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Characterization of vascular impairment in Best vitelliform macular dystrophy (BVMD) is essential for the development of treatment modalities and therapy trials. As such, we seek to characterize the choriocapillaris (CC) at each stage of the disease process in 22 patients (44 eyes) with a diagnosis of BVMD confirmed by genetic sequencing. We utilize optical coherence tomography angiography (OCTA) images to characterize the CC and correlate our findings to the status of the retinal pigment epithelium (RPE) as observed on short-wavelength fundus autofluorescence (SW-AF) images. We observed that in the vitelliruptive stage, the CC appeared as bright and granular in the area where the vitelliform lesion was present. In the atrophic stage, varying degrees of CC atrophy were observed within the lesion area, with the regions of CC atrophy appearing as hypoautofluorescent on SW-AF images. Our results suggest that the CC impairment observed in the vitelliruptive stage of BVMD progressively culminates in the CC atrophy observed at the atrophic stage. As such, OCTA imaging can be used to characterize CC impairment in BVMD patients as part of diagnosis and tracking of disease progression. Our findings suggest that the best window of opportunity for therapeutic approaches is before the atrophic stage, as it is during this stage that CC atrophy is observed.

Background and ObjectiveLittle is known about trajectories of recovery 12 months after hospitalization for severe COVID-19.MethodsWe conducted a prospective, longitudinal cohort study of patients with and without neurologic complications during index hospitalization for COVID-19 from March 10, 2020, to May 20, 2020. Phone follow-up batteries were performed at 6 and 12 months after COVID-19 onset. The primary 12-month outcome was the modified Rankin Scale (mRS) score comparing patients with or without neurologic complications using multivariable ordinal analysis. Secondary outcomes included activities of daily living (Barthel Index), telephone Montreal Cognitive Assessment (t-MoCA), and Quality of Life in Neurologic Disorders (Neuro-QoL) batteries for anxiety, depression, fatigue, and sleep. Changes in outcome scores from 6 to 12 months were compared using nonparametric paired-samples sign test.ResultsTwelve-month follow-up was completed in 242 patients (median age 65 years, 64% male, 34% intubated during hospitalization) and 174 completed both 6- and 12-month follow-up. At 12 months, 197/227 (87%) had ≥1 abnormal metric: mRS >0 (75%), Barthel Index p = 0.037). Significant improvements in outcome trajectories from 6 to 12 months were observed in t-MoCA scores (56% improved, median difference 1 point; p = 0.002) and Neuro-QoL anxiety scores (45% improved; p = 0.003). Nonsignificant improvements occurred in fatigue, sleep, and depression scores in 48%, 48%, and 38% of patients, respectively. Barthel Index and mRS scores remained unchanged between 6 and 12 months in >50% of patients.DiscussionAt 12 months after hospitalization for severe COVID-19, 87% of patients had ongoing abnormalities in functional, cognitive, or Neuro-QoL metrics and abnormal cognition persisted in 50% of patients without a history of dementia/cognitive abnormality. Only fatigue severity differed significantly between patients with or without neurologic complications during index hospitalization. However, significant improvements in cognitive (t-MoCA) and anxiety (Neuro-QoL) scores occurred in 56% and 45% of patients, respectively, between 6 and 12 months. These results may not be generalizable to those with mild or moderate COVID-19.

Patient safety is a primary priority in the conduction of retinal gene therapy trials. An understanding of risk factors and mitigation strategies for post-procedure complications is crucial for the optimization of gene therapy clinical trial protocols. In this review, we synthesize the literature on ocular delivery methods, vector platforms, and treatment-emergent adverse effects in recent gene therapy clinical trials for inherited retinal diseases.

Background Whole exome sequencing (WES) allows for an unbiased search of the genetic cause of a disease. Employing it as a first-tier genetic testing can be favored due to the associated lower incremental cost per diagnosis compared to when using it later in the diagnostic pathway. However, there are technical limitations of WES that can lead to inaccurate negative variant callings. Our study presents these limitations through a re-evaluation of negative WES results using subsequent tests primarily driven by fundoscopic findings. These tests included targeted gene testing, inherited retinal gene panels, whole genome sequencing (WGS), and array comparative genomic hybridization. Results Subsequent genetic testing guided by fundoscopy findings identified the following variant types causing retinitis pigmentosa that were not detected by WES: frameshift deletion and nonsense variants in the RPGR gene, 353-bp Alu repeat insertions in the MAK gene, and large exonic deletion variants in the EYS and PRPF31 genes. Deep intronic variants in the ABCA4 gene causing Stargardt disease and the GUCY2D gene causing Leber congenital amaurosis were also identified. Conclusions Negative WES analyses inconsistent with the phenotype should raise clinical suspicion. Subsequent genetic testing may detect genetic variants missed by WES and can make patients eligible for gene replacement therapy and upcoming clinical trials. When phenotypic findings support a genetic etiology, negative WES results should be followed by targeted gene sequencing, array based approach or whole genome sequencing.

