Vitelliform Macular Dystrophy Research Articles

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients.

To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

Correction: Srinivasan et al. Detection and Grade Classification of Diabetic Retinopathy and Adult Vitelliform Macular Dystrophy Based on Ophthalmoscopy Images. Electronics 2023, 12, 862

There was an error in the original publication [...]

Lack of Response to Intravitreal Ranibizumab Treatment in Adult Onset Foveomacular Vitelliform Dystrophy Complicated with Choroidal Neovascularization: A Case Report

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare disease characterized by accumulation of yellowish deposits in the macula. Rarely, it may be complicated by choroidal neovascularization (CNV). Cases with CNV may be confused with occult CNV in age-related macular degeneration. In our case, we will present the visual and anatomical results of a patient with AOVF-related CNV, in which we administered 3 doses of intravitreal ranibizumab (IVR). A 59-year-old female patient, who attended our clinic with the complaint of decreased vision in both eyes, was diagnosed with AOVF-related CNV in both eyes and was treated with 3 doses of IVR for 3 months. Despite the improvement in visual and anatomical functions 1 month after the first dose, vision decreased, and anatomical functions regressed to the pre-injection state in continued injections. IVR therapy is not an appropriate treatment option in the treatment of AOVF-associated CNV.

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.

Artificial Intelligence (AI) for Early Diagnosis of Retinal Diseases.

Artificial intelligence (AI) has emerged as a transformative tool in the field of ophthalmology, revolutionizing disease diagnosis and management. This paper provides a comprehensive overview of AI applications in various retinal diseases, highlighting its potential to enhance screening efficiency, facilitate early diagnosis, and improve patient outcomes. Herein, we elucidate the fundamental concepts of AI, including machine learning (ML) and deep learning (DL), and their application in ophthalmology, underscoring the significance of AI-driven solutions in addressing the complexity and variability of retinal diseases. Furthermore, we delve into the specific applications of AI in retinal diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), Macular Neovascularization, retinopathy of prematurity (ROP), retinal vein occlusion (RVO), hypertensive retinopathy (HR), Retinitis Pigmentosa, Stargardt disease, best vitelliform macular dystrophy, and sickle cell retinopathy. We focus on the current landscape of AI technologies, including various AI models, their performance metrics, and clinical implications. Furthermore, we aim to address challenges and pitfalls associated with the integration of AI in clinical practice, including the "black box phenomenon", biases in data representation, and limitations in comprehensive patient assessment. In conclusion, this review emphasizes the collaborative role of AI alongside healthcare professionals, advocating for a synergistic approach to healthcare delivery. It highlights the importance of leveraging AI to augment, rather than replace, human expertise, thereby maximizing its potential to revolutionize healthcare delivery, mitigate healthcare disparities, and improve patient outcomes in the evolving landscape of medicine.

Clinical features and possible pathogenesis of multiple evanescent white dot syndrome with different retinal diseases and events: a narrative review.

Multiple evanescent white dot syndrome (MEWDS) is a rare fundus disease, characterized by acute vision loss and visual field defects. Many previous studies have explained the possible pathogenesis and clinical features of primary MEWDS. However, as the number of reported cases increases, secondary MEWDS occurs in other related retinal diseases and injuries, exhibiting some special characteristics. The associated retinal diseases include multifocal choroiditis/punctate inner choroidopathy (MFC/PIC), acute zonal occult outer retinopathy, best vitelliform macular dystrophy, pseudoxanthoma elasticum, and ocular toxoplasmosis. The related retinal injury is laser photocoagulation, surgery, and trauma. Although primary MEWDS often have a self-limiting course, secondary MEWDS may require treatment in some cases, according to the severity of concomitant diseases and complications. Notably, MEWDS secondary to MFC/PIC that is prone to forming choroidal neovascularization and focal choroidal excavation, needs positive treatment with corticosteroids. The possible underlying pathogenesis of secondary MEWDS is the exposure of choroidal antigen after the disruption of Bruch's membrane. The MEWDS-related features in secondary MEWDS are still evanescent under most circumstances. Its prognosis and treatment depend on the severity of complications. Current studies propose that the etiology is associated with immune factors, including viral infection, inflammation in choroid and Bruch's membrane, and antigen exposure caused by retinal and/or choroidal insults. More pathogenic studies should be conducted in the future. Accurate diagnosis for secondary MEWDS could benefit patients in aspects of management and prognosis.

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

PurposeTo explore clinical risk factors and optical coherence tomography (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). DesignSingle-center, retrospective, observational cohort study ParticipantsPatients seen at Duke Eye Center between January 2012 and May 2023 with a diagnosis of AOFVD confirmed via OCT and fundus autofluorescence. MethodsBaseline 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. Outcome MeasuresAssociation 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). Results101 eyes (63 patients) met inclusion criteria for this study, with mean follow-up duration of 48 months (SD 31 months). 51% 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=0.024), increased lesion height and width (p<0.001). Predictors of progression include diabetes mellitus (p=0.012), statin use (p=0.031), presence of hyperreflective foci (p=0.012), and increased lesion width and volume (p=0.034, p=0.040). Predictors of atrophy include the baseline presence of VMT (p=0.018), decreased choroidal thickness (p=0.027), and greater maximal height, width, and volume of the lesion (p=0.031, p=0.020, p=0.009, respectively). Lower baseline VA (p=0.031) and increased lesion volume (p=0.042) were associated with CNV. ConclusionsClinical 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.

