Quantifying the Separation Between the Retinal Pigment Epithelium and Bruch's Membrane using Optical Coherence Tomography in Patients with Inherited Macular Degeneration

Khan, Kamron; Borooah, Shyamanga; Lando, Leonardo; Dans, Kunny; Mahroo, Omar A.; Meshi, Amit; Kalitzeos, Angelos; Agorogiannis, Georgios; Moghimi, Sasan; Freeman, William R.; Webster, Andrew R.; Moore, Anthony T.; McKibbin, Martin; Michaelides, Michel

doi:10.1167/tvst.9.6.26

Cited by 20 publications

(37 citation statements)

References 38 publications

(59 reference statements)

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“…The peripheral lesions in adGALCD are associated with early peripheral visual field loss, while the peripheral visual fields remain intact in LORD even in progressed stages [ 25 ]. Characteristic findings of stage 2 LORD are subretinal deposits which present in a pseudodrusen-like pattern with sub-RPE material and a thickening between RPE and Bruch membrane in the OCT [ 9 , 11 , 21 , 22 , 23 , 28 , 29 , 30 ]. These pseudodrusen-like lesions first develop in the temporal middle periphery progressing to scalloped chorioretinal atrophy as well as pigmentary changes, all of which were not observed in the adGALCD families.…”

Section: Discussionmentioning

confidence: 99%

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Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant

Kellner¹,

Weisschuh

Weinitz³

et al. 2021

IJMS

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We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level.

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Section: Discussionmentioning

confidence: 99%

“…As such, the phenotype in the families presented in this study much more resembles gyrate atrophy than LORD. Distinct characteristics of LORD in FAF and OCT were not observed in adGALCD: no sub-RPE deposits in the OCT and no structural alterations prior to RPE loss in the FAF were detected [ 25 , 26 , 29 , 33 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant

Kellner¹,

Weisschuh

Weinitz³

et al. 2021

IJMS

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“…18 BM and the RPE are occasionally separable in research prototype NIR OCT of normal eyes, 9,19,20 and they are reliably separated by commercial instruments in some pathologies. [21][22][23] Yet, to date, the contributions to the reflectivity of this fourth band have not been conclusively resolved according to anatomic space (e.g., interdigitation zone, apical RPE, basal RPE, and Bruch's membrane) or organelle (e.g., nucleus, mitochondria, lipofuscin, melanosome, melanolipofuscin). Although some acknowledge that melanosomes with melanin are major sources of RPE reflectivity, 8,[24][25][26][27] this viewpoint is not universal.…”

Section: Introductionmentioning

confidence: 99%

Visible Light Optical Coherence Tomography (OCT) Quantifies Subcellular Contributions to Outer Retinal Band 4

Zhang

Kho

Yiu

et al. 2021

Trans. Vis. Sci. Tech.

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Purpose To use visible light optical coherence tomography (OCT) to investigate subcellular reflectivity contributions to the outermost (4th) of the retinal hyperreflective bands visualized by current clinical near-infrared (NIR) OCT. Methods Visible light OCT, with 1.0 µm axial resolution, was performed in 28 eyes of 19 human subjects (21–57 years old) without history of ocular pathology. Two foveal and three extrafoveal hyperreflective zones were consistently depicted within band 4 in all eyes. The two outermost hyperreflective bands, occasionally visualized by NIR OCT, were presumed to be the retinal pigment epithelium (RPE) and Bruch's membrane (BM). RPE thickness, BM thickness, and RPE interior reflectivity were quantified topographically across the macula. Results A method for correcting RPE multiple scattering tails was found to both improve the Gaussian goodness-of-fit for the BM intensity profile and reduce the coefficient of variation of BM thickness in vivo. No major topographical differences in macular BM thickness were noted. RPE thickness decreased with increasing eccentricity. Visible light OCT signal intensity in the RPE was weighted to the apical side and attenuated more across the RPE in the fovea than peripherally. Conclusions Morphometry of the presumed RPE and BM bands is consistent with known anatomy. Weighting of RPE reflectivity toward the apical side suggests that melanosomes are the predominant contributors to RPE backscattering and signal attenuation in young eyes. Translational Relevance By enabling morphometric analysis of the RPE and BM, visible light OCT deciphers the main reflectivity contributions to outer retinal band 4, commonly visualized by commercial OCT systems.