When using spectral domain optical coherence tomography (SD-OCT) to inform the status of outer retina, we have noted discrete hyperreflective lesions extending through photoreceptor-attributable bands that have a similar presentation in multiple retinal diseases. These lesions present as either corrugated thickenings of interdigitation zone and ellipsoid zone bands or in later stages as rectangular or pyramidal shaped foci that extend radially through photoreceptor cell-attributable bands. In ABCA4-related and peripherin-2/RDS-disease (PRPH2/RDS), monogenic forms of retinopathy caused by mutations in proteins expressed in photoreceptor cells, these punctate lesions colocalize with fundus flecks in en face images. In fundus albipunctatus and retinitis punctata albescens, diseases caused by mutations in genes (retinol dehydrogenase 5, RDH5; and retinaldehyde-binding protein 1, RLBP1) encoding proteins of the visual cycle, these lesions manifest as white dot-like puncta. Similar aberrations in photoreceptor cell-attributable SD-OCT reflectivity layers manifest as reticular pseudodrusen (RPD) in short-wavelength fundus autofluorescence and near-infrared fundus autofluorescence fundus images and are linked to age-related macular degeneration a complex disease. Despite differences in the etiologies of retinal diseases presenting as fundus flecks, dots and RPD, underlying degenerative processes in photoreceptor cells are signified in SD-OCT scans by the loss of structural features that would otherwise define healthy photoreceptor cells at these foci.

Leber congenital amaurosis (LCA) refers to a group of recessively inherited, severe rod-cone dystrophies of infantile onset, with symptoms presenting congenitally or within the first few months of ...

We analyze disease progression in retinitis pigmentosa (RP) according to mode of inheritance by quantifying the progressive decrease of the ellipsoid zone (EZ) line width on spectral domain optical coherence tomography (SD-OCT) and of the dimensions of the hyperautofluorescent ring on short-wave fundus autofluorescence (SW-FAF). In this retrospective study of 96 patients, average follow-up time was 3.2 ± 1.9 years. EZ line width declined at a rate of −123 ± 8 µm per year, while the horizontal diameter and ring area declined at rates of −131 ± 9 µm and −0.5 ± 0.05 mm2 per year, respectively. Disease progression was found to be slowest for autosomal dominant RP and fastest for X-linked RP, with autosomal recessive RP progression rates between those of adRP and XLRP. EZ line width and ring diameter rates of disease progression were significantly different between each mode of inheritance. By using EZ line width and horizontal diameter as parameters of disease progression, our results confirm that adRP is the slowest progressing form of RP while XLRP is the fastest. Furthermore, the reported rates can serve as benchmarks for investigators of future clinical trials for RP and its different modes of inheritance.

OBJECTIVE: To evaluate and compare the B-scan OCT loss of ellipsoid zone, OCT en face thickness map constriction, and hyperautofluorescent ring constriction in RP patients. METHODS: Retrospective case series study. Forty-eight eyes of 24 RP patients with a parafoveal hyperautofluorescent ring were studied. The diagnosis of RP was established by the presence of rod response impairment and a prevalent decrease of scotopic over photopic responses on electroretinography. The FAF and spectral-domain optical coherence tomography (SD-OCT) images were obtained from 24 patients with RP. The measurements of the EZ line width on B-scan OCT, hyperautofluorescent ring area on FAF, and hyperautofluorescent ring area on en face thickness map were performed by two independent graders. The measurements of these three parameters were correlated. RESULTS: The mean age of study patients was 46 years old (sd = 19). The external and internal FAF rings involving the fovea were identified in all study eyes. The area of the thickness ring decreased at an average rate of 0.5 (sd 0.4) mm(2) per year (P < 0.001). The average rate of EZ-line constriction was estimated to be 123 (sd 63) μm per year (P < 0.001). The hyperautofluorescent ring area decreased at an average rate of 0.9 (sd 0.98) mm(2) per year (P < 0.001). The strongest correlation was observed between hyperautofluorescent ring area and EZ-line width (r = 0.78). CONCLUSIONS: We observed that the hyperautofluorescent ring area exhibits a faster progression rate than the area of the thickness ring. In addition, we found that the EZ-line width had a high positive correlation with the hyperautofluorescent ring area and a moderate positive correlation with area of the thickness ring.