Choroidal neovascularization as first sign of Best's vitelliform dystrophy in a child

Aims/Purpose: To report a case of choroidal neovascularization secondary to Best's vitelliform dystrophy in a child managed by intravitreal aflibercept.Methods: Interventional, case report.Results: A 9‐year‐old boy reported decreased visual acuity (VA) with metamorphopsia in his right eye (RE) for the previous month. VA was RE 20/100 and left eye (LE) 20/20. Funduscopy revealed right‐eye macular oedema with deep macular haemorrhage associated to a bilateral orange‐yellowish deposit. Optical coherence tomography (OCT) showed sub‐ and intraretinal fluid in the foveal area along with a hyperreflective subretinal deposit and a localized retinal pigment epithelium (RPE) elevation. Blue autofluorescence (BAF) imaging disclosed a central hyper autofluorescence area as well as a larger defect corresponding to the haemorrhage and the subretinal deposit. The LE was positive for a central deposit located under the RPE with hyper autofluorescence at BAF. Familiar history was unknown for ocular conditions and the clinical history was irrelevant for fever, inflammation, adenopathy, articular, neurological or respiratory conditions. The condition was diagnosed as choroidal neovascularization (CNV) secondary to Best's vitelliform dystrophy and a single intravitreal injection of aflibercept was performed under general anaesthesia. Genetic study revealed a likely pathogenic mutation c.874G&gt;C (p.Glu292Gln) in the BEST1 gene (missense change, not previously published) affecting a functional dominion. The subretinal bleeding and fluid resolved after one single injection of aflibercept and VA improved to 20/20. No recurrences have been observed during the subsequent five years in either eye.Conclusions: We report a case of CNV as first manifestation of a previously not reported mutation of Best's vitelliform dystrophy in a 9‐year‐old boy that was successfully treated with one single intravitreal injection of aflibercept.

The importance of having a relevant model system to investigate splicing modulation in the retina: The unforeseen cases of the intronic variants in RPE65 and IMPG2 genes

Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous disorders that can be caused by pathogenic variants in one of the more than 270 genes associated with IRDs. Among them, mutations in RPE65 can lead to Leber congenital amaurosis (LCA) whereas mutations in IMPG2 to vitelliform macular dystrophy (VMD).During my talk, I will provide evidence of the importance of employing the right cellular models to identify disease mechanism(s) and eventually evaluate suitable treatments. For this, I will highlight two intriguing examples of potential splicing defects studied by our group. Such defects are attractive for splicing modulation therapies using antisense oligonucleotides (AONs), a group of versatile molecules that can alter splicing by interacting with the target sequence(s) at pre‐mRNA level. Thus, characterizing the effect of a variant at the RNA level is instrumental to assess the applicability of AON‐based therapeutic intervention.We explored the effect of the homozygous variant c.11 + 5G&gt;A in RPE65 and a heterozygous complex allele consisting of c.3023‐15T&gt;A and c.3023G&gt;A (p.(Gly1008Asp)) in IMPG2. In silico predictions suggested that these variants lead to a splicing defect. To assess the pathogenic effect of these variants, splice reporter assays using midigenes were conducted in HEK293T cells. Initial results pointed towards a 124‐nt exon elongation for the RPE65 variant and an in‐frame deletion of 48‐nt at the beginning of exon 15 for the complex allele in IMPG2.To validate these results, blood cells from the patients harbouring these defects were reprogrammed to induced pluripotent stem cells (iPSCs). Subsequently, iPSCs were differentiated to the retinal cells in which these genes are endogenously expressed. For RPE65, iPSCs were differentiated into retinal pigment epithelium (RPE) cells (&gt;90 days differentiation) or, for IMPG2, into photoreceptor precursor cells (PPCs, 30 days differentiation). For the RPE65 variant, a cell specific effect was observed: while a clear exon elongation was observed in the midigene system, in RPE, the expression of the gene was highly reduced. In addition, no protein was detected and the patient‐derived cells showed differences compared to the control line. For IMPG2, the 48‐nt deletion was detected in a lower percentage in patient‐derived PPCs compared to the levels observed in the midigene system. However, aberrantly spliced IMPG2 transcripts were highly elevated in patient‐derived PPCs in comparison to control PPCs.Overall, our work shows the importance of having the right cellular context to determine the effect of genetic variants on splicing in the retina.

Multimodal imaging in fundus flavimaculatus with macular vitelliform lesion

We report a case of fundus flavimaculatus (FFM) with macular vitelliform lesion. The study was done in a center in eastern India. A 38-year-old male presented with painless diminution of vision. His best corrected visual acuity (BCVA) was 20/60 and 20/25 in the right and left eye, respectively. There were polymorphous, yellowish, mid-peripheral retinal flecks and foveal vitelliform lesions. Investigations were suggestive of FFM. We have described the various multimodal imaging modalities to differentiate FFM and vitelliform dystrophy. It is crucial to differentiate these diseases due to the difference in visual prognosis. We report a case of FFM with a foveal vitelliform lesion.

