Best Disease: Global Mutations Review, Genotype-Phenotype Correlation, and Prevalence Analysis in the Israeli Population.

Purpose: To review all reported disease-causing mutations in BEST1, perform genotype-phenotype correlation, and estimate disease prevalence in the Israeli population. Methods: Medical records of patients diagnosed with Best disease and allied diseases from nine Israeli medical centers over the past 20 years were collected, as were clinical data including ocular findings, electrophysiology results, and retina imaging. Mutation detection involved mainly whole exome sequencing and candidate gene analysis. Demographic data were obtained from the Israeli Bureau of Statistics (January 2023). A bibliometric study was also conducted to gather mutation data from online sources. Results: A total of 134 patients were clinically diagnosed with Best disease and related conditions. The estimated prevalence of Best disease was calculated to be 1 in 127,000, with higher rates among Arab Muslims (1 in 76,000) than Jews (1 in 145,000). Genetic causes were identified in 76 individuals (57%), primarily showing autosomal-dominant inheritance due to BEST1 mutations (58 patients). Critical conserved domains were identified consisting of a high percentage of dominant missense mutations, primarily in transmembrane domains and the intracellular region (Ca2+ binding domain) of the BEST1 protein. Conclusions: This study represents the largest cohort of patients with Best disease reported in Israel and globally. The prevalence in Israel is akin to that in Denmark but is lower than that in the United States. Critical conserved domains within the BEST1 protein are pivotal for normal functioning, and even minor missense alterations in these areas lead to a dominant disease manifestation. Genetic testing is indispensable as the gold standard for Best disease diagnosis due to the variable clinical presentation of the disease.

Typical best vitelliform dystrophy secondary to biallelic variants in BEST1.

BACKGROUND: Pathogenic variants in BEST1 can cause autosomal dominant or autosomal recessive dystrophy, typically associated with distinct retinal phenotypes. In heterozygous cases, the disorder is commonly characterized by yellow sub-macular lesions in the early stages, known as Best vitelliform macular dystrophy (BVMD). Biallelic variants usually cause a more severe phenotype including diffuse retinal pigment epithelial irregularity and widespread generalized progressive retinopathy, known as autosomal recessive bestrophinopathy (ARB). This study describes three cases with clinical changes consistent with BVMD, however, unusually associated with autosomal recessive inheritance. MATERIALS AND METHODS: Detailed ophthalmic workup included comprehensive ophthalmologic examination, multimodal retinal imaging, full-field and pattern electroretinography (ERG; PERG), and electrooculogram (EOG). Genetic analysis of probands and segregation testing and fundus examination of proband relatives was performed where possible. RESULTS: Three unrelated cases presented with a clinical phenotype typical for BVMD and were found to have biallelic disease-causing variants in BEST1. PERG P50 and ERG were normal in all cases. The EOG was subnormal (probands 1 and 3) or normal/borderline (proband 2). Probands 1 and 2 were homozygous for the BEST1 missense variant c.139C>T, p.Arg47Cys, while proband 3 was homozygous for a deletion, c.536_538delACA, p.Asn179del. The parents of proband 1 were phenotypically normal. Parents of proband 1 and 2 were heterozygous for the same missense variant. CONCLUSIONS: Individuals with biallelic variants in BEST1 can present with a phenotype indistinguishable from BVMD. The same clinical phenotype may not be evident in those harboring the same variants in the heterozygous state. This has implications for genetic counselling and prognosticationA.

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.

Quantitative microvascular alterations in butterfly-shaped pattern dystrophy and adult-onset foveomacular vitelliform dystrophy.