Purpose To compare the detection of retinal pigment epithelium (RPE) atrophy in short-wavelength (SW-AF) and near-infrared autofluorescence (NIR-AF) images in Stargardt disease (STGD1) patients. Methods SW-AF and NIR-AF images (115 eyes from 115 patients) were analyzed by two independent graders. Hypoautofluorescent (hypoAF) areas, indicative of RPE atrophy, were measured, and the two modalities were compared. Results Patients were segregated into four groups: nascent (6 [5%]), widespread (21 [18%]), discrete (55 [48%]), and chorioretinal atrophy (33 [29%]). The areas of hypoAF were larger in NIR-AF compared to SW-AF images in discrete (3.9 vs. 2.2 mm2, P < 0.001) and chorioretinal atrophy (12.7 vs. 11.4 mm2, P = 0.015). Similar findings were observed qualitatively in nascent and widespread atrophy patients. Using the area linear model (ALM), lesion area increased at similar rates in SW-AF and NIR-AF images of discrete atrophy (0.20 vs. 0.32 mm2/y, P = 0.275) and chorioretinal atrophy (1.30 vs. 1.74 mm2/y, P = 0.671). Using the radius linear model (RLM), the lesion effective radius also increased similarly in SW-AF and NIR-AF images in discrete (0.03 vs. 0.05 mm2/y, P = 0.221) and chorioretinal atrophy (0.08 vs. 0.10 mm2/y, P = 0.754) patients. Conclusions NIR-AF reveals a larger area of RPE atrophy in STGD1 patients compared to SW-AF images, but rates of lesion enlargement in the two modalities are similar. Translational Relevance Measurements of RPE atrophy by AF imaging are crucial for monitoring STGD1 disease progression and given our findings we advocate greater use of NIR-AF for patients.

Purpose To analyze the progression of choriocapillaris (CC) impairment in recessive Stargardt disease (STGD) and compare it to the progression of retinal pigment epithelium (RPE) atrophy. Methods Fifty-five patients with a clinical diagnosis of STGD and genetic confirmation of pathogenic biallelic variants in ABCA4 were imaged with short-wavelength fundus autofluorescence (SW-AF) and optical coherence tomography angiography (OCTA) at a single clinic visit, whereas a subset of 12 patients were imaged with the same modalities at two different clinic visits. Results We observed three stages of CC impairment: an area of bright yet intact macular CC (11 patients), regions of vascular rarefaction and incomplete CC atrophy within an area of bright CC (10 patients), and areas of extensive CC atrophy (26 patients). These changes correlated to the degree of RPE atrophy observed in SW-AF imaging. Furthermore, 8 patients presented with early changes on SW-AF, but healthy CC. Quantitative analyses of the atrophic changes revealed that the area of RPE atrophy is larger (9.6 ± 1.7 mm2 vs. 6.9 ± 1.3 mm2, P < 0.001) and that it progresses at a faster rate (1.1 ± 0.1 mm2/year vs. 0.8 ± 0.2 mm2/year, P = 0.004) than the corresponding area of CC atrophy. Conclusions CC impairment is progressive and OCTA imaging can be used to demonstrate the stages, which culminate in extensive CC atrophy. Furthermore, CC impairment is secondary to RPE atrophy in STGD. We further advocate the use of SW-AF and OCTA imaging in monitoring the progression of STGD.

