RPE65-associated Retinal Diseases and Ocular Genetic Studies

Inherited retinal degenerations (IRDs) constitute a phenotypically and genetically heterogeneous group of retinal diseases that severely affect vision and are associated with progressive vision loss. Pathogenic variants in more than 270 different genes have been implicated in the etiology of IRDs. Among the various phenotypes within IRDs, retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) represent a spectrum associated with significant visual impairment. LCA, first described by Theodore Leber in 1869, represents a severe recessive early-onset rod-cone dystrophy. A milder form, early-onset severe retinal dystrophy (EOSRD), was described by Leber in 1916. LCA typically presents at birth or within the first year and is characterized by nystagmus, photophobia, and severely impaired rod-cone responses on the electroretinogram (ERG). EOSRD presents within the first five years of life and is characterized by some preservation of vision and minimal ERG responses. RP usually presents within the first or second decade of life and is progressive with progressive vision loss affecting both peripheral and central vision. These disorders exhibit significant genetic heterogeneity across populations, and mutation in the RPE65 gene is one possible cause. Over time, RPE65 mutations associated with LCA, EOSRD, and RP lead to loss of light perception at any intensity and a profound reduction in navigational vision. In this review, the characteristics of the most studied RPE65 gene due to the fact that it can cause IRDs, the details of the most studied RP, LCA and EOSRD diseases from RPE65-related retinal dystrophies and studies on current gene therapies will be discussed.