Vascular Profile of Autosomal Recessive Bestrophinopathy Revealed by Projection-Resolved OCTA

Vascular Profile of Autosomal Recessive Bestrophinopathy Revealed by Projection-Resolved OCTA | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Vascular Profile of Autosomal Recessive Bestrophinopathy Revealed by Projection-Resolved OCTA Xiaona Wang, Szy Yann Chan, Qian Li, Qisheng You, Jie Wang, Yali Jia, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6511487/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: To investigate macular vascular changes in autosomal recessive bestrophinopathy (ARB) using projection-resolved optical coherence tomography angiography (PR-OCTA) and analyze their correlation with visual function and axial length (AL). Methods: This retrospective study included 12 ARB patients and 12 age- and AL-matched healthy controls. All participants underwent comprehensive ocular examinations and PR-OCTA imaging to measure parafoveal vessel density in the superficial vascular complex (SVC), inner capillary plexus (ICP), and deep capillary plexus (DCP). Statistical analyses were performed to compare vessel density and correlate these metrics with best-corrected visual acuity (BCVA) and AL. Results: Compared to controls, ARB patients exhibited significantly reduced parafoveal vessel density in the SVC (53.94 ± 3.85% vs. 57.72 ± 5.82%, P < 0.05), ICP (34.17 ± 4.03% vs. 41.54 ± 5.9%, P < 0.001), and DCP (15.13 ± 7.43% vs. 30.22 ± 7.65%, P < 0.001). Subgroup analysis revealed no significant differences in vessel density between glaucoma and non-glaucoma patients or between those with and without macular schisis. Positive correlations were found between BCVA and vessel density in the ICP (r = 0.502, P = 0.017) and DCP (r = 0.508, P = 0.016). Conclusions: PR-OCTA demonstrated significantly reduced parafoveal vessel density in ARB patients, suggesting vascular impairment associated with retinal dysfunction. These findings provide new insights into ARB pathophysiology and highlight the potential utility of OCTA in evaluating rare retinal disorders. autosomal recessive bestrophinopathy macular schisis glaucoma optical coherence tomography angiography Figures Figure 1 Introduction With advancements in gene sequencing technology, the genotype and phenotypic heterogeneity of BEST1-related diseases have become increasingly recognized[ 1 ]. In addition to Best vitelliform macular dystrophy (BVMD), BEST1 mutations are associated with a spectrum of diseases, including microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (MRCS) syndrome, atypical retinitis pigmentosa, and autosomal recessive bestrophinopathy (ARB)[ 2 ]. ARB, first described in 2008, results from homozygous or compound heterozygous mutations in the BEST1 gene[ 3 ]. Compared to BVMD, ARB is characterized by distinct retinal dystrophy features, including yellowish subretinal lesions scattered in the posterior pole and diffuse fundus autofluorescence abnormalities. Beyond retinal changes, ARB patients often present with systemic ocular abnormalities such as hyperopia, amblyopia, narrow anterior chambers, and angle-closure glaucoma, which are challenging to manage clinically[ 3 ][ 4 ]. Given its genetic basis, ARB affects the retinal pigment epithelium (RPE) through dysfunction of bestrophin-1, a multifunctional protein localized at the basolateral plasma membrane of RPE cells [ 10 ]. Bestrophin-1 is hypothesized to function as a Ca2 + -activated Cl − -channel, a regulator of voltage-gated Ca 2+ -channels, and a bicarbonate (HCO 3 − ​) channel[ 11 ][ 12 ][ 13 ]. While these molecular insights enhance our understanding of RPE biology, the precise pathophysiological mechanisms underlying ARB remain incompletely understood. Notably, RPE dysfunction in ARB is thought to impair anterior and posterior segment development, leading to short axial length (AL), shallow anterior chambers, and associated complications such as angle-closure glaucoma. Optical coherence tomography angiography (OCTA) has emerged as a non-invasive imaging modality for evaluating retinal vasculature. By leveraging eye-tracking technology, OCTA provides high-resolution imaging and reliable quantitative data on vascular profiles[ 5 ]. Recent studies have identified OCTA features in hereditary retinal diseases, such as BVMD and adult-onset foveomacular vitelliform dystrophy (AOFVD)[ 6 ][ 7 ]. However, data on OCTA findings in ARB or other BEST1-related diseases remain limited. This study investigates macular vascular changes in ARB patients using projection-resolved OCTA (PR-OCTA). It evaluates parafoveal vessel density in capillary plexuses and examines correlations with visual acuity and axial length to better understand ARB pathophysiology. Methods This retrospective study included 12 ARB patients from the retina clinic of Beijing Tongren Eye Center (December 2010 to September 2019) and 12 age- and axial length-matched healthy volunteers as controls. The study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Tongren Hospital (Approval Number: TRECKY2019-122). ARB diagnosis was based on criteria described by Boon et al.[ 2 ], including juvenile to adult-onset visual loss or metamorphopsia, bilateral multifocal vitelliform lesions with subretinal fluid, reduced Arden ratio by electrooculography (EOG, < 1.5), and confirmed compound heterozygous or homozygous BEST1 mutations. Patients with ocular conditions confounding OCTA interpretation were excluded. Healthy volunteers underwent systemic and ophthalmological reviews to exclude diseases with ocular involvement. All ARB patients underwent comprehensive ocular examinations, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, Goldmann tonometry, and axial length measurement (IOLMaster 500, Carl Zeiss Meditec). OCTA imaging was performed using a spectral domain OCT system (RTVue XR Avanti, Optovue, Inc., CA, USA) with an A-scan rate of 70,000 scans/s, a light source centered at 840 nm, and a 50 nm bandwidth. Macular images (3×3 mm) were acquired. Scans with low signal strength (SSI < 50), motion artifacts, or off-center alignment were excluded. A reflectance-based projection-resolved (rbPR) OCTA algorithm was applied to enhance flow signal and suppress projection artifacts.[ 8 ] The retina was segmented into layers (inner limiting membrane to outer plexiform layer) and manually classified into the superficial vascular complex (SVC), inner capillary plexus (ICP), and deep capillary plexus (DCP) based on established criteria.