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.

PurposeMutations 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.MethodsWe 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.ResultsThere 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.ConclusionsOur 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.

PurposeTo 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.MethodsThis 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.ResultsBaseline 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.ConclusionsIn 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.