Best Vitelliform Macular Dystrophy Natural History Study Report 1: Clinical Features and Genetic Findings.

PURPOSE: To analyze the genetic findings, clinical spectrum, and natural history of Best vitelliform macular dystrophy (BVMD) in a cohort of 222 children and adults. DESIGN: Single-center retrospective, consecutive, observational study. PARTICIPANTS: Patients with a clinical diagnosis of BVMD from pedigrees with a likely disease-causing monoallelic sequence variant in the BEST1 gene. METHODS: Data were extracted from electronic and physical case notes. Electrophysiologic assessment and molecular genetic testing were analyzed. MAIN OUTCOME MEASURES: Molecular genetic test findings and clinical findings including best-corrected visual acuity (BCVA), choroidal neovascularization (CNV) rates, and electrophysiologic parameters. RESULTS: Two hundred twenty-two patients from 141 families were identified harboring 69 BEST1 variants. Mean age at presentation was 26.8 years (range, 1.3-84.8 years) and most patients (61.5%) demonstrated deterioration of central vision. Major funduscopic findings included 128 eyes (30.6%) with yellow vitelliform lesions, 78 eyes (18.7%) with atrophic changes, 49 eyes (11.7%) with fibrotic changes, 48 eyes (11.5%) with mild pigmentary changes, and 43 eyes (10.3%) showing a vitelliruptive appearance. Mean BCVA was 0.37 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/47) for the right eye and 0.33 logMAR (Snellen equivalent, 20/43) for the left eye at presentation, with a mean annual loss rate of 0.013 logMAR and 0.009 logMAR, respectively, over a mean follow-up of 9.7 years. Thirty-seven patients (17.3%) received a diagnosis of CNV over a mean follow-up of 8.0 years. Eyes with CNV that received treatment with an anti-vascular endothelial growth factor (VEGF) agent showed better mean BCVA compared with eyes that were not treated with an anti-VEGF agent (0.28 logMAR [Snellen equivalent, 20/38] vs. 0.62 logMAR [Snellen equivalent, 20/83]). Most eyes exhibited a hyperopic refractive error (78.7%), and 13 patients (6.1%) received a diagnosis of amblyopia. Among the 3 most common variants, p.(Ala243Val) was associated with a later age of onset, better age-adjusted BCVA, and less advanced Gass stages compared with p.(Arg218Cys) and p.(Arg218His). CONCLUSIONS: BVMD shows a wide spectrum of phenotypic variability. The disease is very slowly progressive, and the observed phenotype-genotype correlations allow for more accurate prognostication and counselling. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.

The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.

RP2-Associated X-linked Retinopathy: Clinical Findings, Molecular Genetics, and Natural History.

PURPOSE: To review and describe in detail the clinical course, functional and anatomic characteristics of RP2-associated retinal degeneration. DESIGN: Retrospective case series. PARTICIPANTS: Male participants with disease-causing variants in the RP2 gene. METHODS: Review of all case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence [FAF] imaging, OCT), and electrophysiology assessment. MAIN OUTCOME MEASURES: Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), qualitative and quantitative retinal imaging analysis, and electrophysiology parameters. RESULTS: Fifty-four molecularly confirmed patients were identified from 38 pedigrees. Twenty-eight disease-causing variants were identified, with 20 not previously clinically characterized. Fifty-three patients (98.1%) presented with retinitis pigmentosa. The mean age of onset (range ± standard deviation [SD]) was 9.6 years (1-57 ± 9.2 years). Forty-four patients (91.7%) had childhood-onset disease, with mean age of onset of 7.6 years. The most common first symptom was night blindness (68.8%). Mean BCVA (range ± SD) was 0.91 logarithm of the minimum angle of resolution (logMAR) (0-2.7 ± 0.80) and 0.94 logMAR (0-2.7 ± 0.78) for right and left eyes, respectively. On the basis of the World Health Organization visual impairment criteria, 18 patients (34%) had low vision. The majority (17/22) showed electroretinogram (ERG) evidence of a rod-cone dystrophy. Pattern ERG P50 was undetectable in all but 2 patients. A range of FAF findings was observed, from normal to advanced atrophy. There were no statistically significant differences between right and left eyes for ellipsoid zone width (EZW) and outer nuclear layer (ONL) thickness. The mean annual rate of EZW loss was 219 µm/year, and the mean annual decrease in ONL thickness was 4.93 µm/year. No patient with childhood-onset disease had an identifiable ellipsoid zone (EZ) after the age of 26 years at baseline or follow-up. Four patients had adulthood-onset disease and a less severe phenotype. CONCLUSIONS: This study details the clinical phenotype of RP2 retinopathy in a large cohort. The majority presented with early-onset severe retinal degeneration, with early macular involvement and complete loss of the foveal photoreceptor layer by the third decade of life. Full-field ERGs revealed rod-cone dystrophy in the vast majority, but with generalized (peripheral) cone system involvement of widely varying severity in the first 2 decades of life. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

X-Linked Retinoschisis: Deep Phenotyping and Genetic Characterization.