PURPOSE: To study retinal microvascular parameters in patients with butterfly-shaped pattern dystrophy (BPD) and adult foveomacular vitelliform dystrophy (AFVD). METHODS: This case-control study included BPD and AFVD patients in a tertiary university hospital. Eyes with known ocular disease and prior ocular surgery other than uncomplicated cataract surgery were excluded. Right eyes of healthy individuals without systemic or ocular disease were included as controls. En face 6×6mm angiograms were obtained with the RTVue XR Avanti (Optovue, USA). We used the Kruskal-Wallis test to compare vessel density (VD) values of the retina, optic disc and foveal avascular zone (FAZ) between groups. Dunn-Bonferroni correction was used for pairwise comparisons. RESULTS: Eighteen eyes of 10 BPD patients, 17 eyes of 9 AFVD patients, and 26 right eyes of 26 controls were included. Six patients in the BPD, 4 patients in the AFVD, and 16 patients in the control group were female. The groups did not differ by sex (P=0.650). AFVD patients were of higher mean age (64.3±7.8) than BPD patients (55.9±11.1) and controls (53.6±5.5) (P=0.008, p=0.009). In BPD (P=0.008, P=0.044) and AFVD (P=0.006, P=0.002), parafoveal and perifoveal vessel density (VD) of the superficial capillary plexus were lower than controls. Parafoveal VD of the deep capillary plexus in AFVD was lower than in controls (P=0.012). There was no difference in the foveal avascular area between groups (P=0.563). Optic discs parameters did not differ. CONCLUSION: A comparable loss in vascular density may indicate shared pathophysiology or represent a common sign of impairment in retinal homeostasis. Further research is needed to clarify underlying microvascular pathogenetic mechanisms in pattern dystrophies.

A case of recurring acute exudative polymorphous vitelliform maculopathy successfully treated with intravitreal Ozurdex injection.

INTRODUCTION: We describe a case of acute exudative polymorphous vitelliform maculopathy (AEPVM) that recurred 9 years after the initial event. To the best of our knowledge, this is the first report of recurrent AEPVM showing recovery of retinal and retinal pigment epithelium (RPE) function and good visual outcome following treatment with intravitreal corticosteroid. CASE DESCRIPTION: A 45-year-old Caucasian woman first presented with AEVPM in 2009. Her condition spontaneously resolved and she remained stable over several years. 9 years later, her condition recurred with bilateral reduction in visual acuity. Fundus examination revealed multiple small yellowish subretinal lesions across the posterior pole in both eyes. Optical coherence tomography (OCT) showed bilateral cystoid macular oedema (CMO). She was referred for electrophysiology and her electrooculogram findings were in keeping with severe generalised RPE dysfunction bilaterally, with a light peak to dark trough ratio (Arden index) of 110%, comparable to her initial presentation 9 years earlier. She was initially treated with oral steroids with some improvement. However, the maculopathy in the left eye recurred on cessation of oral treatment. A sustained-release 700ug dexamethasone intravitreal implant (Ozurdex®) was inserted in the left eye to which she responded remarkably, with improvement in visual acuity and complete resolution of the CMO. A year later, at her most recent clinic visit in March 2021, there was no evidence of any further recurrence. CONCLUSION: Our case demonstrates clinical and imaging findings consistent with recurrence of AEPVM with CMO that has been successfully treated with Ozurdex®.

Novel IMPG2 variant causing adult macular vitelliform dystrophy: A case report.

INTRODUCTION: Adult-onset vitelliform macular dystrophy (AVMD) is an inherited maculopathy characterized by metamorphopsias and decrease in visual acuity occurring between the fourth and the sixth decade. It is characterized by an 'egg yolk' macular lesion eventually evolving towards foveal atrophy and fibrosis. It is usually an autosomal dominant inherited disorder with variable penetrance, mainly related to variants in BEST1, PRPH2, IMPG1, and IMPG2 genes. CASE DESCRIPTION: A 47-year-old woman complaining of "wavy" vision was referred to our clinic. Her past medical history and reported family history did not reveal any ocular disease. Complete ophthalmological evaluation was performed. Funduscopic examination and multimodal imaging revealed a round vitelliform lesion in both eyes, leading to a diagnosis of AVMD. Genetic analysis revealed a novel, likely pathogenetic, heterozygous c.478G > T (p.Glu160Ter), (NM_016247) variant in the IMPG2 gene. DISCUSSION: Our patient exhibits a novel pathogenetic variant in a gene associated with AVMD. Heterozygous variants in the IMPG2 gene have been reported in multiple individuals with vitelliform macular dystrophy, with an autosomal dominant mode of inheritance. Genetic screening is essential to characterize patients, to predict vision loss in patients with a positive family history and to characterize eligible patients for new potential emerging therapies. Genotype-phenotype correlation studies are needed to have a clearer picture of pathogenetic mechanisms. Our study characterizes the phenotype related to a novel IMPG2 pathogenic variant through multimodal imaging.