[ 9 ] Vessel density was defined as the percentage of flow signal pixels in each capillary plexus. Parameters such as macular capillary plexus vessel density and RNFL thickness were quantitatively measured. Two masked investigators (QSY and JW) independently reviewed the OCTA scans. Disagreements were resolved by a senior retinal specialist. Data were analyzed using SPSS (version 23.0; IBM-SPSS, Chicago, IL, USA). Descriptive statistics were expressed as mean ± standard deviation. The Shapiro–Wilk test assessed normality. Between-group comparisons were performed using Student’s t-test, and correlations between BCVA, RNFL thickness, and macular vessel density were analyzed using Pearson correlation. A p-value < 0.05 was considered statistically significant. OCTA parameters were compared between ARB patients and controls (Fig. 1 ). ARB patients were further subdivided into groups based on the presence of macular schisis and intraocular pressure (IOP ≥ 25 mmHg with anti-glaucoma treatment). Differences in OCTA parameters were analyzed to investigate the potential effects of elevated IOP or macular schisis on OCTA changes. Correlations between BCVA, RNFL thickness, and OCTA parameters were also evaluated to explore relationships between OCTA perfusion changes and visual function. Two independent retinal specialists (XNW and QL.) conducted qualitative and quantitative analyses of multimodal retinal and OCTA imaging data. In cases of disagreement, a senior retinal specialist (XYP) reviewed the results and provided final adjudication. Results Study Population The ARB group consisted of 12 patients (24 eyes), including 6 males and 6 females, with a mean age of 29.3 ± 12.5 years (range, 11–49 years; median, 29). The mean BCVA was 0.23 ± 0.19, approximately equivalent to a Snellen acuity of 20/80. All patients presented with narrow anterior chambers, and 4 underwent bilateral trabeculectomy. Among the ARB eyes, 12 exhibited macular schisis, and 8 had glaucoma. The control group included 12 healthy individuals (12 eyes), with a mean age of 28.25 ± 9.91 years (range, 10–45 years; median, 29), comprising 4 males and 8 females. All controls exhibited BCVA equal to or better than 20/20. The demographic and clinical characteristics of the ARB and control groups are summarized in Table 1 . Table 1 Demographic characteristics of ARB patients and control groups People/Eye number Males Females Age (year) AL (mm) BCVA(Snellen) Patients 12/24 6 6 29.3 ± 12.5 22.38 ± 1.16 0.23 ± 0.19 Controls 12/24 4 8 28.25 ± 9.91 22.91 ± 0.66 1.0 P -Value 0.82 0.06 ARB:autosomal recessive bestrophinopathy; AL: axial length; BCVA:best corrected visual acuity Quantitative Analysis of OCTA Images Quantitative OCTA parameters were compared between the ARB and control groups (Table 2 ). Vessel density values in the ARB group were significantly lower than in controls for the SVC (53.94 ± 3.85% vs. 57.72 ± 5.82%, P < 0.05), ICP (34.17 ± 4.03% vs. 41.54 ± 5.9%, P < 0.001), and DCP (15.13 ± 7.43% vs. 30.22 ± 7.65%, P 0.05). Table 2 Comparison of RNFL Thickness and OCTA parameters between ARB and normal groups ARB Controls P RNFL (µm) 102.46 ± 15.21 106.73 ± 8.63 0.26 Macular vessel density (%) SVC 53.94 ± 3.85 57.72 ± 5.82 0.02 ICP 34.17 ± 4.03 41.54 ± 5.9 < 0.001 DCP 15.13 ± 7.43 30.22 ± 7.65 < 0.001 Note: ARB:autosomal recessive bestrophinopathy; RNFL: retinal nerve fiber layer; SVC: superficial vascular complex; ICP: inner capillary plexus; DCP: deep capillary plexus. Subgroup Analysis within ARB Patients Table 3 presents the comparison of axial length (AL), RNFL thickness, and OCTA parameters between ARB subgroups. No significant differences were observed between macular schisis and non-schisis subgroups in any measured parameters. However, in the glaucoma versus non-glaucoma subgroups, the glaucoma group demonstrated significantly shorter AL (21.52 ± 0.62 mm vs. 22.81 ± 1.14 mm, P < 0.05) and reduced RNFL thickness (92.36 ± 18.33 µm vs. 107.51 ± 10.78 µm, P < 0.05). No significant differences were identified in vessel density across the three plexuses between these subgroups. Table 3 Comparison of AL, RNFL thickness and OCTA parameters between ARB groups Macular schisis No macular schisis P1 Glaucoma Non-glaucoma P2 Participants 12 12 8 16 BCVA 0.21 ± 0.15 0.26 ± 0.25 0.56 0.3 ± 0.23 0.2 ± 0.19 0.25 AL (mm) 22.24 ± 1.4 22.53 ± 0.91 0.55 21.52 ± 0.62 22.81 ± 1.14 0.007 RNFL (µm) 105.47 ± 10.28 97.78 ± 16.24 0.18 92.36 ± 18.33 107.51 ± 10.78 0.018 Macular vessel density (%) SVC 55.06 ± 5.77 52.81 ± 3.03 0.25 52.94 ± 5.48 54.43 ± 4.28 0.47 ICP 35.76 ± 2.74 32.57 ± 4.56 0.052 34.76 ± 2.12 33.87 ± 4.74 0.53 DCP 17.75 ± 6.90 13.52 ± 7.89 0.3 16.97 ± 7.09 14.22 ± 7.65 0.41 Note: AL: axial length; RNFL: retinal nerve fiber layer ARB:autosomal recessive bestrophinopathy;SVC: superficial vascular complex; ICP: inner capillary plexus; DCP: deep capillary plexus. Correlation analysis results are summarized in Table 4 . BCVA was positively correlated with vessel density in the ICP (Pearson Coefficient = 0.502, P = 0.017) and DCP (Pearson Coefficient = 0.508, P = 0.016). No significant correlation was found between RNFL thickness and vessel density. Table 4 Correlation of BCVA with other variables Variable Coefficient of correlation P AL -0.21 0.349 RNFL -0.137 0.543 Macular vessel density (%) SVC 0.16 0.474 ICP 0.502 0.017 DCP 0.508 0.016 Note: BCVA:best corrected visual acuity; AL: axial length; RNFL: retinal nerve fiber layer; ARB:autosomal recessive bestrophinopathy; SVC: superficial vascular complex; ICP: inner capillary plexus; DCP: deep capillary plexus. Discussion Autosomal recessive bestrophinopathy is a rare ocular disorder first characterized by Burgess in 2008.[ 3 ] It arises from biallelic mutations in the BEST1 gene, leading to dysfunction of bestrophin-1, a multifunctional protein localized at the basolateral plasma membrane of retinal pigment epithelium (RPE) cells.[ 10 ] Bestrophin-1 is postulated to function as a Ca 2+ -activated Cl − -channel[ 11 ], a regulator of voltage-gated Ca 2+ -channels[ 12 ], and a bicarbonate (HCO 3 − ​) channel in the RPE [ 13 ]. Despite advances in understanding its molecular functions, the precise pathogenesis of ARB remains unclear. Angle-closure glaucoma, linked to short axial length (AL) and shallow anterior chambers, affects approximately 50% of ARB patients [ 4 ]. This has also been observed in other bestrophinopathies[ 14 ][ 15 ], suggesting a shared mechanism of anterior segment anomalies. In this study, the average AL of ARB patients was 22.38 ± 1.16 mm, with the glaucoma subgroup exhibiting significantly shorter AL compared to the non-glaucoma subgroup. These findings support the hypothesis that RPE dysfunction disrupts both anterior and posterior ocular development [ 16 ], leading to hyperopia, short AL, and narrow anterior chambers. Experimental evidence further highlights the critical role of RPE in eye growth and retinal maintenance, with RPE ablation resulting in disrupted retinal lamination and microphthalmia [ 17 ]. To our knowledge, this is the first study to evaluate the vascular profile in ARB patients using OCTA. Compared to controls, ARB patients demonstrated significantly reduced parafoveal vessel density across the superficial vascular complex (SVC), inner capillary plexus (ICP), and deep capillary plexus (DCP). This reduction aligns with findings in other bestrophinopathies, such as BVMD, where progressive vascular impairment correlates with disease severity [ 18 ]. Wang et al. demonstrated microvascular abnormal reconstruction in BVMD patients around FAZ and a significant reduction in SRL vessel density [ 7 ] Reduced vessel density reflects decreased metabolic demand, likely due to photoreceptor loss, as supported by adaptive optics imaging in ARB patients [ 19 ] and similar observations in retinitis pigmentosa (RP) [ 20 ]. The correlation between reduced vessel density and