PURPOSE: To examine the genetic and clinical features in children and adults with X-linked retinoschisis (XLRS). DESIGN: Single-center consecutive, retrospective, observational study. PARTICIPANTS: Adults and children with molecularly confirmed XLRS followed up between 1999 and 2020. METHODS: Analysis of genetic, clinical, and retinal imaging findings, including OCT and fundus autofluorescence (FAF), cross-sectionally and longitudinally, was performed. MAIN OUTCOMES MEASURES: RS1, variants, type of variants and phenotype correlations, age of onset, complications rates and types, fundoscopy findings, OCT metrics, FAF patterns, correlations including between best corrected visual acuity (BCVA) and age, and OCT characteristics. RESULTS: One hundred thirty-two male patients were identified harboring 66 retinoschisin 1 variants, with 7 being novel. The mean age at onset was 16.5 years (range, 0-58 years). Seventy-one patients (71/75 [94.7%]) were symptomatic at presentation; all had decreased best-corrected visual acuity (BCVA). Funduscopy findings were symmetric in 104 patients (104/108 [96.3%]), with the most common finding being macular schisis (82.4%), whereas peripheral retinoschisis was present in 38.9% and macular atrophy was present in 11.1%. Twenty patients (18.5%) demonstrated complications (vitreous hemorrhage, retinal detachment, or both). Mean BCVA was 0.65 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/89) in the right eye and 0.64 logMAR (Snellen equivalent, 20/87) in the left eye. Mean BCVA change over a mean interval of 6.7 years was 0.04 and 0.01 logMAR for right and left eyes, respectively. A normal FAF pattern was identified in 16 of 106 eyes (15.1%); 45 eyes (42.5%) showed a spoke-wheel pattern, 13 eyes (12.3%) showed foveal hyperautofluorescence, and 18 eyes (17.0%) showed a central reduction in signal. In total, 14 patients demonstrated evidence of progression on FAF over time. On OCT, foveoschisis was observed in 172 eyes (172/215 [80%]), parafoveal schisis was observed in 171 eyes (171/215 [79.5%]), and foveal atrophy was observed in 44 eyes (44/215 [20.5%]). Cystoid changes were localized to the inner nuclear layer (172/181 eyes [95%]), the outer nuclear layer (97/181 [53.6%]), and the ganglion cell layer (92/181 [50.8%]). Null variants were associated with worse final BCVA and aforementioned complications. CONCLUSIONS: X-linked retinoschisis is highly phenotypically variable, but with relative foveal and BCVA preservation until late adulthood, allowing more accurate prognostication. The slowly (often minimally) progressive disease course may pose a challenge in identification of early end points for therapeutic trials aimed at altering the kinetics of degeneration.

Autosomal Recessive Bestrophinopathy: Clinical Features, Natural History, and Genetic Findings in Preparation for Clinical Trials.

PURPOSE: To investigate the clinical course, genetic findings, and phenotypic spectrum of autosomal recessive bestrophinopathy (ARB) in a large cohort of children and adults. DESIGN: Retrospective case series. PARTICIPANTS: Patients with a detailed clinical phenotype consistent with ARB, biallelic likely disease-causing sequence variants in the BEST1 gene, or both identified at a single tertiary referral center. METHODS: Review of case notes, retinal imaging (color fundus photography, fundus autofluorescence, OCT), electrophysiologic assessment, and molecular genetic testing. MAIN OUTCOME MEASURES: Visual acuity (VA), retinal imaging, and electrophysiologic changes over time. RESULTS: Fifty-six eyes of 28 unrelated patients were included. Compound heterozygous variants were detected in most patients (19/27), with 6 alleles recurring in apparently unrelated individuals, the most common of which was c.422G→A, p.(Arg141His; n = 4 patients). Mean presenting VA was 0.52 ± 0.36 logarithm of the minimum angle of resolution (logMAR), and final VA was 0.81 ± 0.75 logMAR (P = 0.06). The mean rate of change in VA was 0.05 ± 0.13 logMAR/year. A significant change in VA was detected in patients with a follow-up of 5 years or more (n = 18) compared with patients with a follow-up of 5 years or less (n = 10; P = 0.001). Presence of subretinal fluid and vitelliform material were early findings in most patients, and this did not change substantially over time. A reduction in central retinal thickness was detected in most eyes (80.4%) over the course of follow-up. Many patients (10/26) showed evidence of generalized rod and cone system dysfunction. These patients were older (P < 0.001) and had worse VA (P = 0.02) than those with normal full-field electroretinography results. CONCLUSIONS: Although patients with ARB are presumed to have no functioning bestrophin channels, significant phenotypic heterogeneity is evident. The clinical course is characterized by a progressive loss of vision with a slow rate of decline, providing a wide therapeutic window for anticipated future treatment strategies.

