Al-Khuzaei S, Broadgate S, Foster CR, Shah M, Yu J, Downes SM, Halford S. An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story. Genes (Basel). 2021 Aug 13;12(8):1241. doi: 10.3390/genes12081241. PMID: 34440414; PMCID: PMC8392661.
Abstract
Stargardt disease (STGD1) and ABCA4 retinopathies (ABCA4R) are caused by pathogenic variants in the ABCA4 gene inherited in an autosomal recessive manner. The gene encodes an importer flippase protein that prevents the build-up of vitamin A derivatives that are toxic to the RPE. Diagnosing ABCA4R is complex due to its phenotypic variability and the presence of other inherited retinal dystrophy phenocopies. ABCA4 is a large gene, comprising 50 exons; to date > 2000 variants have been described. These include missense, nonsense, splicing, structural, and deep intronic variants. Missense variants account for the majority of variants in ABCA4. However, in a significant proportion of patients with an ABCA4R phenotype, a second variant in ABCA4 is not identified. This could be due to the presence of yet unknown variants, or hypomorphic alleles being incorrectly classified as benign, or the possibility that the disease is caused by a variant in another gene. This underlines the importance of accurate genetic testing. The pathogenicity of novel variants can be predicted using in silico programs, but these rely on databases that are not ethnically diverse, thus highlighting the need for studies in differing populations. Functional studies in vitro are useful towards assessing protein function but do not directly measure the flippase activity. Obtaining an accurate molecular diagnosis is becoming increasingly more important as targeted therapeutic options become available; these include pharmacological, gene-based, and cell replacement-based therapies. The aim of this review is to provide an update on the current status of genotyping in ABCA4 and the status of the therapeutic approaches being investigated.
The aim of this review article is to give an overview of the current status of genotyping in ABCA4, an update on missing heritability in ABCA4, phenocopies, the effect of genotype on the severity of the phenotype, and assessment techniques to predict the functional consequences of the variants. We will also provide an update on the current therapeutic approaches that are being investigated.
Therapies
Currently there are no commercially available treatments for ABCA4R/STGD1. Patients are currently advised to avoid supplements containing vitamin A, due to lipofuscin accumulation being seen in Abca4 knockout mice that were given vitamin A [163]. Wearing protective, dark-tinted glasses in bright conditions is recommended to reduce short wavelength light reaching the retina, thus reducing the risk of light toxicity [164]. Potential treatments currently being investigated include pharmacological interventions, gene therapy, and stem cell-based therapy approaches (see Table 6). Novel therapies are initially investigated in animal models followed by trials in human subjects. Human trials are divided into four phases: Phase I—to assess the safety of the therapy in a small number of subjects; Phase II—to assess efficacy where patients are randomly placed in treatment and placebo arms; Phase III—similarly assesses efficacy but uses a larger cohort of randomized patients; and Phase IV—monitoring the therapy when it becomes available.
Pharmacological therapies for ABCA4R are mainly based on targeting aspects of the visual cycle in order to reduce the accumulation of lipofuscin deposits. Table 6 details the effect of the compound and trial results if published. The main advantage of these potential therapies is that they can be taken orally, meaning they are less invasive.
Keywords: ABCA4, Stargardt disease, genetic testing, ABCA4-associated retinopathies, phenocopies
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