Adult Vitelliform Macular Dystrophy Research Articles

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

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

Detection and Grade Classification of Diabetic Retinopathy and Adult Vitelliform Macular Dystrophy Based on Ophthalmoscopy Images

Diabetic retinopathy (DR) and adult vitelliform macular dystrophy (AVMD) may cause significant vision impairment or blindness. Prompt diagnosis is essential for patient health. Photographic ophthalmoscopy checks retinal health quickly, painlessly, and easily. It is a frequent eye test. Ophthalmoscopy images of these two illnesses are challenging to analyse since early indications are typically absent. We propose a deep learning strategy called ActiveLearn to address these concerns. This approach relies heavily on the ActiveLearn Transformer as its central structure. Furthermore, transfer learning strategies that are able to strengthen the low-level features of the model and data augmentation strategies to balance the data are incorporated owing to the peculiarities of medical pictures, such as their limited quantity and generally rigid structure. On the benchmark dataset, the suggested technique is shown to perform better than state-of-the-art methods in both binary and multiclass accuracy classification tasks with scores of 97.9% and 97.1%, respectively.

Deep learning to distinguish Best vitelliform macular dystrophy (BVMD) from adult-onset vitelliform macular degeneration (AVMD)

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.

Long-Term Maintenance of Vision and Resolution of Vitelliform Lesions with Systemic Phosphodiesterase 5/6 Treatment (Sildenafil)

BACKGROUND: Adult vitelliform macular dystrophy results in loss of central vision. The use of systemic sildenafil has been proven to increase choroidal blood flow. This is a report of a favorable long-term treatment outcome using systemic sildenafil for a patient with adult onset vitelliform macular dystrophy. CASE PRESENTATION: A 55-year-old woman presenting with bilateral subretinal vitelliform lesions was initially assessed by full-field electroretinogram, electro-oculogram and direct sequencing of the RDS/PRPH2 and BEST1 genes. Best-corrected visual acuity, spectral domain-optical coherence tomography and color fundus photography were obtained and analyzed over a 5-year treatment course which included bevacizumab (Avastin) injections in the right eye and left eye and subsequent ranibizumab (Lucentis) treatments in the left eye. Lipid resolution in the right eye was seen with bevacizumab after two months of treatment, while the left eye was unresponsive to eight subsequent injections of bevacizumab, followed by ranibizumab over a period of twenty months. Systemic sildenafil was started, off label, at 20 months following course of intravitreal injections. Following initiation of sildenafil, there were both measured and patient-reported improvements in the left eye following after two months of sildenafil. CONCLUSIONS: Systemic phosphodiesterase (PDE)-5 and -6 inhibitors may facilitate the removal of lipid and waste from the subretinal space by increasing perfusion in patients with vitelliform lesions and aid in maintaining and/or recovering photoreceptor function.

Inherited Macular Dystrophies in a Tertiary Care Centre.

Inherited macular dystrophies constitute a group of diseases characterized by bilateral central visual loss with symmetrical macular abnormalities usually presenting in the first two decades of life. The aim of this study were to find out the demographic characteristics and disease pattern of inherited retinal dystrophies in subjects attending retina outpatient department in a tertiary care center. An observational study among twenty-six participants diagnosed as macular dystrophy visiting a tertiary care centre in Nepal, during January 2018 to June 2018 were included in the study. Detailed history, slit lamp examination, dilated fundus examination, coloured fundus photography, full field electroretinogram, multifocal electroretinogram, automated visual field and colour vision were done. A total of 52 eyes of 26 subjects were diagnosed with macular dystrophy. The male to female ratio was 1:1. The mean age of presentation was 28.38 years. Most common symptom was blurring of vision seen in 96.15%.The mean visual acuity was 0.67 log mar units in right eye and 0.71 log mar units in the left eye. The most common macular dystrophy was cone dystrophy followed by adult vitelliform macular dystrophy and Stargardts dystrophy. Cone dystrophy is the most common followed by Stargardt's disease and adult vitelliform macular dystrophy. Most presented in the first two decades of life and the most common presenting symptom was blurring of vision.