The Retinal Phenotype Associated with the p.Pro101Thr BEST1 Variant.

PURPOSE: To describe the retinal phenotype associated with the p.Pro101Thr BEST1 variant. DESIGN: Retrospective, observational case series. PARTICIPANTS: Patients diagnosed with bestrophinopathies in which molecular genetic testing identified the p.Pro101Thr BEST1 as well as healthy carriers among their first-degree relatives. METHODS: Medical records were reviewed to obtain data on family history and ophthalmic examinations, including retinal imaging. The imaging protocol included OCT and fundus autofluorescence using Spectralis HRA + OCT (Heidelberg Engineering). Genetic analysis was performed by next-generation sequencing. MAIN OUTCOME MEASURES: Results of ophthalmic examinations and multimodal imaging features of retinal phenotypes. RESULTS: The c.301C>A, p.Pro101Thr BEST1 missense variant was identified as the causative variant in 8 individuals (all men) from 5 families, accounting for 13% of cases (8/61) and 10% of pathogenic alleles (9/93) in our cohort of patients affected by bestrophinopathies. Seven individuals (14 eyes) had the variant in heterozygous status: all eyes had a hyperopic refractive error (median spherical equivalent of + 3.75 diopters [D]) and 4 individuals had a macular dystrophy with mildly reduced visual acuity (median of 20/25 Snellen), whereas the other 3 were asymptomatic carriers. On multimodal retinal imaging, 5 (36%) out of 14 eyes had subclinical bestrophinopathy, 4 (29%) had typical findings of adult-onset foveomacular vitelliform dystrophy (AOFVD), and the remaining 5 (36%) displayed a pattern dystrophy-like phenotype. Follow-up data were available for 6 subjects, demonstrating clinical stability up to 11 years, in both subclinical and clinical forms. An additional patient with autosomal recessive bestrophinopathy was found to harbor the p.Pro101Thr variant in homozygosity. CONCLUSIONS: The p.Pro101Thr BEST1 variant is likely a frequent cause of bestrophinopathy in the Italian population and can result in autosomal dominant macular dystrophies with incomplete penetrance and mild clinical manifestations as well as autosomal recessive bestrophinopathy. The spectrum of autosomal dominant maculopathy includes the typical AOFVD and a pattern dystrophy-like phenotype. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

CHOROIDAL NEVUS ASSOCIATED WITH VITELLIFORM DEPOSITION IN A PATIENT WITH AUTOSOMAL DOMINANT BEST DYSTROPHY.

BACKGROUND/PURPOSE: To describe the clinical, optical coherence tomography (OCT), fundus autofluorescence and ultrasound findings of a patient with a choroidal nevus actively exuding vitelliform material in the setting of autosomal dominant Best dystrophy (BD). METHODS: The patient's clinical course was followed over time with ophthalmic examinations and multimodal imaging. RESULTS: A 71-year-old male patient with BD was referred for evaluation of a choroidal nevus in the right eye. Dilated fundoscopic examination showed a small pigmented choroidal nevus in the temporal periphery. Over a 3-year period, the nevus developed progressive deposition of vitelliform material along its inferior border. Meanwhile, OCT and fundus photography showed only slight growth. Ultrasound showed no change in height; basal measurements were confounded by the increased vitelliform deposits. Genetic testing confirmed a heterozygous mutation in the BEST1 gene and electrophysiology was consistent with BD. CONCLUSIONS: Dysfunction of the retinal pigment epithelium associated with BD may cause novel presentations of other conditions such as choroidal nevi. The implication for malignant transformation of a choroidal nevus associated with vitelliform deposit accumulation in this context is unknown.

COVID-19 VACCINE-INDUCED ACUTE EXUDATIVE POLYMORPHOUS VITELLIFORM MACULOPATHY: CASE REPORTS.

