Leber’s Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations

Abstract

Leber’s congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness. With advances in molecular diagnostic technology, the knowledge about the genetic background of LCA has expanded widely, while disease-causing variants have been identified in 38 genes. Different pathogenetic mechanisms have been found among these varieties of genetic mutations, all of which result in the dysfunction or absence of their encoded proteins participating in the visual cycle. Hence, the clinical phenotypes also exhibit extensive heterogenicity, including the course of visual impairment, involvement of the macular area, alteration in retinal structure, and residual function of the diseased photoreceptor. By reviewing the clinical course, fundoscopic images, optical coherent tomography examination, and electroretinogram, genotype-phenotype correlations could be established for common genetic mutations in LCA, which would benefit the timing of the diagnosis and thus promote early intervention. Gene therapy is promising in the management of LCA, while several clinical trials are ongoing and preliminary success has been announced, focusing on RPE65 and other common disease-causing genes. This review provides an update on the genetics, clinical examination findings, and genotype-phenotype correlations in the most well-established causative genetic mutations of LCA.

Novel homozygous nonsynonymous variant of CNNM4 gene in a Chinese family with Jalili syndrome

“…Xu et al, 2020). The ocular findings of type-A JS mimic some forms of LCA, such as RDH12 and CRB-related LCA (Huang et al, 2021). Patients of these two genotypes of LCA are featured by atrophic maculopathy.…”

“…Notably, the majority of which was initially clinically diagnosed as LCA, as well as our case (Wang et al, 2015 ; K. Xu et al, 2020 ). The ocular findings of type‐A JS mimic some forms of LCA, such as RDH12 and CRB ‐related LCA (Huang et al, 2021 ). Patients of these two genotypes of LCA are featured by atrophic maculopathy.…”

Genetic modifiers of Cep290-mediated retinal degeneration

“…The BXD24- rd16 strain of mice contains a spontaneous in-frame deletion of Cep290 exons 35-39 and homozygosity for the rd16 mutation leads to an early onset retinal degeneration characterized by progressive retinal thinning due to photoreceptor outer segment degeneration, analogous to human LCA patients. Among patients with CEP290-mediated retinal degeneration, the substantial variable expressivity in retinal phenotype and vision 23–26 indicates that other factors, such as genetic modifiers 2,3,12 , are capable of influencing patient outcome.…”

“…However, CEP290 mutations that are severe in one family are sometimes mild in another 23 , and even intrafamilial variability has been observed for CEP290- and other forms of LCA 24–26 . Genetic modifiers are often evoked to explain these types of variability, as well as the overall pleiotropy of LCA 2,3,12 . To date, studies testing this hypothesis directly have largely relied on candidate-driven approaches that typically test interactions between genes with overt disease-causing influences 27–32 , while agnostic genome-wide searches for modifiers with potentially less overt autonomous phenotypes have been uncommon 33 .…”

The Role of Vitamin A in Retinal Diseases

“…LRAT is a 36 kDa protein encoded by LRAT gene located on chromosome 4q32.1 [178]. It converts all-trans-retinol to all-trans-retinyl esters.…”