disease severity highlights the interplay between structural and functional retinal changes. Interestingly, no significant differences in vessel density were observed between glaucoma and non-glaucoma ARB subgroups, suggesting that vascular alterations in ARB are primarily driven by the underlying genetic disorder rather than glaucoma progression. While macular vessel density dropout is a hallmark of glaucoma, the relatively mild visual impairment in this cohort may have limited its impact [ 21 ]. This reinforces the notion that bestrophinopathy is the predominant factor influencing vascular changes in ARB patients. The mechanism underlying macular schisis in ARB remains uncertain. Dysfunction of bestrophin-1 is hypothesized to disrupt ionic homeostasis, resulting in subretinal and intraretinal fluid accumulation [ 22 ]. Although no statistically significant differences in vessel density were detected between macular schisis and non-schisis groups, a trend toward increased vessel density was observed in the macular schisis group. This finding is consistent with studies on RP with macular edema, where increased vessel density is thought to result from compensatory capillary proliferation or displacement due to fluid accumulation[ 23 ]. A significant positive correlation was observed between BCVA and vessel density in the ICP and DCP. The DCP, which supplies oxygen to the avascular outer retina [ 24 ], plays a crucial role in maintaining photoreceptor function. Reduced vessel density in the DCP likely reflects photoreceptor degeneration, contributing to impaired visual function. This finding underscores the importance of DCP integrity in preserving visual acuity in ARB and other retinal diseases. The strengths of this study include its novel evaluation of OCTA vascular profiles in ARB and the integration of structural and functional analyses. However, several limitations should be acknowledged. The small sample size and retrospective design may limit the generalizability of findings. Additionally, the selection bias toward patients with mild visual impairment for imaging quality could underestimate the vascular changes in more advanced cases. Nonetheless, given the rarity of ARB, assembling a larger cohort remains challenging. Future longitudinal studies with expanded parameters, such as retinal thickness and optic disc vessel density, are warranted to further elucidate the morphofunctional changes in ARB. PR-OCTA revealed significantly reduced parafoveal vessel density in all three capillary plexuses in ARB patients, providing novel insights into the vascular pathophysiology of the disease. These findings enhance our understanding of ARB and highlight the potential of OCTA as a non-invasive tool for monitoring vascular and structural changes in rare retinal disorders. Declarations Ethics approval and consent to participate The study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Tongren Hospital (Approval Number: TRECKY2019-122). Consent for publication An informed consent form was signed by patient to publish study. Availability of data and materials Data contain confidential patient records and are available from the ethics committee for researchers meeting criteria. Competing interests The authors declare no competing interests. Funding Supported in part by Research Fund of Capital Health Development Research Project (2018-2-1081). Authors' contributions Szy Yann Chan: data collection,provision of study patients,writing the initial draft; Xiaona Wang: formulation and evolution of overarching research goals and aims,writing the initial draft; Qian Li: provision of study patients; Qisheng You: critical review and revision; Jie Wang:designing computer programs; Yali Jia:Development or design of methodology; Xiaoyan Peng:Management and coordination responsibility for the research activity planning and execution Acknowledgements None References Toto, L., et al. BESTROPHINOPATHY: A Spectrum of Ocular Abnormalities Caused by the c.614T>C Mutation in the BEST1 Gene. Retina 36, 1586-1595 (2016). Boon, C.J., et al. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res 28, 187-205 (2009). Burgess, R., et al. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. American journal of human genetics 82, 19-31 (2008). Boon, C.J., et al. Autosomal recessive bestrophinopathy: differential diagnosis and treatment options. Ophthalmology 120, 809-820 (2013). Jia, Y., et al. Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye. Proceedings of the National Academy of Sciences of the United States of America 112, E2395-2402 (2015). Lupidi, M., Coscas, G., Cagini, C. & Coscas, F. Optical Coherence Tomography Angiography of a Choroidal Neovascularization in Adult Onset Foveomacular Vitelliform Dystrophy: Pearls and Pitfalls. Invest Ophthalmol Vis Sci 56, 7638-7645 (2015). Wang, X.N., et al. Findings of Optical Coherence Tomography Angiography in Best Vitelliform Macular Dystrophy. Ophthalmic research 60, 214-220 (2018). Wang, J., et al. Reflectance-based projection-resolved optical coherence tomography angiography [Invited]. Biomedical optics express 8, 1536 (2017). Patel, R.C., et al. Plexus-Specific Detection of Retinal Vascular Pathologic Conditions with Projection-Resolved OCT Angiography. Ophthalmology Retina 2, 816-826 (2018). Marmorstein, A.D., et al. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proceedings of the National Academy of Sciences of the United States of America 97, 12758-12763 (2000). Davidson, A.E., et al. Functional characterization of bestrophin-1 missense mutations associated with autosomal recessive bestrophinopathy. Invest Ophthalmol Vis Sci 52, 3730-3736 (2011). Rosenthal, R., et al. Expression of bestrophin-1, the product of the VMD2 gene, modulates voltage-dependent Ca2+ channels in retinal pigment epithelial cells. FASEB J 20, 178-180 (2006). Qu, Z. & Hartzell, H.C. Bestrophin Cl- channels are highly permeable to HCO3. American journal of physiology. Cell physiology 294, C1371-1377 (2008). Parameswarappa DC,et al. BEST1 associated bestrophinopathies with angle closure and post-surgical malignant glaucoma. Ophthalmic Genet 45, 571-582 (2024). Wittstrom, E., Ponjavic, V., Bondeson, M.L. & Andreasson, S. Anterior segment abnormalities and angle-closure glaucoma in a family with a mutation in the BEST1 gene and Best vitelliform macular dystrophy. Ophthalmic genetics 32, 217-227 (2011). Shi J, et al. Comprehensive Genetic Analysis Unraveled the Missing Heritability and a Founder Variant of BEST1 in a Chinese Cohort With Autosomal Recessive Bestrophinopathy. Invest Ophthalmol Vis Sci 64, 37 (2023). Luo, J., et al. Novel BEST1 mutations and special clinical characteristics of autosomal recessive bestrophinopathy in Chinese patients. Acta Ophthalmol 97, 247-259 (2019). Battaglia Parodi, M., et al. Retinal Vascular Impairment in Best Vitelliform Macular Dystrophy Assessed by Means of Optical Coherence Tomography Angiography. Am J Ophthalmol 187, 61-70 (2018). Nakanishi, A., et al. Changes of Cone Photoreceptor Mosaic in Autosomal Recessive Bestrophinopathy. Retina (2018). Battaglia Parodi, M., et al. Vessel density analysis in patients with retinitis pigmentosa by means of optical coherence tomography angiography. Br J Ophthalmol 101, 428-432 (2017). Lommatzsch, C., Rothaus, K., Koch, J.M., Heinz, C. & Grisanti, S. OCTA vessel density changes in the macular zone in glaucomatous eyes. Graefes Arch Clin Exp Ophthalmol 256, 1499-1508 (2018). Zhao D, et al. Clinical and genetic features in autosomal recessive bestrophinopathy in Chinese cohort. BMC Ophthalmol 24,308 (2024). Hagag, A.M., et al. Projection-Resolved Optical Coherence Tomographic Angiography of Retinal Plexuses in Retinitis Pigmentosa. Am J Ophthalmol 204, 70-79 (2019). Hagag, A.M., et al. OCT Angiography Changes in the 3 Parafoveal Retinal Plexuses in Response to Hyperoxia. Ophthalmology. Retina 2, 329-336 (2018). