Cone Structure in Patients With Mutations in the Choroideremia Gene

Abstract

Purpose: : To correlate visual function with high-resolution structural imaging in 2 families with choroideremia (CHM).

Methods: : Genetic testing was performed to identify mutations in the REP1 gene. Best-corrected visual acuity (VA), Goldmann kinetic and both automated and fundus-guided microperimetry, and full-field and multifocal electroretinography (ffERG and mfERG) were used to study retinal function in two families carrying mutations in REP1. Clinically affected carrier females from each family were studied, in addition to a male patient from one family. Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO) imaging was performed to correlate macular structure with function.

Results: : Molecular analysis identified a deletion in exons 9-15 in one family and a splice site mutation (G to A) at position 79+1 of exon 1 in the second family. VA in all eyes imaged was correctable to 20/25 or better and foveal thresholds were normal, ranging from 32-37 dB. Fundus exam in all subjects revealed discrete regions of retinal pigment epithelial (RPE) and choroidal atrophy that did not involve the fovea. MfERG amplitudes were decreased with delayed timing in the affected areas of the carriers and below measurable limits in the male patient; ffERG amplitudes were reduced with delayed timing in the more severely affected carrier and were below measurable limits in the male patient. Cones were readily imaged in all subjects using AOSLO. Cone coverage was less contiguous compared to normal and cone spacing did not follow typical changes with retinal eccentricity. Near the fovea, cone spacing was greater than normal (i.e., density was lower) but in the male patient photoreceptor arrays at 2-4 degrees eccentricity had higher than normal density. Hyperreflective regions near the edges of the cone preserved area corresponded to regions of RPE and choriocapillaris atrophy seen on fundus photographs. Scotomas were present in hyperreflective regions in the AOSLO image where no cones were visible.

Conclusions: : AOSLO imaging demonstrates abnormalities in cone spacing that correspond to reduced visual function in a male patient and 2 symptomatic female carriers with mutations in REP1. These high-resolution images provide the first in vivo measures of cone structure and correlations with visual function in patients with REP1mutations. Longitudinal studies may provide insight into the ways cones and RPE cells are affected by REP1 mutations.

Keywords: retinal degenerations: hereditary • imaging/image analysis: clinical • macula/fovea