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 testing, clinical findings including best-corrected visual acuity (BCVA), choroidal neovascularization (CNV) rates, and electrophysiology parameters. 222 patients (127 males and 95 females) from 141 families were identified, harboring 69 BEST1 variants, including 22 novel variants. Mean age at presentation was 26.8 years (range 1.3-84.8 years) and most patients (61.5%) presented with a deterioration of central vision. Major funduscopic findings at presentation 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 LogMAR (20/47) for the right eye and 0.33 LogMAR (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 9.6 years. 37 patients (17.3%) were diagnosed with CNV over a mean follow-up period of 8.0 years (range 0-55 years). Eyes with CNV that received treatment with anti-VEGF had a better mean VA compared to eyes that were not treated with anti-VEGF (0.28 LogMAR (20/38) versus 0.62 LogMAR (20/83). The majority of eyes exhibited a hyperopic refractive error (185/235, 78.7%) and 13 patients (6.1%) were diagnosed with amblyopia. Among the three most common variants, p.A243V was associated with a later age of onset, a better age-adjusted VA and less advanced Gass stages compared to p.R218C and p.R218H. 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.

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.

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.

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

To study retinal microvascular parameters in patients with butterfly-shaped pattern dystrophy (BPD) and adult foveomacular vitelliform dystrophy (AFVD). 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. 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. 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.

The Retinal Phenotype Associated with the p.Pro101Thr BEST1 Variant

To describe the retinal phenotype associated with the p.Pro101Thr BEST1 variant. Retrospective, observational case series. Patients diagnosed with bestrophinopathies in which molecular genetic testing identified the p.Pro101Thr BEST1 as well as healthy carriers among their first-degree relatives. 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. Results of ophthalmic examinations and multimodal imaging features of retinal phenotypes. 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. 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. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Вителлиформная макулярная дистрофия и возрастная макулярная дегенерация: сходство и различия при их выявлении

Background. Adult-onset vitelliform macular dystrophy is one of the pathologies that successfully masks as age-related macular degeneration. Purpose. To assess the incidence of adult-onset vitelliform macular dystrophy and its clinical manifestations. Material and methods. We analyzed frequency cases of adult-onset vitelliform macular dystrophy among 1000 patients aged 40 years and older who applied with various eye complaints. Results. Adult-onset vitelliform macular dystrophy was found in 2 patients – men 43 and 66 years old. In the macular area of both eyes of the 1st patient, rounded yellow lesions in the foveola, local detachment of neuroepithelium, optical dense material deposit on the outer segments of photoreceptors were detected (vitelliruptive stage of adult-onset vitelliform macular dystrophy). On the left eye of the 2nd patient in the foveola, a single rounded yellow focus of 200 µm was determined, optical dense vitelliform material presence between the layers of the pigment epithelium and neuroepithelium without signs of choroidal neovascularization was detected (vitelliform stage of adult-onset vitelliform macular dystrophy). Conclusion. The incidence of adult-onset vitelliform macular dystrophy among patients with various ocular pathologies was 0.2 %. Morphological changes in the macula consist in presence of deposits of vitelliform material, localized between the layers of neuroepithelium and retinal pigment epithelium. Keywords: adult-onset vitelliform macular dystrophy; age-related macular degeneration; optical dense vitelliform material

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.

Adult-onset BEST1-Vitelliform Dystrophy Associated with Angioid Streak-like Changes in Two Siblings.

To describe the association between autosomal dominant Best disease and peripapillary angioid streak-like changes. Case report of two siblings. A 76-year-old Caucasian male was referred for evaluation of bilateral macular changes and worsening visual distortion over the preceding 2 years. Best corrected visual acuity (BCVA) measured 20/30 in the right eye and 20/80 in the left eye. Funduscopic examination revealed multifocal yellow lesions in the posterior pole that were hyper-autofluorescent on short-wavelength excitation and corresponded with subretinal hyperreflective material on optical coherence tomography. The posterior pole examination was interesting due to the juxtapapillary involvement of the vitelliform lesions as well as the presence of bilateral peripapillary angioid streak-like changes despite no history of conditions associated with angioid streaks. On further workup, an electro-oculogram revealed reduced Arden ratios and a known heterozygous missense mutation in BEST1 (c.903T>G; p.D301E) was found. The patient's 69-year-old younger brother was brought in and found to have a remarkably similar phenotype, including the presence of angioid streak-like changes associated with the same BEST1 mutation. These two cases demonstrate the possibility of late-onset multifocal vitelliform disease due to dominantly inherited BEST1. A consistent phenotype in this family with macular lesions extending into the peripapillary region, associated with angioid streak-like changes, suggests susceptibility of this region to changes in dominant BEST1-vitelliform macular dystrophy.

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

BackgroundBest 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 presentationA 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.ConclusionsThis 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.

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.