The Clinical Features and Genetic Spectrum of a Large Cohort of Chinese Patients With Vitelliform Macular Dystrophies

To provide the clinical and genetic characteristics of a large cohort of Chinese patients with vitelliform macular dystrophies. Cross-sectional study. One hundred and thirty-four unrelated Chinese patients diagnosed with Best vitelliform macular dystrophy (BVMD), autosomal recessive bestrophinopathy (ARB), or adult vitelliform macular dystrophy (AVMD) were enrolled. Detailed ophthalmic examinations and genetic testing on vitelliform macular dystrophy-related genes were performed. Genotype and phenotype association were analyzed among different diagnostic groups. In total, 87 BVMD, 30 AVMD, and 17 ARB patients were enrolled in this study. Genetic analysis identified 37 BEST1 mutations in 53 patients with BVMD and ARB. Of these, 5 variants (c.254A>C, c.291C>G, c.722C>G, c.848_850del, c.1740-2A>C) were novel. The variant c.898G>A was a hotspot mutation, which was identified in 13 patients with BVMD and 1 patient with ARB. There were significant differences of ocular biometric parameters among patients with homozygous or compound heterozygous mutations, heterozygous mutations, and those without mutations of BEST1. Homozygous or compound heterozygous patients had shortest axial length (AL), shallowest anterior chamber depth (ACD), and highest intraocular pressure (IOP); patients without mutations had longest AL, deepest ACD, and lowest IOP; and heterozygous patients were in between. Moreover, 7 patients harboring heterozygous mutations in BEST1 and 3 patients without BEST1 mutations showed similar clinical appearance to ARB in our cohort. This is the largest sample size study of Chinese vitelliform macular dystrophy patients. Our results indicated that assessment of angle-closure risk is a necessary consideration for all types of BEST1-related vitelliform macular dystrophies. The study expanded both the clinical and genetic findings of 3 common types of vitelliform macular dystrophies in a Chinese population.

Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1

BEST1 encodes Bestrophin-1 (Best1), a homo-oligomeric, integral membrane protein localized to the basolateral plasma membrane of the retinal pigment epithelium. Mutations in BEST1 cause five distinct retinal degenerative diseases, including adult vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and retinitis pigmentosa (RP). The mechanisms underlying these diseases and why mutations cause one disease over another are, for the most part, unknown. To gain insights into these four diseases, we expressed 28 Best1 mutants fused to YFP in polarized MDCK monolayers and, via confocal microscopy and immunofluorescence, live-cell FRET, and reciprocal co-immunoprecipitation experiments, screened these mutants for defects in localization and oligomerization. All 28 mutants exhibited comparable FRET efficiencies to and co-immunoprecipitated with WT Best1, indicating unimpaired oligomerization. RP- and ADVIRC-associated mutants were properly localized to the basolateral plasma membrane of cells, while two AVMD and most ARB mutants were mislocalized. When co-expressed, all mislocalized mutants caused mislocalization of WT Best1 to intracellular compartments. Our current and past results indicate that mislocalization of Best1 is not an absolute feature of any individual bestrophinopathy, occurring in AVMD, BVMD, and ARB. Furthermore, some ARB mutants that do not also cause dominant disease cause mislocalization of Best1, indicating that mislocalization is not a cause of disease, and that absence of Best1 activity from the plasma membrane is tolerated. Lastly, we find that the ARB truncation mutants L174Qfs*57 and R200X can form oligomers with WT Best1, indicating that the first ∼174 amino acids of Best1 are sufficient for oligomerization to occur.

Heavy silicone oil effective in macular hole surgery associated with adult vitelliform macular dystrophy

Heavy silicone oil effective in macular hole surgery associated with adult vitelliform macular dystrophy

Phenotypic Variability and Long-term Follow-up of Patients With Known and Novel PRPH2/RDS Gene Mutations

To describe the phenotypic variability in 22 patients with PRPH2 gene mutations and to report six novel mutations. Retrospective study. Clinical examinations included color vision testing, perimetry, fundus autofluorescence (FAF), fluorescein angiography, optical coherence tomography (OCT), and full-field and multifocal electroretinography (International Society for Clinical Electrophysiology of Vision standards). Blood samples were taken for deoxyribonucleic acid (DNA) extraction and mutation screening was performed by direct sequencing of polymerase chain reaction amplicons. Eleven unrelated patients and four unrelated families each with two affected members as well as one family with three affected members were examined. Diagnoses included central areolar choroidal dystrophy (CACD; n = 9), autosomal dominant retinitis pigmentosa (adRP; n = 7), adult vitelliform macular dystrophy (n = 3), and cone-rod dystrophy (CRD; n = 3). FAF was abnormal in all patients and showed various retinal pigment epithelial alterations, in CACD with a speckled FAF pattern. OCT revealed reduced retinal thickness, mostly in CACD, subretinal lesions, macula edema, or was normal. Follow-up (n = 12; range, 1.3 to 26 years) showed a slow progression of the retinal dystrophies. DNA testing revealed previously reported PRPH2 mutations in two families and eight individuals of whom two carried the same mutation but had different phenotypes. Novel PRPH2 mutations were detected in two families with adRP, in identical twins with CACD, and in each of an individual with CACD, CRD, and adRP. This series describes the broad spectrum of phenotypes associated with PRPH2 mutations. FAF and OCT are helpful tools for diagnosis and evaluation of disease progression. We report novel PRPH2 mutations in patients with CACD, CRD, and adRP.

