Macular Dystrophy Research Articles

IS/OS-Ellipsoid Zone Complex Anomaly of Benign Concentric Annular Macular Dystrophy

Aim: To report IS/OS-Ellipsoid zone complex anomaly of benign concentric annular macular dystrophy. Methods: A case of adult-onset macular dystrophy was observed with BCAMD associated with the IS/OS-Ellipsoid zone complex anomaly by CFP, OCT, en-face analysis, FA and FAF, etc. Results: CFP revealed concentric rings in the parafoveal area prominent and drusen in the macula of right eye and not concentric rings in the left eye. No concentric ring changes were observed in FA and FAF. En-face analysis found that the IS/OS-Ellipsoid complex was obviously abnormal. Although the left eye did not show the concentric ring-like changes in the CFP, but IS/OS-Ellipsoid complex was abnormal with semi-annular blotch-like dark areas. Conclusion: BCAMD is a rare macular dystrophy. En-face analysis found that the IS/OS-Ellipsoid complex was obviously abnormal.

Genotypic Profile and Clinical Characteristics of CRX-Associated Retinopathy in Koreans.

This study aimed to investigate the clinical characteristics of Korean patients with retinal dystrophy associated with pathogenic variants of cone rod homeobox-containing gene (CRX). We retrospectively enrolled Korean patients with CRX-associated retinal dystrophy (CRX-RD) who visited two tertiary referral hospitals. Pathogenic variants were identified using targeted panel sequencing or whole-exome sequencing. We analyzed clinical features and phenotypic spectra according to genotype. Eleven patients with CRX-RD were included in this study. Six patients with cone-rod dystrophy (CORD), two with macular dystrophy (MD), two with Leber congenital amaurosis (LCA), and one with retinitis pigmentosa (RP) were included. One patient (9.1%) had autosomal recessive inheritance, and the other ten patients (90.9%) had autosomal dominant inheritance. Six patients (54.5%) were male, and the mean age of symptom onset was 27.0 ± 17.9 years. At the first presentation, the mean age was 39.4 ± 20.6 years, and best-corrected visual acuity (BCVA) (logMAR) was 0.76 ± 0.90 in the better eye. Negative electroretinography (ERG) was observed in seven (63.6%) patients. Nine pathogenic variants were identified, including two novel variants, c.101-1G>A and c.898T>C:p.(*300Glnext*118). Taken together with the variants reported in prior studies, all variants within the homeodomain are missense variants, whereas most variants downstream of the homeodomain are truncating variants (88%). The clinical features of pathogenic variants within the homeodomain are either CORD or MD with bull's eye maculopathy, whereas variants downstream of the homeodomain cause more diverse phenotypes, with CORD and MD in 36%, LCA in 40%, and RP in 24%. This is the first case series in Korea to investigate the CRX-RD genotype-phenotype correlation. Pathogenic variants downstream of the homeodomain of the CRX gene are present as RP, LCA, and CORD, whereas pathogenic variants within the homeodomain are mainly present as CORD or MD with bull's eye maculopathy. This trend was similar to previous genotype-phenotype analyses of CRX-RD. Further molecular biologic research on this correlation is required.

Fixation Location and Stability in Best Vitelliform Macular Dystrophy

To analyze fixation location and stability in best vitelliform macular dystrophy (BVMD) and test their association with best-corrected visual acuity (BCVA). Observational, cross-sectional study. Thirty patients (55 eyes) affected by genetically confirmed BVMD were followed up at the Retinal Heredodystrophies Unit of IRCCS San Raffaele Scientific Institute, Milan. Patients underwent testing with macular integrity assessment (MAIA) microperimeter. Fixation location was measured as distance in degrees (°) between preferred retinal locus (PRL) and estimated fovea location (EFL); fixation was defined as eccentric when the distance between PRL and EFL exceeded 2°. Fixation stability was graded as stable, relatively unstable, or unstable and expressed as bivariate contour ellipse area (BCEA, °2). Fixation location and stability. The median distance of the PRL from the anatomic fovea was 0.7°, and fixation location was eccentric in 27% of eyes. Fixation was graded as stable in 64% of eyes, relatively unstable in 13%, and unstable in 24%, with a median 95% BCEA of 6.2°2. The atrophic/fibrotic stage was associated with worse fixation parameters (all P<0.01). Both PRL eccentricity and fixation stability were linearly associated with BCVA: every 1° increase in PRL eccentricity was associated with a 0.07 logarithm of the minimum angle of resolution (logMAR) worse BCVA (P<0.0001) while every 1°2 increase in 95% BCEA was associated with a 0.01 logMAR worse BCVA (P<0.001). No significant intereye correlation was found for PRL eccentricity and fixation stability, as well as no association between the patient's age and fixation parameters. We demonstrated that most eyes affected by BVMD retain a central stable fixation and provided evidence that both fixation eccentricity and stability are strongly associated with visual acuity in BVMD. These parameters may serve as secondary end points for future clinical trials. Proprietary or commercial disclosure may be found after the references.

