Absent or Minimal Fundus Autofluorescence in Patients with Early Onset Retinal Degeneration Associated with the RPE65 Genotype

Abstract

Abstract: : Background: Fundus autofluorescence (AF) is assigned to accumulation of lipofuscin granules in the cells of the retinal pigment epithelium (RPE) as the result of incomplete digestion of shedded photoreceptor outer segment discs. Alteration in AF reflects changes in lipofuscin contents of the RPE that may not be visible on ophthalmoscopy. Mutations in the RPE65 gene abolish or largely decrease the formation of rhodopsin due to a defect in the retinol cycle of the RPE. AF may therefore be altered. Methods: A total of 10 patients from 6 families suffering from an early onset retinal degeneration associated with compound heterozygous or homozygous mutations in the RPE65 gene were examined. Four of the patients were children aged 10-14 years, the adults were aged 19-55 years. All patients were examined clinically. Fundus autofluorescence (AF) was recorded using a confocal scanning laser ophthalmoscope (HRA). Four single heterozygous parents were also examined clinically and by AF. Results: Visual acuity ranged from light localisation to 0.3. Fundus changes on ophthalmoscopy varied with both, age and interindividually, and included decreased macular reflex, increased granularity, thinning of retinal arteries and areas of geographic atrophy. Absent or minimal AF was found in all young patients with known RPE65 genotype. In older patients some autofluorescence could be detected. AF was normal in all single heterozygotes. Conclusions: The lack of AF in the RPE of young patients with early onset retinal degeneration associated with the RPE65 genotype is in accordance with the biochemical defect. As mutant RPE65 impairs the retinoid cycle, 11-cis retinal (11cRAl) supply is limited preventing activation of opsin by binding the chromophore. On illumination all-trans retinylester (atRy) will accumulate from bleached chromophore. atRy does not present with AF when illuminated at 488 nm. Lipofuscin will only accumulate over a prolonged time due to reduced supply of 11cRAl. Lack of AF in young patients with early onset retinal degeneration indicates the RPE65 genotype.

Keywords: retinal degenerations: hereditary • imaging/image analysis: clinical • mutations