Inherited retinal diseases: Therapeutics, clinical trials and end points-A review.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders characterised by photoreceptor degeneration or dysfunction. These disorders typically present with severe vision loss that can be progressive, with disease onset ranging from congenital to late adulthood. The advances in genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRDs, with the first approved gene therapy and the commencement of multiple clinical trials. The scope of this review is to familiarise clinicians and scientists with the current management and the prospects for novel therapies for: (1) macular dystrophies, (2) cone and cone-rod dystrophies, (3) cone dysfunction syndromes, (4) Leber congenital amaurosis, (5) rod-cone dystrophies, (6) rod dysfunction syndromes and (7) chorioretinal dystrophies. We also briefly summarise the investigated end points for the ongoing trials.

Optimal timing of imaging in gastric emptying scintigraphy for the detection of delayed emptying.

OBJECTIVE: The purpose of this study was to evaluate a standard 4-h imaging protocol for gastric emptying scintigraphy (GES) in detecting delayed gastric emptying (GE). SUBJECTS AND METHODS: Gamma camera imaging was performed in the anterior and posterior views at 0, 0.5, 1, 1.5, 2, 2.5 and 4-h as per established Miami method (MIA) and National Standard Protocol (NSP), in accordance with the consensus guidelines of the ANMS/SNM [SNMMI] Societies. Patients (N=1002) received a standardized solid meal radiolabeled with 1mCi of technetium-99 (99mTc) sulfur colloid. Quantitative analysis was performed using geometric mean calculation of decay-corrected counts at each imaging time point, expressed as percent emptying or retention. RESULTS: In our patient cohort, 21% had delayed GE at 4h, whereas 79% had normal emptying with less than 10% retention at 4h. There was a 25% increase in delayed GE studies at 4h versus 2h. From those patients who had delayed GE at 2h, 30% normalized at 4h, while 10% of patients with normal GE at 2h became delayed at 4h thus indicating that more studies changed from abnormal to normal than from normal to abnormal at 4h. Greater than 90% GE was found in 9% of patients at 2 h and 25% of patients at 2.5h and this persisted at 4h. The study at 2h as compared with 4h, had 56% sensitivity, 95% specificity, 70% PPV and 91% NPV. CONCLUSION: The 4-h imaging was very important in detecting cases that were delayed at 2h but normalized at 4h, and also cases with normal GE at 2h that became abnormal at 4h. These findings support the ANMS/SNM [SNMMI] recommendations. Gastric emptying value ≥90% at 2.5h can be used as threshold in predicting normal GE and the study could be terminated without additional imaging.

Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom.

PURPOSE: In a large cohort of molecularly characterized inherited retinal disease (IRD) families, we investigated proportions with disease attributable to causative variants in each gene. DESIGN: Retrospective study of electronic patient records. PARTICIPANTS: Patients and relatives managed in the Genetics Service of Moorfields Eye Hospital in whom a molecular diagnosis had been identified. METHODS: Genetic screening used a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. For this study, genes listed in the Retinal Information Network online resource (https://sph.uth.edu/retnet/) were included. Transcript length was extracted for each gene (Ensembl, release 94). MAIN OUTCOME MEASURES: We calculated proportions of families with IRD attributable to variants in each gene in the entire cohort, a cohort younger than 18 years, and a current cohort (at least 1 patient encounter between January 1, 2017, and August 2, 2019). Additionally, we explored correlation between numbers of families and gene transcript length. RESULTS: We identified 3195 families with a molecular diagnosis (variants in 135 genes), including 4236 affected individuals. The pediatric cohort comprised 452 individuals from 411 families (66 genes). The current cohort comprised 2614 families (131 genes; 3130 affected individuals). The 20 most frequently implicated genes overall (with prevalence rates per families) were as follows: ABCA4 (20.8%), USH2A (9.1%), RPGR (5.1%), PRPH2 (4.6%), BEST1 (3.9%), RS1 (3.5%), RP1 (3.3%), RHO (3.3%), CHM (2.7%), CRB1 (2.1%), PRPF31 (1.8%), MY07A (1.7%), OPA1 (1.6%), CNGB3 (1.4%), RPE65 (1.2%), EYS (1.2%), GUCY2D (1.2%), PROM1 (1.2%), CNGA3 (1.1%), and RDH12 (1.1%). These accounted for 71.8% of all molecularly diagnosed families. Spearman coefficients for correlation between numbers of families and transcript length were 0.20 (P = 0.025) overall and 0.27 (P = 0.017), -0.17 (P = 0.46), and 0.71 (P = 0.047) for genes in which variants exclusively cause recessive, dominant, or X-linked disease, respectively. CONCLUSIONS: Our findings help to quantify the burden of IRD attributable to each gene. More than 70% of families showed pathogenic variants in 1 of 20 genes. Transcript length (relevant to gene delivery strategies) correlated significantly with numbers of affected families (but not for dominant disease).

