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

PURPOSE: To analyze the genetic findings, clinical spectrum, and natural history of Best vitelliform macular dystrophy (BVMD) in a cohort of 222 children and adults. DESIGN: Single-center retrospective, consecutive, observational study. PARTICIPANTS: Patients with a clinical diagnosis of BVMD from pedigrees with a likely disease-causing monoallelic sequence variant in the BEST1 gene. METHODS: Data were extracted from electronic and physical case notes. Electrophysiologic assessment and molecular genetic testing were analyzed. MAIN OUTCOME MEASURES: Molecular genetic test findings and clinical findings including best-corrected visual acuity (BCVA), choroidal neovascularization (CNV) rates, and electrophysiologic parameters. RESULTS: 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). CONCLUSIONS: 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. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Varied clinical presentations of RP1L1 variants in Chinese patients: a study of occult macular dystrophy and vitelliform macular dystrophy.

BACKGROUND: Occult Macular Dystrophy (OMD), primarily caused by retinitis pigmentosa 1-like 1 (RP1L1) variants, is a complex retinal disease characterised by progressive vision loss and a normal fundus appearance. This study aims to investigate the diverse phenotypic expressions and genotypic correlations of OMD in Chinese patients, including a rare case of Vitelliform Macular Dystrophy (VMD) associated with RP1L1. METHODS: We analysed seven OMD patients and one VMD patient, all with heterozygous pathogenic RP1L1 variants. Clinical assessments included Best Corrected Visual Acuity (BCVA), visual field testing, Spectral Domain Optical Coherence Tomography (SD-OCT), multifocal Electroretinograms (mfERGs), and microperimetry. Next-generation sequencing was utilised for genetic analysis. RESULTS: The OMD patients displayed a range of phenotypic variability. Most (5 out of 7) had the RP1L1 variant c.133 C > T; p.R45W, associated with central vision loss and specific patterns in SD-OCT and mfERG. Two patients exhibited different RP1L1 variants (c.3599G > T; p.G1200V and c.2880G > C; p.W960C), presenting milder phenotypes. SD-OCT revealed photoreceptor layer changes, with most patients showing decreased mfERG responses in the central rings. Interestingly, a unique case of VMD linked to the RP1L1 variant was observed, distinct from traditional OMD presentations. CONCLUSIONS: This study highlights the phenotypic diversity within OMD and the broader spectrum of RP1L1-associated macular dystrophies, including a novel association with VMD. The findings emphasise the complexity of RP1L1 variants in determining clinical manifestations, underscoring the need for comprehensive genetic and clinical evaluations in macular dystrophies.

SHORT-TERM MODIFICATIONS OF ELLIPSOID ZONE IN BEST VITELLIFORM MACULAR DYSTROPHY.

PURPOSE: To assess ellipsoid zone (EZ) alterations in Best vitelliform macular dystrophy using spectral-domain optical coherence tomography. METHODS: Prospective, observational case series. Forty-three patients (43 eyes) underwent complete ophthalmological examination at baseline and at 24 months: best-corrected visual acuity (BCVA), biomicroscopy, fundus photography, and spectral-domain optical coherence tomography were performed. Acquisition protocol included 19-line raster scan. Alterations in EZ were marked on spectral-domain optical coherence tomography, and the area was manually calculated on a near-infrared reflectance image. Three patterns were identified: A (decrease >0.25 mm2), B (±0.25 mm2), and C (increase >0.25 mm2). Primary outcome was to describe different patterns of EZ alteration. Secondary outcomes included their correlation with BCVA and the description of a central optically preserved islet. RESULTS: At baseline, altered EZ was identified in 40 eyes. Worse BCVA significantly correlated with larger EZ alterations but not with lesion extension on fundus photograph. Only "pattern-C" eyes unveiled BCVA worsening at follow-up. Optically preserved islet was detected in 16 eyes (37%), disclosing significantly better vision; its disappearance at follow-up (n = 7; 44% of 16 eyes) correlated with a decrease in BCVA. CONCLUSION: The assessment of EZ status might represent a valuable functional marker in Best vitelliform macular dystrophy because stable alterations and the maintenance of a central optically preserved islet are associated with better visual acuity.

