Best Vitelliform Macular Dystrophy Research Articles

BEST1 associated bestrophinopathies with angle closure and post-surgical malignant glaucoma

ABSTRACT Introduction Mutations in BEST1 gene have been linked to the development of refractory angle closure glaucoma (ACG). This study aims to delineate the clinical characteristics, genetic mutations, and disease progression in patients with autosomal recessive bestrophinopathy (ARB) and autosomal dominant Best vitelliform macular dystrophy (BVMD) who are presented with treatment-resistant ACG. Methods This retrospective analysis encompasses a comprehensive ophthalmic assessment, retinal imaging, and mutational profiling of six patients diagnosed with bestrophinopathy and concurrent ACG, with a particular emphasis on the risk of post-glaucoma filtration surgery malignant glaucoma (MG). Exome sequencing was conducted utilizing a next-generation sequencing (NGS) based gene panel. Results The cohort included five patients with ARB and one with BVMD, with a mean (±SD) age at ACG diagnosis of 35.1 ± 6.9 years. NGS analysis revealed homozygous BEST1 variants in four patients (ARB; cases 1–4) and a heterozygous BEST1 variant in one patient (BVMD; case 5). One patient (ARB; case 6), despite a recessive pedigree, showed a single heterozygous variant, suggesting the presence of an undetected heterozygous variant indicative of compound heterozygous autosomal recessive inheritance. A novel non-frameshift deletion (c.841_843delTTC; p.Phe281del) was identified in case 2. Surgical intervention was required due to uncontrolled glaucoma in all cases except case 4. All five cases that underwent glaucoma filtration surgery developed MG, which was effectively managed with combined iridozonulo-hyaloido-vitrectomy (IZHV) and pars plana vitrectomy (PPV). Cases 5 and 6, harboring a heterozygous pathogenic variant (c.241 G>A; p.Val81Met), experienced refractory MG and corneal decompensation necessitating multiple interventions. Conclusion Genomic analysis plays a pivotal role in the management of bestrophinopathies with ACG. Characterization of mutational types facilitates prognostication and enables timely interventions. IZHV with PPV emerges as a promising standalone or adjunctive procedure for the management of glaucoma among patients with BEST1 mutations and ACG.

An Overview of Best Disease

The German ophthalmologist Friedrich Best named Best vitelliform macular dystrophy (BVD), sometimes referred to as Best disease, in 1905 when he discovered a family with a history of early-onset macular degeneration. A Swedish study assessed the frequency of BVMD to be 2 in 10,000, whereas a Danish examination found 1.5 in 100,000 cases. If a parent with the condition has a kid with an unaffected spouse, there is a 50% chance that the child will inherit the condition from the parent. The syndrome is caused by a mutation in the VMD2 or BEST1 gene found at chromosome 11q12-q13. It is yet unclear how bestrophinopathies pathophysiologically operate. An ionic imbalance in the RPE milieu, which BEST1 gene mutations can bring on, can lead to impaired RPE functions. The best sickness is in five phases. There is currently no recognized treatment for the best sickness. One treatment option for CNV is VEFG injections, either used alone or in conjunction with photodynamic therapy (PDT). Anti-vascular endothelial growth factor (Anti- VEGF) treatments can prevent or reduce the creation of new blood vessels. This can postpone the onset of blindness and slow down the rate at which they leak.

Demonstrationof CicatricialStagewith Optical CoherenceTomography in A Child with Best VitelliformMacularDystrophy

Demonstrationof CicatricialStagewith Optical CoherenceTomography in A Child with Best VitelliformMacularDystrophy

Nationwide epidemiologic survey on incidence of macular dystrophy in Japan.