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6511487","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":460591580,"identity":"1860f784-c5c4-4935-ba6d-56c38e938bb1","order_by":0,"name":"Xiaona Wang","email":"","orcid":"","institution":"Peking University Third Hospital, Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaona","middleName":"","lastName":"Wang","suffix":""},{"id":460591581,"identity":"8c8324c5-399a-4c9e-92fa-9f706c8b78d4","order_by":1,"name":"Szy Yann Chan","email":"","orcid":"","institution":"Peking University Third Hospital, Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Szy","middleName":"Yann","lastName":"Chan","suffix":""},{"id":460591583,"identity":"029da1a5-237a-4482-ba31-ec54ba597f6a","order_by":2,"name":"Qian Li","email":"","orcid":"","institution":"Beijing Tongren Eye Center, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Li","suffix":""},{"id":460591585,"identity":"da3956ec-6d79-4b75-9eae-ce3dbf0ad821","order_by":3,"name":"Qisheng You","email":"","orcid":"","institution":"Oregon Health and Science University","correspondingAuthor":false,"prefix":"","firstName":"Qisheng","middleName":"","lastName":"You","suffix":""},{"id":460591588,"identity":"b632b781-c304-4d5d-9617-ac695e1d2d4f","order_by":4,"name":"Jie Wang","email":"","orcid":"","institution":"Oregon Health and Science University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Wang","suffix":""},{"id":460591590,"identity":"f40a1af2-fc00-43e3-9c73-8653633bd181","order_by":5,"name":"Yali Jia","email":"","orcid":"","institution":"Oregon Health and Science University","correspondingAuthor":false,"prefix":"","firstName":"Yali","middleName":"","lastName":"Jia","suffix":""},{"id":460591592,"identity":"ffe778fc-4ca9-4a90-8e81-cf1e5fd165a3","order_by":6,"name":"Xiaoyan Peng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYDCCA1Can5n58APStEi2s6UZkKbF4DyPggRROvhunz34uODX4cTNh3kYDBhqbKIJapE8l5dsPLMvLXHbYd4DDxiOpeU2ENJicIbHTJq3xwaohS/BgLHhMFFazH/z9kgkbm7mMZAgVosZM88Pm8QNzMRqkTzDlyzN25BmPOMwMJATiPEL3xneg595/hyW7e8/fPjBhxobwloYGHgYGBjbGBzBKhMIK4dqYfjDYE+c4lEwCkbBKBiRAABnwEDTVtqtKwAAAABJRU5ErkJggg==","orcid":"","institution":"Peking University Third Hospital, Peking University Third Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xiaoyan","middleName":"","lastName":"Peng","suffix":""}],"badges":[],"createdAt":"2025-04-23 10:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6511487/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6511487/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83420896,"identity":"2a9ca861-4815-4eb4-9579-40845b328413","added_by":"auto","created_at":"2025-05-26 01:55:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4804697,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOptical coherence tomography angiography (OCTA) and optical coherence tomography (OCT) scans from ARB patients and control.\u003c/strong\u003e(A) Scans from healthy control. (B) Scans from ARB patient without macular schisis. (C) Scans from ARB patient with macular schisis. (A1~C1) Superficial vascular complex. (A2~C2) Intermediate capillary plexus. (A3~C3) Deep capillary plexus. (A4~C4) OCT scans.\u003c/p\u003e","description":"","filename":"ARB.png","url":"https://assets-eu.researchsquare.com/files/rs-6511487/v1/5535779cd68c8144d81837d1.png"},{"id":86729762,"identity":"1456828d-9d2f-407c-92ba-c50826ac0cbd","added_by":"auto","created_at":"2025-07-15 03:46:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5447355,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6511487/v1/4ee2b011-b54e-4930-8312-11796d06f840.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Vascular Profile of Autosomal Recessive Bestrophinopathy Revealed by Projection-Resolved OCTA","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWith advancements in gene sequencing technology, the genotype and phenotypic heterogeneity of BEST1-related diseases have become increasingly recognized[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In addition to Best vitelliform macular dystrophy (BVMD), BEST1 mutations are associated with a spectrum of diseases, including microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (MRCS) syndrome, atypical retinitis pigmentosa, and autosomal recessive bestrophinopathy (ARB)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. ARB, first described in 2008, results from homozygous or compound heterozygous mutations in the BEST1 gene[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Compared to BVMD, ARB is characterized by distinct retinal dystrophy features, including yellowish subretinal lesions scattered in the posterior pole and diffuse fundus autofluorescence abnormalities. Beyond retinal changes, ARB patients often present with systemic ocular abnormalities such as hyperopia, amblyopia, narrow anterior chambers, and angle-closure glaucoma, which are challenging to manage clinically[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e][\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven its genetic basis, ARB affects the retinal pigment epithelium (RPE) through dysfunction of bestrophin-1, a multifunctional protein localized at the basolateral plasma membrane of RPE cells [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Bestrophin-1 is hypothesized to function as a Ca2\u003csup\u003e+\u003c/sup\u003e-activated Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e-channel, a regulator of voltage-gated Ca\u003csup\u003e2+\u003c/sup\u003e-channels, and a bicarbonate (HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e​) channel[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e][\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. While these molecular insights enhance our understanding of RPE biology, the precise pathophysiological mechanisms underlying ARB remain incompletely understood. Notably, RPE dysfunction in ARB is thought to impair anterior and posterior segment development, leading to short axial length (AL), shallow anterior chambers, and associated complications such as angle-closure glaucoma.\u003c/p\u003e \u003cp\u003eOptical coherence tomography angiography (OCTA) has emerged as a non-invasive imaging modality for evaluating retinal vasculature. By leveraging eye-tracking technology, OCTA provides high-resolution imaging and reliable quantitative data on vascular profiles[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Recent studies have identified OCTA features in hereditary retinal diseases, such as BVMD and adult-onset foveomacular vitelliform dystrophy (AOFVD)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e][\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, data on OCTA findings in ARB or other BEST1-related diseases remain limited.