An Atypical Mild Phenotype of Autosomal Recessive RPE65-Associated Retinitis Pigmentosa

Introduction

Retinoid isomerohydrolase (RPE65) is a key enzyme in the visual cycle. It is predominantly expressed in the retinal pigment epithelium (RPE) and plays a crucial role in the regeneration of the visual pigment rhodopsin in the rod photoreceptor cells. RPE65 is a member of the family of carotenoid oxygenases, and its main function is to catalyze the isomerization of the all-trans retinyl ester to 11-cis retinol, which is then oxidized to 11-cis retinaldehyde by RDH5. 11-cis Retinaldehyde is a crucial component of rhodopsin [1]. The absence of functional RPE65 leads to the accumulation of the all-trans retinyl ester in the RPE, contributing to the degeneration of the photoreceptors and subsequent visual impairment [2].

Mutations in RPE65 are associated with a variety of mostly autosomal recessively inherited retinal diseases, including Leber congenital amaurosis (LCA) and early onset retinitis pigmentosa [3]. In recent years, subretinal gene therapy has emerged as a promising treatment for RPE65-associated retinal diseases and led to the FDA and EMA approval of voretigene neparvovec. The approach involves delivering a functional copy of the RPE65 gene to the affected cells using a viral vector, with the aim of restoring the enzymatic activity and preventing the degeneration of the photoreceptor cells [4].

RPE65-associated retinal diseases are typically diagnosed in infancy or childhood. In some cases, the disease may be detected shortly after birth due to the presence of nystagmus or lack of visual responsiveness. However, the age of diagnosis can vary depending on the specific mutation and disease severity, with some individuals not being diagnosed until later in life, although night blindness or at least difficulties to see in low luminance conditions are almost always present since childhood [5]. Early diagnosis and subsequent intervention are usually critical for optimizing outcomes.

Here, we present the case of a male who received the final diagnosis of RPE65-associated retinitis pigmentosa at 69 years of age, presenting with a very slowly progressing and mild phenotype that may qualify for subretinal gene therapy with voretigene neparvovec.

Publication History

Received: 01 October 2023

Accepted: 29 January 2024

Article published online:
20 March 2024

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