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A longitudinal natural history of RPE65-associated retinopathies in Italy showed specific genotype-phenotype characteristics

An Italian consortium of clinical researches from fourteen institutes has reported a longitudinal natural history of RPE65-assocaited retinopathies.  The report, led Dr. Francesco Testa at the Eye Clinic, University of Campania Luigi Vanvitelli, Naples, presented the study at the IOVS (2022;63(2):13).  The report of the researchers showed that the study “described the natural course of RPE65-associated IRD in an Italian cohort showing for the first time a specific genotype-phenotype association. Our findings can contribute to a better management of RPE65-associated IRD patients”.  As is well known, natural history study data are of enormous value for the research community, not least of all allowing how clinical cohorts compare outcomes for future potential therapies.


Previously defined as a juvenile form of retinitis pigmentosa (RP), Leber congenital amaurosis (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. LCA was originally identified by a German clinical ophthalmologist, Theodor von Leber in 1869 and this disorder was primarily based on the early infant-onset form of non-syndromic inherited visual loss.  However, following the original description of the infantile disorder, a subsequent milder form of the same disease presented in the 6th and 7th years of life and led to blindness by the age of 30 years, considered to be on the same spectrum as LCA.  This later-onset disease has been referenced by several different names including juvenile and early-onset retinitis pigmentosa, childhood-onset severe retinal dystrophy, Early Onset Severe Retinal Dystrophy (EOSRD) and Severe Early Childhood Onset Retinal Dystrophy (SECORD). Regardless, 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 (e.g., RPE65-related LCA), is preferable.  As of latest reporting with RetNet, there are at least 25 genes causative for LCA.


In the current natural history report by the Italian team, researchers used a longitudinal multicentric retrospective chart-review study, designed to collect best corrected visual acuity (BCVA), Goldman visual field, optical coherence tomography (OCT), and electroretinography (ERG) measurements.  The results of the study showed that an overall cohort of 60 Italian patients from 56 families with RPE65-associated of inherited retinal degenerations (IRD) was recruited. Of these, 43 patients (mean age, 27.8 ± 19.7 years) were included and showed a mean BCVA of 2.0 ± 1.0 logMAR. The report showed that a time-to-event analysis revealed a median age of 33.8 years and 41.4 years to reach low vision and blindness based on BCVA, respectively. As anticipated, ERG data available for 34 patients showed undetectable responses in most patients (26; 76.5%) while OCT data available for 31 patients revealed epiretinal membranes in five patients (16.1%). Central foveal thickness significantly decreased with age at a mean annual rate of −0.6%/y (P = 0.044). In summary, the researchers commented that “[w]e identified 43 different variants in the RPE65 gene in the entire cohort. Nine variants were novel. Finally, to assess genotype-phenotype correlations, patients were stratified according to the number of RPE65 loss-of-function (LoF) alleles. Patients without LoF variants showed significantly (P < 0.05) better BCVA compared to patients with one or two LoF alleles”.  This valuable work will likely support and expand future data providing significant information on how to catalogue both diagnostic and therapeutic outcomes in the coming decade.