\u003c/p\u003e \u003cp\u003eThis study investigates macular vascular changes in ARB patients using projection-resolved OCTA (PR-OCTA). It evaluates parafoveal vessel density in capillary plexuses and examines correlations with visual acuity and axial length to better understand ARB pathophysiology.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective study included 12 ARB patients from the retina clinic of Beijing Tongren Eye Center (December 2010 to September 2019) and 12 age- and axial length-matched healthy volunteers as controls. The study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Tongren Hospital (Approval Number: TRECKY2019-122).\u003c/p\u003e \u003cp\u003eARB diagnosis was based on criteria described by Boon et al.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], including juvenile to adult-onset visual loss or metamorphopsia, bilateral multifocal vitelliform lesions with subretinal fluid, reduced Arden ratio by electrooculography (EOG, \u0026lt;\u0026thinsp;1.5), and confirmed compound heterozygous or homozygous BEST1 mutations. Patients with ocular conditions confounding OCTA interpretation were excluded. Healthy volunteers underwent systemic and ophthalmological reviews to exclude diseases with ocular involvement.\u003c/p\u003e \u003cp\u003eAll ARB patients underwent comprehensive ocular examinations, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, Goldmann tonometry, and axial length measurement (IOLMaster 500, Carl Zeiss Meditec).\u003c/p\u003e \u003cp\u003eOCTA imaging was performed using a spectral domain OCT system (RTVue XR Avanti, Optovue, Inc., CA, USA) with an A-scan rate of 70,000 scans/s, a light source centered at 840 nm, and a 50 nm bandwidth. Macular images (3\u0026times;3 mm) were acquired. Scans with low signal strength (SSI\u0026thinsp;\u0026lt;\u0026thinsp;50), motion artifacts, or off-center alignment were excluded. A reflectance-based projection-resolved (rbPR) OCTA algorithm was applied to enhance flow signal and suppress projection artifacts.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe retina was segmented into layers (inner limiting membrane to outer plexiform layer) and manually classified into the superficial vascular complex (SVC), inner capillary plexus (ICP), and deep capillary plexus (DCP) based on established criteria.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Vessel density was defined as the percentage of flow signal pixels in each capillary plexus. Parameters such as macular capillary plexus vessel density and RNFL thickness were quantitatively measured.\u003c/p\u003e \u003cp\u003eTwo masked investigators (QSY and JW) independently reviewed the OCTA scans. Disagreements were resolved by a senior retinal specialist.\u003c/p\u003e \u003cp\u003eData were analyzed using SPSS (version 23.0; IBM-SPSS, Chicago, IL, USA). Descriptive statistics were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. The Shapiro\u0026ndash;Wilk test assessed normality. Between-group comparisons were performed using Student\u0026rsquo;s t-test, and correlations between BCVA, RNFL thickness, and macular vessel density were analyzed using Pearson correlation. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eOCTA parameters were compared between ARB patients and controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). ARB patients were further subdivided into groups based on the presence of macular schisis and intraocular pressure (IOP\u0026thinsp;\u0026ge;\u0026thinsp;25 mmHg with anti-glaucoma treatment). Differences in OCTA parameters were analyzed to investigate the potential effects of elevated IOP or macular schisis on OCTA changes. Correlations between BCVA, RNFL thickness, and OCTA parameters were also evaluated to explore relationships between OCTA perfusion changes and visual function.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTwo independent retinal specialists (XNW and QL.) conducted qualitative and quantitative analyses of multimodal retinal and OCTA imaging data. In cases of disagreement, a senior retinal specialist (XYP) reviewed the results and provided final adjudication.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eThe ARB group consisted of 12 patients (24 eyes), including 6 males and 6 females, with a mean age of 29.3\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5 years (range, 11\u0026ndash;49 years; median, 29). The mean BCVA was 0.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19, approximately equivalent to a Snellen acuity of 20/80. All patients presented with narrow anterior chambers, and 4 underwent bilateral trabeculectomy. Among the ARB eyes, 12 exhibited macular schisis, and 8 had glaucoma.\u003c/p\u003e \u003cp\u003eThe control group included 12 healthy individuals (12 eyes), with a mean age of 28.25\u0026thinsp;\u0026plusmn;\u0026thinsp;9.91 years (range, 10\u0026ndash;45 years; median, 29), comprising 4 males and 8 females. All controls exhibited BCVA equal to or better than 20/20. The demographic and clinical characteristics of the ARB and control groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of ARB patients and control groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePeople/Eye number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMales\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemales\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003e(year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAL (mm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBCVA(Snellen)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29.3\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eControls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12/24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.25\u0026thinsp;\u0026plusmn;\u0026thinsp;9.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-Value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003eARB:autosomal recessive bestrophinopathy; AL: axial length; BCVA:best corrected visual acuity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eQuantitative Analysis of OCTA Images\u003c/h3\u003e\n\u003cp\u003eQuantitative OCTA parameters were compared between the ARB and control groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Vessel density values in the ARB group were significantly lower than in controls for the SVC (53.94\u0026thinsp;\u0026plusmn;\u0026thinsp;3.85% vs. 57.72\u0026thinsp;\u0026plusmn;\u0026thinsp;5.82%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), ICP (34.17\u0026thinsp;\u0026plusmn;\u0026thinsp;4.03% vs. 41.54\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and DCP (15.13\u0026thinsp;\u0026plusmn;\u0026thinsp;7.43% vs. 30.22\u0026thinsp;\u0026plusmn;\u0026thinsp;7.65%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, no significant difference was found in RNFL thickness between the two groups (102.46\u0026thinsp;\u0026plusmn;\u0026thinsp;15.21 \u0026micro;m vs. 106.73\u0026thinsp;\u0026plusmn;\u0026thinsp;8.63 \u0026micro;m, P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of RNFL Thickness and OCTA parameters between ARB and normal groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eARB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControls\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRNFL (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102.46\u0026thinsp;\u0026plusmn;\u0026thinsp;15.