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

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

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

BackgroundBest vitelliform macular dystrophy (BVMD), caused by pathogenic variants of the BEST1 gene, has not been reported in association with cataracts and ocular malformations. We reported a case with a complex ocular phenotype comprising microphthalmia, microcornea, cataract, and vitelliform macular dystrophy.Case presentationA six-year-old girl manifested photophobia and a poor visual behavior. A thorough ophthalmic examination revealed the patient to have bilateral microphthalmia, microcornea, congenital cataract, and Best vitelliform macular dystrophy (BVMD). Whole exome sequencing (WES) identified one variant in the BEST1 and one variant in CRYBB2 genes: c.218 T > G p.(Ile73Arg) and c.479G > C p.(Arg160Pro). The first variant was inherited from the proband’s father, who was diagnosed with subclinical BVMD, while the second was a de novo variant. A minigene assay showed that c.218 T > G in BEST1 did not affect pre-mRNA splicing.ConclusionsThis case suggests that the complex ocular phenotype comprising BVMD and congenital cataract with microphthalmia cannot be explained by variation in one gene but is caused by variants in BEST1 and CRYBB2. This case highlights the importance of general clinical evaluation and comprehensive genetic testing for diagnosing complex eye diseases.

The pseudohypopyon stage in adult-onset foveomacular vitelliform dystrophy.

To gain insight into the pathogenesis of adult-onset foveomacular vitelliform dystrophy (AFVD) via assessment of its pseudohypopyon stage (PHS). Retrospectively, data were collected in a tertiary center from established cohorts of a genetically evaluated AFVD and best vitelliform macular dystrophy (BVMD) eyes in the pseudohypopyon stage. Best-corrected visual acuity (BCVA, LogMAR), lesion characterization, including lesion dimensions, liquefaction areas and patterns (altitudinal or lateral), and ellipsoid zone integrity were analyzed from spectral-domain optical coherence tomography images. Out of 167 eyes of 90 AFVD patients and 56 eyes of 28 BVMD patients, 8 eyes of six AFVD patients and five eyes of four BVMD patients were at the PHS were included. The mean LogMAR BCVA ± SD was 0.21 ± 0.20 and 0.41 ± 0.10 in AFVD and BVMD diseases, respectively (p = 0.13). Seven AFVD eyes (87.5%) demonstrated lateral liquefaction, while all BVMD eyes demonstrated an altitudinal pattern (p = 0.005). Maximal horizontal lesion diameters were 1.41 ± 0.46mm and 2.64 ± 0.77mm in AFVD and BVMD, respectively (p = 0.02). AFVD patients were older (69 ± 14) than BVMD patients (22 ± 13; p = 0.009). The pseudohypopyon stage in AFVD is often characterized by a lateral liquefaction pattern, unlike the altitudinal pattern characterizing BVMD. Age, lesion size, or pathogenesis pathways may underline the different pseudohypopyon stage patterns in AFVD and BVMD.

Macular corneal dystrophy with keratoconus – Case report and review of literature

We report a case of macular corneal dystrophy with suspected keratoconus on clinical examination in a 20-year-old female. On Scheimpflug imaging, anterior sagittal and posterior sagittal maps were suggestive of keratoconus. Anterior segment optical coherence tomography showed focal areas of hyperreflectivity in the anterior stroma with diffuse thinning. We report this case to illustrate that high astigmatism and thinning, commonly present in macular dystrophy, may have features suggestive of keratoconus. Corneal haze precludes an accurate assessment of the posterior corneal curvature.

A case of choroidal neovascular membrane in Best vitelliform macular dystrophy treated with intravitreal brolucizumab

A 21-year-old healthy male presented with loss of vision associated with metamorphopsia in the right eye of 6 weeks duration. The patient was a known case of best vitelliform macular dystrophy in both eyes. Clinical and imaging studies lead to a diagnosis of the choroidal neovascular membrane (CNVM). The diseased eye was treated with a single dose of intravitreal brolucizumab. Significant gains in visual acuity and reduction in the subretinal fluid were noted over 2 months of follow-up. Intravitreal brolucizumab can be an effective option in treating CNVMs associated with macular dystrophy.

Clinical Heterogeneity in Two Siblings Harbouring a Heterozygous PRPH2 Pathogenic Variant.