Novel BEST1 gene mutations associated with two different forms of macular dystrophy in Tunisian families.

BACKGROUND: Epidemiological studies of hereditary eye diseases allowed us to identify two Tunisian families suffering from macular dystrophies: Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). The purpose of the current study was to investigate the clinical characteristics and the underlying genetics of these two forms of macular dystrophy. METHODS: Complete ophthalmic examination was performed including optical coherence tomography, electroretinography, electrooculography and autofluoresence imaging in all patients. Genomic DNA was extracted from peripheral blood collected from patients and family members. RESULTS: Sanger sequencing of all exons of the BEST1 gene in both families identified two new mutations: a missense mutation c.C91A [p.L31 M] at the N-terminal transmembrane domain within the ARB family and a nonsense mutation C1550G (p.S517X) in the C-terminal domain segregating in the BVMD family. CONCLUSIONS: Several mutations of the BEST1 gene have been reported which are responsible for numerous ocular pathologies. To the best of our knowledge, it is the first time we report mutations in this gene in Tunisian families presenting different forms of macular dystrophy. Our report also expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis.

Idiopathic Acute Exudative Polymorphous Vitelliform Maculopathy: Clinical Spectrum and Multimodal Imaging Characteristics.

PURPOSE: To describe clinical findings in patients with acute exudative polymorphous vitelliform maculopathy (AEPVM). DESIGN: Retrospective, observational, multicenter case series review. PARTICIPANTS: Consecutive patients diagnosed with idiopathic AEPVM. METHODS: Review of clinical charts, multimodal imaging, electrophysiologic findings, and genetic findings in previously unpublished patients and review of the literature. MAIN OUTCOME MEASURES: Clinical features of idiopathic AEPVM and differential diagnosis. RESULTS: Eighteen patients (age range, 21-74 years) with typical features of AEPVM, including initial localized, serous detachments followed by the development of characteristic yellow-white deposits in the vitelliform space. Over time, this hyperautofluorescent material gravitated within the larger lesions, resulting in typical curvilinear deposits characteristic of later stages. Symptoms and clinical findings lasted from weeks to several years. Some patients showed previously undescribed features such as fluorescein-negative intraretinal cystic changes, choroidal neovascularization, serous retinal elevations mimicking retinal folds, increased choroidal thickness, lack of rapid visual recovery, and recurrence years after complete resolution of initial manifestations. CONCLUSIONS: Acute exudative polymorphous vitelliform maculopathy can present with a more variable natural course than previously described. Paraneoplastic retinopathy and autosomal recessive bestrophinopathy closely resemble AEPVM, necessitating medical and hereditary evaluation to exclude these clinical possibilities. This series of patients with AEPVM expands the clinical spectrum of the disorder, including demographics, clinical manifestations, imaging features, natural course, and visual prognosis.

Quantitative changes in flow density in patients with adult-onset foveomacular vitelliform dystrophy: an OCT angiography study.

PURPOSE: To quantitatively compare the flow density, the retinal thickness, and the area of the foveal avascular zone (FAZ) between patients with adult-onset foveomacular vitelliform dystrophy (AOFVD) and a healthy controls. METHODS: Thirteen eyes (eight patients) with AOFVD and 13 matched eyes (13 patients) without any ocular pathology were included in this study. A 6 × 6 mm optical coherence tomography angiography (OCTA) scan was performed for every included eye. The flow density (superficial retinal vascular layer, deep retinal vascular layer and choriocapillary layer), retinal thickness and FAZ (superficial retinal vascular layer and deep retinal vascular layer) were subsequently analyzed. RESULTS: The mean flow density was decreased in the AOFVD patients in all measured vascular layers. The difference from the control group was statistically significant in the parafoveal sector of the deep retinal vascular layer (P = 0.02), and a clear trend was found in the superficial retinal vascular layer (P = 0.05). Both groups had comparable FAZs in the superficial and deep retinal vascular layers. The retinal thickness values were higher in the fovea (P = 0.840) and lower in the parafoveal sectors (P = 0.125). The difference was significant in the superior parafoveal sector (P = 0.034). CONCLUSIONS: Flow densities as measured by OCTA are decreased in the superficial retinal vascular layer and the deep retinal vascular layer in patients with AOFVD. These findings could be helpful for diagnosing and understanding the pathogenesis of this disease.

