ABSTRACT
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.
Subject(s)
Electroretinography , Eye Proteins , Microtubule-Associated Proteins , Tomography, Optical Coherence , Visual Acuity , Vitelliform Macular Dystrophy , Humans , Male , Female , Tomography, Optical Coherence/methods , Adult , Middle Aged , Eye Proteins/genetics , Visual Acuity/physiology , Vitelliform Macular Dystrophy/genetics , Vitelliform Macular Dystrophy/physiopathology , Vitelliform Macular Dystrophy/diagnosis , Microtubule-Associated Proteins/genetics , Visual Fields/physiology , China/epidemiology , Young Adult , Visual Field Tests , Pedigree , Adolescent , Phenotype , Mutation , Macular Degeneration/genetics , Macular Degeneration/diagnosis , Macular Degeneration/physiopathology , Asian People/genetics , Aged , East Asian PeopleABSTRACT
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.
Subject(s)
Bestrophins , Electroretinography , Visual Acuity , Vitelliform Macular Dystrophy , Humans , Vitelliform Macular Dystrophy/genetics , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/physiopathology , Male , Female , Retrospective Studies , Child , Visual Acuity/physiology , Adult , Bestrophins/genetics , Middle Aged , Child, Preschool , Adolescent , Aged , Young Adult , Aged, 80 and over , Infant , Tomography, Optical Coherence , Pedigree , Fluorescein Angiography , Choroidal Neovascularization/genetics , Choroidal Neovascularization/diagnosis , Choroidal Neovascularization/physiopathology , Mutation , ElectrooculographyABSTRACT
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.
Subject(s)
Retinal Dystrophies , Vitelliform Macular Dystrophy , Humans , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/genetics , Vitelliform Macular Dystrophy/pathology , Angiotensin Receptor Antagonists , Chloride Channels/genetics , Eye Proteins/genetics , Pedigree , DNA Mutational Analysis , Angiotensin-Converting Enzyme Inhibitors , Bestrophins/genetics , Phenotype , Mutation , Tomography, Optical CoherenceABSTRACT
Best Vitelliform Macular Dystrophy (BVMD) is a dominantly inherited retinal disease caused by dominant variants in the BEST1 gene. The original classification of BVMD is based on biomicroscopy and color fundus photography (CFP); however, advancements in retinal imaging provided unique structural, vascular, and functional data and novel insights on disease pathogenesis. Quantitative fundus autofluorescence studies informed us that lipofuscin accumulation, the hallmark of BVMD, is unlikely to be a primary effect of the genetic defect. It could be due to a lack of apposition between photoreceptors and retinal pigment epithelium in the macula with subsequent accumulation of shed outer segments over time. Optical Coherence Tomography (OCT) and adaptive optics imaging revealed that vitelliform lesions are characterized by progressive changes in the cone mosaic corresponding to a thinning of the outer nuclear layer and then disruption of the ellipsoid zone, which are associated with a decreased sensitivity and visual acuity. Therefore, an OCT staging system based on lesion composition, thus reflecting disease evolution, has been recently developed. Lastly, the emerging role of OCT Angiography proved a greater prevalence of macular neovascularization, the majority of which are non-exudative and develop in late disease stages. In conclusion, effective diagnosis, staging, and clinical management of BVMD will likely require a deep understanding of the multimodal imaging features of this disease.
