Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations

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.

Retinal Boundary Segmentation in Stargardt Disease Optical Coherence Tomography Images Using Automated Deep Learning

“…Therefore, there is an unmet clinical need to improve current OCT segmentation algorithms for each type of retinal pathology to allow accurate monitoring of the rate of retinal degeneration in this era of increasing therapeutic options to arrest disease progression. 7 , 8 …”

Pathogenic Mechanisms Underlying Stargardt Macular Degeneration Linked to Mutations in the Transmembrane Domains of ABCA4

“…N1868I is another mild variant for which there is considerable genetic and clinical data (Zernant, Lee et al 2017, Runhart, Sangermano et al 2018. The genetic frequency and penetrance of the N1868I mutations has led to considerable discussion about whether this variant is benign or pathogenic (Cremers, Lee et al 2020). Support for the pathogenic nature of this variant comes from analysis of STGD1 patients harboring the N1868I variant in trans with a severe variant.…”

“…The importance of ABCA4 is highlighted by the finding that mutations in the gene encoding ABCA4 are responsible for autosomal recessive Stargardt disease (STGD1:MIM 248200) as well as recessive forms of cone-rod dystrophy and retinitis pigmentosa (Allikmets, Singh et al 1997, Nasonkin, Illing et al 1998, Klevering, Blankenagel et al 2002, Charbel Issa, Barnard et al 2013, Cornelis, Bax et al 2017, Tanna, Strauss et al 2017, Cremers, Lee et al 2020. Stargardt disease, the most common inherited macular degeneration, is characterized by loss in central vision, progressive bilateral atrophy of the macula including the underlying retinal pigment epithelial (RPE) cells, impaired color vision, delayed dark adaptation, and accumulation of fluorescent yellow-white flecks around the macula and midretinal periphery.…”

“…These include missense mutations, frameshifts, truncations, small deletions, insertions, splice site mutations, and deep intronic mutations. Over 60% are missense mutations resulting in amino acid substitutions spread throughout the protein (Cornelis, Bax et al 2017, Cremers, Lee et al 2020.…”

Practical guide to genetic screening for inherited eye diseases

“…For example, Stargardt disease is a macular dystrophy with a prevalence of ~1:8000–10,000 predominantly caused by biallelic variants in ABCA4 , which determine the onset and severity of the phenotype. 18 , 19 Some disease-causing variants in the same gene can be associated with syndromic or nonsyndromic disorders, for example, USH2A biallelic variants can be associated with type II Usher syndrome in 85% of cases, characterised by vision and hearing loss, or nonsyndromic RP in 20% of RP cases. 20 – 22 Although the majority of bilateral microphthalmia/anophthalmia cases are due to dominant monoallelic mutations, homozygous and compound heterozygous loss-of-function variants are found in STRA6 and RAX .…”