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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Porto
Fernanda B O
FB
Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM Université Louis Pasteur EMI 9918, Clinique Médicale A, CHUR Strasbourg, BP. 426, 1 Place de l'Hôpital, 67091 Strasbourg Cedex, France.
Perrault
Isabelle
I
Hicks
David
D
Rozet
Jean-Michel
JM
Hanoteau
Noëlle
N
Hanein
Sylvain
S
Kaplan
Josseline
J
Sahel
José Alain
JA
D037881:Aborted Fetus / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008126:Lod Score; D008297:Male; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D010375:Pedigree; D012160:Retina / Q000473:pathology*; D017949:Retinal Cone Photoreceptor Cells / Q000276:immunology / Q000473:pathology; D017299:Rod Opsins / Q000276:immunology
D017299:Rod Opsins