Purpose To analyze the appearance of structural abnormalities due to hydroxychloroquine (HCQ) toxicity by spectral-domain optical coherence tomography (SD-OCT) and short-wavelength autofluorescence (SW-AF) and near-infrared fundus autofluorescence (NIR-AF) imaging. Methods This retrospective cohort study included 88 eyes from 44 patients who had a history of or were currently taking HCQ. SD-OCT, SW-AF, and NIR-AF images were analyzed by two independent graders for the detection of HCQ-associated abnormalities. Results Sixty eyes (30 patients, 68%) presented with no abnormalities for either imaging modality. Twenty eyes (10 patients, 23%) presented with parafoveal abnormalities (ellipsoid zone attenuation and/or interdigitation zone continuity loss) in SD-OCT scans but with qualitatively normal SW-AF and NIR-AF images. Eight eyes (four patients, 9%) presented with bull's-eye maculopathy in SW-AF and NIR-AF images, with corresponding outer retinal structures disrupted parafoveally in SD-OCT scans ("flying saucer" sign). No patients presented with normal SD-OCT scans and concurrent abnormalities in SW-AF or NIR-AF images. Conclusions SD-OCT was more sensitive in detecting structural abnormalities than either SW-AF or NIR-AF imaging, suggesting its superiority as a screening imaging modality for HCQ toxicity. Maculopathy and abnormalities in the retinal pigment epithelium from HCQ toxicity can be appreciated in both SW-AF and NIR-AF images. Translational relevance Although debate exists regarding the best imaging modalities for screening patients for potential HCQ toxicity, our study supports the use of SD-OCT over both SW-AF and NIR-AF imaging as a screening modality.

PURPOSE: To quantitatively compare near-infrared autofluorescence (NIR-AF) and short-wave autofluorescence (SW-AF) as imaging modalities used to monitor retinitis pigmentosa (RP) disease progression, measured as a function of hyperautofluorescent ring constriction over time. DESIGN: Retrospective cohort study. METHODS: NIR-AF and SW-AF images were acquired from 22 participants (44 eyes) at two clinic visits separated by an average of 2 years. On the images from each modality, the horizontal and vertical diameters and area of the hyperautofluorescent rings were measured twice, two weeks apart. A progression rate for each parameter was obtained. Descriptive and comparative statistics were calculated to analyze these parameters and their respective progression rates. RESULTS: At both visits, the hyperautofluorescent ring exhibited a larger horizontal diameter (both visits: P

Optical coherence tomography angiography (OCT-A) is a non-invasive alternative to fluorescein angiography that allows for the study of the retinal and choroidal vasculatures. In this retrospective cohort study of 28 patients with retinitis pigmentosa (RP), we used OCT-A to quantify changes in perfusion density, foveal avascular zone (FAZ) area, and choriocapillaris blood flow over time and correlated these variables with ellipsoid zone (EZ) line width and best-corrected visual acuity (BCVA). Perfusion density decreased by 2.42 ± 0.62% per year at the superior capillary plexus (SCP) (P = 0.001) and 2.41 ± 0.76% per year at the deep capillary plexus (DCP) (P = 0.004). FAZ area increased by 0.078 ± 0.021 mm2 per year (P = 0.001) at the SCP and 0.152 ± 0.039 mm2 per year (P = 0.001) at the DCP. No changes were observed in the choriocapillaris blood flow. EZ line width had the strongest correlation to perfusion density at the SCP (r = 0.660 and 0.635, first and second visit, respectively, P = 0.001), while BCVA most strongly correlated with FAZ area at the SCP (r = 0.679 and 0.548, P = 0.001 and 0.003). Our results suggest that OCT-A is a useful tool for monitoring RP disease progression and may be used to measure retinal vascular parameters as outcomes in clinical trials.

Background SLIT2 is a protein ligand for the Roundabout (ROBO) receptor and was found to play a major role in repulsive midline axon guidance in central nervous system development. Based on studies utilizing knockout models, it has been postulated that SLIT2 is important for preventing inappropriate axonal routing during mammalian optic chiasm development. Methods Case report. Results Here, we report a case of congenital myopia, anisometropia, and obesity in a patient with a SLIT2 point mutation. Examination of the patient’s skin biopsy revealed abnormalities in elastin and collagen fibrils that suggest an underlying connective tissue disorder. Structural modeling placed the novel mutation (p.D1407G) in the EGF-like domain 8 and was predicted to affect interactions with SLIT2 binding partners. Conclusions To the authors’ knowledge, this is the first report of a SLIT2 variant in the context of these ocular findings.