MORPHOLOGY AND FUNCTIONAL CHARACTERISTICS IN ADULT VITELLIFORM MACULAR DYSTROPHY

Detailed morphologic and functional evaluation of adult vitelliform macular dystrophy (AVMD). The records of 61 consecutive AVMD patients (inclusion criterion: vitelliform lesion smaller than one disk diameter at least in one eye) were evaluated retrospectively regarding visual acuity, color vision, perimetry, retinal pigment epithelium (RPE) autofluorescence, fluorescein angiography, electro-oculography, full-field and multifocal electroretinography, and molecular genetic evaluation of the VMD2 and RDS/peripherin genes. The mean age of subjects was 54.6 years. Visual loss was variable (median, 0.6; range, 1.25-0.05). Color vision and visual field were normal in about half of the patients but presented defects with high variability in the remaining patients. Autofluorescence findings showed increased fluorescence within the foveal yellow lesion in 76%. In the majority of eyes, the amplitude of the 30 Hz flicker response of the full-field electroretinogram (72%) and the central P1 amplitude of the multifocal electroretinogram (63%) were reduced. Mutational analyses revealed a potentially disease-associated mutation in the RDS/peripherin gene in one patient. AVMD is characterized by late onset, slow progression, good prognosis, and high variability of morphologic and functional abnormalities resulting frequently in misdiagnosis. Autofluorescence findings indicate lipofuscin accumulation in the yellow lesion. Electroretinography revealed a generalized cone system dysfunction with increasing severity toward the fovea.

Clinical diagnostic prerequisites for adult vitelliform macular dystrophy

Adult vitelliform macular dystrophy (AVMD) was first described in 1974 (Gass) but is still often misdiagnosed. Large studies using modern morphological and functional diagnostic methods do not exist. The records of 67 consecutive AVMD patients (1994-2003) were reviewed regarding color vision, perimetry, RPE autofluorescence, fluorescein angiography, EOG, ERG, and mfERG. The mean age was 54.8 years. Symptoms, visual loss, color vision deficits, and visual field defects were highly variable. Autofluorescence was increased centrally in 77% of the eyes. In the ERG, the 30 Hz flicker response was reduced in 71% of the eyes. MfERGs showed a marked central amplitude reduction in 62% of the eyes and a continual normalization of the P1 amplitude towards the periphery. The enhanced autofluorescence indicates increased lipofuscin in the vitelliform lesions. The electroretinographic recordings reveal a moderate generalized cone dysfunction with increased severity towards the fovea. Ophthalmoscopy, autofluorescence, and recording of mfERG are prerequisites to diagnose AVMD correctly.

Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.

Recently, the VMD2 gene has been identified as the causative gene in juvenile-onset vitelliform macular dystrophy (Best disease), a central retinopathy primarily characterised by an impaired function of the retinal pigment epithelium. In this study we have further characterised the spectrum of VMD2 mutations in a series of 41 unrelated Best disease patients. Furthermore we expanded our analysis to include 32 unrelated patients with adult vitelliform macular dystrophy (AVMD) and 200 patients with age-related macular degeneration (AMD). Both AVMD and AMD share some phenotypic features with Best disease such as abnormal subretinal accumulation of lipofuscin material, progressive geographic atrophy and choroidal neovascularisation, and may be the consequence of a common pathogenic mechanism. In total, we have identified 23 distinct disease-associated mutations in Best disease and four different mutations in AVMD. Two of the mutations found in the AVMD patients were also seen in Best disease suggesting a considerable overlap in the aetiology of these two disorders. There were no mutations found in the AMD group. In addition, four frequent intragenic polymorphisms did not reveal allelic association of the VMD2 locus with AMD. These data exclude a direct role of VMD2 in the predisposition to AMD.

VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies.

Mutations in the gene VMD2 are associated with autosomal dominant vitelliform macular dystrophy (Best disease). VMD2 is expressed in the retinal pigment epithelium and codes for a 585 amino acid putative transmembrane protein with undetermined functional properties. To date, 48 different mutations, predominantly missense, have been described in Best disease families. These mutations generally affect amino acids in the first 50% of the protein, and occur in four distinct clusters possibly representing regions of functional importance. VMD2 has also been investigated in other macular diseases. Mutations have been documented in a significant percentage of patients with adult vitelliform macular dystrophy (AVMD) and in a single case of "bull's-eye" maculopathy. Results of analysis in two large series of individuals with age-related macular degeneration (AMD) suggest that VMD2 does not play a major role in this prevalent disorder.