Subject(s)
Macula Lutea , Vitelliform Macular Dystrophy , Humans , Vitelliform Macular Dystrophy/diagnostic imaging , Vitelliform Macular Dystrophy/genetics , Retina/pathology , Retinal Pigment Epithelium/pathology , Macula Lutea/pathology , Tomography, Optical Coherence/methods , Fluorescein Angiography/methods , Multimodal Imaging , Bestrophins/geneticsABSTRACT
PURPOSE: To describe the retinal phenotype associated with the p.Pro101Thr BEST1 variant. DESIGN: Retrospective, observational case series. PARTICIPANTS: Patients diagnosed with bestrophinopathies in which molecular genetic testing identified the p.Pro101Thr BEST1 as well as healthy carriers among their first-degree relatives. METHODS: Medical records were reviewed to obtain data on family history and ophthalmic examinations, including retinal imaging. The imaging protocol included OCT and fundus autofluorescence using Spectralis HRA + OCT (Heidelberg Engineering). Genetic analysis was performed by next-generation sequencing. MAIN OUTCOME MEASURES: Results of ophthalmic examinations and multimodal imaging features of retinal phenotypes. RESULTS: The c.301C>A, p.Pro101Thr BEST1 missense variant was identified as the causative variant in 8 individuals (all men) from 5 families, accounting for 13% of cases (8/61) and 10% of pathogenic alleles (9/93) in our cohort of patients affected by bestrophinopathies. Seven individuals (14 eyes) had the variant in heterozygous status: all eyes had a hyperopic refractive error (median spherical equivalent of + 3.75 diopters [D]) and 4 individuals had a macular dystrophy with mildly reduced visual acuity (median of 20/25 Snellen), whereas the other 3 were asymptomatic carriers. On multimodal retinal imaging, 5 (36%) out of 14 eyes had subclinical bestrophinopathy, 4 (29%) had typical findings of adult-onset foveomacular vitelliform dystrophy (AOFVD), and the remaining 5 (36%) displayed a pattern dystrophy-like phenotype. Follow-up data were available for 6 subjects, demonstrating clinical stability up to 11 years, in both subclinical and clinical forms. An additional patient with autosomal recessive bestrophinopathy was found to harbor the p.Pro101Thr variant in homozygosity. CONCLUSIONS: The p.Pro101Thr BEST1 variant is likely a frequent cause of bestrophinopathy in the Italian population and can result in autosomal dominant macular dystrophies with incomplete penetrance and mild clinical manifestations as well as autosomal recessive bestrophinopathy. The spectrum of autosomal dominant maculopathy includes the typical AOFVD and a pattern dystrophy-like phenotype. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Subject(s)
Eye Diseases, Hereditary , Retinal Diseases , Retinal Dystrophies , Vitelliform Macular Dystrophy , Adult , Male , Humans , Retrospective Studies , Mutation , Pedigree , DNA Mutational Analysis , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/genetics , Vitelliform Macular Dystrophy/pathology , Phenotype , Bestrophins/geneticsABSTRACT
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.
Subject(s)
Vitelliform Macular Dystrophy , Female , Humans , Middle Aged , Bestrophins/genetics , Extracellular Matrix Proteins/genetics , Eye Proteins/genetics , Genetic Testing , Mutation , Phenotype , Proteoglycans/genetics , Retina/pathology , Tomography, Optical Coherence , Vision Disorders , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/geneticsABSTRACT
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.
Subject(s)
Choroid Neoplasms , Nevus, Pigmented , Nevus , Skin Neoplasms , Vitelliform Macular Dystrophy , Male , Humans , Aged , Vitelliform Macular Dystrophy/complications , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/genetics , Retinal Pigment Epithelium/pathology , Choroid Neoplasms/diagnosis , Choroid Neoplasms/pathology , Nevus, Pigmented/pathology , Tomography, Optical Coherence/methods , Skin Neoplasms/pathology , BestrophinsABSTRACT
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.
Subject(s)
Cataract , Corneal Diseases , Eye Abnormalities , Microphthalmos , Vitelliform Macular Dystrophy , Humans , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/genetics , Bestrophins/genetics , Microphthalmos/diagnosis , Microphthalmos/genetics , Mutation , Pedigree , Phenotype , Eye Proteins/genetics , Eye Abnormalities/diagnosis , Eye Abnormalities/genetics , Cataract/diagnosis , Cataract/genetics , Tomography, Optical CoherenceABSTRACT
Vitelliform lesions (VLs) are associated with a wide array of macular disorders but are the result of one common pathway: retinal pigment epithelium (RPE) impairment and phagocytic dysfunction. VLs are defined by the accumulation of yellowish subretinal material. In the era of multimodal advanced retinal imaging, VLs can be further characterized by subretinal hyperreflectivity with optical coherence tomography and hyperautofluorescence with fundus autofluorescence. VLs can be the result of genetic or acquired retinal diseases. In younger patients, VLs usually occur in the setting of Best disease. Additional genetic causes of VL include pattern dystrophy or adult-onset vitelliform macular dystrophy. In older patients, acquired VLs can be associated with a broad spectrum of etiologies, including tractional, paraneoplastic, toxic, and degenerative disorders. The main cause of visual morbidity in eyes with VLs is the onset of macular atrophy and macular neovascularization. Histopathological studies have provided new insights into the location, nature, and lifecycle of the vitelliform material comprised of melanosomes, lipofuscin, melanolipofuscin, and outer segment debris located between the RPE and photoreceptor layer. Impaired phagocytosis by the RPE cells is the unifying pathway leading to VL development. We discuss and summarize the nature, pathogenesis, multimodal imaging characteristics, etiologies, and natural course of vitelliform maculopathies.