Fibrotic pillar leads to focal choroidal excavation in Best vitelliform dystrophy.

PURPOSE: To study focal choroidal excavations in patients with Best vitelliform dystrophy using optical coherence tomography and their topographical relation with fibrotic pillars. METHODS: This is a retrospective cross-sectional study of consecutive patients diagnosed with Best vitelliform dystrophy at a tertiary eye care center. Records of patients with Best vitelliform dystrophy were reviewed for best-corrected visual acuity, color fundus photographs, shortwave autofluorescence, optical coherence tomography, and electrooculogram with special emphasis on the presence of focal choroidal excavation (FCE) and fibrotic pillar. Main outcome measure was to study the fibrotic pillar in relation to the FCE. RESULTS: Thirty-eight eyes of 19 patients with mean age of 34.6 years were enrolled in the study. FCE was seen in eight eyes of six patients. Two patients had bilateral FCE and all the FCEs were located in the area of vitelliform lesion. Six out of eight eyes with FCE were in vitelliruptive stage of disease; one was in pseudohypopyon stage and one in atrophic stage. A fibrotic pillar was seen lying directly above the FCE in seven eyes. In one eye, hyper-reflective material not amounting to fibrotic pillar was seen lying above the FCE. CONCLUSION: A focal choroidal excavation in the setting of Best vitelliform dystrophy is seen predominantly in the vitelliruptive stage of the disease. Fibrotic pillars appear to play a role in the formation of these FCEs.

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FEATURES IN DIFFERENT STAGES OF BEST VITELLIFORM MACULAR DYSTROPHY.

PURPOSE: To provide a systematic classification of findings regarding the different stages of vitelliform macular dystrophy on spectral domain optical coherence tomography (SD-OCT). METHODS: Ninety-four eyes of 47 patients were recruited in a prospective cross-sectional study. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, biomicroscopy, and SD-OCT. The findings assessed included vitelliform material, neurosensory detachment, status of external limiting membrane, ellipsoid zone and retinal pigment epithelium, choroidal excavation, foveal cavitation, choroidal neovascularization, vitreomacular traction, and macular hole. The primary outcome measure was the identification of SD-OCT findings in each vitelliform macular dystrophy stage. Secondary outcomes included the correlations between SD-OCT features and visual acuity changes. RESULTS: The outer retinal layers (external limiting membrane, ellipsoid zone, and retinal pigment epithelium) were found to be more commonly disrupted in Stages 2 to 4 (range: 86%-100%), whereas their absence was more typical of Stage 5 (71%-86%). Vitelliform material was found in 100% of Stages 2 and 3, 93% of Stage 4, and interestingly in 43% of Stage 5. Eyes characterized by vitelliform material showed a greater correlation with higher best-corrected visual acuity than eyes without it (0.35 logarithm of the minimum angle of resolution vs. 0.80 ± 0.36 logarithm of the minimum angle of resolution, approximately 20/45 and 20/125 Snellen equivalent, respectively) (t = 3.726, P < 0.05). Moreover, its absence was associated with a best-corrected visual acuity of 0.5 logarithm of the minimum angle of resolution or worse (approximately 20/63 Snellen equivalent; P < 0.05). Subretinal fluid was more common in Stages 3 and 4 (72.7% and 75%, respectively) than Stages 2 and 5 (P = 0.004). Eyes with subretinal fluid were significantly associated with a visual acuity of 0.2 logarithm of the minimum angle of resolution or worse (approximately 20/32 Snellen equivalent; P = 0.04). CONCLUSION: Spectral domain optical coherence tomography assessment primarily indicates an outer retinal layer disruption in Stages 2 to 4, along with the presence of vitelliform material extending into the more advanced clinical stages too. Eyes characterized by the persistence of vitelliform material show better best-corrected visual acuity. Future investigations based on a longitudinal follow-up are warranted to correlate SD-OCT modifications with functional responses to identify SD-OCT indicators for prognostic and therapeutic purposes.