The aim of the study was to describe the clinical and genetic correlation of a c.469 G>A p.(Asp157Asn) heterozygous pathogenic variant in PRPH2 in two siblings of Italian origin. Both patients underwent ophthalmic examination, electrophysiological testing, autofluorescence imaging, and optical coherence tomography (OCT). Screening for pathogenic variants of the obtained DNA from the family members was carried out. The 52-year-old (♀, index patient) and 50-year-old (♂) siblings had BCVA (OD and OS) of 20/20 and 20/16 (♀) and 20/25 and 20/40 (♂), respectively, and suffered increased sensitivity to glare. Yellow irregular macular deposits, numerous small irregular hypo- and hyperreflective spots at the posterior pole, a patchy loss of photoreceptors, and retinal pigment epithelium (RPE) in the perifoveal region were seen. Electrophysiology showed dysfunction of rods and cones, with more affected cone dysfunction in the index patient, contrary to the generalised rod dysfunction in the brother of the index patient. The clinical, electrophysiological, and multimodal imaging findings of both siblings pointed towards Stargardt retinopathy with heterogenic presentation. The DNA analysis identified an autosomal dominant c.469 G>A p.(Asp157Asn) heterozygous pathogenic variant in PRPH2 associated with autosomal dominant cone-rod dystrophy and rod-cone dystrophy. PRPH2 codes for peripherin-2, a membrane protein that consists of 346 amino acids. Our findings confirm a heterogeneity in clinical presentation associated with pathogenic variants in PRPH2. It may follow either an autosomal dominant or an autosomal recessive mode of inheritance and show a very heterogeneous clinical manifestation of retinal degeneration, e.g., autosomal dominant retinitis pigmentosa (♂ sibling; II-3) and autosomal dominant cone-rod dystrophy (index ♀ sibling; II-2), autosomal dominant macular dystrophy, and also autosomal recessive retinitis pigmentosa.

Pentosan polysulfate maculopathy: a brief primer for general practitioners, ophthalmologists, optometrists and urologists.

Pentosan polysulfate maculopathy: a brief primer for general practitioners, ophthalmologists, optometrists and urologists.

Multimodal imaging in Best Vitelliform Macular Dystrophy: Literature review and novel insights.

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.

Age maculodystrophia: the hypothesis of etiopathogenesis

Age-related macular dystrophy (AMD) is one of the main causes of vision loss in old age. The etiopathogenesis of AMD has not been fully elucidated, therefore there is no radical treatment of AMD. The proposed hypothesis is that the trigger of AMD may be a genetically determined weakness of accommodation (related to an excessively small distance "ciliary body - lens equator"). It is necessary to carry out objective accomodometry, OCT diagnostics of the distance "ciliary body - lens equator" in older people with healthy eyes and with ophthalmopathology (including AMD). If the hypothesis is confirmed, it is proposed to: a) surgically expand the ring of the ciliary body; b) to form a simple direct myopic astigmatism of up to 1.5 diopters on an artificial eye with AMD (by calculating the optical power of the IOL or modeling the corneal surface with a femtosecond laser).

Management of Stromal Corneal Dystrophies; Review of the Literature with a Focus on Phototherapeutic Keratectomy and Keratoplasty.

Corneal dystrophies are a group of non-inflammatory inherited disorders of the cornea. This review considers treatment options for epithelial-stromal and stromal corneal dystrophies: namely Reis-Bücklers, Thiel-Behnke, lattice, Avellino, granular, macular and Schnyder corneal dystrophies. Where there is visual reduction, treatment options may include either phototherapeutic keratectomy (PTK) or corneal transplantation. Due to the anterior location of the deposits in Reis-Bücklers and Thiel-Behnke dystrophies, PTK is considered the treatment of choice. For lattice, Avellino, granular and macular corneal dystrophies, PTK provides temporary visual improvement; however, with recurrences, repeat PTK or a corneal transplant would be needed. For Schnyder dystrophy, should treatment be required, PTK may be the preferred option due to the potential for recurrence of the disease in corneal transplantation. This review discusses the literature and evidence base for the treatment of corneal dystrophies in terms of visual outcomes and recurrence rate.

CRISPR/Cas9 mediated specific ablation of vegfa in retinal pigment epithelium efficiently regresses choroidal neovascularization

The CRISPR/Cas9 system easily edits target genes in various organisms and is used to treat human diseases. In most therapeutic CRISPR studies, ubiquitously expressed promoters, such as CMV, CAG, and EF1α, are used; however, gene editing is sometimes necessary only in specific cell types relevant to the disease. Therefore, we aimed to develop a retinal pigment epithelium (RPE)-specific CRISPR/Cas9 system. We developed a CRISPR/Cas9 system that operates only in retinal pigment epithelium (RPE) by expressing Cas9 under the RPE-specific vitelliform macular dystrophy 2 promoter (pVMD2). This RPE-specific CRISPR/pVMD2-Cas9 system was tested in human retinal organoid and mouse model. We confirmed that this system works specifically in the RPE of human retinal organoids and mouse retina. In addition, the RPE-specific Vegfa ablation using the novel CRISPR-pVMD2-Cas9 system caused regression of choroidal neovascularization (CNV) without unwanted knock-out in the neural retina in laser-induced CNV mice, which is a widely used animal model of neovascular age-related macular degeneration. RPE-specific Vegfa knock-out (KO) and ubiquitous Vegfa KO were comparable in the efficient regression of CNV. The promoter substituted, cell type-specific CRISPR/Cas9 systems can be used in specific ‘target cell’ therapy, which edits genes while reducing unwanted off- ‘target cell’ effects.

