To describe the clinical outcome and late-stage findings of extensive macular atrophy with pseudodrusen-like appearance (EMAP). Retrospective cohort study. Seventy-eight patients (156 eyes) affected by EMAP. We collected data on best-corrected visual acuity, kinetic perimetry, OCT, short-wavelength autofluorescence, and near-infrared autofluorescence findings. Genetic testing for the TIMP3 and C1QTNF5 genes was performed via Sanger sequencing for 58 patients, with no pathogenic variants identified. The primary outcomes were best-corrected visual acuity at the last examination, visual field at the last examination, and incidence rates and time-to-event curves for blindness with the United States Social Security Administration and World Health Organization (WHO) criteria, foveal involvement, and atrophy enlargement beyond the 30° and 55° field of view. Imaging findings at the last examination were secondary outcomes. At the most recent visit, mean age was 70.9 ± 5.2 years. Using United States criteria, 58.1% of the patients were blind, and 25.8% were blind according to WHO criteria. All eyes showed large central scotomas, which were associated with visual field constriction in 22.2% of eyes. We detected focal openings or large dehiscences of Bruch's membrane (BM) in 25.4% of eyes. Near-infrared autofluorescence showed increased visibility of the choroidal vessels beyond the atrophy in 87.2% of eyes. The incidence rates for blindness were 3.95 per 100 patient-years with United States criteria and 1.54 per 100 patient-years according to WHO criteria. The incidence rates were 22.8 per 100 eye-years for foveal involvement, 12.0 per 100 eye-years for atrophy enlargement beyond 30°, and 6.6 per 100 eye-years for atrophy enlargement beyond 55°. The estimates were not influenced by the age at onset. We identified characteristic imaging findings, including BM ruptures, in elder patients with EMAP and calculated incidence rates for different functional and anatomic outcomes. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

Purpose: To investigate the clinical and imaging features associated with retinal sensitivity in Best vitelliform macular dystrophy (BVMD). Methods: This was a cross-sectional, single-center, observational study. Each patient underwent optical coherence tomography (OCT), near-infrared fundus autofluorescence, and OCT angiography. Macular integrity assessment microperimetry under mesopic conditions was performed to obtain retinal sensitivity thresholds from 68 testing points in the central macula. Structural OCT was used to classify BVMD lesions into four types according to their composition: vitelliform, mixed, subretinal fluid, and atrophy. Multilevel, mixed-effects linear regression was used to determine the factors associated with retinal sensitivity. Results: The study included 57 eyes of 30 patients with BVMD, 48 of which (84%) were in a clinical stage. Mean retinal sensitivity varied according to the composition of the lesion: the vitelliform type registering the highest (22 ± 4.1 dB), followed by mixed (18.73 ± 2.7 dB), subretinal fluid (15.68 ± 4.2 dB), and atrophy types (11.85 ± 4.6 dB). The factors most strongly associated with mean retinal sensitivity in BVMD proved to be the OCT lesion type and outer nuclear layer thickness. Conclusions: Retinal sensitivity in BVMD is influenced by lesion composition and outer nuclear layer thickness. Further studies with long-term follow-up are warranted to examine retinal sensitivity over time and to validate retinal sensitivity changes as biomarkers for BVMD. Translational Relevance: Assessing retinal sensitivity in BVMD provides a new instrument in the clinical characterization of the disease and offers the opportunity to identify imaging biomarkers for use as outcome measures in future clinical trials.

Progressive inherited retinal degenerations (IRDs) affecting rods and cones are clinically and genetically heterogeneous and can lead to blindness with limited therapeutic options. The major gene defects have been identified in subjects of European and Asian decent with only few reports of North African descent. Genome, targeted next-generation and Sanger sequencing was applied to cohort of ∼4000 IRDs cases. Expression analyses were performed including Chip-seq database analyses, on human-derived retinal organoids (ROs), retinal pigment epithelium (RPE) cells and zebrafish. Variants' pathogenicity was accessed using 3D-modeling and/or ROs. Here we identified a novel gene defect with three distinct pathogenic variants in UBAP1L in four independent autosomal recessive IRD cases from Tunisia. UBAP1L is expressed in the RPE and retina, specifically in rods and cones, in line with the phenotype. It encodes Ubiquitin-associated protein 1-like, containing a solenoid of overlapping ubiquitin associated (SOUBA) domain, predicted to interact with ubiquitin. In silico and in vitro studies, including 3D-modeling and ROs revealed that the SOUBA domain is truncated and thus ubiquitin binding most likely abolished secondary to all variants identified herein. Biallelic UBAP1L variants are a novel cause of IRDs, most likely enriched in the North African population.