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Objective To report the development of focal bullous retinal detachments (bullae) in dogs with different forms of progressive retinal atrophy (PRA). Procedures Dogs with three distinct forms of PRA (PRA-affected Whippets, German Spitzes and CNGB1-mutant Papillon crosses) were examined by indirect ophthalmoscopy and spectral domain optical coherence tomography (SD-OCT). Retinal bullae were monitored over time. One CNGB1-mutant dog was treated with gene augmentation therapy. The canine BEST1 gene coding region and flanking intronic sequence was sequenced in at least one affected dog of each breed. Results Multiple focal bullous retinal detachments (bullae) were identified in PRA-affected dogs of all three types. They developed in 4 of 5 PRA-affected Whippets, 3 of 8 PRA-affected Germans Spitzes and 15 of 20 CNGB1-mutant dogs. The bullae appeared prior to marked retinal degeneration and became less apparent as retinal degeneration progressed. Bullae were not seen in any heterozygous animals of any of the types of PRA. Screening of the coding region and flanking intronic regions of the canine BEST1 gene failed to reveal any associated pathogenic variants. Retinal gene augmentation therapy in one of the CNGB1-mutant dogs appeared to prevent formation of bullae. Conclusions Retinal bullae were identified in dogs with three distinct forms of progressive retinal atrophy. The lesions develop prior to retinal thinning. This clinical change should be monitored for in dogs with PRA.

Purpose We describe the long-term follow-up of a patient with multifocal Best disease with chronic bilateral serous macular detachment and unusual peripheral findings associated with a novel mutation in the BEST1 gene. Methods Case report. Results A 59-year-old white woman was referred for an evaluation of her macular findings in 1992. There was a family history of Best disease in the patient's mother and a male sibling. Her medical history was unremarkable. Best-corrected visual acuity was 20/20 in her right eye and 20/25 in her left eye. The anterior segment examination was normal in both eyes. Funduscopic examination showed multifocal hyperautofluorescent vitelliform deposits with areas of subretinal fibrosis in both eyes. An electrooculogram showed Arden ratios of 1.32 in the right eye and 1.97 in the left eye. Ultra-widefield color and fundus autofluorescence imaging showed degenerative retinal changes in areas throughout the entire fundus in both eyes. Optical coherence tomography, including annual eye-tracked scans from 2005 to 2016, showed persistent bilateral serous macular detachments. Despite chronic foveal detachment, visual acuity was 20/25 in her right eye and 20/40 in her left eye, 24 years after initial presentation. Genetic testing showed a novel c.238T>A (p.Phe80Ile) missense mutation in the BEST1 gene. Conclusion Some patients with Best disease associated with chronic serous macular detachment can maintain good visual acuity over an extended follow-up. To our knowledge, this is the first report of Best disease associated with this mutation in the BEST1 gene.

Best disease (BD), also known as vitelliform macular dystrophy, is an inherited disease of the central retina caused by more than 300 pathogenic variants in the BEST1 gene. The phenotype of BD is variable, and there are just a few reports on the histopathology of eyes from donors with BD. Here, we describe the histopathological comparison of donor’s eyes from two patients with BD. Eyes obtained from 85-year-old (donor 1) and 65-year-old (donor 2) donors were fixed within 25 h postmortem. Perifoveal and peripheral retinal regions were processed for histology and immunocytochemistry using retinal-specific and retinal pigment epithelium (RPE)-specific antibodies. Three age-matched normal eyes were used as controls. DNA was obtained from donor blood samples. Sequence analysis of the entire BEST1 coding region was performed and identified a c.886A > C (p.Asn296His) variant in donor 1 and a c.602T > C (p.Ile201Thr) variant in donor 2; both mutations were heterozygous. Fundus examination showed that donor 1 displayed a macular lesion with considerable scarring while donor 2 displayed close to normal macular morphology. Our studies of histology and molecular pathology in the perifovea and periphery of these two BD donor eyes revealed panretinal abnormalities in both photoreceptors and RPE cellular levels in the periphery; donor 1 also displayed macular lesion. Our findings confirm the phenotypic variability of BD associated with BEST1 variants.

