Mutations in RPE65 Cause an Infantile Rod Cone Dystrophy and Absence of Retinal Autofluorescence

Abstract

Abstract: : Purpose:To refine the genotype–phenotype correlation in a subset of patients with Leber’s Congenital Amaurosis (LCA) or early onset retinal dystrophies (EORD) who have RPE65 gene defects. Methods:Patients with LCA or EORD including Autosomal Recessive Retinitis Pigmentosa (ARRP) were screened for mutations in the RPE65 gene. DNA was extracted from blood and direct sequencing of each of the 14 exons was performed. All patients in the study underwent full clinical examination, electroretinography and, where possible, Goldman visual fields, fundus photography, fundus autofluorescence imaging (FAF), OCT, biometry, keratometry and refraction. Results:100 patients have been screened and 12 patients with mutations in the RPE65 gene have been identified to date, including eight from three families. All of the mutations, but one, have been previously described. On going work will enable us to refine the nature of the novel mutation(IVS1+5G>A; IVS1–2A>G). The patients ranged in age from 3–66 years. Of those with LCA or EORD, poor vision and nystagmus from early infancy was a universal feature. Severe night blindness and staring at lights were prominent early symptoms. Visual acuities in early childhood ranged from 0.7 to 1.5(Log Mar) and there was a gradual decline to the level of 1.8 by 18 years of age though one patient has kept vision in one eye of 0.8 at 21 years. Fundus findings ranged from a normal appearance to white dots at the level of the RPE or a retinal atrophy with vessel attenuation which was seen at a later stage. There is little retinal pigment seen at any age. Refraction revealed moderate myopia or low hyperopia in all patients. Flash ERG showed an unrecordable response in 9 patients with very low amplitude residual 30hz flicker in two. FAF imaging showed a characteristic abnormality with absence of the normal fundus autofluorescence. OCT findings, though, were unremarkable. Conclusions:The RPE65 gene is known to cause a form of LCA in 3–16% of affected patients. Gene therapy has been demonstrated to be effective in restoring visual function in mouse and dog models. The first gene therapy trials in children with RPE65 are planned in the next 3–5 years. The emergence of a characteristic phenotype, with an absence of fundus autofluorescence being a useful screening tool, is important for the identification of such patients.

Keywords: retinal degenerations: hereditary • genetics • retinal pigment epithelium