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“…[35] BlamD are also found in aging retinas, albeit to a much lesser extent than in SFD, and there is a strong relationship between macular BlamD and the formation of exudative age-related macular degeneration (AMD). [36] The accumulation of BlamD causes the RPE to slowly separate from the underlying BrM, likely affecting nutrient transport and RPE function. [8,37] While no animal model has reproduced the BlamD accumulations seen in SFD patients, [34,38,39] We found these components highly expressed in the BlamD of SFD eyes, and in the sub-RPE deposits of SFD iPSC RPE.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix Dysfunction in Sorsby Patient-Derived Retinal Pigment Epithelium

Engel

Wang

Khuu

et al. 2021

Preprint

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Sorsby Fundus Dystrophy (SFD) is a rare form of macular degeneration that is clinically similar to age-related macular degeneration (AMD). SFD results from mutations found in the tissue inhibitor of metalloproteinase 3 (TIMP3) gene. TIMP3 is secreted by the retinal pigmented epithelium (RPE) into the underlying Bruch’s membrane (BrM), and it plays a critical role in maintaining extracellular matrix (ECM) homeostasis. A characteristic feature of post-mortem SFD globes is a thick layer of sub-RPE deposits overlying a disorganized BrM. Although likely central to the pathogenesis of SFD, no animal models have reproduced this phenotype. We generated induced pluripotent stem cell (iPSC)-derived RPE lines from SFD family members with the S204C TIMP3 mutation and observed that SFD RPE have highly dysregulated ECM and form large basal deposits by ~30 days in culture. The sub-RPE deposits are similar in ultrastructure and composition when compared to SFD family member globes. Mutant TIMP3 correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in the reversal of sub-RPE calcium deposition. We found that SFD TIMP3 has decreased inhibition of secreted matrix metalloproteinases. ECM dysfunction substantially impacts cellular metabolism. Targeted metabolomics data showed that intracellular 4-hydroxyproline, a major breakdown product of collagen, is significantly elevated in SFD RPE. Further, SFD RPE also has decreased intracellular reduced glutathione and is more vulnerable to oxidative stress. These findings suggest that key elements of SFD pathology can be recapitulated in culture which may lead to insights into disease mechanisms and potential treatments.Significance StatementThis study demonstrates that retinal pigmented epithelial (RPE) cells generated from patients with Sorsby Fundus Dystrophy (SFD) produce highly dysregulated extracellular matrices. SFD RPE form large basal deposits in culture that are similar in composition to what is observed in donated SFD post-mortem globes from family members. Further, SFD RPE demonstrate high levels of 4-hydroxyproline, a major breakdown product of collagen. SFD RPE are also more vulnerable to oxidative stress. Our studies indicate that key elements of SFD pathology can be recapitulated in culture, and ECM dysregulation may lead to metabolic changes detrimental to RPE health.

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Quantifying the Separation Between the Retinal Pigment Epithelium and Bruch's Membrane using Optical Coherence Tomography in Patients with Inherited Macular Degeneration

Abstract: Quantifying the separation between the retinal pigment epithelium and Bruch's membrane using optical coherence tomography in patients with inherited macular degeneration.

Cited by 20 publications

References 38 publications

Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant

Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant

Visible Light Optical Coherence Tomography (OCT) Quantifies Subcellular Contributions to Outer Retinal Band 4

Extracellular Matrix Dysfunction in Sorsby Patient-Derived Retinal Pigment Epithelium

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