The aim of this study was to estimate the number of patients in Japan who had visited an ophthalmologist for macular dystrophy of various types, including Best vitelliform macular dystrophy (BVMD), Stargardt disease, occult macular dystrophy (OMD), cone (-rod) dystrophy, X-linked retinoschisis (XLRS), and central areolar choroid dystrophy (CACD). Nationwide epidemiologic survey METHODS: Questionnaires were distributed to 965 major facilities, including all the university hospitals in Japan. The aim of the questionnaire was to determine the number of patients with each type of macular dystrophy who had visited an outpatient clinic during the past 5 years (January 2015 to December 2019). Over 70% of the patients were diagnosed and followed up at university hospitals. The estimated annual number of newly diagnosed cases was as follows: 55.3 for BVMD, 36.7 for Stargardt disease, 35.8 for OMD, 160.6 for cone (-rod) dystrophy, 31.0 for XLRS, 29.8 for CACD, and 174.1 for other types of macular dystrophy. The total number of patients with macular dystrophy diagnosed and followed at major institutions was estimated to be 6651. This was the first nationwide survey of macular dystrophy in Japan and provided an approximate number of affected patients. The diagnosis of macular dystrophy is primarily carried out at facilities with affiliated specialists, such as university hospitals. By examining the incidence of multiple diseases simultaneously, we were able to compare the incidence of each type of macular dystrophy.

Макулярная неоваскуляризация при вителлиформной дистрофии: анализ эффективности антиангиогенной терапии на примере клинических случаев

Best vitelliform macular dystrophy (BVMD) is caused by BEST1 mutation and leads to the accumulation of vitelliform material in the subretinal space. The formation of subretinal neovascular membrane can be one of BVMD complications. Herein, we discuss the criteria for initiating anti-VEGF therapy and efficacy assessment in two patients (3 eyes) with vitelliform macular dystrophy. Keyword: macular neovascularization, vitelliform macular dystrophy, optical coherence tomography, anti-VEGF therapy

Best Vitelliform Macular Dystrophy Natural History Study Report 1: Clinical Features and Genetic Findings

To analyze the genetic findings, clinical spectrum, and natural history of Best vitelliform macular dystrophy (BVMD) in a cohort of 222 children and adults. Single-center retrospective, consecutive, observational study. Patients with a clinical diagnosis of BVMD from pedigrees with a likely disease-causing monoallelic sequence variant in the BEST1 gene. Data were extracted from electronic and physical case notes. Electrophysiologic assessment and molecular genetic testing were analyzed. Molecular genetic test findings and clinical findings including best-corrected visual acuity (BCVA), choroidal neovascularization (CNV) rates, and electrophysiologic parameters. Two hundred twenty-two patients from 141 families were identified harboring 69 BEST1 variants. Mean age at presentation was 26.8 years (range, 1.3-84.8 years) and most patients (61.5%) demonstrated deterioration of central vision. Major funduscopic findings included 128 eyes (30.6%) with yellow vitelliform lesions, 78 eyes (18.7%) with atrophic changes, 49 eyes (11.7%) with fibrotic changes, 48 eyes (11.5%) with mild pigmentary changes, and 43 eyes (10.3%) showing a vitelliruptive appearance. Mean BCVA was 0.37 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/47) for the right eye and 0.33 logMAR (Snellen equivalent, 20/43) for the left eye at presentation, with a mean annual loss rate of 0.013 logMAR and 0.009 logMAR, respectively, over a mean follow-up of 9.7 years. Thirty-seven patients (17.3%) received a diagnosis of CNV over a mean follow-up of 8.0 years. Eyes with CNV that received treatment with an anti-vascular endothelial growth factor (VEGF) agent showed better mean BCVA compared with eyes that were not treated with an anti-VEGF agent (0.28 logMAR [Snellen equivalent, 20/38] vs. 0.62 logMAR [Snellen equivalent, 20/83]). Most eyes exhibited a hyperopic refractive error (78.7%), and 13 patients (6.1%) received a diagnosis of amblyopia. Among the 3 most common variants, p.(Ala243Val) was associated with a later age of onset, better age-adjusted BCVA, and less advanced Gass stages compared with p.(Arg218Cys) and p.(Arg218His). BVMD shows a wide spectrum of phenotypic variability. The disease is very slowly progressive, and the observed phenotype-genotype correlations allow for more accurate prognostication and counselling. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

BEST1 Variant Associated with an Atypical Macular and Peripheral Retinal Phenotype.

