Leber congenital amaurosis

Leber's congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies responsible for congenital blindness. Gen etic heterogeneity of LCA has been suspected since the report by Waardenbur g of normal children born to affected parents. In 1995, we localized the fi rst disease causing gene, LCA1, to chromosome 17p13 and confirmed the genet ic heterogeneity. In 1996, Fee ascribed LCA1 to mutations in the photorecep tor-specific guanylate cyclase gene (retGC1). RetGC1 is an essential protei n implicated in the phototransduction cascade, especially in the recovery o f the dark state after the excitation process of photoreceptor cells by Lig ht stimulation. In 1997, mutations in a second gene were reported in LCA, t he RPE65 gene, which is the first specific retinal pigment epithelium gene. The protein RPE65 is implicated in the metabolism of vitamin A, the precur sor of the photoexcitable retinal pigment (rhodopsin). Finally, a third gen e, CRX, implicated in photoreceptor development, has been suspected of caus ing a few cases of LCA. Taken together, these three genes account for only 27% of LCA cases in our series. The three genes encode proteins that are in volved in completely different physiopathologic pathways. Based on these st riking differences of physiopathologic processes, we reexamined all clinica l physiopathological discrepancies and the results strongly suggested that retGC1 gene mutations are responsible for congenital stationary severe cone -rod dystrophy, while RPE65 gene mutations are responsible for congenital s evere but progressive rod-cone dystrophy. It is of tremendous importance to confirm and to refine these genotype-phenotype correlations on a large sca le in order to anticipate the final outcome in a blind infant, on the one h and, and to further guide genetic studies in older patients on the other ha nd. (C) 1999 Academic Press.