Purpose The aim of this study was to describe the genetic and clinical characteristics of Chinese patients with autosomal recessive bestrophinopathy (ARB). Methods This study presents a retrospective observational case series. Twenty-one ARB patients and 25 clinically healthy family members were recruited. The coding regions and adjacent intronic regions of BEST1 were analysed via Sanger sequencing. Clinical examinations, including ultrasound biomicroscopy, A-scan, optical coherence tomography, fundus autofluorescence, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA) and visual electrophysiology, were reviewed. Results Six novel mutations (c.380C>T, p.T127M; c.397A>G, p.N133D; c.500A>G, p.E167G; c.817G>A, p.V273M; c.174_176del, p.Q58del; and c.950_955del, p.S318_L319) and 8 previously reported mutations were identified. The p.R255W mutation had the highest frequency in our cohort. Twenty patients had serous retinal detachment with multifocal subretinal vitelliform deposits in the posterior poles. One patient exhibited chorioretinal atrophy. FFA revealed peripheral vascular leakage in 10 patients, and ICGA revealed hyperfluorescent spots in 8 patients. Visual electrophysiology was abnormal in all patients. Fifteen patients with angle closure (AC) or angle-closure glaucoma (ACG) had shallower anterior chambers and shorter axial lengths than the patients with open angle, contributing to their risk of developing AC/ACG. One patient developed AC during the 7-year follow-up period. The misdiagnosis and missed rates were 35.3% and 58.8%, respectively. Conclusion The six novel mutations and high frequency of p.R255W suggest ethnical differences in the BEST1 mutation spectrum among Chinese patients. BEST1 gene screening and detailed clinical examinations help establishing a diagnosis of ARB. Clinical evaluations of the risk of developing AC/ACG are recommended for ARB patients.

Background Autosomal recessive bestrophinopathy is part of the diverse spectrum of retinal diseases caused by mutations in the BEST1 gene. Methods A case report. Results We present a case that highlights the classic retinal findings of autosomal recessive bestrophinopathy with an emphasis on modern multimodal imaging. Conclusion We describe modern multimodal imaging in an individual with a BEST1 gene mutation and clinical findings consistent with an autosomal recessive bestrophinopathy.

Mutations in BEST1 cause several phenotypes including autosomal dominant (AD) Best vitelliform macular dystrophy type 2 (BVMD), AD vitreo-retino-choroidopathy (ADVIRC), and retinitis pigmentosa-50 (RP50). A rare subtype of Bestrophinopathy exists with biallelic mutations in BEST1. Its frequency is estimated to be 1/1,000,000 individuals. Here we report 6 families and searched for a genotype-phenotype correlation. All patients were referred due to reduced best-corrected visual acuity (BCVA), ranging from 0.1/10 to 3/10. They all showed vitelliform lesions located at the macula, sometimes extending into the midperiphery, along the vessels and the optic disc. Onset of the disease varied from the age of 3 to 25 years. Electrooculogram (EOG) revealed reduction in the EOG light rise in all patients. Molecular analysis revealed previously reported mutations p.(E35K), (E35K), p.(L31M), (L31M), p.(R141H), (A195V), p.(R202W), (R202W), and p.(Q220*), (Q220*) in five families. One family showed a novel mutation: p.(E167G), (E167G). All mutations were heterozygous in the parents. In one family, heterozygous children showed various reductions in the EOG light rise and autofluorescent deposits. Autosomal recessive Bestrophinopathy (ARB), although rare, can be recognized by its phenotype and should be validated by molecular analysis. Genotype-phenotype correlations are difficult to establish and will require the analysis of additional cases.

