Clinical Vision And Molecular Loss: Integrating Visual Psychophysics With Molecular Genetics Reveals Key Details Of Normal And Abnormal Visual Processing

Over the past two decades we have developed techniques and models to investigate the ways in which known molecular defects affect visual performance. Because molecular defects in retinal signalling invariably alter the speed of visual processing, our strategy has been to measure the resulting changes in flicker sensitivity. Flicker measurements provide not only straightforward clinical assessments of visual performance but also reveal fundamental details about the functioning of both abnormal and normal visual systems. Here, we bring together our past measurements of patients with pathogenic variants in the GNAT2, RGS9, GUCA1A, RPE65, OPA1, KCNV2 and NR2E3 genes and analyse the results using a standard model of visual processing. The model treats flicker sensitivity as the result of the actions of a sequence of simple processing steps, one or more of which is altered by the genetic defect. Our analyses show that most defects slow down the visual response directly, but some speed it up. Crucially, however, other steps in the processing sequence can make compensatory adjustments to offset the abnormality. For example, if the abnormal step slows down the visual response, another step is likely to speed up or attenuate the response to rebalance system performance. Such compensatory adjustments are probably made by steps in the sequence that usually adapt to changing light levels. Our techniques and modelling also allow us to tease apart stationary and progressive effects, and the localised molecular losses help us to unravel and characterise individual steps in the normal and abnormal processing sequences.