In hereditary progressive retinopathies, degeneration of photoreceptors with age generally coincides with a predictable loss of photoreceptor function (Machida et al., 2000
). Young RPE65-deficient mice and dogs do not fit this predictive relationship as their near-normal retinal architecture is associated with a severe loss of function. This dysfunction is dominated by reduced quantum catch and reduced dark current within photoreceptors secondary to the block of the normal visual cycle at the RPE. As retinal degeneration sets in, an additional component of vision loss is expected due to photoreceptor apoptosis, shortening of surviving photoreceptor OS, and possible modifications of the OS/RPE interface. Thus, for the majority of the life span of the human, mouse and dog species involved, RPE65 disease is a complex
retinopathy involving components with degeneration and dysfunction. It is important to understand the relative proportion of these components in order to predict which treatments are most applicable at different disease stages.
In human patients, the relationship between retinal architecture and co-localized visual function was examined using in vivo
measures of photoreceptor (ONL) structure and function (dark-adapted visual sensitivity) at selected locations known to have the highest densities of cones or rods in normal retinas (Curcio et al., 1990
). Data from a cohort of human retinal degeneration patients known to not carry RPE65
mutations established the relationship of visual loss to cell loss (). Patient results were compared to an idealized model of the expected relationship in photoreceptor degenerations (Jacobson et al., 2005
). The model assumes that photoreceptor function is proportional to the product of the number of surviving photoreceptors and the length of their outer segments; both of these parameters are proportional to ONL thickness (Machida et al., 2000
). Thus, to a first approximation, loss of light sensitivity (in linear units) would be expected to be proportional to the square of ONL thinning (Jacobson et al., 2005
). The model has been subsequently tested on patients with retinopathy due to mutations in CACNA1F
, or USH2A
genes (Jacobson et al., 2007b
) and ungenotyped patients with retinitis pigmentosa (Rangaswamy et al., 2010
Figure 9 Retinas of patients with RPE65-LCA can have more photoreceptor nuclear layer than predicted from vision. (A) Foveal outer nuclear layer (ONL) thickness as a function of dark-adapted cone-mediated sensitivity (650 nm). (B and C) ONL thickness as a function (more ...)
Once the non-RPE65 relationship between retinal architecture and visual function was defined, RPE65-LCA could be examined quantitatively (). At the fovea, in non-RPE65 patients, ONL thickness reduction was predictably related to central visual function over a 3 log unit range from normal to severely abnormal vision. In 8 of 11 RPE65-LCA patients, ONL thickness was greater than expected for the level of dysfunction. At two rod-rich regions, 3.6 mm temporal or superior to the fovea, non-RPE65 patients showed ONL thickness reductions predictably related to dark-adapted vision over a 5 log unit range from normal to severely abnormal. Whereas in RPE65-LCA, 5 of 11 patients showed a substantially greater amount of ONL thickness preservation for their severity of visual loss. These data provide quantitative evidence on the complex but interpretable relationship between retinal architecture and visual function in human RPE65-LCA. Visual loss greater than expected from the corresponding co-localized photoreceptor loss is a necessary prerequisite for therapeutic options aiming to restore vision.