Autosomal recessive bestrophinopathy (ARB) is a retinal disease caused by biallelic mutations of the BEST1 gene. It has a variable phenotype with white flecks in the retina, multifocal yellow subretinal deposits, macular edema, choroidal neovascularization, hyperopia, and electrophysiological abnormalities. We describe a family with ARB and multigenerational inheritance.Three generations of a Middle Eastern family (a woman, one son, and two grandchildren) were evaluated by our ocular genetics team. Eye examinations, fundus photography, and optical coherence tomography (OCT) were performed. Genetic testing was obtained on examined patients and available relatives.The proband demonstrated counting fingers vision and white flecks in the retinal periphery, with macular subretinal fluid (SRF), loss of outer photoreceptor segments, and epiretinal membrane (ERM) on OCT. Two grandchildren demonstrated decreased vision, multifocal yellow subretinal deposits, and SRF on OCT. Two grandchildren examined elsewhere were reported to be similarly affected. A son's examination was normal except for extra-macular scars (from prior toxoplasmosis) and ERM. Genetic history revealed consanguinity and testing showed homozygosity for BEST1 mutations in the proband and two grandchildren c.473GA/c.473GA (R218H /R218H) and heterozygosity in two unaffected sons and two unaffected daughters-in-law c.473GA/WT (p.R218H/WT).We present a consanguineous family of five affected individuals with ARB and four confirmed carriers. Their pedigree was consistent with dominant inheritance and incomplete penetrance. Genetic testing clarified the diagnosis and mode of inheritance. We describe the genetic findings, phenotypic variability, and recessive inheritance of an often dominantly inherited mutation as notable elements in their case.

Purpose Abnormalities in the BEST1 gene have recently been recognised as causing autosomal recessive bestrophinopathy (ARB). ARB has been noted to have a variable phenotypic presentation, distinct from that of autosomal dominant Best vitelliform macular dystrophy (BVMD). Both conditions are associated with deposits in the retina, a reduced or absent electro-oculography (EOG) light rise, and the risk of developing angle-closure glaucoma. Herein, we describe the clinical and genetic characteristics of a young male diagnosed with ARB associated with angle-closure glaucoma resulting from a novel homozygous mutation in BEST1. Methods All research involved in this case adhered to the tenets of the Declaration of Helsinki. The proband underwent slitlamp examination, retinal autofluorescence imaging and optical coherence tomography after presenting with deteriorating vision. The findings prompted genetic testing with bi-directional DNA sequencing of coding and flanking intronic regions of BEST1. The proband’s family members were subsequently screened. Results A provisional diagnosis of ARB was made based on the findings of subretinal and schitic lesions on fundoscopy and retinal imaging, together with abnormal EOG and electroretinography. Genetic testing identified a novel homozygous mutation in BEST1, c.636+1 G>A. Family members were found to carry one copy of the mutation and had no clinical or electrophysiological evidence of disease. The proband was additionally diagnosed with angle-closure glaucoma requiring topical therapy, peripheral iridotomies and phacoemulsification. Conclusions Phenotypic overlap, reduced penetrance, variable expressivity and the ongoing discovery of new forms of bestrophinopathies add to the difficulty in distinguishing these retinal diseases. All patients diagnosed with ARB or BVMD should be examined for narrow angles and glaucoma, given their frequent association with these conditions.

A 1-year-old Australian Shepherd (AS) was presented for a routine hereditary eye examination. During the examination multiple raised, brown to orange lesions were noted in the fundus, which could not be attributed to a known retinal disease in this breed. As they clinically most closely resembled canine multifocal retinopathy (cmr) and no indication of an acquired condition was found, genetic tests for BEST1 gene mutations were performed. These showed the dog to be homozygous for the cmr1 (C73T/R25X) gene defect. Furthermore, ultrasound (US), electroretinography (ERG), and optical coherence tomography were performed, confirming changes typical for cmr. Subsequently, the AS pedigree members were genetically and clinically tested, demonstrating autosomal recessive inheritance with no clinical symptoms in carrier animals, as was previously described for cmr. To our knowledge, this is the first reported case of canine multifocal retinopathy in the AS breed. Further investigations are under way.

The purpose of this study was to investigate the BEST1 gene mutations in Chinese patients with Best vitelliform macular dystrophy (BVMD).Twenty-six subjects from 7 Chinese families with BVMD and 100 unrelated healthy Chinese subjects without a family history of BVMD were screened for mutations in the BEST1 gene by direct sequencing. The subjects underwent complete ophthalmologic examination and BEST1 gene screening.Six novel missense mutations (Thr2Asn, Leu75Phe, Ser144Asn, Arg255Trp, Pro297Thr, and Asp301Gly) and 1 previously reported mutation (Arg218Cys) were identified. Each family was found to have a unique BEST1 mutation that segregated with the disease. Two of the six novel mutations are located within the four previously reported common mutation clusters within the BEST1 gene. One family with patients having homozygous Leu75Phe mutations did not have the more severe BVMD phenotype. None of the patients with mutations was identified among the 100 healthy control subjects.A large number of unique novel missense mutations was found in Chinese patients with BVMD, suggesting considerable interethnic differences between the mutation sites in the BEST1 gene in different populations. The few truncating BEST1 mutations and the lack of a more severe phenotype in homozygous patients suggest that the missense BEST1 mutation may produce a dominant negative effect on wild-type BEST1 gene.