Mutations in the gene RPE65 (OMIM: 180069) are recessively inherited and known to cause Leber congenital amaurosis. Recently, the mutation D477G in RPE65 has been identified as a cause of autosomal dominant retinitis pigmentosa (RP). Variable expressivity of this disease has been reported, as carrier individuals can present with mild, nonpenetrant, or, most commonly, a severe chorioretinal phenotype that resembles choroideremia. We report the case of a 57-yr-old male who presented to our clinic with nyctalopia and decreasing visual acuity for 1 yr. Dilated fundus examination revealed retinal atrophy and peripheral mottling of the retinal pigment epithelium (RPE). SW-AF revealed patchy hypoautofluorescence throughout the posterior pole with separate lacunae-like areas in the macula of severe RPE atrophy along with foveal sparing. Full-field electroretinogram suggested a rod–cone dystrophy. Whole-exome sequencing revealed the heterozygous mutation c.1430A > G (p.D477G) in the RPE65 gene. This phenotype of peripheral RPE mottling and severe macular lacunae-like atrophy has not been previously reported with RPE65 autosomal dominant RP, supporting the variable expressivity of the disease and expanding the known phenotypic presentations.

BackgroundLittle is known regarding long-term outcomes of patients hospitalized with COVID-19.MethodsWe conducted a prospective study of 6-month outcomes of hospitalized COVID-19 patients. Patients with new neurological complications during hospitalization who survived were propensity score-matched to COVID-19 survivors without neurological complications hospitalized during the same period. The primary 6-month outcome was multivariable ordinal analysis of the modified Rankin Scale(mRS) comparing patients with or without neurological complications. Secondary outcomes included: activities of daily living (ADLs;Barthel Index), telephone Montreal Cognitive Assessment and Neuro-QoL batteries for anxiety, depression, fatigue and sleep.ResultsOf 606 COVID-19 patients with neurological complications, 395 survived hospitalization and were matched to 395 controls; N=196 neurological patients and N=186 controls completed follow-up. Overall, 346/382 (91%) patients had at least one abnormal outcome: 56% had limited ADLs, 50% impaired cognition, 47% could not return to work and 62% scored worse than average on ≥1 Neuro-QoL scale (worse anxiety 46%, sleep 38%, fatigue 36%, and depression 25%). In multivariable analysis, patients with neurological complications had worse 6-month mRS (median 4 vs. 3 among controls, adjusted OR 2.03, 95%CI 1.22-3.40, P=0.01), worse ADLs (aOR 0.38, 95%CI 0.29-0.74, P=0.01) and were less likely to return to work than controls (41% versus 64%, P=0.04). Cognitive and Neuro-QOL metrics were similar between groups.ConclusionsAbnormalities in functional outcomes, ADLs, anxiety, depression and sleep occurred in over 90% of patients 6-months after hospitalization for COVID-19. In multivariable analysis, patients with neurological complications during index hospitalization had significantly worse 6-month functional outcomes than those without.

Retinitis pigmentosa (RP) is described as a bilateral disease with inter-eye symmetry that presents on short-wavelength fundus autofluorescence (SW-AF) imaging with hyperautofluorescent (hyperAF) rings with an ellipsoid shape and regular borders. Nevertheless, both asymmetry and irregular ring morphologies are also observed. In this retrospective study of 168 RP patients, we characterize the degree of inter-eye asymmetry and frequency of irregular hyperAF ring morphologies according to mode of inheritance and disease-causing gene by using SW-AF imaging and spectral-domain optical coherence tomography (SD-OCT) scans. We observed that from 336 eyes, 290 (86%) presented with regular hyperAF rings and 46 (14%) presented with irregular shapes. From the 168 patients, 23 (14%) presented with asymmetric disease, with 16 (70%) of these patients also presenting with irregular ring shapes. Patients with autosomal dominant RP (adRP) had the highest proportion of irregular ring shapes (21%) and disease asymmetry (23%) in comparison to other modes of inheritance. Furthermore, both RP1 and RHO-adRP had the highest proportions of both disease asymmetry and irregular ring morphology. Our results suggest that in patients presenting with either irregular ring shapes or asymmetric disease, emphasis should be placed in targeted gene sequencing of genes known to cause adRP, such as RHO and RP1.

Autoimmune retinopathy (AIR) is a rare inflammatory condition characterized by progressive visual loss, abnormalities in visual fields and electroretinographic exams, along with presence of circulating anti-retinal antibodies. There are two main forms of AIR: paraneoplastic AIR (pAIR) and presumed non-paraneoplastic AIR (npAIR). NpAIR is considered a diagnosis of exclusion, since it is typically made after other causes of retinopathy have been investigated and the absence of malignancy is confirmed. Work-up of a npAIR case is challenging since there are no standartizaded protocols for diagnosis and treatment. The treatment regimen may vary from case to case, and it can be best guided by a set of parameters including electrophysiological responses, visual outcomes, and presence of anti-retinal antibodies. The purpose of this review is to summarize the principal clinical features, investigation, and management of npAIR.

