Abstract
The ABCA4 protein (then called a “rim protein”) was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types – missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy – clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches.
Highlights
The ABCA4 protein was first identified in 1978 in the rims and incisures of rod photoreceptors
From his investigation of fundoscopic and electrophysiological findings of 38 patients, Fishman classified the severity of STGD1 across the following stages: Stage I: Confined central macular lesions ranging from irregular pigmentary mottling to well-defined lesions of retinal pigment epithelium (RPE) atrophy with a characteristic “beaten-bronze” or “snail-slime” appearance underlying central or paracentral scotomas
This feature is most conspicuous on short-wavelength autofluorescence (SW-AF) as intensely fluorescent foci distributed across the macula or extending far across the posterior pole at more advanced disease stages (Chen et al, 2019; Cideciyan et al, 2015)
Summary
Hereditary dystrophies of the macula reminiscent of autosomal recessive Stargardt disease (STGD1) have been documented from as early as the end of the 19th century (Lang, 1885). Progress in Retinal and Eye Research 79 (2020) 100861 distinct disease entity, Gerald Fishman, of the Illinois Eye and Ear Infirmary in Chicago, recognized differences in clinical expression and established a four-tier classification system (Fishman, 1976) that to this day remains influential to ophthalmologists around the world From his investigation of fundoscopic and electrophysiological findings of 38 patients, Fishman classified the severity of STGD1 across the following stages: Stage I: Confined central macular lesions ranging from irregular pigmentary mottling to well-defined lesions of RPE atrophy with a characteristic “beaten-bronze” or “snail-slime” appearance underlying central or paracentral scotomas. Cumulative advances over the last three decades have provided a defining foundation for understanding what we know to be the most common inherited Mendelian eye disorder in the world
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