RELEVANCE This prospective study investigating the effects of multispot laser PRP on retinal sensitivity demonstrates a high likelihood of retaining eligibility to drive based on adequate visual field. A mild loss of retinal sensitivity was detected at 6 months after completion of laser treatment. Further change to visual fields may have occurred with longer follow-up. This study provides information that might be used to counsel patients requiring PRP and informs the debate regarding the role of anti-vascular endothelial growth factor therapy in patients with PDR who might otherwise receive laser treatment.

Reliability and Repeatability of Cone Density Measurements in Patients With Stargardt Disease and RPGR-Associated Retinopathy.

Purpose To assess reliability and repeatability of cone density measurements by using confocal and (nonconfocal) split-detector adaptive optics scanning light ophthalmoscopy (AOSLO) imaging. It will be determined whether cone density values are significantly different between modalities in Stargardt disease (STGD) and retinitis pigmentosa GTPase regulator (RPGR)–associated retinopathy. Methods Twelve patients with STGD (aged 9–52 years) and eight with RPGR-associated retinopathy (aged 11–31 years) were imaged using both confocal and split-detector AOSLO simultaneously. Four graders manually identified cone locations in each image that were used to calculate local densities. Each imaging modality was evaluated independently. The data set consisted of 1584 assessments of 99 STGD images (each image in two modalities and four graders who graded each image twice) and 928 RPGR assessments of 58 images (each image in two modalities and four graders who graded each image twice). Results For STGD assessments the reliability for confocal and split-detector AOSLO was 67.9% and 95.9%, respectively, and the repeatability was 71.2% and 97.3%, respectively. The differences in the measured cone density values between modalities were statistically significant for one grader. For RPGR assessments the reliability for confocal and split-detector AOSLO was 22.1% and 88.5%, respectively, and repeatability was 63.2% and 94.5%, respectively. The differences in cone density between modalities were statistically significant for all graders. Conclusions Split-detector AOSLO greatly improved the reliability and repeatability of cone density measurements in both disorders and will be valuable for natural history studies and clinical trials using AOSLO. However, it appears that these indices may be disease dependent, implying the need for similar investigations in other conditions.

Cone Photoreceptor Structure in Patients With X-Linked Cone Dysfunction and Red-Green Color Vision Deficiency

Purpose Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction. Methods We recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family. Results There were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array. Conclusions Our findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus.

Quantitative Analysis of Retinal Structure Using Spectral-Domain Optical Coherence Tomography in RPGR-Associated Retinopathy

Purpose To quantify retinal structure and progression using spectral-domain optical coherence tomography (SDOCT) in patients with retinitis pigmentosa (RP) associated with retinitis pigmentosa GTPase regulator gene (RPGR) mutations. Design Retrospective observational case series. Methods Setting: Moorfields Eye Hospital, London, United Kingdom. Subjects: Both eyes of 32 patients. SDOCT follow-up period of >1 year (3.1 ± 1.4 years). Main Outcome Measures: Ellipsoid zone (EZ) width (EZW) and outer nuclear layer (ONL) and inner retinal layer (IRL) thickness measurements. Progression rates, interocular symmetry, and association with age and genotype were investigated. Results Significant differences were observed between baseline and final measurements of EZW and ONL thickness, but not for IRL thickness. Baseline and final EZWs were 2438 ± 1646 μm and 1901 ± 1423 μm for right eyes (P < .0001); 2420 ± 1758 μm and 1922 ± 1482 μm for left eyes (P < .0001). EZW constriction rates were 176.6 ± 130.1 μm/year and 173.1 ± 146.8 μm/year for right and left eyes. ONL thinning rates were 2.58 ± 2.85 μm/year and 2.52 ± 3.54 μm/year for right and left eyes. Interocular differences in EZW and ONL progression were not significant (P = .8609 and P = .6735, respectively). Strong correlations were found between EZW constriction rates of right and left eyes (rs = 0.627, P = .0002) and between EZW constriction and baseline EZW (rs = 0.714, P < .0001). There was moderate negative correlation between EZW constriction and age (rs = −0.532, P < .0001). Correlation between ONL thinning and age was not significant, as were differences between EZW and ONL progression rates with respect to genotype. Conclusions This study provides SDOCT progression rates for RPGR-associated RP. There is overall interocular symmetry with implications for future treatment trials where 1 eye could serve as a control.

