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.

Keywords: (MeSH terms): retinal diseases; early onset severe retinal dystrophy; eosrd; gene therapy; lca; leber congenital amaurosis; retinal cone photoreceptor cells; review; rtinal rod photoreceptor cells; secord; severe early childhood onset retinal dystrophy.

Figure 1

Spatial representation of expression of LCA/EOSRD genes, grouped according to their proposed function. EOSRD, early-onset severe retinal dystrophy; LCA, Leber congenital amaurosis.

Figure 2

Colour fundus photographs of patients with recognisable LCA/EOSRD clinical phenotypes. (A) RPE65-retinopathy, associated with a blonde fundus, peripheral, white punctate lesions and normal central macular appearance in keeping with central preservation of outer retina. (B) CRB1-retinopathy characterised by nummular pigmentation, periarteriolar sparing of the RPE and macular atrophy. (C) RDH12-retinopathy with characteristic dense intraretinal pigmentation and macular atrophy with pigmentation and yellowing. EOSRD, early-onset severe retinal dystrophy; LCA, Leber congenital amaurosis; RPE, retinal pigment epithelium.