BACKGROUND: Acute exudative polymorphous vitelliform maculopathy is a presumed retinal pigment epithelium abnormality that has been reported in patients with neoplasms and under certain classes of drugs. The pathophysiology remains unclear, despite the typical clinical features. PURPOSE: To report two cases of acute exudative polymorphous vitelliform maculopathy occurring after vaccination with a COVID-19 vaccine. CASE REPORTS: Two adult patients presented with visual disturbance after inoculation with a COVID-19 vaccine. The patients were otherwise healthy and have no family history of retinal dystrophies. Both cases exhibited the following features on multimodal imaging: multifocal hyporeflective lesions involving the macula, elongated photoreceptors, accumulated vitelliform material exhibiting autofluorescence, and lack of fluorescein dye leakage. Evidence of retinal pigment epithelium dysfunction was confirmed by electrooculography. CONCLUSION: Two cases of acute exudative polymorphous vitelliform maculopathy occurring after COVID-19 vaccination were reported. A relationship between the vaccine and the retinal pigment epithelial abnormality development that led to acute exudative polymorphous vitelliform maculopathy was postulate, possibly through autoantibodies against the severe acute respiratory syndrome coronavirus 2 virus structural surface glycoprotein antigens that cross react with the normal retinal pigment epithelial cells.

Retinal sensitivity and fundus autofluorescence in adult-onset foveomacular vitelliform dystrophy.

The present study aimed to compare retinal sensitivity (RS) at each stage and to evaluate the relationship between RS and fundus autofluorescence (FAF) pattern in adult-onset foveomacular vitelliform dystrophy (AOFVD). We retrospectively reviewed 17 eyes of 13 patients with AOFVD. In addition to best-corrected visual acuity (VA), RS within the affected lesion and optical coherence tomography (OCT) measurements were carried out in each participant. All the examined eyes were classified into 4 stages and 3 FAF patterns. RS was superimposed on OCT fundus image and RS within the affected lesion was calculated in each eye. The relationships between visual functions (VA and RS within the affected lesion) and stages and also FAF patterns were analyzed using the linear mixed model. As a result, RS within the affected lesion was significantly associated with FAF pattern, but not with stage. In contrast, VA was correlated with neither stages nor FAF patterns. Our current result suggested that RS within the affected lesion was related to FAF patterns but this was not the case with VA in eyes with AOFVD, demonstrating the usefulness of measuring RS, not only VA, to comprehend the disease status in AOFVD.

Condition optimization of eco-friendly RP-HPLC and MCR methods via Box-Behnken design and six sigma approach for detecting antibiotic residues.

A precise, Eco-friendly, and highly sensitive RP-HPLC method was employed using quality-by-design principles to concurrently identify cephalexin and cefixime residues in the manufacturing machines using a hypersil BDS C18 column (250 × 4.6 mm, 5 µm) at wavelength 254 nm. The Box-Behnken design was applied to obtain the best chromatographic conditions with the fewest possible trials. Three independent factors viz organic composition, flow rate, and pH were used to assess their effects on the responses' resolution and retention time. Overlay plot and desirability functions were implemented to predict responses of the high resolution and relatively short retention time using a mobile phase composed of acidic water: acetonitrile (85:15, v/v) at pH 4.5 adjusted by phosphoric acid with a flow rate of 2.0 mL/min. The spectral overlapping of the drugs was successfully resolved by the mean centering ratio (MCR) spectra approach at 261 nm and 298 nm for cephalexin and cefixime, respectively. Good linearity results were obtained for the suggested HPLC and MCR methods over the concentration range of (0.05-10 ppm) and (5-30 ppm) with a detection limit of 0.003, 0.004, 0.26, and 0.23 ppm, and quantitation limits of 0.008, 0.013, 0.79, and 0.68 ppm for cephalexin and cefixime, respectively, with a correlation coefficient of ≥ 0.9998 and good swab recovery results of 99-99.5%. A process capability index was accomplished for chemical and micro results, illustrating that both are extremely capable. The suggested method was effectively validated using ICH recommendations.

Choroidal neovascularization associated with butterfly-shaped pattern dystrophy - a case report.