Best vitelliform macular dystrophy (BVMD) is an inherited macular dystrophy associated with over 250 pathogenic variants of the Bestrophin-1 (BEST1) gene. While several of the types of lesions of BVMD are well-described, reports of phenotypic variations associated with rare genetic variants are limited. Retrospective case-series performed in 2021 at a tertiary eye care center. Three members of one family referred to a tertiary eye care clinic for evaluation of their autosomal dominant macular dystrophy. Study subjects presented with atypical findings of peripheral schisis-like lesions and atrophy with abnormal electroretinogram (ERG) in addition to typical macular lesions found in BVMD. Genetic analyses identified a heterozygous BEST1 c.227T>A, p.(Ile76Asn) pathogenic variant in all three subjects. This study represents the first report of the phenotype associated with the c.227T>A, p.(Ile76Asn) BEST1 variant, which - while mentioned twice in the literature - has not been previously described. The phenotype is unique, comprising features of typical BVMD with ERG and peripheral findings, suggestive of a panretinal dysfunction.

Clinical presentation and outcomes of trivial trauma-associated giant macular holes in children with Best vitelliform macular dystrophy

We present three cases of children with giant macular holes in relation to trivial trauma. These children had brittle retina secondary to Best vitelliform macular dystrophy (BVMD) which made them vulnerable to the irreversible complications. None of the three cases had any signs of trauma in the anterior segment pointing to trivial nature of the trauma. Two cases progressed to retinal detachment. This series highlights the importance of ocular protection and special care needed for children with BVMD.

Fixation Location and Stability in Best Vitelliform Macular Dystrophy

To analyze fixation location and stability in best vitelliform macular dystrophy (BVMD) and test their association with best-corrected visual acuity (BCVA). Observational, cross-sectional study. Thirty patients (55 eyes) affected by genetically confirmed BVMD were followed up at the Retinal Heredodystrophies Unit of IRCCS San Raffaele Scientific Institute, Milan. Patients underwent testing with macular integrity assessment (MAIA) microperimeter. Fixation location was measured as distance in degrees (°) between preferred retinal locus (PRL) and estimated fovea location (EFL); fixation was defined as eccentric when the distance between PRL and EFL exceeded 2°. Fixation stability was graded as stable, relatively unstable, or unstable and expressed as bivariate contour ellipse area (BCEA, °2). Fixation location and stability. The median distance of the PRL from the anatomic fovea was 0.7°, and fixation location was eccentric in 27% of eyes. Fixation was graded as stable in 64% of eyes, relatively unstable in 13%, and unstable in 24%, with a median 95% BCEA of 6.2°2. The atrophic/fibrotic stage was associated with worse fixation parameters (all P<0.01). Both PRL eccentricity and fixation stability were linearly associated with BCVA: every 1° increase in PRL eccentricity was associated with a 0.07 logarithm of the minimum angle of resolution (logMAR) worse BCVA (P<0.0001) while every 1°2 increase in 95% BCEA was associated with a 0.01 logMAR worse BCVA (P<0.001). No significant intereye correlation was found for PRL eccentricity and fixation stability, as well as no association between the patient's age and fixation parameters. We demonstrated that most eyes affected by BVMD retain a central stable fixation and provided evidence that both fixation eccentricity and stability are strongly associated with visual acuity in BVMD. These parameters may serve as secondary end points for future clinical trials. Proprietary or commercial disclosure may be found after the references.

The pseudohypopyon stage in adult-onset foveomacular vitelliform dystrophy.