Subject(s)
Vitelliform Macular Dystrophy , Adult , Humans , Aged , Fluorescein Angiography/methods , Vitelliform Macular Dystrophy/etiology , Vitelliform Macular Dystrophy/genetics , Retinal Pigment Epithelium/pathology , Fundus Oculi , Tomography, Optical Coherence/methodsABSTRACT
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.
Subject(s)
Color Vision Defects , Vitelliform Macular Dystrophy , Humans , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/genetics , Color Vision Defects/diagnosis , Color Vision Defects/genetics , Bestrophins/genetics , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Tomography, Optical CoherenceABSTRACT
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.
Subject(s)
Vitelliform Macular Dystrophy , Humans , Bestrophins/genetics , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/genetics , Vitelliform Macular Dystrophy/pathology , Chloride Channels/genetics , Eye Proteins/genetics , Angiotensin Receptor Antagonists , Pedigree , Angiotensin-Converting Enzyme Inhibitors , Phenotype , Mutation, MissenseABSTRACT
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.
Subject(s)
Vitelliform Macular Dystrophy , Humans , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/genetics , Eye Proteins/genetics , Tomography, Optical Coherence/methods , Visual Field Tests , Mutation , Bestrophins/geneticsABSTRACT
Several pathogenic variants have been reported in the IMPG1 gene associated with the inherited retinal disorders vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). IMPG1 and its paralog IMPG2 encode for two proteoglycans, SPACR and SPACRCAN, respectively, which are the main components of the interphotoreceptor matrix (IPM), the extracellular matrix surrounding the photoreceptor cells. To determine the role of SPACR in the pathological mechanisms leading to RP and VMD, we generated a knockout mouse model lacking Impg1, the mouse ortholog. Impg1-deficient mice show abnormal accumulation of autofluorescent deposits visible by fundus imaging and spectral-domain optical coherence tomography (SD-OCT) and attenuated electroretinogram responses from 9 months of age. Furthermore, SD-OCT of Impg1-/- mice shows a degeneration of the photoreceptor layer, and transmission electron microscopy shows a disruption of the IPM and the retinal pigment epithelial cells. The decrease in the concentration of the chromophore 11-cis-retinal supports this loss of photoreceptors. In conclusion, our results demonstrate the essential role of SPACR in maintaining photoreceptors. Impg1-/- mice provide a novel model for mechanistic investigations and the development of therapies for VMD and RP caused by IMPG1 pathogenic variants.
