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.

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.

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.

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®.

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.

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.

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.

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.

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.

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

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

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

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.

ADULT-ONSET BEST1 -VITELLIFORM DYSTROPHY ASSOCIATED WITH ANGIOID STREAK-LIKE CHANGES IN TWO SIBLINGS.

BACKGROUND/PURPOSE: To describe the association between autosomal dominant Best disease and peripapillary angioid streak-like changes. METHODS: Case report of two siblings. RESULTS: A 76-year-old White man was referred for evaluation of bilateral macular changes and worsening visual distortion over the preceding 2 years. Best-corrected visual acuity 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 hyperautofluorescent on short-wavelength excitation and corresponded with subretinal hyperreflective material on optical coherence tomography. The posterior pole examination was interesting because of the juxtapapillary involvement of the vitelliform lesions and the presence of bilateral peripapillary angioid streak-like changes despite no history of conditions associated with angioid streaks. On further workup, an electrooculogram 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. CONCLUSION: 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.

Photoreceptor Function and Structure in Autosomal Dominant Vitelliform Macular Dystrophy Caused by BEST1 Mutations.

Purpose: The purpose of this study was to evaluate rod and cone function and outer retinal structure within macular lesions, and surrounding extralesional areas of patients with autosomal dominant Best vitelliform macular dystrophy caused by BEST1 mutations. Methods: Seventeen patients from seven families were examined with dark- and light-adapted chromatic perimetry and optical coherence tomography. Subsets of patients had long-term follow-up (14-22 years, n = 6) and dark-adaptation kinetics measured (n = 5). Results: Within central lesions with large serous retinal detachments, rod sensitivity was severely reduced but visual acuity and cone sensitivity were relatively retained. In surrounding extralesional areas, there was a mild but detectable widening of the subretinal space in some patients and some retinal areas. Available evidence was consistent with subretinal widening causing slower dark-adaptation kinetics. Over long-term follow-up, some eyes showed formation of de novo satellite lesions at retinal locations that years previously demonstrated subretinal widening. A subclinical abnormality consisting of a retina-wide mild thickening of the outer nuclear layer was evident in many patients and thickening increased in the subset of patients with long-term follow-up. Conclusions: Outcome measures for future clinical trials should include evaluations of rod sensitivity within central lesions and quantitative measures of outer retinal structure in normal-appearing regions surrounding the lesions.

Photoreceptor and Retinal Pigment Epithelium Relationships in Eyes With Vitelliform Macular Dystrophy Revealed by Multimodal Adaptive Optics Imaging.

Purpose: To assess the structure of cone photoreceptors and retinal pigment epithelial (RPE) cells in vitelliform macular dystrophy (VMD) arising from various genetic etiologies. Methods: Multimodal adaptive optics (AO) imaging was performed in 11 patients with VMD using a custom-assembled instrument. Non-confocal split detection and AO-enhanced indocyanine green were used to visualize the cone photoreceptor and RPE mosaics, respectively. Cone and RPE densities were measured and compared across BEST1-, PRPH2-, IMPG1-, and IMPG2-related VMD. Results: Within macular lesions associated with VMD, both cone and RPE densities were reduced below normal, to 37% of normal cone density (eccentricity 0.2 mm) and to 8.4% of normal RPE density (eccentricity 0.5 mm). Outside of lesions, cone and RPE densities were slightly reduced (both to 92% of normal values), but with high degree of variability in the individual measurements. Comparison of juxtalesional cone and RPE measurements (<1 mm from the lesion edge) revealed significant differences in RPE density across the four genes (P < 0.05). Overall, cones were affected to a greater extent than RPE in patients with IMPG1 and IMPG2 pathogenic variants, but RPE was affected more than cones in BEST1 and PRPH2 VMD. This trend was observed even in contralateral eyes from a subset of five patients who presented with macular lesions in only one eye. Conclusions: Assessment of cones and RPE in retinal locations outside of the macular lesions reveals a pattern of cone and RPE disruption that appears to be gene dependent in VMD. These findings provide insight into the cellular pathogenesis of disease in VMD.

Clinical and visual electrophysiological characteristics of vitelliform macular dystrophies in the first decade of life.

Purpose: To evaluate patterns of pediatric vitelliform macular dystrophy (PVMD). Methods: This is a retrospective analysis of Indian children with vitelliform macular dystrophy (VMD) presenting within the first decade of life. Records were evaluated for clinical findings, family screening, and investigative findings including optical coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinogram (ERG) and electrooculogram (EOG). Electrophysiology was scrutinized and audited for acquisition and interpretation errors. Findings on follow-up were also recorded. Results: 46 eyes of 24 patients were included. Mean age at presentation was 7.17 ± 2.17 years. Mean follow-up duration was 1.55 ± 1.69 years. Best disease was the commonest type of VMD detected (21 patients), while autosomal recessive bestrophinopathy was seen in three cases. Mean logMAR BCVA was 0.364 which decreased to 0.402 on follow-up. Hyperopia was noted in 29 out of 46 eyes (mean being +3.87 D, range ebing +0.75 to +8.75 D). Four eyes of four children had choroidal neovascular membrane at presentation, while another child developed while in follow-up. Solid type subretinal deposit was the commonest OCT finding (n = 29/38) and central hyper FAF was the commonest pattern (n = 18/32). EOG was available for review in 32 eyes, but was unreliable in 11 eyes. Seven eyes demonstrated complete absence of light rise on EOG. Conclusion: PVMD can present in advanced forms. Progression to complications with loss of visual acuity can happen within the first decade of life. EOG shows grossly suppressed waveforms in the light phase in a large number of such children.

Identification of a Complex Allele in IMPG2 as a Cause of Adult-Onset Vitelliform Macular Dystrophy.

Purpose: Inherited retinal diseases are a group of clinically and genetically heterogeneous disorders with approximately 270 genes involved. IMPG2 is associated with adult-onset vitelliform macular dystrophy. Here, we investigated two unrelated patients with vitelliform macular dystrophy to identify the underlying genetic cause. Methods: Whole-exome sequencing identified a putative causal complex allele consisting of c.3023-15T>A and c.3023G>A (p.(Gly1008Asp)) in IMPG2 in both individuals. To assess its effect, in vitro splice assays in HEK293T and further characterization in patient-derived photoreceptor precursor cells (PPCs) were conducted. Results: The results of the midigene splice assays in HEK293T showed that the complex allele causes a variety of splicing defects ranging from a small deletion to (multiple-)exon skipping. This finding was further validated using patient-derived PPCs that showed a significant increase of out-of-frame transcripts lacking one or multiple exons compared to control-derived PPCs. Overall, control PPCs consistently showed low levels of aberrantly spliced IMPG2 transcripts that were highly elevated in patient-derived PPCs. These differences were even more obvious upon inhibition of nonsense-mediated decay with cycloheximide. Conclusions: We report a heterozygous complex allele in IMPG2 causative for adult-onset vitelliform macular dystrophy in two unrelated individuals with mild visual loss and bilateral vitelliform lesions. The predicted causal missense mutation c.3023G>A, located in the consensus splice acceptor site, enhances the splicing effect of the upstream variant c.3023-15T>A, leading to the generation of aberrant transcripts that decrease the full-length IMPG2 levels. These results suggest a haploinsufficiency mechanism of action and highlight the complementarity of using different models to functionally assesses splicing defects.