To gain insight into the pathogenesis of adult-onset foveomacular vitelliform dystrophy (AFVD) via assessment of its pseudohypopyon stage (PHS). Retrospectively, data were collected in a tertiary center from established cohorts of a genetically evaluated AFVD and best vitelliform macular dystrophy (BVMD) eyes in the pseudohypopyon stage. Best-corrected visual acuity (BCVA, LogMAR), lesion characterization, including lesion dimensions, liquefaction areas and patterns (altitudinal or lateral), and ellipsoid zone integrity were analyzed from spectral-domain optical coherence tomography images. Out of 167 eyes of 90 AFVD patients and 56 eyes of 28 BVMD patients, 8 eyes of six AFVD patients and five eyes of four BVMD patients were at the PHS were included. The mean LogMAR BCVA ± SD was 0.21 ± 0.20 and 0.41 ± 0.10 in AFVD and BVMD diseases, respectively (p = 0.13). Seven AFVD eyes (87.5%) demonstrated lateral liquefaction, while all BVMD eyes demonstrated an altitudinal pattern (p = 0.005). Maximal horizontal lesion diameters were 1.41 ± 0.46mm and 2.64 ± 0.77mm in AFVD and BVMD, respectively (p = 0.02). AFVD patients were older (69 ± 14) than BVMD patients (22 ± 13; p = 0.009). The pseudohypopyon stage in AFVD is often characterized by a lateral liquefaction pattern, unlike the altitudinal pattern characterizing BVMD. Age, lesion size, or pathogenesis pathways may underline the different pseudohypopyon stage patterns in AFVD and BVMD.

Multimodal imaging in Best Vitelliform Macular Dystrophy: Literature review and novel insights.

Best Vitelliform Macular Dystrophy (BVMD) is a dominantly inherited retinal disease caused by dominant variants in the BEST1 gene. The original classification of BVMD is based on biomicroscopy and color fundus photography (CFP); however, advancements in retinal imaging provided unique structural, vascular, and functional data and novel insights on disease pathogenesis. Quantitative fundus autofluorescence studies informed us that lipofuscin accumulation, the hallmark of BVMD, is unlikely to be a primary effect of the genetic defect. It could be due to a lack of apposition between photoreceptors and retinal pigment epithelium in the macula with subsequent accumulation of shed outer segments over time. Optical Coherence Tomography (OCT) and adaptive optics imaging revealed that vitelliform lesions are characterized by progressive changes in the cone mosaic corresponding to a thinning of the outer nuclear layer and then disruption of the ellipsoid zone, which are associated with a decreased sensitivity and visual acuity. Therefore, an OCT staging system based on lesion composition, thus reflecting disease evolution, has been recently developed. Lastly, the emerging role of OCT Angiography proved a greater prevalence of macular neovascularization, the majority of which are non-exudative and develop in late disease stages. In conclusion, effective diagnosis, staging, and clinical management of BVMD will likely require a deep understanding of the multimodal imaging features of this disease.

Elaborate Evaluation of Farnsworth Dichotomous D-15 Panel Test Can Help Differentiate between Best Vitelliform Macular Dystrophy and Autosomal Recessive Bestrophinopathy

Introduction: The colour vision in bestrophinopathies has not been assessed in detail so far. The aim of this study was to explore the extent to which distinct types of bestrophinopathies differ in regard to colour vision deficiencies using Farnsworth Dichotomous D-15 and Lanthony Desaturated D-15 panel tests. Methods: Both D-15 tests were performed in 52 eyes of 26 patients with Best vitelliform macular dystrophy (BVMD) and 10 eyes of 5 patients with autosomal recessive bestrophinopathy (ARB). Two methods were used for a quantitative assessment of the colour vision deficiencies: moment of inertia method and Bowman method. The following parameters were calculated: confusion angle, confusion index (C-index), selectivity index (S-index), total error score (TES), and colour confusion index (CCI). Results: The median value of confusion angle for all stages of BVMD fell into a narrow range around 62, indicating normal results. The median confusion angle value was 57 in ARB patients within a very wide range down to −82, indicating non-specific deficits. These differences were statistically significant. Significantly abnormal C-index and CCI values were found only in ARB patients, being 2.0 and 1.49, respectively. The majority of parameters of D-15 tests were independent of the visual acuity in both bestrophinopathies. Conclusions: Elaborate evaluation of the D-15 panel tests might help establish a differential diagnosis between different bestrophinopathies, as the pattern of the colour vision loss is different between BVMD and ARB. The quantitative parameters of colour vision tests in bestrophinopathies are independent of the visual acuity.