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e106.73\u0026thinsp;\u0026plusmn;\u0026thinsp;8.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMacular vessel density (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.94\u0026thinsp;\u0026plusmn;\u0026thinsp;3.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57.72\u0026thinsp;\u0026plusmn;\u0026thinsp;5.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eICP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.17\u0026thinsp;\u0026plusmn;\u0026thinsp;4.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41.54\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.13\u0026thinsp;\u0026plusmn;\u0026thinsp;7.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30.22\u0026thinsp;\u0026plusmn;\u0026thinsp;7.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eNote: ARB:autosomal recessive bestrophinopathy; RNFL: retinal nerve fiber layer; SVC: superficial vascular complex; ICP: inner capillary plexus; DCP: deep capillary plexus.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eSubgroup Analysis within ARB Patients\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the comparison of axial length (AL), RNFL thickness, and OCTA parameters between ARB subgroups. No significant differences were observed between macular schisis and non-schisis subgroups in any measured parameters. However, in the glaucoma versus non-glaucoma subgroups, the glaucoma group demonstrated significantly shorter AL (21.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62 mm vs. 22.81\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14 mm, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and reduced RNFL thickness (92.36\u0026thinsp;\u0026plusmn;\u0026thinsp;18.33 \u0026micro;m vs. 107.51\u0026thinsp;\u0026plusmn;\u0026thinsp;10.78 \u0026micro;m, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). No significant differences were identified in vessel density across the three plexuses between these subgroups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of AL, RNFL thickness and OCTA parameters between ARB groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMacular schisis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo macular schisis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP1\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGlaucoma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNon-glaucoma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eP2\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParticipants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCVA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAL (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.24\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22.81\u0026thinsp;\u0026plusmn;\u0026thinsp;1.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRNFL (\u0026micro;m)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105.47\u0026thinsp;\u0026plusmn;\u0026thinsp;10.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97.78\u0026thinsp;\u0026plusmn;\u0026thinsp;16.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e92.36\u0026thinsp;\u0026plusmn;\u0026thinsp;18.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e107.51\u0026thinsp;\u0026plusmn;\u0026thinsp;10.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMacular vessel density (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.06\u0026thinsp;\u0026plusmn;\u0026thinsp;5.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52.81\u0026thinsp;\u0026plusmn;\u0026thinsp;3.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e52.94\u0026thinsp;\u0026plusmn;\u0026thinsp;5.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e54.43\u0026thinsp;\u0026plusmn;\u0026thinsp;4.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eICP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.76\u0026thinsp;\u0026plusmn;\u0026thinsp;2.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.57\u0026thinsp;\u0026plusmn;\u0026thinsp;4.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34.76\u0026thinsp;\u0026plusmn;\u0026thinsp;2.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33.87\u0026thinsp;\u0026plusmn;\u0026thinsp;4.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.75\u0026thinsp;\u0026plusmn;\u0026thinsp;6.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.52\u0026thinsp;\u0026plusmn;\u0026thinsp;7.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16.97\u0026thinsp;\u0026plusmn;\u0026thinsp;7.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.22\u0026thinsp;\u0026plusmn;\u0026thinsp;7.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eNote: AL: axial length; RNFL: retinal nerve fiber layer ARB:autosomal recessive bestrophinopathy;SVC: superficial vascular complex; ICP: inner capillary plexus; DCP: deep capillary plexus.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCorrelation analysis results are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. BCVA was positively correlated with vessel density in the ICP (Pearson Coefficient\u0026thinsp;=\u0026thinsp;0.502, P\u0026thinsp;=\u0026thinsp;0.017) and DCP (Pearson Coefficient\u0026thinsp;=\u0026thinsp;0.508, P\u0026thinsp;=\u0026thinsp;0.016). No significant correlation was found between RNFL thickness and vessel density.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelation of BCVA with other variables\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCoefficient of correlation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.349\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRNFL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.543\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMacular vessel density (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.474\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eICP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.502\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDCP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.508\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eNote: BCVA:best corrected visual acuity; AL: axial length; RNFL: retinal nerve fiber layer; ARB:autosomal recessive bestrophinopathy; SVC: superficial vascular complex; ICP: inner capillary plexus; DCP: deep capillary plexus.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAutosomal recessive bestrophinopathy is a rare ocular disorder first characterized by Burgess in 2008.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] It arises from biallelic mutations in the BEST1 gene, leading to dysfunction of bestrophin-1, a multifunctional protein localized at the basolateral plasma membrane of retinal pigment epithelium (RPE) cells.