Differential Disease Progression in Atrophic Age-Related Macular Degeneration and Late-Onset Stargardt Disease

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PURPOSE. To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1). METHODS. Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253þ43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769-784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs). RESULTS. Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253þ43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253þ43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253þ43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253þ43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e.,~30% of the c.769-784C>T allele alone). CONCLUSIONS. Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene.

Section: Discussionmentioning

confidence: 99%

Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles

Runhart

Valkenburg

Cornelis

et al. 2019

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“…The well-preserved visual acuity leads to patient's delay and at the time of the first ophthalmologic consultation large areas of atrophy are already present. We know from this and other studies that the atrophy progression rate is relatively slow, [39][40][41] disease-specific changes have therefore been present for years. In the 37 patients with foveal sparing in this study, only one patient experienced a scotoma as initial symptom.…”

Section: Discussionmentioning

confidence: 68%

“…In such cases, an alternative outcome measure like atrophy progression, or change in the size of the spared fovea over time, is preferable. 41 In summary, the phenomenon of foveal sparing was observed in several distinct retinal dystrophies. All patients presented with late-onset disease, and the pattern of perifoveal RPE atrophy progression was identical in all conditions.…”

Section: Discussionmentioning

confidence: 93%

Foveal Sparing in Central Retinal Dystrophies

Valkenburg

Lambertus

et al. 2019

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PURPOSE. To describe foveal sparing (FS) in central retinal dystrophies (RD). METHODS. Participants for this retrospective study were identified from the retinal dystrophy database of the Department of Ophthalmology at Radboud University Medical Center. FS was defined as an intact foveal structure surrounded by at least 1808 of chorioretinal atrophy, and a best-corrected visual acuity (BCVA) of <1.0 logMAR (>20/200 Snellen). Eligible eyes were identified using fundus autofluorescence (FAF) images, and FS was confirmed using nearinfrared reflectance (NIR) imaging and spectral-domain optical coherence tomography when available. Clinical and demographic data were extracted from medical records. We performed quantification of FS and chorioretinal atrophic areas using semiautomated software on fundus autofluorescence and NIR images. We calculated the chronologic change using eye-wise linear regression. RESULTS. We identified 36 patients (56 eyes) with FS. RDs included: Stargardt disease (STGD1;20 patients), central areolar choroidal dystrophy (CACD; 7 patients), mitochondrial retinal dystrophy (MRD; 6 patients), pseudo-Stargardt pattern dystrophy (PSPD; 3 patients). Median age at first presentation was 60 (interquartile range [IQR] 54-63) years. Median BCVA at first presentation ranged from 20/25 Snellen in STGD1, to 20/38 Snellen in MRD. Progression of the chorioretinal atrophic area ranged from 0.26 (0.25-0.28) mm/year in PSPD, to 0.14 (0.11-0.22) in CACD. Change in FS area over time was similar between the different dystrophies. CONCLUSIONS. The presence of FS in different RDs suggests a disease-independent mechanism that prolongs the survival of the fovea. The associated preservation of BCVA is important for the individual prognosis and has implications for the design of therapeutic trials for RDs. Keywords: foveal sparing, retinal dystrophy, Stargardt disease, central areolar choroidal dystrophy, mitochondrial retinal dystrophy (STGD1), 8,10-13 central areolar choroidal dystrophy (CACD), 14 and maternally inherited diabetes and deafness (MIDD). 15,16 Geographic atrophy and reticular pseudo-drusen in age-related macular degeneration may also show a tendency to spare the fovea for a prolonged period of time. 7,9,17-20 Although there is no consensus definition of the term ''foveal sparing,'' it could be distinguished from a perimacular ring scotoma, which is located more peripherally in the macula, resulting in a central visual island frequently observed in retinitis pigmentosa (RP). 21 Bull's eye maculopathy is another separate entity, where an intact fovea is surrounded by ausually oval shaped-area of outer retinal atrophy. Historically, the term ''foveal sparing'' was coined by Hart et al. 22 to describe the sparing of the fovea from hemifield defects. In the context of macular disorders, Hart et al. 22 were the first

“…28 Previously, slower progression of RPE atrophy in STGD1 as compared to AMD was observed, implicating a relatively earlier onset of RPE atrophy in late-onset STGD1 as compared to AMD. 52 Potentially, this difference in disease duration may explain to some extent the diverging degree of vascular density within RPE atrophy between these two disease entities.…”

Section: Discussionmentioning

confidence: 99%

Choroidal Flow Signal in Late-Onset Stargardt Disease and Age-Related Macular Degeneration: An OCT-Angiography Study

Müller

Pfau

Möller

et al. 2018

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PURPOSE. To investigate the choroidal blood flow in areas within and adjacent to retinal pigment epithelium (RPE) atrophy secondary to late-onset Stargardt disease (STGD1) and agerelated macular degeneration (AMD). METHODS.A total of 43 eyes (23 STGD1 and 20 AMD) of patients with RPE atrophy and 25 eyes of healthy controls without ocular pathology underwent multimodal imaging including optical coherence tomography angiography (OCT-A; PLEX Elite 9000 Swept-Source OCT). Using an exploratory approach, choriocapillaris and deeper choroid OCT-A slabs were evaluated in order to detect differences between STGD1 and AMD. The magnitude of absenceof-flow signal (AFS) was investigated in terms of area-fraction and size-frequency distribution. RESULTS.Qualitative and quantitative analysis of areas of RPE atrophy revealed more pronounced rarefaction of the choriocapillaris flow signal in STGD1 as compared to AMD (AFS area fraction: 33.15% 6 6.86% vs. 31.68% 6 8.39%; P ¼ 0.517), while outside RPE atrophy rarefaction was less pronounced in STGD1 (AFS area fraction: 17.41% 6 5.67% vs. 21.59% 6 6.90%; P < 0.001), to the level of nonsignificance compared to controls (13.27% 6 2.99%, P ¼ 0.368). Given this discrepancy, the ratio of the AFS area fraction within/outside of RPE atrophy could be used to differentiate between STGD1 and AMD with 65.0% sensitivity and 92.3% specificity. CONCLUSIONS.Using OCT-A, comparison of choroidal flow signal within and outside the area of RPE atrophy revealed distinct differences between STGD1 and AMD, potentially implicating a differential role of the choroid in the pathogenesis of RPE atrophy in these two diseases.