Photoreceptor cells as a source of fundus autofluorescence in recessive Stargardt disease

Abstract

Bisretinoid fluorophores form in photoreceptor outer segments from nonenzymatic reactions of vitamin A aldehyde. The short-wavelength autofluorescence (SW-AF) of fundus flecks in recessive Stargardt disease (STGD1) suggests a connection to these fluorophores. Through multimodal imaging, we sought to elucidate this link. Flecks observed in SW-AF images often colocalized with foci exhibiting reduced or absent near-infrared autofluorescence signal, the source of which is melanin in retinal pigment epithelial (RPE) cells. With serial imaging, changes in near-infrared autofluorescence (NIR-AF) preceded the onset of fleck hyperautofluorescence in SW-AF images and fleck profiles in NIR-AF images tended to be larger. Flecks in SW-AF and NIR-AF images also corresponded to hyperreflective lesions traversing photoreceptor-attributable bands in horizontal SD-OCT scans. The hyperreflective lesions interrupted adjacent OCT reflectivity bands and were associated with thinning of the outer nuclear layer. These SD-OCT findings are attributable to photoreceptor cell degeneration. Progressive increases and decreases in the SW-AF intensity of flecks were evident in color-coded quantitative fundus autofluorescence maps. In some cases, flecks appeared to spread radially from the fovea to approximately 8° of eccentricity, beyond which a circumferential spread characterized the distribution. Since the NIR-AF signal is derived from melanin and loss of this autofluorescence is indicative of RPE atrophy, the SW-AF of flecks cannot be accounted for by bisretinoid lipofuscin in RPE. Instead, we suggest that the bisretinoid serving as the source of the SW-AF signal, resides in photoreceptors, the cell that is also the site of bisretinoid synthesis.