Subject(s)
Extracellular Matrix Proteins , Eye Proteins , Proteoglycans , Retinitis Pigmentosa , Vitelliform Macular Dystrophy , Animals , Extracellular Matrix/genetics , Extracellular Matrix/pathology , Extracellular Matrix Proteins/genetics , Eye Proteins/genetics , Mice , Photoreceptor Cells/pathology , Proteoglycans/genetics , Retinal Pigment Epithelium/pathology , Retinal Pigments , Retinaldehyde , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/pathology , Vitelliform Macular Dystrophy/geneticsABSTRACT
Variants in BEST1 are one of the most common cause of retinopathy mainly involving the retinal pigment epithelium with both dominant and recessive traits. This study aimed to describe the characteristics of potential pathogenic variants (PPVs) in BEST1 and their associated clinical features. Variants in BEST1 were collected from our in-house exome sequencing data and systematically evaluated by in silico prediction tools as well as genotype-phenotype analysis. The pathogenicity features of the BEST1 variants were further assessed through database comparison among the in-house data, Genome Aggregation Database from the general population, and all previously published literature. The clinical information of the in-house patients was summarized. The PPVs in BEST1 were identified in 66 patients from 59 families, including 32 families with Best vitelliform macular dystrophy (BVMD) and 27 families with autosomal recessive bestrophinopathy (ARB). These PPVs included 31 missense variants, seven truncation variants, one in-frame deletion, and a known 3-untranslated region variant. All the truncations detected in our study were exclusively involved in ARB but not BVMD. Among the 31 missense variants, 18 missenses associated with BVMD in the dominant trait were clustered in four hotspot regions with statistically significant differences from the recessive missenses. Except for distinct macular changes, there were no statistically significant differences among the other associated clinical features between BVMD and ARB, including peripheral retinopathy, high hyperopia, and angle-closure glaucoma. In conclusion, BEST1-associated dominant retinopathy was preferentially caused by missense variants located in important functional regions. Truncations were most likely benign in heterozygous status. Future studies are expected to elucidate the mystery of the same missense variants contributing to both BVMD and ARB.
Subject(s)
Retinal Diseases , Vitelliform Macular Dystrophy , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Bestrophins/genetics , China/epidemiology , Chloride Channels/genetics , Eye Proteins/genetics , Humans , Mutation , Pedigree , Retinal Diseases/genetics , Tomography, Optical Coherence , Untranslated Regions , Vitelliform Macular Dystrophy/geneticsABSTRACT
Initial stages of Best vitelliform macular dystrophy (BVMD) and adult vitelliform macular dystrophy (AVMD) harbor similar blue autofluorescence (BAF) and optical coherence tomography (OCT) features. Nevertheless, BVMD is characterized by a worse final stage visual acuity (VA) and an earlier onset of critical VA loss. Currently, differential diagnosis requires an invasive and time-consuming process including genetic testing, electrooculography (EOG), full field electroretinogram (ERG), and visual field testing. The aim of our study was to automatically classify OCT and BAF images from stage II BVMD and AVMD eyes using a deep learning algorithm and to identify an image processing method to facilitate human-based clinical diagnosis based on non-invasive tests like BAF and OCT without the use of machine-learning technology. After the application of a customized image processing method, OCT images were characterized by a dark appearance of the vitelliform deposit in the case of BVMD and a lighter inhomogeneous appearance in the case of AVMD. By contrast, a customized method for processing of BAF images revealed that BVMD and AVMD were characterized respectively by the presence or absence of a hypo-autofluorescent region of retina encircling the central hyperautofluorescent foveal lesion. The human-based evaluation of both BAF and OCT images showed significantly higher correspondence to ground truth reference when performed on processed images. The deep learning classifiers based on BAF and OCT images showed around 90% accuracy of classification with both processed and unprocessed images, which was significantly higher than human performance on both processed and unprocessed images. The ability to differentiate between the two entities without recurring to invasive and expensive tests may offer a valuable clinical tool in the management of the two diseases.
Subject(s)
Deep Learning , Vitelliform Macular Dystrophy , Adult , Bestrophins/genetics , Humans , Neoplasm Recurrence, Local , Tomography, Optical Coherence/methods , Visual Acuity , Vitelliform Macular Dystrophy/diagnostic imaging , Vitelliform Macular Dystrophy/geneticsABSTRACT
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.
Subject(s)
Vitelliform Macular Dystrophy , Bestrophins/genetics , Extracellular Matrix Proteins/genetics , Eye Proteins/chemistry , Eye Proteins/genetics , Humans , Optics and Photonics , Proteoglycans/genetics , Retinal Cone Photoreceptor Cells/pathology , Retinal Pigment Epithelium/pathology , Tomography, Optical Coherence/methods , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/geneticsABSTRACT
Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1, and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease.
