Mutations in retinol dehydrogenase 12 (RDH12) cause a severe early-onset retinal degeneration, for which there is no treatment. RDH12 is involved in photoreceptor retinoid metabolism and is a potential target for gene therapy, which has been successful in treating RPE65-associated LCA. RDH12-associated retinal degeneration is particularly devastating due to early macular atrophy, which will likely impact therapeutic outcomes. Defining the unique features and natural history of disease associated with RDH12 mutations is a critical first step in developing treatments. The purpose of this review is to aggregate and summarize the body of literature on phenotypes in RDH12-associated retinal degeneration to help map the natural history of disease and identify phenotypic milestones in disease progression. The results reveal a severe blinding disorder with onset in early childhood and frequent retention of reduced yet useful vision until adolescence. The severity is associated with genotype in some cases. Distinct phenotypic features include macular atrophy followed by bone spicule pigment early in life, in contrast to other forms of LCA which often have a relatively normal fundus appearance in childhood despite severe visual dysfunction. Formal natural history studies are needed to define milestones in disease progression and identify appropriate outcome measures for future therapy trials.
Keywords: Leber congenital amaurosis; Natural history; Phenotype; RDH12.