Benign concentric annular macular dystrophy with early Retinitis Pigmentosa-like features

Benign concentric annular macular dystrophy with early Retinitis Pigmentosa-like features

RPE-Directed Gene Therapy Improves Mitochondrial Function in Murine Dry AMD Models.

Age-related macular degeneration (AMD) is the most common cause of blindness in the aged population. However, to date there is no effective treatment for the dry form of the disease, representing 85-90% of cases. AMD is an immensely complex disease which affects, amongst others, both retinal pigment epithelium (RPE) and photoreceptor cells and leads to the progressive loss of central vision. Mitochondrial dysfunction in both RPE and photoreceptor cells is emerging as a key player in the disease. There are indications that during disease progression, the RPE is first impaired and RPE dysfunction in turn leads to subsequent photoreceptor cell degeneration; however, the exact sequence of events has not as yet been fully determined. We recently showed that AAV delivery of an optimised NADH-ubiquinone oxidoreductase (NDI1) gene, a nuclear-encoded complex 1 equivalent from S. cerevisiae, expressed from a general promoter, provided robust benefit in a variety of murine and cellular models of dry AMD; this was the first study employing a gene therapy to directly boost mitochondrial function, providing functional benefit in vivo. However, use of a restricted RPE-specific promoter to drive expression of the gene therapy enables exploration of the optimal target retinal cell type for dry AMD therapies. Furthermore, such restricted transgene expression could reduce potential off-target effects, possibly improving the safety profile of the therapy. Therefore, in the current study, we interrogate whether expression of the gene therapy from the RPE-specific promoter, Vitelliform macular dystrophy 2 (VMD2), might be sufficient to rescue dry AMD models.

Electrophysiological Evaluation of Macular Dystrophies

Macular dystrophies are a heterogeneous group of genetic disorders that often severely threatens the bilateral central vision of the affected patient. While advances in molecular genetics have been instrumental in the understanding and diagnosis of these disorders, there remains significant phenotypical variation among patients within any particular subset of macular dystrophies. Electrophysiological testing remains a vital tool not only to characterize vision loss for differential diagnosis but also to understand the pathophysiology of these disorders and to monitor the treatment effect, potentially leading to therapeutic advances. This review summarizes the application of electrophysiological testing in macular dystrophies, including Stargardt disease, bestrophinopathies, X-linked retinoschisis, Sorsby fundus dystrophy, Doyne honeycomb retina dystrophy, autosomal dominant drusen, occult macular dystrophy, North Carolina macular dystrophy, pattern dystrophy, and central areolar choroidal dystrophy.

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.

Clinical, genetic, and electron microscopy of hair findings in a patient with CDH3 -related hypotrichosis with juvenile macular dystrophy.

Clinical, genetic, and electron microscopy of hair findings in a patient with CDH3 -related hypotrichosis with juvenile macular dystrophy.

A customized regimen of intravitreal aflibercept for the treatment of choroidal neovascularization secondary to different chorioretinal diseases

BackgroundTo assess the response of CNV secondary to chorioretinal diseases to IVA and to explore the adequate dosing regimen and the long-term results.MethodsA retrospective study including patients with treatment-naïve active CNV secondary to chorioretinal diseases. All patients received an initial IVA injection followed by a PRN regimen. The main outcome measures were improvement of BCVA, improvement of anatomical morphology and vascularity of the CNV on SS-OCT, and SS-OCTA, respectively, and ocular or systemic complications attributed to IVA.ResultsThe study included 17 eyes of 15 patients. Nine patients (60%) were females. The median age was 20 years. The main primary chorioretinal disease was vitelliform macular dystrophy (29%). The mean baseline BCVA was 0.16. The mean follow-up period was 15 months. Final BCVA improved by a mean of 6 lines. The CNV regressed or became inactive in all eyes. The median number of IVA injections was 2. There were no ocular or systemic complications attributed to IVA.ConclusionThe customized IVA regimen is effective in inducing long-term regression of secondary CNV and in improving BCVA. Multimodal imaging is fundamental in establishing the diagnosis of CNV, and in monitoring its response to IVA.