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

Abstract

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.

Keywords: Epidemiology; Inherited retinal dystrophies (IRD); Leber congenital amaurosis (LCA); Prevalence; RPE65 gene; Retinitis pigmentosa (RP); Systematic review.

Fig. 1

PRISMA flow diagram of included and excluded publications

Fig. 2

Proportion of RPE65 gene mutation in clinically diagnosed LCA patients. Source: Whelan et al. [5], Thompson et al. [14], Sitorus et al. [29], Verma et al. [31], Lotery et al. [32], Xu et al. [37], Booij et al. [38], Eisenberger et al. [39], Vallespin et al. [40], Henderson et al. [41], Weisschuh et al. [42], Simonelli et al. [43], Bocquet et al. [44], Dharmaraj et al. [45], Zernant et al. [46], Galvin et al. [47], Simovich et al. [48], Morimura et al. [49], Glen et al. [50], Heon et al. [51], Viswarubhiny et al. [55], Zenteno et al. [56], El Matri et al. [59], Haer-Wigman et al. [76], Astuti et al. [102], Coppieters et al. [107], Mamatha et al. [108], Sundaresan et al. [109], Srikrupa et al. [110], Thompson et al. [111], Lamey et al. [112], Surl et al. [113], Seong et al. [114], Liu, Bu [115], Li et al. [116], Chen et al. [117], Zhong et al. [118], Xu et al. [119]. The high RPE65-LCA 16.67% in South India [31] is based on 27/30 probands born through consanguineous marriage. The high RPE65-LCA 35.82% in Canada [51] is probably related to the paper’s methodology to analyse only LCA patients with clinically and molecularly confirmed diagnosis identified at one of the hospitals with an ethnically diverse population. The very high prevalence of RPE65 mutations (95%) in Costa Rica [50] is due to four founder mutations in RPE65 which have been maintained in this genetically isolated population. The paper’s methodology was to analyse samples from affected children and their immediate family members only. Additional data by families (not shown in Fig. 2): The Chinese paper [120] had reported RPE65 mutations in 1% (1/100) families with LCA. The Chinese paper [82] had reported biallelic RPE65 mutations in 2.97% (8/269) families with LCA. The Saudi Arabia paper [121] had reported RPE65 mutations in 5.41% (2/37) consanguineous families with LCA. The Spanish paper [122] had reported RPE65 mutations in 16.51% (18/109) families with LCA. The Indian paper [123] had reported RPE65 mutations in 18.18% (2/11) families with LCA. Worldwide paper [36] had reported RPE65 mutations in 6.15% (11/179) families with LCA. Key messages from Fig. 2 on proportions of RPE65 gene mutations in clinically diagnosed cases of LCA: The proportions of RPE65-LCA across the world ranged between 1.26% in China to 22.22% in the Netherlands (excluding outliers from Costa Rica and Canada). The proportions of RPE65-LCA in the EU-5 counties ranged between 1.79% in Germany to 16% in France. The proportions of RPE65-LCA across the European region ranged between 1.79% in Germany to 22.22% in the Netherlands. The proportions of RPE65-LCA in the Americas region ranged between 1.69% in Canada to 15.55% in the US (excluding outliers from Costa Rica and Canada). The proportions of RPE65-LCA in the Asian region ranged between 1.26% in China to 16.67% in India. The proportion of RPE65-LCA across the US and Europe was at 11.4%

Fig. 3

Country-wise RP prevalence. Source: Bertelsen et al. [34], Hu [60], Haim [61], O'Neill et al. [62], Puech et al. [63], Grondahl [64], Bunker et al. [65], Bundey, Crews [66], Chizzolini et al. [67], Peterlin et al. [68], Rim et al. [69], Ammann et al. [70], Najera et al. [71], Na et al. [72], Sharon et al. [73]. The high prevalence (47.62) of RP in Israel [73] is based on consanguineous populations