Choroidal Neovascularization Is Common in Best Vitelliform Macular Dystrophy and Plays a Role in Vitelliform Lesion Evolution

Choroidal neovascularization (CNV) is usually considered to be a late-stage complication in Best vitelliform macular dystrophy (BVMD) and can be difficult to diagnose with fluorescein angiography. This study used swept-source (SS) OCT angiography (OCTA) to evaluate the prevalence of CNV in BVMD, identify structural features associated with CNV, and provide insight into the role of CNV in vitelliform lesion evolution. Institutional review board-approved, retrospective, cross-sectional, and longitudinal study. Patients with molecularly confirmed BVMD. Charts from consecutive patients with BVMD imaged with SS-OCTA (PLEX Elite 9000, Carl-Zeiss Meditec Inc) at the University of Iowa from September 2017 to October 2021 were reviewed. Clinical data, including age, gender, best-corrected visual acuity (BCVA), and treatment with intravitreal anti-VEGF injections were recorded. The presence of CNV on SS-OCTA was determined by expert graders and correlated with structural features, such as interstitial fluid, subretinal fluid, nodular subretinal pillar, focal choroidal excavation (FCE), and subfoveal choroidal thickness, with a P value of < 0.05 considered statistically significant. Presence of CNV on SS-OCTA and correlation with structural features on SS-OCT. A total of 53 eyes from 27 patients (13 women; 48.1%) were included. The mean age was 45 years (range, 8-79 years), and the mean logarithm of the minimum angle of resolution BCVA was 0.38 (range, 0-1). Choroidal neovascularization was identified on SS-OCTA in 27 eyes (50.9%), of which 63.0% had a vitelliform (Gass stage 2) lesion. In 40.7% (11 of 27) of eyes, there was no prior clinical diagnosis of CNV. Other structural features associated with CNV included FCEs (15.1%, 8 of 53 eyes) and nodular pillars (15.1%, 8 of 53 eyes) (P < 0.01). Seven patients had available longitudinal imaging, and most of these patients had CNV visible on SS-OCTA (71.4%; 10 of 14 eyes). Choroidal neovascularization is common in BVMD, including in the early stages of the disease. The presence of FCEs or nodular pillars should heighten the clinical suspicion of CNV, which may accelerate vitelliform lesion evolution. Proprietary or commercial disclosure may be found after the references.

Clinical Correlation Between Optical Coherence Tomography Biomarkers and Retinal Sensitivity in Best Vitelliform Macular Dystrophy.

PurposeTo investigate the clinical and imaging features associated with retinal sensitivity in Best vitelliform macular dystrophy (BVMD).MethodsThis was a cross-sectional, single-center, observational study. Each patient underwent optical coherence tomography (OCT), near-infrared fundus autofluorescence, and OCT angiography. Macular integrity assessment microperimetry under mesopic conditions was performed to obtain retinal sensitivity thresholds from 68 testing points in the central macula. Structural OCT was used to classify BVMD lesions into four types according to their composition: vitelliform, mixed, subretinal fluid, and atrophy. Multilevel, mixed-effects linear regression was used to determine the factors associated with retinal sensitivity.ResultsThe study included 57 eyes of 30 patients with BVMD, 48 of which (84%) were in a clinical stage. Mean retinal sensitivity varied according to the composition of the lesion: the vitelliform type registering the highest (22 ± 4.1 dB), followed by mixed (18.73 ± 2.7 dB), subretinal fluid (15.68 ± 4.2 dB), and atrophy types (11.85 ± 4.6 dB). The factors most strongly associated with mean retinal sensitivity in BVMD proved to be the OCT lesion type and outer nuclear layer thickness.ConclusionsRetinal sensitivity in BVMD is influenced by lesion composition and outer nuclear layer thickness. Further studies with long-term follow-up are warranted to examine retinal sensitivity over time and to validate retinal sensitivity changes as biomarkers for BVMD.Translational RelevanceAssessing retinal sensitivity in BVMD provides a new instrument in the clinical characterization of the disease and offers the opportunity to identify imaging biomarkers for use as outcome measures in future clinical trials.