THE FUNDUS PHENOTYPE ASSOCIATED WITH THE p.Ala243Val BEST1 MUTATION.

PURPOSE: To describe a highly recognizable and reproducible retinal phenotype associated with a specific BEST1 mutation-p.Ala243Val. METHODS: Retrospective review of consecutive cases where genetic testing has identified p.Ala243Val BEST1 as the cause of disease. Electronic patient records were used to extract demographic, as well as functional and anatomical data. These data were compared with those observed with the most common BEST1 genotype, p.Arg218Cys. RESULTS: Eight individuals (six families) were identified with the p.Ala243Val BEST1 mutation and seven patients with the pathologic variant p.Arg218Cys. No patients with mutation of codon 243 knowingly had a family history of retinal disease, whereas all patients with the p.Arg218Cys variant did. The maculopathy was bilateral in all cases. The p.Ala243Val mutation was associated with a pattern dystrophy-type appearance, most visible with near-infrared reflectance and fundus autofluorescence imaging. This phenotype was never observed with any other genotype. This mutation was associated with an older median age of symptom onset (median = 42, interquartile range = 22) compared with those harboring the p.Arg218Cys mutation (median = 18, interquartile range = 12; Mann-Whitney U test; P < 0.05). Despite their older age, the final recorded acuity seemed to be better in the p.Ala243Val group (median = 0.55, interquartile range = 0.6475; median = 0.33, interquartile range = 0.358), although this did not reach statistical significance (Mann-Whitney U test; P > 0.05). CONCLUSION: The mutation p.Ala243Val is associated with highly recognizable and reproducible pattern dystrophy-like phenotype. Patients develop symptoms at a later age and tend to have better preservation of electrooculogram amplitudes.

MICROPERIMETRY IN BEST VITELLIFORM MACULAR DYSTROPHY.

PURPOSE: To investigate retinal sensitivity in eyes with all the clinical stages of Best vitelliform macular dystrophy (VMD). METHODS: Thirty-two patients affected by VMD in subclinical, vitelliform, pseudohypopyon, vitelliruptive, and atrophic stages were enrolled in this prospective cross-sectional study. Patients underwent a complete ophthalmologic examination, including determination of best-corrected visual acuity (BCVA), staging of the disease (Gass's classification), and microperimetry by means of the macular integrity assessment microperimeter. The primary outcome measure was to describe the alterations in the retinal sensitivity of eyes affected by VMD in different stages. Secondary outcome measures included correlations between retinal sensitivity and best-corrected visual acuity and the correlation between the VMD stage and the specific microperimetry pattern. RESULTS: Mean retinal sensitivity was reduced in all the VMD stages. Nevertheless, vitelliform, pseudohypopyon, and vitelliruptive stages turned out to be very similar, especially within 10°. Fixation was classified as stable in 27 eyes (44.2%), relatively unstable in 16 eyes (26.2%), and unstable in 18 eyes (29.5%). Fixation stability correlated both with the disease stage and best-corrected visual acuity. CONCLUSION: VMD is characterized by complex microperimetric abnormalities, involving the whole macular area. Microperimetry may contribute to the global clinical assessment of patients affected by VMD and could be used in future therapeutic approaches.

Treatment of Macular Degeneration with Sildenafil: Results of a Two-Year Trial.