Purpose To characterize and bring awareness to the disease spectrum of female choroideremia patients, as severity can vary from mild to severe disease, comparable to that observed in male patients. Design Retrospective cohort study. Methods Twelve female carriers of disease-causing variants in the CHM gene confirmed by molecular genetic sequencing were characterized clinically and imaged with short-wave fundus autofluorescence (SW-FAF), spectral-domain optical coherence tomography (OCT), and color fundus imaging. Results Twelve unrelated female patients with a clinical and genetic diagnosis of choroideremia carriers were included in this study. Disease severity among these phenotypes ranged from mild to severe, resembling the typical presentation of choroideremia in male patients. Mild disease presented with retinal pigment epithelium mottling, a patchy pattern of hypoautofluorescent speckles on SW-FAF, and intact retinal layers on spectral-domain OCT. Severe disease presented with widespread chorioretinal atrophy as shown by SW-FAF and spectral-domain OCT. Each of the identified genetic variants in CHM was predicted to be disease-causing according to in silico prediction software. Disease progression analysis of 4 patients with follow-up showed a decline in visual acuity for 2 patients, with progression observed on spectral-domain OCT in 1 of the patients. No significant disease progression on SW-FAF was observed for any of the patients. Conclusions Female carriers of choroideremia can present with a wide range of clinical phenotypes and disease severity, from mild to severe disease, similar to male subjects. Symptomatic female subjects should be considered for current and upcoming gene replacement therapy clinical trials.

There is a lack of studies which seek to discern disease expression in patients with mutations that alter retinal ceramide metabolism, specifically in the ceramide kinase like (CERKL) gene. This cross-sectional case series reports a novel phenotypic manifestation of CERKL-associated retinopathy. Four unrelated patients with homozygous CERKL mutations underwent a complete ocular exam, spectral-domain optical coherence tomography, short-wavelength fundus autofluorescence (SW-AF), quantitative autofluorescence (qAF), and full-field electroretinogram (ffERG). Decreased visual acuity and early-onset maculopathy were present in all patients. All four patients had extensive hyperautofluorescent foci surrounding an area of central atrophy on SW-AF imaging, which has not been previously characterized. An abnormal spatial distribution of qAF signal was seen in one patient, and abnormally elevated qAF8 signal in another patient. FfERG recordings showed markedly attenuated rod and cone response in all patients. We conclude that these patients exhibit several features that, collectively, may warrant screening of CERKL as a first candidate: early-onset maculopathy, severe generalized retinal dysfunction, peripheral lacunae, intraretinal pigment migration, and hyperautofluorescent foci on SW-AF.

Mutations in the gene SCAPER (S-phase CyclinA Associated Protein residing in the Endoplasmic Reticulum) have recently been identified as causing syndromic autosomal recessive retinitis pigmentosa with the extraocular manifestations of intellectual disability and attention-deficit/hyperactivity disorder. We present the case of an 11-year-old boy that presented to our clinic with the complaint of decreased night vision. Clinical presentation, family history, and diagnostic imaging were congruent with the diagnosis of autosomal recessive retinitis pigmentosa. Genetic testing of the patient and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Unique to our patient's presentation is the absence of intellectual disability and attention-deficit/hyperactivity disorder, suggesting that SCAPER-associated retinitis pigmentosa can also present without systemic manifestations.

Mutations in the gene RPE65 (OMIM: 180069) are recessively inherited and known to cause Leber congenital amaurosis. Recently, the mutation D477G in RPE65 has been identified as a cause of autosomal dominant retinitis pigmentosa (RP). Variable expressivity of this disease has been reported, as carrier individuals can present with mild, nonpenetrant, or, most commonly, a severe chorioretinal phenotype that resembles choroideremia. We report the case of a 57-yr-old male who presented to our clinic with nyctalopia and decreasing visual acuity for 1 yr. Dilated fundus examination revealed retinal atrophy and peripheral mottling of the retinal pigment epithelium (RPE). SW-AF revealed patchy hypoautofluorescence throughout the posterior pole with separate lacunae-like areas in the macula of severe RPE atrophy along with foveal sparing. Full-field electroretinogram suggested a rod–cone dystrophy. Whole-exome sequencing revealed the heterozygous mutation c.1430A > G (p.D477G) in the RPE65 gene. This phenotype of peripheral RPE mottling and severe macular lacunae-like atrophy has not been previously reported with RPE65 autosomal dominant RP, supporting the variable expressivity of the disease and expanding the known phenotypic presentations.

