Leber congenital amaurosis: from darkness to spotlight

Almost 150 years ago, Theodor Leber described a severe form of vision loss at or near birth which was later given his name. During the century that followed this description, ophthalmologists dedicated efforts to give an accurate definition of the disease but patients were neglected because of the inability of physicians to provide them with treatment. In the 90s, at the time of the Golden Age of Linkage, the first LCA locus was mapped to a human chromosome and shortly after identified as the gene for guanylate cyclase. This discovery was the spark that made the disease emerge from the shadows as illustrated by the flood of LCA genes identified in the following ten-year period. During the same time period, the clinical variability of the disease was rediscovered and an unexpected physiopathological heterogeneity demonstrated. In the beginning of the third millennium, LCA came out definitively from the tunnel to shine under the bright spotlights with the RPE65 gene therapy trial that succeeded to restore vision in a dog model and opened the door to gene therapy trials in humans.