In vivo fundus autofluorescence in macular dystrophies.

To document the deviation from normal of fundus autofluorescence in patients with inherited macular dystrophies. The intensity and spatial distribution of fundus autofluorescence was documented in 118 patients with inherited macular dystrophies by means of a confocal laser scanning ophthalmoscope, and the images were compared with the fundus appearance and fluorescein angiograms. Background autofluorescence appears to be elevated in all forms of macular dystrophies examined. The pale deposits at the level of the retinal pigment epithelium in disorders such as Best disease, adult vitelliform macular dystrophy, and fundus flavimaculatus were consistently associated with higher levels of autofluorescence than the background signal. There was no strong correlation between the intensity of autofluorescence and the fluorescein angiographic sign of a dark choroid. Increased levels of autofluorescence were present in a subject with a mutation known to cause macular dystrophy but in whom there were no manifest ophthalmoscopic or functional abnormalities. All dystrophies examined have in common accumulation of autofluorescent material in the retinal pigment epithelium to a greater degree than that seen with age. The abnormal high background autofluorescence associated with inherited macular dystrophies confirms the impression derived from histological studies that these disorders affect the entire retinal pigment epithelium. The lack of correlation between autofluorescence and the presence of a dark choroid implies that there may be different fluorophores in different disorders. The pale deposits at the level of the retinal pigment epithelium-Bruch membrane seen in macular dystrophies have similar autofluorescence characteristics. This technique may be useful in detecting the abnormal phenotype in early disease.

Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene.

Mutations in the peripherin/RDS gene, which encodes a photoreceptor-specific membrane glycoprotein, have been identified in a variety of retinal phenotypes. However, the mechanisms by which specific mutations in this gene can cause typical features of retinal dystrophies clinically as distinct as retinitis pigmentosa or macular degeneration are still unknown. Recently, a single case of adult vitelliform macular dystrophy (AVMD) has been associated with a Y258Stop mutation. To assess the frequency of peripherin/RDS mutations in the clinically heterogeneous group of AVMD, we analyzed the entire coding region of the gene in 28 unrelated patients. We identified five novel mutations including two presumed null allele mutations. Thus, our results demonstrate that a significant portion of AVMD patients (18%) carry point mutations in peripherin/RDS, suggesting that this gene is frequently involved in the pathogenesis of this macular disorder. In addition, this study shows that the variable phenotypes in AVMD are due, at least in part, to genetic heterogeneity and are likely to be caused by mutations in disease genes thus far unknown.

Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene

Mutations in the peripherin/RDS gene, which encodes a photoreceptor-specific membrane glycoprotein, have been identified in a variety of retinal phenotypes. However, the mechanisms by which specific mutations in this gene can cause typical features of retinal dystrophies clinically as distinct as retinitis pigmentosa or macular degeneration are still unknown. Recently, a single case of adult vitelliform macular dystrophy (AVMD) has been associated with a Y258Stop mutation. To assess the frequency of peripherin/RDS mutations in the clinically heterogeneous group of AVMD, we analyzed the entire coding region of the gene in 28 unrelated patients. We identified five novel mutations including two presumed null allele mutations. Thus, our results demonstrate that a significant portion of AVMD patients (18%) carry point mutations in peripherin/RDS, suggesting that this gene is frequently involved in the pathogenesis of this macular disorder. In addition, this study shows that the variable phenotypes in AVMD are due, at least in part, to genetic heterogeneity and are likely to be caused by mutations in disease genes thus far unknown. Hum Mutat 10:301–309, 1997. © 1997 Wiley-Liss, Inc.

Adult vitelliform macular dystrophy

Adult vitelliform macular dystrophy was first described by Gass as giving rise to bilateral, round or oval, yellow, symmetrical, subretinal lesions typically one-third to one-half disc diameter in size. Although Gass proposed that this was an autosomal dominant disease, doubt has been expressed as to whether or not it is heritable. We investigated the families of 12 patients who presented to our clinic with foveal lesions typical of adult vitelliform macular dystrophy and found familial involvement compatible with an autosomal dominant inheritance in ten, although it has not been conclusively proven in all families. In the remaining two patients, no familial involvement was detected, but in neither family were both parents available for examination so that autosomal dominant inheritance could not be ruled out. Over half (14/25) the patients with abnormal fundi were asymptomatic, and most had good visual acuity. However, two had visual acuities of less than 6/18 in both eyes. We conclude that adult vitelliform macular dystrophy is an autosomal dominant disorder, and the term would be best reserved for foveal lesions similar to that described by Gass with a dominant pattern of inheritance.