Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

Abstract

Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70–80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention.

Contribution of non-coding mutations to RPGRIP1-mediated inherited retinal degeneration

“…Our finding of 3 families out of 1719 (0.17%) with biallelic inactivation in the coding sequence corresponds with the reported rate of RPGRIP1-mutant IRDs in the literature, that is ~0.2% (5,63,71). While most of the coding mutations led to frameshifts and premature terminations affecting a significant portion of the encoded protein ( Figure 6), the c.3793ins4 (p.V1265Gfs*19) variant occurs in the last exon hence its significance was not as clear.…”

“…It has a prevalence of 1 in 33000 to 81000, and comprises an estimated 18% of blind children and 5% of IRDs (2)(3)(4)(5). Mutations in 25 genes have been linked to LCA and can explain up to 70% of cases .…”

“…Mutations in 25 genes have been linked to LCA and can explain up to 70% of cases . It should be noted however that mutations in LCA associated genes can also cause other IRD phenotypes and thus that inclusion of the genetic cause of disease in patient's diagnoses is a desirable goal (5,39). One of the historically LCA-associated genes is RPGRIP1, mutations in which are reported to cause 4-5% of LCA (32,33) and thus approximately 0.2% of IRDs.…”

RPE65 and retinal dystrophy: Report of new and recurrent mutations

“…To date, several hundred genes have been identified in which pathogenic mutations are associated with IRDs . Leber congenital amaurosis (LCA) is a form of intense and early onset of IRDs, at birth or in the first few months of life . Specifically, approximately 25 genes have been introduced for LCA .…”

AIPL1: A specialized chaperone for the phototransduction effector

“…LCA is a severe, early-onset, inherited retinopathy that causes blindness in early childhood [2]. Various forms of LCA are currently linked to 25 genes, but the AIPL1 -related LCA4 is one of the most clinically severe forms [3, 4]. The name AIPL1 reflects its high sequence homology (49% identity) and similar domain organization with the ubiquitously expressed aryl hydrocarbon receptor (AhR)-interacting protein (AIP) [1].…”