Subject(s)
Bestrophins , Induced Pluripotent Stem Cells , Vitelliform Macular Dystrophy , Bestrophins/genetics , Bestrophins/metabolism , Chloride Channels/genetics , Chloride Channels/metabolism , Eye Proteins/genetics , Eye Proteins/metabolism , Humans , Induced Pluripotent Stem Cells/metabolism , Mutation , Retinal Pigment Epithelium/metabolism , Vitelliform Macular Dystrophy/genetics , Vitelliform Macular Dystrophy/metabolism , Vitelliform Macular Dystrophy/pathologyABSTRACT
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.
Subject(s)
Vitelliform Macular Dystrophy , Adult , Alleles , HEK293 Cells , Humans , Mutation , Proteoglycans/genetics , RNA Splice Sites , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/genetics , Exome SequencingABSTRACT
BACKGROUND: To report the ophthalmological findings of a new phenotypical variant of RP1L1 maculopathy in an Indian patient with a homozygous variant in the RP1L1 gene. MATERIALS AND METHODS: A 39-year-old male presented with complaints of disturbance in the central field of vision in both eyes (BE) for a duration of 6 months. He underwent ophthalmic examinations and diagnostic imaging. A complete retinal degeneration panel consisting of 228 genes was evaluated for pathologic variations using next-generation sequencing (NGS), which showed a variant in the RP1L1 gene. RESULTS: On fundus examination, he was found to have ill-defined foveal mottling in BE. Spectral domain optical coherence tomography (SD-OCT) showed sub-foveal hyper-reflective deposits and outer retinal layer disruption. A provisional diagnosis of the atypical variant of adult-onset foveomacular vitelliform dystrophy (AOFVD) was made on the basis of clinical, OCT, Fundus autofluorescence (FAF) and electrophysiological features. Genetic assessment of the proband revealed the presence of a homozygous base pair deletion in exon 4 of RP1L1 gene (chr8:g.10468194_10468195del), which results in frameshift and premature truncation of the protein 24 amino acids downstream to codon 1138 (p.Lys1138SerfsTer24). This variant was confirmed in the proband's parents by Sanger sequencing. The diagnosis was revised to RP1L1 maculopathy, as the RP1L1 gene variant is most commonly associated with this entity. CONCLUSION: This report presents the multimodal imaging of a previously unreported phenotype of RP1L1 maculopathy associated with a genetic variant of RP1L1 gene, thereby expanding the spectrum associated with RP1L1 maculopathy.
Subject(s)
Eye Proteins , Vitelliform Macular Dystrophy , Eye Proteins/genetics , Fluorescein Angiography , Fundus Oculi , Humans , Male , Phenotype , Tomography, Optical Coherence , Vitelliform Macular Dystrophy/diagnosis , Vitelliform Macular Dystrophy/geneticsABSTRACT
PURPOSE: To analyse the spectrum of clinical features and molecular genetic data in a series of patients carrying likely disease-associated variants in the BEST1 gene. METHODS: Retrospective observational analysis of clinical data extracted from the medical records of visual function, multimodal imaging and electrophysiology of 62 eyes of 31 patients. Molecular genetic analysis was performed by means of panel-based NGS or Sanger sequencing. RESULTS: The spectrum of variants in the BEST1 gene comprised 19 different variants and three of which are novel. Fundus photographs and OCT images allowed categorization of 52 eyes as Best vitelliform macular dystrophy (BVMD) with stages 1 to 5 and 10 eyes with autosomal recessive bestrophinopathy (ARB), with more severe phenotype. One patient was shown to be heterozygous for a variant, which has so far been described only in ARB, but this patient had the BVMD phenotype. There was no significant progression of the visual acuity during the follow-up period of 5 years both in BVMD and ARB. The most prevalent pattern of fundus autofluorescence (FAF) in BVMD was 'patchy'. There were diverse visual field defects in static automated perimetry (SAP) depending on the stage. The Arden ratio was significantly lower in ARB patients and in eyes with stage 5 of BVMD. CONCLUSIONS: The genotype does not always predict the phenotype in patients with BVMD and ARB; however, having two mutations in the BEST1 gene causes a more severe phenotype. FAF helped to distinguish ARB from BVMD. Most of the observed eyes did not progress functionally during the follow-up. ARB and the atrophic stage of BVMD as the disease end-stage had the worst visual functions and EOG results.