OBJECTIVE: To evaluate PDE5/6 inhibition with sildenafil to reduce choroidal ischemia and treat age-related macular degeneration. METHODS: Sildenafil was prescribed to treat participants with macular degenerations or macular dystrophies measured by spectral-domain optical coherence tomography, color fundus photography, enhanced depth imaging, and best-corrected visual acuity. RESULTS: No change in calcified drusen was noted. Vitelliform-type soft drusen were not substantially changed. A participant with Best vitelliform macular dystrophy had a significant improvement in vision as well as in photoreceptor and ellipsoid layers. CONCLUSIONS: Our research supports sildenafil as a safe treatment for age-related and vitelliform macular degenerations. Thickened Bruch's membrane reduces the beneficial effect of perfusion increase, but all eyes appear to benefit from PDE6. Notably, maintenance or improvement in the photoreceptor layer may be the most significant result of sildenafil and is consistent with PDE6 inhibition. Thus, sil-denafil treatment of macular degeneration offers significant potential for vision retention and recovery.

Best Vitelliform Macular Dystrophy.

Best vitelliform macular dystrophy (VMD or BVMD) is one of the most common macular dystrophies, affecting 1 in 10,000 individuals. The clinical presentation varies, depending on the stage of the disease at which the patient presents, usually one of these five stages: Previtelliform Vitelliform (Figs. 16.1, 16.2, 16.3 and 16.4) Pseudohypopyon Vitelliruptive (Fig. 16.5) Atrophic.

Best Vitelliform Macular Dystrophy.

Autosomal recessive bestrophinopathy (ARB) results from a total absence of functional bestrophin-1 protein owing to two BEST1 mutations, one on each of the chromosomes. If present at an early age, the presenting feature could be decreased vision due to amblyopia. Refractive error is hyperopia, predisposing these eyes for acute angle-closure glaucoma. The yellowish lesions are larger and more extensive-extending beyond the arcades-than in the typical autosomal dominant Best disease. Some of the eyes also show numerous yellowish subretinal dots. Lesions are multifocal (Fig. 29.1). Subretinal fibrosis in the macular area is a common feature. Optical coherence tomography (OCT) may show cystoid changes in the neurosensory retina. Fundus autofluorescence (FAF): Increased AF reflects lipofuscin accumulation in the RPE; decreased AF reflects RPE atrophy. Electroretinography (ERG): As panretinal photoreceptor dysfunction progresses with advancing age, full-field (FF) ERG shows delayed rod and cone responses. Electrooculography (EOG): Abnormal Arden ratio.

FUNCTIONAL AND ANATOMICAL OUTCOMES OF CHOROIDAL NEOVASCULARIZATION COMPLICATING BEST1-RELATED RETINOPATHY.

PURPOSE: To describe the presenting features and functional outcomes in a series of patients with choroidal neovascular membrane complicating BEST1-related retinopathy (Best disease and autosomal recessive bestrophinopathy). METHODS: Retrospective review of consecutive cases at a tertiary care eye hospital. Patients were identified retrospectively over an 11-year period. Records were reviewed to extract demographic as well as functional and anatomical outcome data. RESULTS: Fourteen eyes of 12 patients were identified (11 Best disease and 1 autosomal recessive bestrophinopathy). Median follow-up was 2.8 years (range 0.8-6). The median age at choroidal neovascular membrane discovery was 15.5 years (range 6-72). Choroidal neovascular membranes were active early in the disease course before vitelliruption. Seven eyes were treated with intravitreal bevacizumab, 7 eyes were monitored by observation alone. On average, patients required a single treatment (median = 1, range 1-10). The median gain in visual acuity was greater in the treated versus the observed group-0.46 versus 0.17 decimalized units of Snellen acuity, respectively (P < 0.05 Mann-Whitney U test). Although a significant reduction in central macular thickness was evident in both groups, 150 µm (treated) and 104 µm (observed), active treatment was not associated with greater thinning than observation (P > 0.05 Mann-Whitney U test). CONCLUSION: There is a high rate of spontaneous recovery of BEST1-related choroidal neovascular membrane, and overall the authors observed a gain in visual acuity associated with a reduction in central macular thickness. Active treatment, here with intravitreal bevacizumab, is associated with better functional outcomes than observation alone.

Functional assessment of the fundus autofluorescence pattern in Best vitelliform macular dystrophy.

