Epidemiology of Mutations in the 65-kDa Retinal Pigment Epithelium (RPE65) Gene-Mediated Inherited Retinal Dystrophies: A Systematic Literature Review.

INTRODUCTION: Inherited retinal dystrophies (IRDs) represent a genetically diverse group of progressive, visually debilitating diseases. Adult and paediatric patients with vision loss due to IRD caused by biallelic mutations in the 65-kDa retinal pigment epithelium (RPE65) gene are often clinically diagnosed as retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA). This study aimed to understand the epidemiological landscape of RPE65 gene-mediated IRD through a systematic review of the literature, as the current evidence base for its epidemiology is very limited. METHODS: Medline, Embase, and other databases were searched for articles on the epidemiology of RPE65 gene-mediated IRDs from inception until June 2021. Studies were included if they were original research articles reporting the epidemiology of RP and LCA and/or proportion of RPE65 gene mutations in these clinically diagnosed or molecularly confirmed IRDs patients. RESULTS: A total of 100 studies with relevant data were included in this systematic review. The range for prevalence of LCA and RP in the literature was 1.20-2.37 and 11.09-26.43 per 100,000, respectively. The proportion of RPE65 mutations in clinically diagnosed patients with LCA was found to be between ~ 2-16% within the US and major European countries (France, Germany, Italy, Spain, and the UK). This range was also comparable to our findings in the Asian region for RPE65-LCA (1.26-16.67%). Similarly, for these European countries, RPE65-RP was estimated between 0.23 and 1.94%, and RPE65-IRD range was 1.2-14%. Further, in the Americas region, mutations in RPE65 were reported to cause 1-3% of RP and 0.8-3.7% of IRD cases. Lastly, the RPE65-IRD range was 4.81-8% in the Middle East region. CONCLUSIONS: There are significant variations in reporting of RPE65 proportions within countries as well as regions. Generating robust epidemiological evidence on RPE65 gene-mediated IRDs would be fundamental to support rare disease awareness, timely therapeutic intervention, and public health decision-making.