Prenatal human ocular degeneration occurs in Leber's congenital amaurosis (LCA2)

Leber's congenital amaurosis (LCA) encompasses the most precocious and severe forms of inherited retinal dystrophy, displaying very significant visual handicap at or soon after birth. Among the currently identified mutations, alterations in the gene coding for retinal pigment epithelium 65-kDa protein (RPE65) lead to LCA2. Existing animal models for LCA2 (RPE65(-/-) null mice and naturally occurring RPE65(-/-) Briard dogs) exhibit near normal retinal histology at birth, although no recordable photofunction can be detected. Structural degeneration in both cases occurs with delayed onset, cone death generally preceding that of rods.

We obtained retinal tissue from a voluntarily aborted embryo of an LCA2 carrier in order to compare histopathology and immunohistochemistry with age-matched normal foetal retina.

Compared to normal retinas, affected retina displayed cell loss and thinning of the outer nuclear (photoreceptor) layer, decreased immunoreactivity for key phototransduction proteins, and aberrant synaptic and inner retinal organisation. The gene mutation abolished detectable expression of RPE65 within the retinal pigment epithelium (RPE) of affected eyes, and ultrastructural examination revealed the presence of lipid and vesicular inclusions not seen in normal RPE. In addition, mutant eyes demonstrated thickening, detachment and collagen fibril disorganisation in the underlying Bruch's membrane, and the choroid was distended and abnormally vascularised, in comparison with controls.

Such data contrast with the late-onset ocular changes observed in animal models, indicating caution should be exercised when inferring human retinal pathophysiology from information based on other species.