Contains fulltext : 79544.pdf (Publisher’s version ) (Closed access) PURPOSE: To describe the phenotype of Best vitelliform macular dystrophy (BVMD) and to evaluate genotype-phenotype and histopathologic correlations. METHODS: Retrospective analysis of patients with BVMD who underwent an extensive ophthalmic examination, including best-corrected Snellen visual acuity, fundus examination by indirect ophthalmoscopy, fundus photography, fundus autofluorescence, optical coherence tomography, fundus fluorescein angiography, and electrooculography. In addition, molecular genetic analysis of the BEST1 gene was performed in all patients. RESULTS: We examined 40 eyes of 20 patients with BVMD. Sixteen eyes (40%) had a well-defined BVMD stage, whereas 18 eyes displayed characteristics attributable to different stages. Six eyes had an atypical form of BVMD. Fundus autofluorescence and optical coherence tomography frequently detected abnormalities that were not visible on ophthalmoscopy. All patients carried a mutation in the BEST1 gene. Molecular genetic analysis identified 8 different BEST1 mutations in 15 families, including 2 novel mutations (p.Gly299Ala and p.Ile3Thr). Genotype-phenotype correlation was limited, as we observed a broad phenotypic range in association with a single BEST1 mutation. However, the p.Ala243Val seems to cause a mild and relatively invariable BVMD phenotype. CONCLUSION: A broad phenotypic variability may be observed in BVMD, even with a single BEST1 mutation. Fundus autofluorescence and optical coherence tomography are valuable noninvasive imaging techniques for phenotyping and follow-up of BVMD patients.

To describe the genotype and phenotype of patients with autosomal recessive bestrophinopathy (ARB), and heterozygous carriers.The members of three unrelated ARB families were investigated. Molecular genetic analysis was performed on 11 members of these families. Ten members were examined clinically; including visual acuity, slit-lamp examination, biomicroscopy, fundus photography, and Goldmann applanation tonometry. Measurements were also made of the anterior chamber depth and axial length, and optical coherence tomography (OCT), electrooculography (EOG), and full-field electroretinography (full-field ERG) were performed. Multifocal electroretinography (mfERG) was performed on eight members of these families.Two novel combinations of missense mutations in the BEST1 gene were identified: p.R141H/p.M325T in three patients with ARB in two unrelated Norwegian families, and p.R141H/p.I201T was found in an ARB patient in a Swedish family. All four patients with ARB had clinical and electrophysiological features of ARB. All the heterozygous carriers of the p.R141H mutation were clinically normal, and showed normal OCT, EOG and full-field ERG findings, but had mildly abnormal mfERG results. Only one heterozygous carrier of the p.M325T mutation was studied and he was clinically normal, showing normal OCT and full-field ERG results, but subnormal EOG and mfERG findings. The heterozygous carrier of the p.I201T mutation was clinically normal, showing normal OCT, EOG and full-field ERG results, but subnormal mfERG results.We have shown that the two novel combinations of compound heterozygous mutations p.R141H/p.M325T and p.R141H/p.I201T in the BEST1 gene can also lead to the ARB phenotype.

Human bestrophinopathies, a group of inherited retinal disorders caused by mutations in BEST1, are one of the most common early-onset macular dystrophies still considered incurable. The disease is usually diagnosed in early childhood or adolescence, and primarily affects macular region leading to major declines in central vision later in life. Canine multifocal retinopathy, a spontaneous animal model of BEST1-associated retinopathies in man, captures the full spectrum of clinical and molecular features observed in human disease, including the salient predilection of lesions to the canine fovea-like region, and constitutes an important translational model for development and testing of therapeutic strategies. We have previously shown that rAAV2-mediated BEST1 gene delivery controlled by human VMD2 promoter specifically targets RPE cells, and is well tolerated in the wt canine retina. Here, we demonstrate that rAAV2-mediated BEST1 gene augmentation reverses the characteristic BEST1 lesions and pathology in cmr models up to 23 months post-injection. The talk will highlight the natural history of the disease and elaborate on the potential of rAAV2-mediated BEST1 gene replacement therapy for prevention as well as reversal of disease.