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Bestrophin-1 is postulated to function as a Ca\u003csup\u003e2+\u003c/sup\u003e-activated Cl\u003csup\u003e\u0026minus;\u003c/sup\u003e-channel[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], a regulator of voltage-gated Ca\u003csup\u003e2+\u003c/sup\u003e-channels[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and a bicarbonate (HCO\u003csub\u003e3\u003c/sub\u003e\u003csup\u003e\u0026minus;\u003c/sup\u003e​) channel in the RPE [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Despite advances in understanding its molecular functions, the precise pathogenesis of ARB remains unclear.\u003c/p\u003e \u003cp\u003eAngle-closure glaucoma, linked to short axial length (AL) and shallow anterior chambers, affects approximately 50% of ARB patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This has also been observed in other bestrophinopathies[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e][\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], suggesting a shared mechanism of anterior segment anomalies. In this study, the average AL of ARB patients was 22.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16 mm, with the glaucoma subgroup exhibiting significantly shorter AL compared to the non-glaucoma subgroup. These findings support the hypothesis that RPE dysfunction disrupts both anterior and posterior ocular development [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], leading to hyperopia, short AL, and narrow anterior chambers. Experimental evidence further highlights the critical role of RPE in eye growth and retinal maintenance, with RPE ablation resulting in disrupted retinal lamination and microphthalmia [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first study to evaluate the vascular profile in ARB patients using OCTA. Compared to controls, ARB patients demonstrated significantly reduced parafoveal vessel density across the superficial vascular complex (SVC), inner capillary plexus (ICP), and deep capillary plexus (DCP). This reduction aligns with findings in other bestrophinopathies, such as BVMD, where progressive vascular impairment correlates with disease severity [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Wang et al. demonstrated microvascular abnormal reconstruction in BVMD patients around FAZ and a significant reduction in SRL vessel density [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Reduced vessel density reflects decreased metabolic demand, likely due to photoreceptor loss, as supported by adaptive optics imaging in ARB patients [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and similar observations in retinitis pigmentosa (RP) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The correlation between reduced vessel density and disease severity highlights the interplay between structural and functional retinal changes.\u003c/p\u003e \u003cp\u003eInterestingly, no significant differences in vessel density were observed between glaucoma and non-glaucoma ARB subgroups, suggesting that vascular alterations in ARB are primarily driven by the underlying genetic disorder rather than glaucoma progression. While macular vessel density dropout is a hallmark of glaucoma, the relatively mild visual impairment in this cohort may have limited its impact [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This reinforces the notion that bestrophinopathy is the predominant factor influencing vascular changes in ARB patients.\u003c/p\u003e \u003cp\u003eThe mechanism underlying macular schisis in ARB remains uncertain. Dysfunction of bestrophin-1 is hypothesized to disrupt ionic homeostasis, resulting in subretinal and intraretinal fluid accumulation [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Although no statistically significant differences in vessel density were detected between macular schisis and non-schisis groups, a trend toward increased vessel density was observed in the macular schisis group. This finding is consistent with studies on RP with macular edema, where increased vessel density is thought to result from compensatory capillary proliferation or displacement due to fluid accumulation[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA significant positive correlation was observed between BCVA and vessel density in the ICP and DCP. The DCP, which supplies oxygen to the avascular outer retina [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], plays a crucial role in maintaining photoreceptor function. Reduced vessel density in the DCP likely reflects photoreceptor degeneration, contributing to impaired visual function. This finding underscores the importance of DCP integrity in preserving visual acuity in ARB and other retinal diseases.\u003c/p\u003e \u003cp\u003eThe strengths of this study include its novel evaluation of OCTA vascular profiles in ARB and the integration of structural and functional analyses. However, several limitations should be acknowledged. The small sample size and retrospective design may limit the generalizability of findings. Additionally, the selection bias toward patients with mild visual impairment for imaging quality could underestimate the vascular changes in more advanced cases. Nonetheless, given the rarity of ARB, assembling a larger cohort remains challenging. Future longitudinal studies with expanded parameters, such as retinal thickness and optic disc vessel density, are warranted to further elucidate the morphofunctional changes in ARB.\u003c/p\u003e \u003cp\u003ePR-OCTA revealed significantly reduced parafoveal vessel density in all three capillary plexuses in ARB patients, providing novel insights into the vascular pathophysiology of the disease. These findings enhance our understanding of ARB and highlight the potential of OCTA as a non-invasive tool for monitoring vascular and structural changes in rare retinal disorders.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study adhered to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Tongren Hospital (Approval Number: TRECKY2019-122).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn informed consent form was signed by patient to publish study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData contain confidential patient records and are available from the ethics committee for researchers meeting criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupported in part by Research Fund of Capital Health Development Research Project (2018-2-1081).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSzy Yann Chan: data collection,provision of study patients,writing the initial draft; Xiaona Wang: formulation and evolution of overarching research goals and aims,writing the initial draft; Qian Li: provision of study patients; Qisheng You: critical review and revision; Jie Wang:designing computer programs; Yali Jia:Development or design of methodology; Xiaoyan Peng:Management and coordination responsibility for the research activity planning and execution\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eToto, L., et al. BESTROPHINOPATHY: A Spectrum of Ocular Abnormalities Caused by the c.614T\u0026gt;C Mutation in the BEST1 Gene. Retina 36, 1586-1595 (2016).\u003c/li\u003e\n \u003cli\u003eBoon, C.J., et al. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res 28, 187-205 (2009).