Optical Coherence Tomography-Based Choroidal Structural Analysis and Vascularity Index in Best Vitelliform Macular Dystrophy.

This study investigated choroidal structural changes on optical coherence tomography (OCT) using choroidal vascularity index (CVI) and choroidal thickness (CT) in patients with Best vitelliform macular dystrophy (BVMD). This retrospective case control study included 78 patients with BVMD of different clinical stages and 242 age- and gender-matched healthy controls. Subfoveal OCT scans were analysed. Total choroidal area (TCA), luminal area (LA) and CT were measured after image segmentation and binarization. CVI, a novel marker for choroidal angioarchitecture, was defined as the ratio of LA to TCA. CVI and CT were compared between BVMD and control group, as well as among the BVMD subgroups. Mean CVI was lower in eyes with BVMD (65.0 ± 3.5%) compared to that in control eyes (67.5 ± 3.9%) and this was statistically significant (p < 0.0001). There was no significant difference in subfoveal CT between BVMD (302.88 ± 81.68μm) and control (309.31 ± 65.46μm) eyes (p = 0.4799). In the subgroup analysis, all stages of BVMD showed lower CVI compared to control while SFCT remained similar. Within the BVMD subgroups, CVI and subfoveal CT did not differ significantly and both were not shown to be associated with visual acuity. Decreased CVI was shown in eyes with BVMD compared to control eyes, while no significant difference in subfoveal CT was seen. CVI may be helpful in the understanding of choroidal pathology in BVMD.

Genetic and clinical features of BEST1-associated retinopathy based on 59 Chinese families and database comparisons

Variants in BEST1 are one of the most common cause of retinopathy mainly involving the retinal pigment epithelium with both dominant and recessive traits. This study aimed to describe the characteristics of potential pathogenic variants (PPVs) in BEST1 and their associated clinical features. Variants in BEST1 were collected from our in-house exome sequencing data and systematically evaluated by in silico prediction tools as well as genotype-phenotype analysis. The pathogenicity features of the BEST1 variants were further assessed through database comparison among the in-house data, Genome Aggregation Database from the general population, and all previously published literature. The clinical information of the in-house patients was summarized. The PPVs in BEST1 were identified in 66 patients from 59 families, including 32 families with Best vitelliform macular dystrophy (BVMD) and 27 families with autosomal recessive bestrophinopathy (ARB). These PPVs included 31 missense variants, seven truncation variants, one in-frame deletion, and a known 3-untranslated region variant. All the truncations detected in our study were exclusively involved in ARB but not BVMD. Among the 31 missense variants, 18 missenses associated with BVMD in the dominant trait were clustered in four hotspot regions with statistically significant differences from the recessive missenses. Except for distinct macular changes, there were no statistically significant differences among the other associated clinical features between BVMD and ARB, including peripheral retinopathy, high hyperopia, and angle-closure glaucoma. In conclusion, BEST1-associated dominant retinopathy was preferentially caused by missense variants located in important functional regions. Truncations were most likely benign in heterozygous status. Future studies are expected to elucidate the mystery of the same missense variants contributing to both BVMD and ARB.

Deep learning to distinguish Best vitelliform macular dystrophy (BVMD) from adult-onset vitelliform macular degeneration (AVMD)