BACKGROUND: The RPE65 gene was recently described to cause autosomal dominant retinitis pigmentosa (adRP), presenting with a phenotype resembling choroideremia. This study presents the 2-year progression of RPE65 adRP in a patient. METHODS: This is an observational case report of one patient. The patient received a full ophthalmic examination during both visits, including diagnostic imaging such as spectral domain optical coherence tomography (SD-OCT), OCT-angiography (OCT-A), short-wave fundus autofluorescence (FAF), and fundus photography. Genetic characterization was obtained by DNA sequencing from peripheral blood lymphocytes obtained during the first visit. RESULTS: RPE65 adRP phenocopied choroideremia at the initial fundoscopy. Upon the patient’s return to our clinic 2 years later, DNA sequencing revealed a heterozygous mutation in the RPE65 gene. Diagnostic imaging by SD-OCT and FAF suggested disease progression. In conjunction with clinical examination and imaging, the diagnosis was revised to autosomal dominant retinitis pigmentosa caused by RPE65. CONCLUSION: adRP due to a mutation in the gene encoding RPE65 phenocopied choroideremia. Based on our analysis of the 2-year disease progression in this patient, RPE65 adRP is mild and has a slow rate of disease progression.

Microglia cells (MGCs) play a key role in scavenging pathogens and phagocytosing cellular debris in the central nervous system and retina. Their activation, however, contributes to the progression of multiple degenerative diseases. Given the potential damage created by MGCs, it is important to better understand their mechanism of activation. Here, we explored the role of MGCs in the context of retinitis pigmentosa (RP) by using four independent preclinical mouse models. For therapeutic modeling, tamoxifen-inducible CreER was introduced to explore changes in MGCs when RP progression halted. The phenotypes of the MGCs were observed using live optical coherence tomography, live autofluorescence, and immunohistochemistry. We found that, regardless of genetic background, MGCs were activated in neurodegenerative conditions and migrated beyond the layers where they are typically found to the inner and outer segments, where degeneration was ongoing. Genetic rescue not only halted degeneration but also deactivated MGCs, regardless of whether the intervention occurred at the early, middle, or late stage of the disease. These findings suggest that halting long-term disease progression may be more successful by downregulating MGC activity while co-administering the therapeutic intervention.

PURPOSE: Gyrate atrophy (GA) is a rare chorioretinal degeneration that results in the deterioration of night and peripheral vision, eventually leading to blindness. The disorder is caused by mutations in the gene encoding ornithine amino transferase (OAT), causing increased levels of plasma ornithine. Treatment revolves around lowering plasma ornithine levels, with vitamin B6 supplementation being the preferred treatment. Nevertheless, most patients do not respond to this therapy. Here we report a rare case of vitamin B6-responsive GA caused by a novel mutation in OAT and characterize the presentation with multimodal imaging. METHODS: This is a single-patient case report with a clinical diagnosis based on history, multimodal retinal imaging, laboratory findings, and DNA sequencing analysis. We include a 3D structure prediction of the novel mutant protein. RESULTS: DNA sequencing analysis demonstrated that there is a homozygous, novel variant c.473A>C: p.Y158S in OAT. Upon undergoing two weeks of vitamin B6 supplementation, the patient exhibited a 28.5% reduction in plasma ornithine levels. In a follow-up visit two years later, plasma ornithine levels were reduced by 24.1% from the levels at initial presentation and disease progression was retarded based on clinical findings. CONCLUSION: One novel homozygous missense mutation in OAT was identified and considered to be pathogenic in a patient with GA. The response for the vitamin B6 supplementation was positive, which is rare in all the GA cases reported in the literature. Our data suggests that further studies regarding the relationship between genotype and responsiveness to vitamin B6 should be conducted.