\u003c/li\u003e\n \u003cli\u003eBurgess, R., et al. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. American journal of human genetics 82, 19-31 (2008).\u003c/li\u003e\n \u003cli\u003eBoon, C.J., et al. Autosomal recessive bestrophinopathy: differential diagnosis and treatment options. Ophthalmology 120, 809-820 (2013).\u003c/li\u003e\n \u003cli\u003eJia, Y., et al. Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye. Proceedings of the National Academy of Sciences of the United States of America 112, E2395-2402 (2015).\u003c/li\u003e\n \u003cli\u003eLupidi, M., Coscas, G., Cagini, C. \u0026amp; Coscas, F. Optical Coherence Tomography Angiography of a Choroidal Neovascularization in Adult Onset Foveomacular Vitelliform Dystrophy: Pearls and Pitfalls. Invest Ophthalmol Vis Sci 56, 7638-7645 (2015).\u003c/li\u003e\n \u003cli\u003eWang, X.N., et al. Findings of Optical Coherence Tomography Angiography in Best Vitelliform Macular Dystrophy. Ophthalmic research 60, 214-220 (2018).\u003c/li\u003e\n \u003cli\u003eWang, J., et al. Reflectance-based projection-resolved optical coherence tomography angiography [Invited]. Biomedical optics express 8, 1536 (2017).\u003c/li\u003e\n \u003cli\u003ePatel, R.C., et al. Plexus-Specific Detection of Retinal Vascular Pathologic Conditions with Projection-Resolved OCT Angiography. Ophthalmology Retina 2, 816-826 (2018).\u003c/li\u003e\n \u003cli\u003eMarmorstein, A.D., et al. Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium. Proceedings of the National Academy of Sciences of the United States of America 97, 12758-12763 (2000).\u003c/li\u003e\n \u003cli\u003eDavidson, A.E., et al. Functional characterization of bestrophin-1 missense mutations associated with autosomal recessive bestrophinopathy. Invest Ophthalmol Vis Sci 52, 3730-3736 (2011).\u003c/li\u003e\n \u003cli\u003eRosenthal, R., et al. Expression of bestrophin-1, the product of the VMD2 gene, modulates voltage-dependent Ca2+ channels in retinal pigment epithelial cells. FASEB J 20, 178-180 (2006).\u003c/li\u003e\n \u003cli\u003eQu, Z. \u0026amp; Hartzell, H.C. Bestrophin Cl- channels are highly permeable to HCO3. American journal of physiology. Cell physiology 294, C1371-1377 (2008).\u003c/li\u003e\n \u003cli\u003eParameswarappa DC,et al. \u003cem\u003eBEST1\u003c/em\u003e associated bestrophinopathies with angle closure and post-surgical malignant glaucoma. Ophthalmic Genet 45, 571-582 (2024).\u003c/li\u003e\n \u003cli\u003eWittstrom, E., Ponjavic, V., Bondeson, M.L. \u0026amp; Andreasson, S. Anterior segment abnormalities and angle-closure glaucoma in a family with a mutation in the BEST1 gene and Best vitelliform macular dystrophy. Ophthalmic genetics 32, 217-227 (2011).\u003c/li\u003e\n \u003cli\u003eShi J, et al. Comprehensive Genetic Analysis Unraveled the Missing Heritability and a Founder Variant of BEST1 in a Chinese Cohort With Autosomal Recessive Bestrophinopathy. Invest Ophthalmol Vis Sci 64, 37 (2023).\u003c/li\u003e\n \u003cli\u003eLuo, J., et al. Novel BEST1 mutations and special clinical characteristics of autosomal recessive bestrophinopathy in Chinese patients. Acta Ophthalmol 97, 247-259 (2019).\u003c/li\u003e\n \u003cli\u003eBattaglia Parodi, M., et al. Retinal Vascular Impairment in Best Vitelliform Macular Dystrophy Assessed by Means of Optical Coherence Tomography Angiography. Am J Ophthalmol 187, 61-70 (2018).\u003c/li\u003e\n \u003cli\u003eNakanishi, A., et al. Changes of Cone Photoreceptor Mosaic in Autosomal Recessive Bestrophinopathy. Retina (2018).\u003c/li\u003e\n \u003cli\u003eBattaglia Parodi, M., et al. Vessel density analysis in patients with retinitis pigmentosa by means of optical coherence tomography angiography. Br J Ophthalmol 101, 428-432 (2017).\u003c/li\u003e\n \u003cli\u003eLommatzsch, C., Rothaus, K., Koch, J.M., Heinz, C. \u0026amp; Grisanti, S. OCTA vessel density changes in the macular zone in glaucomatous eyes. Graefes Arch Clin Exp Ophthalmol 256, 1499-1508 (2018).\u003c/li\u003e\n \u003cli\u003eZhao D, et al. Clinical and genetic features in autosomal recessive bestrophinopathy in Chinese cohort. BMC Ophthalmol 24,308 (2024).\u003c/li\u003e\n \u003cli\u003eHagag, A.M., et al. Projection-Resolved Optical Coherence Tomographic Angiography of Retinal Plexuses in Retinitis Pigmentosa. Am J Ophthalmol 204, 70-79 (2019).\u003c/li\u003e\n \u003cli\u003eHagag, A.M., et al. OCT Angiography Changes in the 3 Parafoveal Retinal Plexuses in Response to Hyperoxia. Ophthalmology. Retina 2, 329-336 (2018).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"autosomal recessive bestrophinopathy, macular schisis, glaucoma, optical coherence tomography angiography","lastPublishedDoi":"10.21203/rs.3.rs-6511487/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6511487/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: To investigate macular vascular changes in autosomal recessive bestrophinopathy (ARB) using projection-resolved optical coherence tomography angiography (PR-OCTA) and analyze their correlation with visual function and axial length (AL).\u003c/p\u003e\n\u003cp\u003eMethods: This retrospective study included 12 ARB patients and 12 age- and AL-matched healthy controls. All participants underwent comprehensive ocular examinations and PR-OCTA imaging to measure parafoveal vessel density in the superficial vascular complex (SVC), inner capillary plexus (ICP), and deep capillary plexus (DCP). Statistical analyses were performed to compare vessel density and correlate these metrics with best-corrected visual acuity (BCVA) and AL.\u003c/p\u003e\n\u003cp\u003eResults: Compared to controls, ARB patients exhibited significantly reduced parafoveal vessel density in the SVC (53.94 ± 3.85% vs. 57.72 ± 5.82%, P \u0026lt; 0.05), ICP (34.17 ± 4.03% vs. 41.54 ± 5.9%, P \u0026lt; 0.001), and DCP (15.13 ± 7.43% vs. 30.22 ± 7.65%, P \u0026lt; 0.001). Subgroup analysis revealed no significant differences in vessel density between glaucoma and non-glaucoma patients or between those with and without macular schisis. Positive correlations were found between BCVA and vessel density in the ICP (r = 0.502, P = 0.017) and DCP (r = 0.508, P = 0.016).\u003c/p\u003e\n\u003cp\u003eConclusions: PR-OCTA demonstrated significantly reduced parafoveal vessel density in ARB patients, suggesting vascular impairment associated with retinal dysfunction. These findings provide new insights into ARB pathophysiology and highlight the potential utility of OCTA in evaluating rare retinal disorders.\u003c/p\u003e","manuscriptTitle":"Vascular Profile of Autosomal Recessive Bestrophinopathy Revealed by Projection-Resolved OCTA","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-26 01:55:35","doi":"10.21203/rs.3.rs-6511487/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cd0ebd48-e762-4996-912a-c60656c98746","owner":[],"postedDate":"May 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-15T03:38:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-26 01:55:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6511487","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6511487","identity":"rs-6511487","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}