Central Structural and Functional Abnormalities in Choroideremia: Longitudinal and Cross-sectional Observations from a Large Cohort of Patients

Abstract

Purpose : To describe in detail the natural history of the central retinal structural and functional changes of a large group of patients with choroideremia (CHM).

Methods : Patients with CHM, ages 6 to 70 years (n= 133), had a comprehensive ophthalmologic evaluation and retinal imaging with spectral domain optical coherence tomography (SD-OCT). OCT cross sections were quantified along the horizontal meridian and related to co-localized visual thresholds measured with automated two-color static perimetry. A subset of patients (n=45) had longitudinal evaluations, which were used to validate predictions from much larger cross-sectional observations.

Results : Most patients (88%) retained visual acuity (VA) better than 0.3 logMAR until the fifth decade of life. VA decline below this level was associated with shortening of the inner segment ellipsoid (EZ) to RPE/BrM band thickness to ~half the normal value, coinciding with approximation of the transitions zones (TZs) of degeneration to the foveal center. No such relationship was identified between VA and outer nuclear layer (ONL) thickness or foveal sensitivity. Earliest abnormalities in regions with normally appearing retinal pigment epithelium (RPE) were the loss of the photoreceptor outer segment (POS) and RPE interdigitation zone associated with rod dysfunction. We confirmed that cone function may remain normal over an extended range when rod sensitivity has fallen well-below normal limits and prior to demonstrable changes in ONL thickness. TZs from relatively preserved retina to severe ONL thinning and inner retinal thickening moved centripetally with age, in either cross-sectional or longitudinal observations. In general, RPE abnormalities paralleled photoreceptor degeneration although there were regions with detectable but abnormally thin ONL co-localizing with severe RPE depigmentation and choroidal thinning.

Conclusions : We found that visual acuity decline in choroideremia relates well to shortening of the POS but not as well with ONL thickness or foveal sensitivity as measured by static perimetry. We confirmed that rod sensitivity loss is the earliest and most sensitive measure of visual function. These results have implications for further gene therapy clinical trials. The relationships established may help outline the eligibility criteria and outcome measures for clinical trials for CHM.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.