A morphogenetic model for radial streaking in the fundus of the carrier state of X-linked albinism

A 60 year-old woman was referred for evaluation of non-specific visual complaints and abnormal fundus pigmentation. She was thought to have a possible retinal dystrophy. The patient’s complaints were limited to difficulty seeing clearly while driving at night, and difficulty seeing clearly at near. Both eyes were affected equally, and the symptoms had been present for several months. Past medical history was unremarkable for any chronic medical conditions, and she took no oral medications. The patient had no significant past ocular history. Family history was significant for a father and a son with ocular albinism. She, therefore, was an obligate carrier of this disease.

Her distance and near vision were correctable to 20/20 in both eyes. Pupillary reactions were normal, as were intraocular pressures, extraocular movements, confrontational visual fields, and ocular alignment. Slit lamp examination was remarkable only for moderate nuclear sclerosis in each eye. No iris transillumination was noted on careful examination. Dilated examination revealed clear media in each eye, pink optic nerves with normally small cups, flat maculae and normal retinal vessels bilaterally. The posterior pole appeared to have a splotchy pattern of pigmentation, as seen on fundus autofluorescence (Figure 1). The peripheral fundus had alternating radial streaks of hyperpigmentation and hypopigmentation (Figure 2a) at the level of the retinal pigmented epithelium (RPE) typical of the X-linked ocular albinism carrier state. Fluorescein angiography showed normal retinal vasculature with areas of blocking and window defects corresponding to hyperpigmented and hypopigmented regions, respectively (Figure 2b). OCT scanning of the macula and full-field ERG testing were normal in both eyes. Her visual complaints were consistent with presbyopia and cataract.

Figure 1.

Fundus autofluorescence of the posterior pole of the right eye of the X-linked ocular albinism obligate carrier, demonstrating the typical mud-splattered appearance of the retinal pigmented epithelium (RPE). Hypoautofluorescent areas correspond to hyperpigmented areas of RPE. Similarly, hyperautofluorescent areas correspond to hypopigmented areas on the color fundus photograph.

Figure 2.

Color fundus photograph (A) on a wide-angle instrument of the right eye of the X-linked ocular albinism obligate carrier, demonstrating the typical mud-splattered appearance of the posterior pole and the characteristic alternating hyperpigmented and hypopigmented peripheral streaks at the level of the retinal pigmented epithelium (RPE). Late phase fluorescein angiogram (B) of the same eye shows normal retinal vasculature, blocking in hyperpigmented areas and window defects in hypopigmented areas. Hypofluorescent areas correspond to hyperpigmented areas of RPE. Similarly, hyperfluorescent areas correspond to hypopigmented areas on the color fundus photograph.

Ocular albinism is an X-linked disease characterized in affected males by poor vision, nystagmus, iris transillumination, hypopigmented fundus, foveal hypoplasia, and an increased proportion of crossed ganglion cell fibers at the optic chiasm. Mutation of the OA1 (GPR143) gene on the X-chromosome is responsible for this condition. The skin and hair pigmentation appears clinically normal, but skin histology reveals macromelanosomes in melanocytes [1]. Carriers of the condition are rarely symptomatic, but often have signs of their carrier status. Female carriers have macromelanosomes in the skin, though they are fewer in number than in affected males. The eyes of carriers often show iris transillumination (80%) and a mud-splattered appearance of the posterior pole with typical pigmentary streaks in the peripheral fundus (92%) [2]. The pathogenesis of these streaks has not been understood.

Recent studies using four-dimensional imaging with custom cell-tracking software and photoactivatable fluorophore labeling to determine the cellular dynamics underlying optic cup morphogenesis in the zebrafish shed light onto the fundus pattern in the above patient. Kwan and colleagues [3] identified two major RPE cell movements during eye development: pinwheeling and spreading. An initial pinwheel-like movement of RPE cells during the optic vesicle elongation phase gives rise to a discrete RPE domain that can be further subdivided within posterior, central and anterior subdomains (corresponding to temporal, central and nasal in humans). Immediately afterward, during optic vesicle invagination, RPE cells corresponding to the temporal and nasal domains undergo a posterior-to-anterior radial migration (spreading), while RPE cells located in the central domain maintain their relative central position. The authors replicated these studies on chick embryos, finding similar movements, thereby suggesting that optic cup morphogenesis may be evolutionarily conserved across vertebrate species. Time-lapse photography ([3]; also available online at http://www.youtube.com/watch?v=VyJ4M_1HEzY) demonstrates these dramatic movements and migration of RPE precursor cells.

Bodenstein and Sidman [4] studied RPE development in mice using pigmented-albino mouse chimeras and X-inactivation mosaics. They found that posterior RPE precursors (corresponding to the central domain in zebrafish) become post-mitotic sooner than in peripheral RPE precursors. Therefore, these posterior RPE precursors stay relatively localized, allowing more “cell mixing.” Conversely, peripheral RPE precursors divide more, since they stay mitotically active longer, and add cells in an “edge-biased” fashion, producing less cell-mixing and accounting for groups of clones in the peripheral fundus.

We propose that these morphogenetic movements of RPE precursors during eye development may constitute the basis of the characteristic radial streaking phenotype observed in carriers of X-linked ocular albinism. This model is based on the premise that female carriers have a mixed population of both pigmented and non-pigmented RPE precursor cells due to lyonization of the X-chromosome. During the early stages of optic vesicle development, this mixed population of RPE precursors will undergo pinwheel movements and give rise to temporal, central and nasal RPE subdomains characterized by a pigmented/non-pigmented mosaic pattern. As development proceeds, the mud-splattered pattern of the posterior pole would originate from the central RPE subdomain through the generation of localized pigmented versus non-pigmented clones by relatively fewer cell divisions and less migratory activity. On the other hand, the radial streaks seen in the periphery would originate from the posterior-to-anterior migration of RPE cells from the temporal and nasal RPE subdomains, and the “edge-biased” pattern and relatively increased mitotic activity of the peripheral clonal cell populations (Figure 3). A computer animation of the proposed model is presented in Movie 1. Further molecular histopathology in human samples and experiments in knockout mice may lend further evidence in support of this model in mammalian species.

Figure 3.

Schematic model of clonal populations of retinal pigmented epithelial (RPE) precursor cells proliferating and migrating in the peripheral fundus to produce the typical pattern of alternating hyperpigmented and hypopigmented streaks at the level of the RPE. (Artist: David Rini, Associate Professor, The Johns Hopkins University School of Medicine, Department of Art as Applied to Medicine, 2012).

Supplementary Material

Supplemental Movie. eMovie 1.

Computer animation of the morphogenetic model for radial streaking in the fundus of the carrier state of X-linked albinism. Initially, the RPE subdomains are characteized by a pigment mosaicism due to X-linked lyonization, where pigmented RPE precursors (orange circles) randomly alternate with unpigmented RPE precursors (white circles). As development proceeds, RPE precursors within the central domain follow a spotty clonal growth maintaining their relative central position, while RPE precursors within the temporal and nasal domains undergo significant anterior-to-posterior migration and radial clonal growth. File format: .mov.