Deep Scleral Exposure: A Degenerative Outcome of End-Stage Stargardt Disease

Lee, Winston; Zernant, Jana; Nagasaki, Takayuki; Tsang, Stephen H.; Allikmets, Rando

doi:10.1016/j.ajo.2018.07.018

Cited by 10 publications

(12 citation statements)

References 65 publications

(56 reference statements)

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“…Further deterioration of the underlying choroidal layers (Sattler and Haller) may occur in response to the rapid demise of RPE ( Bertelsen et al, 2014 ; Muller et al, 2017 ; Tanaka et al, 2018 ) or progressively to a stage at which the underlying sclera may be visible on fundoscopy depending on the duration of disease ( Fig. 1 ) ( Lee et al, 2018 ).…”

Section: Clinical Hallmarks Of Abca4 -Associated Rmentioning

confidence: 99%

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

Cremers

Lee

Collin

et al. 2020

Progress in Retinal and Eye Research

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227

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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.

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Section: Clinical Hallmarks Of Abca4 -Associated Rmentioning

confidence: 99%

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

Cremers

Lee

Collin

et al. 2020

Progress in Retinal and Eye Research

Self Cite

205

227

View full text Add to dashboard Cite

show abstract

“…( 4) Consistent with the model that clinical phenotypes are dependent on the residual activity of ABCA4 protein, (5,6) variants resulting in null alleles such as stop-gain, frameshift, canonical splice site and large copy number variants have been documented in the most severe phenotypes such as cone-rod dystrophy, rapid-onset chorioretinopathy (ROC) and even generalized choriocapillaris dystrophies with retinitis pigmentosa-like features. (6)(7)(8)(9)(10) More recently, the complex genetic architecture of milder ABCA4 disease manifestations has been uncovered. The most frequent pathogenic allele, c.5882G>A p.(Gly1961Glu), is associated with a slow-progressing disease trajectory in patients who often present with transient phenotypes such as bull's eye maculopathy and occult macular dystrophy.…”

Section: Introductionmentioning

confidence: 99%

“…While the patient cohort is large considering the rarity of this disease, not all possible ABCA4 genotypes are represented. Notably, biallelic PVS1 genotypes which are known to underlie the most severe ABCA4 disease phenotypes such as RP-like, ROC and cone-rod dystrophy were not included (6)(7)(8)(9)(10). Prognostic assessment in these cases, however, usually unambiguous as visual deterioration begins early in life and disease progresses rapidly.…”

mentioning

confidence: 99%

A genotype-phenotype correlation matrix for ABCA4 disease based on long-term prognostic outcomes

Lee¹,

Zernant²,

Su³

et al. 2022

JCI Insight

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“…For this publication, the term ABCA4R will be used for the wide range of phenotypes previously reported in association with variants in ABCA4. These include bull's eye maculopathy (BEM) [57,58], retinitis pigmentosa with bone spicule pigmentary deposition [59,60], cone rod dystrophy [61], choriocapillaris dystrophy [62], and rapid onset chorioretinopathy [63].…”

Section: Clinical Phenotypes and Phenocopies In Abca4 Retinopathies (Abca4r)mentioning

confidence: 99%

An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

Al‐Khuzaei

Broadgate

Foster

et al. 2021

Genes

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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.

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Deep Scleral Exposure: A Degenerative Outcome of End-Stage Stargardt Disease

Cited by 10 publications

References 65 publications

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

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

A genotype-phenotype correlation matrix for ABCA4 disease based on long-term prognostic outcomes

An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story

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