PURPOSE: To identify the fundus autofluorescence (FAF) patterns in Best vitelliform macular dystrophy (VMD). METHODS: Patients affected by VMD in vitelliform, pseudohypopyon, and vitelliruptive stages underwent a complete ophthalmological examination, including best-corrected visual acuity (BCVA), short-wavelength FAF (SW-FAF), near-infrared FAF (NIR-FAF) and microperimetry. MAIN OUTCOME MEASURES: the identification of the correlation between SW-FAF and NIR-FAF patterns of the foveal region with BCVA, and central retinal sensitivity in eyes affected by VMD. The secondary outcomes included the definition of the frequency of foveal patterns on SW-FAF and NIR-FAF. RESULTS: Thirty-seven of 64 (58 %), 8 of 64 (12.5 %) and 19 of 64 (29.5 %) eyes showed vitelliform, pseudohypopyon, and vitelliruptive stages respectively. Three main FAF patterns were identified on both techniques: hyper-autofluorescent pattern, hypo-autofluorescent pattern, and patchy pattern. BCVA was significantly different in eyes with hypo-autofluorescent and patchy patterns with respect to eyes showing a hyper-autofluorescent pattern. Similar differences were registered in the FS according to SW-FAF classification. However, the FS differed in each subgroup in the NIR-FAF analysis. Subgroup analyses were performed on the patchy pattern, combining FAF and fundus abnormalities. Considering both FAF techniques, the BCVA differed between the vitelliform and pseudohypopyon stages, and between the vitelliform and vitelliruptive stages. In the NIR-FAF classification, there was a significant statistical difference in the FS between each subgroup; in the SW-FAF, there was a significant difference between the vitelliform and pseudohypopyon stages and the vitelliform and vitelliruptive stages. CONCLUSIONS: Three main FAF patterns can be identified in VMD. The patchy pattern is the most frequent, accounting for 70 % of eyes on SW-FAF and 80 % of eyes on NIR-FAF. A tighter correlation links the classification of NIR-FAF patterns and FS. Longitudinal investigations are warranted to evaluate the course of FAF patterns and their role in disease monitoring.

A NOVEL P.ASP304GLY MUTATION IN BEST1 GENE ASSOCIATED WITH ATYPICAL BEST VITELLIFORM MACULAR DYSTROPHY PHENOTYPE AND HIGH INTRAFAMILIAL VARIABILITY.

PURPOSE: To report the atypical phenotypic characteristics of patients with a novel p.Asp304Gly mutation in BEST1. METHODS: Affected individuals underwent a complete ophthalmic examination, including best-corrected visual acuity, fundus autofluorescence, spectral domain optical coherence tomography, and electrophysiologic testing. All individuals were screened for mutations in the BEST1 gene. RESULTS: Five patients of the same Italian family were clinically examined. All patients complained of decreased vision as the initial symptom. Best-corrected visual acuity ranged from 20/800 to 20/32. On fundus examination, all patients showed atypical Best vitelliform macular dystrophy phenotype with multifocal macular and extramacular involvement. The spectral domain optical coherence tomography characteristics of central macular and extramacular lesions varied in each patient and included "giant" choroidal excavation, extensive flat macular elevation with hyporeflective subretinal material accumulation surrounded by hyperautofluorescent spots/annulus, and extensive hypoautofluorescent extramacular atrophic areas. Electrooculogram was always abnormal with Arden ratio lower than 1.55, whereas electroretinogram was normal in the two younger patients and abnormal (low amplitude) in the three older patients. Genetic analysis revealed a novel missense mutation in BEST1, substituting aspartate for glycine at amino acid 304. CONCLUSION: We describe the atypical phenotype and high intrafamilial variability associated with a new mutation in the BEST1 gene in an Italian family affected with Best vitelliform macular dystrophy. Clinicians should consider screening the BEST1 gene even in the absence of the typical phenotype and in case of high intrafamilial variability.

iPS cell modeling of Best disease: insights into the pathophysiology of an inherited macular degeneration.