Initial stages of Best vitelliform macular dystrophy (BVMD) and adult vitelliform macular dystrophy (AVMD) harbor similar blue autofluorescence (BAF) and optical coherence tomography (OCT) features. Nevertheless, BVMD is characterized by a worse final stage visual acuity (VA) and an earlier onset of critical VA loss. Currently, differential diagnosis requires an invasive and time-consuming process including genetic testing, electrooculography (EOG), full field electroretinogram (ERG), and visual field testing. The aim of our study was to automatically classify OCT and BAF images from stage II BVMD and AVMD eyes using a deep learning algorithm and to identify an image processing method to facilitate human-based clinical diagnosis based on non-invasive tests like BAF and OCT without the use of machine-learning technology. After the application of a customized image processing method, OCT images were characterized by a dark appearance of the vitelliform deposit in the case of BVMD and a lighter inhomogeneous appearance in the case of AVMD. By contrast, a customized method for processing of BAF images revealed that BVMD and AVMD were characterized respectively by the presence or absence of a hypo-autofluorescent region of retina encircling the central hyperautofluorescent foveal lesion. The human-based evaluation of both BAF and OCT images showed significantly higher correspondence to ground truth reference when performed on processed images. The deep learning classifiers based on BAF and OCT images showed around 90% accuracy of classification with both processed and unprocessed images, which was significantly higher than human performance on both processed and unprocessed images. The ability to differentiate between the two entities without recurring to invasive and expensive tests may offer a valuable clinical tool in the management of the two diseases.

Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation.

Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1, and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease.

Novel mutations in the BEST1 gene cause distinct retinopathies in two Chinese families.

To describe the clinical heterogeneity of patients with novel mutations in BEST1. All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity, slit-lamp examination, applanation tonometry, and dilated fundus examination. Fundus autofluorescence, fundus fluorescein angiography, spectral-domain optical coherence tomography, electrooculography, and electroretinogram were also performed. Genomic DNA was extracted from venous blood for all the participants. The targeted next-generation sequencing of inherited retinal disease-associated genes was conducted to identify the causative mutation. A novel BEST1 missense mutation c.41T>C (p.Leu14Ser) was identified in Family 1. It was co-segregated with the phenotype of best vitelliform macular dystrophy (BVMD) and bioinformatics analysis confirmed it was harmful. Another novel BEST1 frameshift mutation c.345_346insGGCAAGGACG (p.Glu119Glyfs*116) and a novel USH2A missense mutation c.12560G>A, p.Arg4187His were identified in family 2 with retinitis pigmentosa (RP), which might interact and lead to the phenotype of RP. Two novel mutations in the BEST1 gene in two unrelated families with distinct phenotypes and BEST1 mutation accompanied with USH2A mutation would result in RP, which could be enormously helpful in understanding the pathogenesis of the inherited retinal disease caused by a BEST1 mutation.

Choroidal Neovascularization Associated with Best Vitelliform Macular Dystrophy.

Objectives:The aim of the study was to evaluate the clinical and optical coherence tomography (OCT) findings of patients with choroidal neovascularization (CNV) due to best vitelliform macular dystrophy (BVMD).Methods:Six eyes that were diagnosed with CNV associated with BVMD were evaluated retrospectively. A standard ophthalmologic examination, a fundus fluorescein angiography (FA), and the OCT findings of the patients were examined. Anatomical and functional changes seen after treatment were evaluated.Results:One (16%) of the cases was female and five (83%) were male. The mean age was calculated as 36.3±24.9 years (range 11–73 years). The mean follow-up period of the cases after detecting CNV was determined as 26 months (range 6–168 months). Best corrected visual acuities were 0.65±0.39 logMAR (1.0–0.2 logMAR) when CNV was detected and 0.42±0.25 logMAR (limits 0.7–0.2 logMAR) at the end of the follow-up. Photodynamic therapy was applied to one (17%) of the cases, and intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment was applied to the others (83%). The mean number of intravitreal injections was found to be 3±1.37 (range 2–4).In all cases, intraretinal fluid (IRF), subretinal fluid (SRF), external limiting membrane, and irregularities in inner retinal layers were observed in the initial OCT examinations. In all cases, it was observed that the IRF regressed with treatment and SRF continued in five eyes. Hypertrophic outer retinal scarring developed in all cases.Conclusion:In cases with CNV due to BVMD, regression in CNV activity was achieved with intravitreal anti-VEGF injection treatment. The IRF is a marker that can be used both in the diagnosis and treatment monitoring of CNV associated with BVMD.