Complexity of the Class B Phenotype in Autosomal Dominant Retinitis Pigmentosa Due to Rhodopsin Mutations

Abstract

PurposePreviously, patients with RHO mutations and a class A phenotype were found to have severe early-onset loss of rod function, whereas patients with a class B phenotype retained rod function at least in certain retinal regions. Here class B patients were studied at different disease stages to understand the topographic details of the phenotype in preparation for therapies of this regionalized retinopathy.MethodsA cohort of patients with RHO mutations and class B phenotype (n = 28; ages 10–80 years) were studied with rod and cone perimetry and optical coherence tomography (OCT).ResultsAt least three components of the phenotype were identified in these cross-sectional studies. Patients could have hemifield dysfunction, pericentral loss of function, or a diffuse rod sensitivity loss across the visual field. Combinations of these different patterns were also found. Colocalized photoreceptor layer thicknesses were in agreement with the psychophysical results.ConclusionsThese disorders with regional retinal variation of severity require pre-evaluations before enrollment into clinical trials to seek answers to questions about where in the retina would be appropriate to deliver focal treatments, and, for retina-wide treatment strategies, where in the retina should be monitored for therapeutic efficacy (or safety).

Regional Differences of Choroidal Structure Determined by Wide-Field Optical Coherence Tomography

“…This difference was largely due to the differences of the luminal area rather than the stromal area. In the macular area, the photoreceptor density is highest, 44,45 and thus outer nuclear layer is thickest. 45 All this taken together, there is higher metabolic need in the macular area, and thus the macular retina requires higher blood circulation than the peripheral retina.…”

“…In the macular area, the photoreceptor density is highest, 44,45 and thus outer nuclear layer is thickest. 45 All this taken together, there is higher metabolic need in the macular area, and thus the macular retina requires higher blood circulation than the peripheral retina. In addition, there is the asymmetric dorsoventral gradient in photoreceptor density in the posterior pole of the retina.…”

Progression in X-linked Retinitis Pigmentosa Due toORF15-RPGRMutations: Assessment of Localized Vision Changes Over 2 Years

“…[27][28][29][30][31][32][33] This reduction in ''photon catch'' typically occurs due to the degeneration (loss) of a subset of rod photoreceptors and shortening of outer segments in surviving photoreceptors: two processes that tend to co-occur through a mechanism currently not well understood. [34][35][36][37] Changes in photon catch would predictably correspond to changes in absolute sensitivity to detect dim lights in the dark, assuming all else (e.g., phototransduction and post-phototransduction signaling) being equal. Computerized static perimetry performed under dark-adapted conditions is one of the most practical methods that provides a topographical map of absolute sensitivity across the retina, and thus can provide an estimate of local photoreceptor structure at the sampled locations under simplifying assumptions.…”

Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector

“…Patients with class A mutations have severe loss of rods from early life, and realistic therapeutic approaches should be directed at prolonging cone survival. On the other hand, patients with class B mutations can have rods that survive for decades into late adult life in some retinal regions or throughout the retina and could benefit from a gene therapy aimed at rescuing the remaining rods and preventing secondary cone cell loss (20).…”