Best disease (BD) is an inherited degenerative disease of the human macula that results in progressive and irreversible central vision loss. It is caused by mutations in the retinal pigment epithelium (RPE) gene BESTROPHIN1 (BEST1), which, through mechanism(s) that remain unclear, lead to the accumulation of subretinal fluid and autofluorescent waste products from shed photoreceptor outer segments (POSs). We employed human iPS cell (hiPSC) technology to generate RPE from BD patients and unaffected siblings in order to examine the cellular and molecular processes underlying this disease. Consistent with the clinical phenotype of BD, RPE from mutant hiPSCs displayed disrupted fluid flux and increased accrual of autofluorescent material after long-term POS feeding when compared with hiPSC-RPE from unaffected siblings. On a molecular level, RHODOPSIN degradation after POS feeding was delayed in BD hiPSC-RPE relative to unaffected sibling hiPSC-RPE, directly implicating impaired POS handling in the pathophysiology of the disease. In addition, stimulated calcium responses differed between BD and normal sibling hiPSC-RPE, as did oxidative stress levels after chronic POS feeding. Subcellular localization, fractionation and co-immunoprecipitation experiments in hiPSC-RPE and human prenatal RPE further linked BEST1 to the regulation and release of endoplasmic reticulum calcium stores. Since calcium signaling and oxidative stress are critical regulators of fluid flow and protein degradation, these findings likely contribute to the clinical picture of BD. In a larger context, this report demonstrates the potential to use patient-specific hiPSCs to model and study maculopathies, an important class of blinding disorders in humans.

Frequency and clinical pattern of vitelliform macular dystrophy caused by mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes.

PURPOSE: To assess the frequency of and to characterize the clinical spectrum and optical coherence tomography findings of vitelliform macular dystrophy linked to IMPG1 and IMPG2, 2 new causal genes expressed in the interphotoreceptor matrix. DESIGN: Retrospective epidemiologic, clinical, electrophysiologic, and molecular genetic study. PARTICIPANTS: The database of a national referral center specialized in genetic sensory diseases was screened for patients with a macular vitelliform dystrophy without identified mutation or small deletion or large rearrangement in BEST1 and PRPH2 genes. Forty-nine families were included. METHODS: Clinical, imaging, and electro-oculogram findings were reviewed. Mutation screening of IMPG1 and IMPG2 genes were performed systematically. MAIN OUTCOME MEASURES: Frequency, inheritance, and clinical pattern of vitelliform dystrophy associated with IMPG1 and IMPG2 mutations were characterized. RESULTS: IMPG1 was the causal gene in 3 families (IMPG1 1-3, 11 patients) and IMPG2 in a fourth family (2 patients). With an autosomal dominant transmission, families 1 and 2 had the c.713T→G (p.Leu238Arg) mutation in IMPG1 and family 4 had the c.3230G→T (p.Cys1077Phe) mutation in IMPG2. Patients with IMPG1 or IMPG2 mutations had a late onset and moderate visual impairment (mean visual acuity, 20/40; mean age of onset, 42 years), even in the sporadic case of family 3 with a presumed recessive transmission (age at onset, 38 years; mean visual acuity, 20/50). Drusen-like lesions adjacent to the vitelliform deposits were observed in 9 of 13 patients. The vitelliform material was above the retinal pigment epithelium (RPE) at any stage of the macular dystrophy, and this epithelium was well preserved and maintained its classical reflectivity on spectral-domain optical coherence tomography (SD-OCT). Electro-oculogram results were normal or borderline in 9 cases. CONCLUSIONS: IMPG1 and IMPG2 are new causal genes in 8% of families negative for BEST1 and PRPH2 mutations. These genes should be screened in adult-onset vitelliform dystrophy with (1) moderate visual impairment, (2) drusen-like lesions, (3) normal reflectivity of the RPE line on SD-OCT, and (4) vitelliform deposits located between ellipsoid and interdigitation lines on SD-OCT. These clinical characteristics are not observed in the classical forms of BEST1 or PRPH2 vitelliform dystrophies.