The pattern dystrophies (PDs) are a group of primarily autosomal dominant inherited macular diseases that cause the deposition of lipofuscin in retinal pigment epithelium (RPE) and may lead to significant vision loss in later life. Patients can develop choroidal neovascularization (CNV) and/ or geographic atrophy (GA) and for this reason they are often misdiagnosed as age-related macular degeneration (AMD). We presented a case of a 66-year-old patient complaining of vision loss in the right eye (RE) for 8 months. At the initial examination, his best corrected visual acuity (BCVA) was 0.6 in the RE. Optical coherence tomography angiography (OCTA), fundus autofluorescence (FAF) and fundus fluorescein angiography (FFA) allowed to diagnose butterfly-shaped PD in both eyes with choroidal neovascularization (CNV) in the RE. The patient was treated with three intravitreal anti-vascular epithelial growth factor (anti-VEGF, ranibizumab) injections during six weeks intervals, which improved and stabilized the BCVA of the RE to 0.7 during the over two-year observation period. Our report contributes to the still limited data regarding CNV associated with butterfly-shaped PDs and the results of treatment with ranibizumab. Abbreviations: AMD = age-related macular degeneration, anti-VEGF = anti-vascular epithelial growth factor, AOFVD = adult-onset foveomacular vitelliform dystrophy, BCVA = best corrected visual acuity, CNV = choroidal neovascularization, FAF = fundus autofluorescence, FFA = fundus fluorescein angiography, GA = geographic atrophy, LE = left eye, MIDD = maternally inherited diabetes and deafness, OCT = optical coherence tomography, OCTA = optical coherence tomography angiography, OU = oculus uterque, both eyes, PD = pattern dystrophy, PDSFF = pattern dystrophy simulating fundus flavimaculatus, PDT = photodynamic therapy, PRPH2 = peripherine-2, RE = right eye, RPE = retinal pigment epithelium, VA = visual acuity.

The pseudohypopyon stage in adult-onset foveomacular vitelliform dystrophy.

PURPOSE: To gain insight into the pathogenesis of adult-onset foveomacular vitelliform dystrophy (AFVD) via assessment of its pseudohypopyon stage (PHS). METHODS: 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. RESULTS: 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 ± 0.46 mm and 2.64 ± 0.77 mm in AFVD and BVMD, respectively (p = 0.02). AFVD patients were older (69 ± 14) than BVMD patients (22 ± 13; p = 0.009). CONCLUSION: 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.

Variants of BEST1 and CRYBB2 cause a complex ocular phenotype comprising microphthalmia, microcornea, cataract, and vitelliform macular dystrophy: case report.

BACKGROUND: Best vitelliform macular dystrophy (BVMD), caused by pathogenic variants of the BEST1 gene, has not been reported in association with cataracts and ocular malformations. We reported a case with a complex ocular phenotype comprising microphthalmia, microcornea, cataract, and vitelliform macular dystrophy. CASE PRESENTATION: A six-year-old girl manifested photophobia and a poor visual behavior. A thorough ophthalmic examination revealed the patient to have bilateral microphthalmia, microcornea, congenital cataract, and Best vitelliform macular dystrophy (BVMD). Whole exome sequencing (WES) identified one variant in the BEST1 and one variant in CRYBB2 genes: c.218 T > G p.(Ile73Arg) and c.479G > C p.(Arg160Pro). The first variant was inherited from the proband's father, who was diagnosed with subclinical BVMD, while the second was a de novo variant. A minigene assay showed that c.218 T > G in BEST1 did not affect pre-mRNA splicing. CONCLUSIONS: This case suggests that the complex ocular phenotype comprising BVMD and congenital cataract with microphthalmia cannot be explained by variation in one gene but is caused by variants in BEST1 and CRYBB2. This case highlights the importance of general clinical evaluation and comprehensive genetic testing for diagnosing complex eye diseases.

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.

Vitelliform maculopathy: Diverse etiologies originating from one common pathway.