Aims: It was the aim of this study to report on a patient in whom a novel mutation in the BEST1 gene was responsible for unilateral vitelliform phenotype in autosomal recessive bestrophinopathy (ARB). Methods: An 8-year-old young girl (proband) with unilateral vitelliform phenotype underwent a complete ophthalmologic examination at baseline (time of diagnosis) and 2 years later. Genomic DNA was extracted to look for BEST1 gene mutations in the patient and her parents. Results: Fundus autofluorescence imaging and spectral-domain optical coherence tomography showed unchanged findings in the right eye over the 2-year follow-up period. Conversely, both fundus autofluorescence imaging and spectral-domain optical coherence tomography showed a partial reabsorption of the hyper-autofluorescent/hyper-reflective subretinal material in the left macula over the 2-year follow-up period. On BEST1 gene analysis, the patient presented a novel mutation c.535_537delAAC (p.Asn179del) in homozygous condition; interestingly, despite the absence of parents' consanguinity, both the father and mother showed the same novel mutation in heterozygous condition. Conclusion: This case of unilateral vitelliform phenotype further supports the notion that ARB represents a disease spectrum in terms of severity, age at onset and heritability. Copyright (C) 2012 S. Karger AG, Basel Aims: It was the aim of this study to report on a patient in whom a novel mutation in the BEST1 gene was responsible for unilateral vitelliform phenotype in autosomal recessive bestrophinopathy (ARB). Methods: An 8-year-old young girl (proband) with unilateral vitelliform phenotype underwent a complete ophthalmologic examination at baseline (time of diagnosis) and 2 years later. Genomic DNA was extracted to look for BEST1 gene mutations in the patient and her parents. Results: Fundus autofluorescence imaging and spectral-domain optical coherence tomography showed unchanged findings in the right eye over the 2-year follow-up period. Conversely, both fundus autofluorescence imaging and spectral-domain optical coherence tomography showed a partial reabsorption of the hyper-autofluorescent/hyper-reflective subretinal material in the left macula over the 2-year follow-up period. On BEST1 gene analysis, the patient presented a novel mutation c.535_537delAAC (p.Asn179del) in homozygous condition; interestingly, despite the absence of parents' consanguinity, both the father and mother showed the same novel mutation in heterozygous condition. Conclusion: This case of unilateral vitelliform phenotype further supports the notion that ARB represents a disease spectrum in terms of severity, age at onset and heritability. Copyright (C) 2012 S. Karger AG, Basel

Aims: To describe clinical and genetic findings in an Italian family affected by Best disease. Methods: Five related patients underwent a complete ophthalmological assessment; genetic testing was performed by single-strand conformation polymorphism analysis and direct sequencing of the BEST1 gene. Results: In three of five family members, the sequence analysis of the BEST1 gene revealed a single Phe-to-Leu transition at nucleotide 305 associated with clinical evidence of Best disease. Surprisingly, the electrooculogram was normal in all affected patients. Conclusion: This study reveals a de novo mutation in the BEST1 gene never described before, sustaining the autosomal-dominant pattern of inheritance of the disease. Clinical evaluation showed phenotypic variability between affected members. In addition, these data suggest that a normal electro-oculography (EOG) does not rule out a diagnosis of Best disease, supporting instead the crucial role of molecular analysis. Aims: To describe clinical and genetic findings in an Italian family affected by Best disease. Methods: Five related patients underwent a complete ophthalmological assessment; genetic testing was performed by single-strand conformation polymorphism analysis and direct sequencing of the BEST1 gene. Results: In three of five family members, the sequence analysis of the BEST1 gene revealed a single Phe-to-Leu transition at nucleotide 305 associated with clinical evidence of Best disease. Surprisingly, the electrooculogram was normal in all affected patients. Conclusion: This study reveals a de novo mutation in the BEST1 gene never described before, sustaining the autosomal-dominant pattern of inheritance of the disease. Clinical evaluation showed phenotypic variability between affected members. In addition, these data suggest that a normal electro-oculography (EOG) does not rule out a diagnosis of Best disease, supporting instead the crucial role of molecular analysis.