Electrooculography and optical coherence tomography reveal late-onset Best disease.

PURPOSE: Best vitelliform macular dystrophy, also known as Best disease, is a macular dystrophy characterized by bilateral yellowish egg yolk-like lesion(s) present within the maculae. It is a slowly progressive disease that usually presents at childhood. Best vitelliform macular dystrophy frequently proceeds through stages, beginning with a classic presentation described as vitelliform. A similar condition, known as adult-onset foveomacular vitelliform dystrophy, has been described among adult patients. Although the two maculopathies may look similar, they are considered two separate entities, because of the age of onset and overall clinical presentation. CASE REPORT: A 54-year-old man presented with gradual-onset blurred near vision in each eye. Previous records showed a history of unremarkable dilated fundus examinations for the past 8 years. Best-corrected distance acuities measured 20/20 OD and 20/20 OS. Amsler grid testing revealed a mild metamorphopsia OD and OS. Dilated fundoscopy revealed macular pseudohypopyon in each eye. In vivo imaging of the maculae was obtained with spectral-domain optical coherence tomography findings. Electrooculography findings were consistent with Best vitelliform macular dystrophy of atypical, late onset. CONCLUSIONS: Best vitelliform macular dystrophy may vary in its presentation. Electrooculography and spectral-domain optical coherence tomography can aid in establishing the definitive diagnosis.

Risk Factors for Worsening Morphology and Visual Acuity in Eyes with Adult-Onset Foveomacular Vitelliform Dystrophy.

PURPOSE: To explore clinical risk factors and OCT features associated with worse visual acuity (VA), progression of disease, choroidal neovascularization (CNV), and atrophy in eyes with adult-onset foveomacular vitelliform dystrophy (AOFVD). DESIGN: Single-center, retrospective, observational cohort study. PARTICIPANTS: Patients seen at Duke Eye Center between January 2012 and May 2023 with a diagnosis of AOFVD confirmed via OCT and fundus autofluorescence. METHODS: Baseline and final-visit images from eyes with AOFVD were examined. Disease stage was assigned, and presence of atrophy or CNV was determined. Clinical and OCT features associated with progression to atrophy and CNV were determined using t tests and chi-square analysis. Correlation with lower VA was determined using linear regression. MAIN OUTCOME MEASURES: Association of clinical characteristics and OCT features with worse VA, progression of disease, CNV, and atrophy as determined by independent t tests, chi-square analysis, and linear regression (P < 0.05). RESULTS: One hundred one eyes (63 patients) met inclusion criteria for this study, with mean follow-up duration of 48 months (standard deviation, 31 months). Fifty-one percent of eyes progressed beyond baseline staging during follow-up; among baseline stage 1 eyes, incidence of atrophy was 0.068/person-year; incidence of CNV was 0.022/person-year. Risk factors for worse final VA were baseline presence of vitreomacular traction ([VMT], P = 0.006), ellipsoid zone attenuation (P = 0.02), and increased lesion height and width (P < 0.001). Predictors of progression include diabetes mellitus (P = 0.01), statin use (P = 0.03), presence of hyperreflective foci (P = 0.01), and increased lesion width and volume (P = 0.03 and P = 0.04, respectively). Predictors of atrophy include the baseline presence of VMT (P = 0.02), decreased choroidal thickness (P = 0.03), and greater maximal height, width, and volume of the lesion (P = 0.03, P = 0.02, and P = 0.009, respectively). Lower baseline VA (P = 0.03) and increased lesion volume (P = 0.04) were associated with CNV. CONCLUSIONS: Clinical and OCT imaging features at baseline may prove useful in stratifying patient risk for progression, atrophy, CNV, and worse VA. Features such as statin use, diabetes, baseline VA, and laterality should be accounted for. OCT features, such as lesion size, VMT, ellipsoid zone attenuation, choroidal thickness, and hyperreflective foci, may impart greater risk of poor outcomes. Future prospective analysis accounting for the time to development of atrophy and CNV is needed. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.