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Clinical and genetic profile of retinopathies among LCA patients in a large German cohort.

Researchers at the Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, have reported results on the prevalence of disease-causing variants in LCA-associated genes in a large German cohort at a single clinical site.  CEP290 (centrosomal protein 290 for photoreceptor ciliary transport; LCA10, chromosome 12q21.32) and CRB1 (crumbs homologue 1 for photoreceptor morphogenesis; LCA8, chromosome 1q31.32.1) were the most frequently mutated gene. The purpose of the study was to document valuable genetic and phenotypic details in preparation of gene therapeutic trials.  The researches stated that “for any therapeutic gene intervention, the disease-causing genotype is the primary criterion for treatment access, but the clinical diagnosis, state of the retina, number of to be treated target cells, and the time point of treatment will be crucial”.

LCA is a severe congenital or early infant-onset form of non-syndromic retinal disease characterized 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.  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). Historically, the clinical diagnosis did 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.  At present, there are at least 25 genes causative for LCA including a broad range of functions of phototransduction, the visual cycle and photoreceptor cell development and maintenance, photoreceptor morphogenesis, retinal differentiation, ciliary transport process, phototransduction, retinoid cycle, guanine synthesis and signal transduction causing early loss of vision. In addition, there over >400 mutations linked with LCA genes are reported in the literature.

A summary of the results from the German cohort showed a total of 105 patients (53 female, 52 male, age 3-76 years) reporting disease-causing variants in 16 LCA-associated genes. The genetic spectrum displayed variants in the following genes, in order of the most frequently mutated gene: CEP290 (21%), CRB1 (21%), RPE65 (14%), RDH12 (13%), AIPL1 (6%), TULP1 (6%), and IQCB1 (5%), including pathogenic variants in LRAT, CABP4, NMNAT1, RPGRIP1, SPATA7, CRX, IFT140, LCA5, and RD3 (altogether accounting for 14%). According to the study, the researchers commented that the “study fills the gap in the literature on the prevalence of LCA subtypes in Germany and provides for the first time a detailed clinical and genetic characterization of one of the largest cohorts in Europe. The results will help to prepare upcoming gene therapeutic trials and to better counsel affected patients. Genetic testing, demographic evaluation of the distribution of different genotypes, and extensive natural history studies in order to describe the course of the disease, identify treatable cells in the retina, define the window of opportunity, and the develop suitable clinical endpoints are highly needed”.