Vitelliform lesions (VLs) are associated with a wide array of macular disorders but are the result of one common pathway: retinal pigment epithelium (RPE) impairment and phagocytic dysfunction. VLs are defined by the accumulation of yellowish subretinal material. In the era of multimodal advanced retinal imaging, VLs can be further characterized by subretinal hyperreflectivity with optical coherence tomography and hyperautofluorescence with fundus autofluorescence. VLs can be the result of genetic or acquired retinal diseases. In younger patients, VLs usually occur in the setting of Best disease. Additional genetic causes of VL include pattern dystrophy or adult-onset vitelliform macular dystrophy. In older patients, acquired VLs can be associated with a broad spectrum of etiologies, including tractional, paraneoplastic, toxic, and degenerative disorders. The main cause of visual morbidity in eyes with VLs is the onset of macular atrophy and macular neovascularization. Histopathological studies have provided new insights into the location, nature, and lifecycle of the vitelliform material comprised of melanosomes, lipofuscin, melanolipofuscin, and outer segment debris located between the RPE and photoreceptor layer. Impaired phagocytosis by the RPE cells is the unifying pathway leading to VL development. We discuss and summarize the nature, pathogenesis, multimodal imaging characteristics, etiologies, and natural course of vitelliform maculopathies.

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

OBJECTIVE: 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. DESIGN: Institutional review board-approved, retrospective, cross-sectional, and longitudinal study. PARTICIPANTS: Patients with molecularly confirmed BVMD. METHODS: 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. MAIN OUTCOME MEASURES: Presence of CNV on SS-OCTA and correlation with structural features on SS-OCT. RESULTS: 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). CONCLUSION: 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. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

BEST1 novel mutation causes Bestrophinopathies in six families with distinct phenotypic diversity.

PURPOSE: To report novel BEST1 variants in six Chinese families with bestrophinopathies of two different inheritance modes and analyze the intrafamilial phenotypic diversity. METHOD: A total of 25 participants including 13 patients and 12 healthy family members from 6 Chinese families with bestrophinopathies were available for genetic and clinical analysis. All of the patients were subjected to comprehensive ophthalmic evaluations and exome sequencing was performed on the probands to detect the causative variants. The pathogenicity of gene variants was predicted using silico analysis and evaluated according to ACMG guidelines. All (likely) pathogenic variants were determined by Sanger sequencing and co-segregation analyses were performed on available family members. The relevant original literature previously reported was retrieved to explore the relationship between BEST1-related gene variants and clinical features. RESULTS: In the 6 families, 3 families (10 patients) were assigned as autosomal dominant bestrophinopathies (VMD) and 3 families (3 patients) were assigned as Autosomal recessive Bestrophinopathies (ARB). A total of 9 variants on the BEST1 gene were identified, containing 7 missense variants, 1 nonsense variant, and 1 frameshift variant, respectively, of which 3 variants c.88A > G (p.Lys30Glu), c.764G > A (p.Arg255Gln) and c.233dupT (p.Ser79Phefs*153) were novel variants. Three families with ARB were detected with heterozygous variants on the BEST1 gene.2 families (8 patients) with BVMD showed markedly irregular dominant inheritance, and the severity of macular lesions varies greatly among individuals of the same family. Among them, the probands showed typical vitelliform lesions in the macula, while the other six patients had no visible signs of the disease by fundus photography (ophthalmoscopy) and minor lesions could be detected on OCT in two patients, the continuity of the ellipsoidal band was interrupted with the chimeric band. The phenotypes of the patients in the three ARB families ranged from typical/atypical vitelliform lesions to extensive extramacular deposits (peripheral spots). CONCLUSION: This study provided evidence that the phenotype of BVMD manifested irregular dominant inheritance, with patients carrying a pathogenic heterozygous variant of BEST1 to develop obvious intrafamilial phenotypic diversity, and the patients who harbor two pathogenic alleles showed recessive inheritance bestrophinopathies with distinct phenotypic diversity. Our study also emphasized the importance of comprehensive genetic analysis in patients with bestrophinopathies, and in such challenging families with distinct intrafamilial phenotypic diversity, it shall provide novel insights into phenotypic assessments of bestrophinopathies, and contribute to better diagnosis, prognosis, and treatment for these patients.