A systematic literature review on the epidemiology of RPE65 mutations report significant variations in the literature within countries as well as regions.

A systematic review on the epidemiology of RPE65 mutations reported in the literature showed that there were significant variations of RPE65 proportions within countries as well as regions. Data for RPE65-mediated inherited retinal dystrophies (IRD) indicated that the limited assessments of prevalence and incidence were challenging.  While the prevalence of Leber congenital amaurosis (LCA) was estimated to be 1.20–2.37 per 100,000, the proportion of RPE65 mutations in clinically diagnosed cases of LCA ranged between 1.79 and 22.22% in the European region and ranged between 1.69 and 15.55% in the Americas region. The US and major European countries (France, Germany, Italy, Spain, and the UK) ranged between ~2 and 16% and in the Asian region, the data ranged between 1.26 and 16.67% (comparable to US and major European countries findings).

LCA is a severe congenital or early infant-onset form of non-syndromic retinal disease, characterised by severe retinal dystrophy, vision loss, nystagmus, an absence of a normal pupil response and an almost non-recordable ERG.  The clinical diagnosis does not have a well agreed-upon definition and therefore a more recent structure for nomenclature, aiming to define the basis as being on genotype, rather than phenotype.  To date, there are now 25 genes causative for LCA.  Most of the 25 genes translate proteins for a broad range of functions including phototransduction, the visual cycle and photoreceptor cell development and maintenance, specifically photoreceptor morphogenesis (CRB1, CRX, GDF6), retinal differentiation (OTX2), ciliary transport process (CEP290, IQCB1, LCA5, RPGRIP, SPATA7, TULP1), phototransduction (AIPL1, GUCY2D) retinoid cycle (LRAT, RDH12, RPE65), guanine synthesis (IMPDH1) and signal transduction (CABP4, KCNJ13) causing early loss of vision. In addition, there over >400 mutations linked with LCA gene s reported in the literature.  RPE65, focused on the current systematic review, was previously estimated to account for approximately 5% – 10% of LCA, approximately 1% – 2% of retinitis pigmentosa.  RPE65 gene (LCA2) is localized to chromosome 1p31, comprising of 14 exons encoding the retinal pigment epithelium-specific 65-Kd protein (RPE65). RPE65 is a key component of the retinoid visual cycle expressed in the retinal pigment epithelium (RPE) which together with LRAT is involved in continuous regeneration of the visual chromophore.

In the review, 1,066 abstracts were collected and a total of 100 studies with relevant data were included in this research. 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. As mentioned, 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). In addition, the researchers commented further details that “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”.