Retinal degeneration in choroideremia follows an exponential decay function

Abstract

Purpose : Choroideremia (CHM) is a monogenic retinal dystrophy caused by mutations in the CHM gene encoding REP1, and is phenotypically unique in displaying an island of surviving retina, which undergoes progressive shrinkage with age and can be quantified using fundus autofluorescence imaging (AF). Cross-sectional analysis has suggested that AF area in CHM undergoes exponential decline, however, longitudinal data are lacking, and it is not known whether individuals progress at different rates depending on genetic, epigenetic and environmental factors. We conducted a retrospective, observational study characterising the rate and pattern of retinal degeneration by measuring the loss of AF over time, and correlated disease progression with levels of CHM gene expression.

Methods : The residual areas of retinal AF were serially measured in 31 early stage CHM patients (mean age 28 years) over two years using Heidelberg Eye Explorer. Mathematical modelling of area shrinkage and analysis of inter-eye symmetry were undertaken. In 10 patients, the levels of CHM mRNA and REP1 protein expression were measured in primary fibroblasts. Pearson r correlation coefficient, ANOVA and two-tailed t-tests were used to assess the significance of correlation between two variables as the data were normally distributed.

Results : The rate of AF loss was strongly correlated to baseline AF area (multiple regression coefficient = 0.81, P < 0.01) but independent of age (correlation coefficient = -0.005, P = 0.06), supporting an exponential decay model with a mean half-life of 5.5 years (95%CI 5.0 – 6.1). The age of onset of degeneration involving the 55° posterior pole was mathematically predicted and shown to span from 0 - 20 years. Inter-eye symmetry was observed in the shape of surviving AF islands, suggesting underlying anatomical factors that influence the pattern of degeneration. All patients were found to be null for REP1, despite individual variations in the rate of disease progression.

Conclusions : The data suggest that the rate of degeneration in CHM, in terms of half-life, is similar across all patients. As with all half-life functions, the absolute loss of cells becomes progressively less as the residual area decreases. The apparent variation in disease severity between patients is most likely determined not by the rate of decay, but by the age at which the degeneration starts.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.