Inherited retinal diseases (IRDs) are a major cause of incurable familial blindness in the Western world. In the pediatric population, IRDs are a major contributor to the 19 million children worldwide with visual impairment. Unfortunately, the road to the correct diagnosis is often complicated in the pediatric population, as typical diagnostic tools such as fundus examination, electrodiagnostic studies, and other imaging modalities may be difficult to perform in the pediatric patient. In this review, we describe the most significant IRDs with onset during the pediatric years (ie, before the age of 18). We describe the pathogenesis, clinical presentation, and potential treatment of these diseases. In addition, we advocate the use of a pedigree (family medical history), electroretinography, and genetic testing as the 3 most crucial tools for the correct diagnosis of IRDs in the pediatric population.

RPGR -associated retinitis pigmentosa (RP) is a progressive disease with retina degeneration. Optical coherence tomography angiography (OCTA) is an imaging technique that provides novel insights. The authors report two affected male siblings who underwent OCTA imaging. The area of the foveal avascular zone (FAZ) was measured. Although the younger sibling exhibited more advanced clinical disease, his visual acuity was superior to his older sibling. OCTA imaging revealed a better preserved FAZ in the younger sibling as the reason for this. It also highlighted attenuation of choriocapillaris / choroid layers as biomarkers for disease severity. This provides new insights into retinal degeneration in RPGR -associated RP. [ Ophthalmic Surg Lasers Imaging Retina. 2019;50:e44–e48.]

Purpose To develop a universal gene therapy to overcome the genetic heterogeneity in retinitis pigmentosa (RP) resulting from mutations in rhodopsin ( RHO ). Design Experimental study for a combination gene therapy that uses both gene ablation and gene replacement. Participants This study included 2 kinds of human RHO mutation knock-in mouse models: Rho P23H and Rho D190N . In total, 23 Rho P23H/P23H , 43 Rho P23H/+ , and 31 Rho D190N/+ mice were used for analysis. Methods This study involved gene therapy using dual adeno-associated viruses (AAVs) that (1) destroy expression of the endogenous Rho gene in a mutation-independent manner via an improved clustered regularly interspaced short palindromic repeats-based gene deletion and (2) enable expression of wild-type protein via exogenous cDNA. Main Outcome Measures Electroretinographic and histologic analysis. Results The thickness of the outer nuclear layer (ONL) after the subretinal injection of combination ablate-and-replace gene therapy was approximately 17% to 36% more than the ONL thickness resulting from gene replacement-only therapy at 3 months after AAV injection. Furthermore, electroretinography results demonstrated that the a and b waves of both Rho P23H and Rho D190N disease models were preserved more significantly using ablate-and-replace gene therapy ( P Conclusions As a proof of concept, our results suggest that the ablate-and-replace strategy can ameliorate disease progression as measured by photoreceptor structure and function for both of the human mutation knock-in models. These results demonstrate the potency of the ablate-and-replace strategy to treat RP caused by different Rho mutations. Furthermore, because ablate-and-replace treatment is mutation independent, this strategy may be used to treat a wide array of dominant diseases in ophthalmology and other fields. Clinical trials using ablate-and-replace gene therapy would allow researchers to determine if this strategy provides any benefits for patients with diseases of interest.

Cdc48 (also known as p97 or VCP) is an essential and highly abundant, double-ring AAA+ ATPase, which is ubiquitous in archaea and eukaryotes. In archaea, Cdc48 ring hexamers play a direct role in quality control by unfolding and translocating protein substrates into the degradation chamber of the 20S proteasome. Whether Cdc48 and 20S cooperate directly in protein degradation in eukaryotic cells is unclear. Two regions of Cdc48 are important for 20S binding, the pore-2 loop at the bottom of the D2 AAA+ ring and a C-terminal tripeptide. Here, we identify an aspartic acid in the pore-2 loop as an important element in 20S recognition. Importantly, mutation of this aspartate in human Cdc48 has been linked to familial amyotrophic lateral sclerosis (ALS). In archaeal or human Cdc48 variants, we find that mutation of this pore-2 residue impairs 20S binding and proteolytic communication but does not affect the stability of the hexamer or rates of ATP hydrolysis and protein unfolding. These results suggest that human Cdc48 interacts functionally with the 20S proteasome.

Proteasomes are ubiquitous ATP-dependent proteases that function in eukarya, archaea, and actinobacteria. These proteolytic machines employ a barrel-shaped 20S core peptidase and a hexameric AAA+ u...