Figure 3.

Genetic disease-causing changes in the visual cycle.A, monogenic diseases can be caused by genetic changes such as base substitution, deletion, or insertion. These changes can cause loss of function (LoF) pertinent to normal cellular development and maintenance and visual processing and simultaneous gain and loss of function (GLF) and gain of a new detrimental function (GoF). Aging is a complex process that generally accelerates the deterioration of visual function (light blue color) involving many different genes and typically leads to a decrease in chromophore production and concomitant decline in dark adaptation (see (184)). B, mutations in one gene can cause several diseases, e.g., mutations in RGR and RPE65 can cause autosomal dominant retinitis pigmentosa (adRP), but a mutation in RPE65 can cause autosomal recessive RP (arRP); changes in rhodopsin (Rho) can lead to adRP, arRP, or congenital stationary night blindness (CSNB); mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) transporter can cause arRP and a unique disease with characteristics of juvenile macular degeneration known as Stargardt disease. Mutations in one gene, e.g., retinol dehydrogenase 5 (RDH5), can cause Fundus albipunctatus. Thus, LoF, GLF, and GoF can be associated with one gene that will manifest in different disease states, or one clinically recognized disease can be caused by a mutation in different genes. C, age-related macular degeneration (AMD). Alterations in biochemical pathways in the retina, including those comprising the visual cycle, can alter retinal integrity in disease states such as AMD, as shown in the upper row of fundus images and in the lower set of images obtained by optical coherence tomography (OCT). Drusen are not seen beneath the retina in normal eyes. Drusen are biochemical waste products appearing as yellow spots on color fundus photographs (black arrows) or bumpy elevations in the RPE on OCT (white arrows). Drusen are the hallmark of early AMD and increase in size and number in intermediate AMD. In advanced dry AMD, patches of RPE death produce areas of geographic atrophy eccentric to or involving the fovea (green arrow). These images are provided to illustrate typical disease features, not to report new research findings.