Characterization of Visual Function, Interocular Variability and Progression Using Static Perimetry–Derived Metrics in RPGR-Associated Retinopathy

Purpose To characterize bilateral visual function, interocular variability and progression by using static perimetry–derived volumetric and pointwise metrics in subjects with retinitis pigmentosa associated with mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Methods This was a prospective longitudinal observational study of 47 genetically confirmed subjects. Visual function was assessed with ETDRS and Pelli-Robson charts; and Octopus 900 static perimetry using a customized, radially oriented 185-point grid. Three-dimensional hill-of-vision topographic models were produced and interrogated with the Visual Field Modeling and Analysis software to obtain three volumetric metrics: VTotal, V30, and V5. These were analyzed together with Octopus mean sensitivity values. Interocular differences were assessed with the Bland-Altman method. Metric-specific exponential decline rates were calculated. Results Baseline symmetry was demonstrated by relative interocular difference values of 1% for VTotal and 8% with V30. Degree of symmetry varied between subjects and was quantified with the subject percentage interocular difference (SPID). SPID was 16% for VTotal and 17% for V30. Interocular symmetry in progression was greatest when quantified by VTotal and V30, with 73% and 64% of subjects possessing interocular rate differences smaller in magnitude than respective annual progression rates. Functional decline was evident with increasing age. An overall annual exponential decline of 6% was evident with both VTotal and V30. Conclusions In general, good interocular symmetry exists; however, there was both variation between subjects and with the use of various metrics. Our findings will guide patient selection and design of RPGR treatment trials, and provide clinicians with specific prognostic information to offer patients affected by this condition.

Natural History Study of Retinal Structure, Progression and Symmetry Using Ellipzoid Zone Metrics in RPGR-Associated Retinopathy

Purpose This is a quantitative study of retinal structure, progression rates, and interocular symmetry in retinitis pigmentosa GTPase regulator gene (RPGR)-associated retinopathy using spectral-domain optical coherence tomography (OCT). Design Prospective, observational cohort study. Methods Thirty-eight subjects at Moorfields Eye Hospital in London were assessed with 2 spectral-domain OCT–derived ellipzoid zone (EZ) metrics with repeatability assessments. EZ width (EZW) measurements were made on transfoveal line scans. En face images of the EZ area (EZA) were generated from high-density macular volume scans and were quantified. Baseline size, progression rate, symmetry, associations with age and genotype, and baseline structure–function correlation were investigated. Results Baseline EZW and EZA measurements were 1963.6 μm and 3.70 mm2, respectively. The mean EZW progression rate was 233.6 μm per year, and the mean EZA rate was 0.67 mm2 per year. Relative interocular difference as an index of symmetry was 3% for both metrics, indicating good baseline symmetry in general—although significant variation existed across the cohort. Analysis of variance found a significant effect of age but not genotype on EZ dimension and progression rates. Larger EZ dimension and greater progression were seen in younger subjects. A positive correlation between EZ dimension and progression was evident. Overall exponential decline rates of 8.2% with EZW and 15.5% with EZA were obtained. Good functional correlation was found with EZW demonstrating stronger correlation; however, EZA correlation with function was also significant. Conclusions EZ metrics are sensitive structural biomarkers for measuring residual extent and progression in RPGR-associated retinopathy. Our elucidation of the natural history will provide clinicians and patients with more knowledge about the condition and inform the design and interpretation of interventional trials.

QUANTITATIVE ANALYSIS OF HYPERAUTOFLUORESCENT RINGS TO CHARACTERIZE THE NATURAL HISTORY AND PROGRESSION IN RPGR-ASSOCIATED RETINOPATHY

Purpose: Quantitative analysis of hyperautofluorescent rings and progression in subjects with retinitis pigmentosa associated with retinitis pigmentosa GTPase regulator (RPGR) gene mutations. Methods: Prospective observational study of 46 subjects. Ring area, horizontal and vertical diameter measurements taken from outer and inner ring borders. Intraobserver repeatability, baseline measurements, progression rates, interocular symmetry, and association with age and genotype were investigated. Results: Baseline ring area was 11.8 ± 13.4 mm2 and 11.4 ± 13.2 mm2 for right and left eyes, respectively, with very strong interocular correlation (r = 0.9398; P < 0.0001). Ring area constriction was 1.5 ± 2.0 mm2/year and 1.3 ± 1.9 mm2/year for right and left eyes, respectively, with very strong interocular correlation (r = 0.878, P < 0.0001). Baseline ring area and constriction rate correlated negatively with age (r = −0.767; P < 0.0001 and r = −0.644, P < 0.0001, respectively). Constriction rate correlated strongly with baseline area (r = 0.850, P < 0.0001). Age, but not genotype, exerted a significant effect on constriction rates (P < 0.0001), with greatest rates of progression seen in younger subjects. An exponential decline overall was found. Conclusion: This study provides disease-specific baseline values and progression rates together with a repeatability assessment of fundus autofluorescence metrics. Our findings can guide future treatment trials and contribute to the clinical care of patients with RPGR-associated retinitis pigmentosa.