Gastric Emptying Scintigraphy Protocol Optimization Using Machine Learning for the Detection of Delayed Gastric Emptying.

PURPOSE: The purpose of this study is to examine the feasibility of a machine learning (ML) system for optimizing a gastric emptying scintigraphy (GES) protocol for the detection of delayed gastric emptying (GE), which is considered a primary indication for the diagnosis of gastroparesis. METHODS: An ML model was developed using the JADBio AutoML artificial intelligence (AI) platform. This model employs the percent GE at various imaging time points following the ingestion of a standardized radiolabeled meal to predict normal versus delayed GE at the conclusion of the 4 h GES study. The model was trained and tested on a cohort of 1002 patients who underwent GES using a 70/30 stratified split ratio for training vs. testing. The ML software automated the generation of optimal predictive models by employing a combination of data preprocessing, appropriate feature selection, and predictive modeling analysis algorithms. RESULTS: The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was employed to evaluate the predictive modeling performance. Several models were developed using different combinations of imaging time points as input features and methodologies to achieve optimal output. By using GE values at time points 0.5 h, 1 h, 1.5 h, 2 h, and 2.5 h as input predictors of the 4 h outcome, the analysis produced an AUC of 90.7% and a balanced accuracy (BA) of 80.0% on the test set. This performance was comparable to the training set results (AUC = 91.5%, BA = 84.7%) within the 95% confidence interval (CI), demonstrating a robust predictive capability. Through feature selection, it was discovered that the 2.5 h GE value alone was statistically significant enough to predict the 4 h outcome independently, with a slightly increased test set performance (AUC = 92.4%, BA = 83.3%), thus emphasizing its dominance as the primary predictor for delayed GE. ROC analysis was also performed for single time imaging points at 1 h and 2 h to assess their independent predictiveness of the 4 h outcome. Furthermore, the ML model was tested for its ability to predict "flipping" cases with normal GE at 1 h and 2 h that became abnormal with delayed GE at 4 h. CONCLUSIONS: An AI/ML model was designed and trained for predicting delayed GE using a limited number of imaging time points in a 4 h GES clinical protocol. This study demonstrates the feasibility of employing ML for GES optimization in the detection of delayed GE and potentially shortening the protocol's time length without compromising diagnostic power.

Longitudinal Imaging of the Foveal Cone Mosaic in CNGA3-Associated Achromatopsia.

Purpose: The purpose of this study was to assess the natural history of the foveal cone mosaic in CNGA3-associated achromatopsia (ACHM). Methods: Thirteen eyes from 10 genetically confirmed patients underwent longitudinal imaging with optical coherence tomography (OCT) and non-confocal split detection adaptive optics scanning light ophthalmoscopy (AOSLO). OCT scans assessed outer nuclear layer (ONL) thickness, foveal ellipsoid zone (EZ) disruption, and foveal hypoplasia. AOSLO images were analyzed to calculate peak foveal cone density (PCD) and mean inter-cell distance (ICD) between cones. Mixed effects models were used to analyze the rate of annual change of PCD and ICD. Results: Mean (±SD) age at visits was 29 ± 10 years, with a follow-up of 2.6 ± 1 years. There was no change in ONL thickness, degree of EZ disruption, or foveal hypoplasia over the follow-up period. We also observed a stable foveal cone mosaic using AOSLO imaging, with no significant change in PCD or ICD. Mean PCD was 15,346 cones/mm² at the mean age of 29 years old (cf. 64,000-324,000 cones/mm² in previously reported healthy controls), with a mean rate of change of -117.79 cones/mm² (0.8%) per year, P = 0.130. Mean ICD at the mean age was 13.82 µm, with a rate of change of 0.17 µm per year, P = 0.83. Conclusions: CNGA3-associated ACHM displays stable foveal cone structure over time with a similar rate of change to CNGB3-associated ACHM (2% decline per year). The stable PCD, small cohort, and large variability within the cohort means significant age associations were not detected.

Cataract Surgery Outcomes in Retinitis Pigmentosa A Comparative Clinical Database Study.

PURPOSE: To report visual acuity (VA) outcomes, intraoperative and postoperative complications of isolated cataract surgery in eyes with retinitis pigmentosa (RP), compared with non-RP-affected eyes. DESIGN: Retrospective clinical cohort study. METHODS: A total of 113,389 eyes underwent cataract surgery between July 2003 and March 2015 at 8 clinical sites in the United Kingdom. Eyes with RP as the only comorbid pathology and eyes without any ocular comorbidities (controls) undergoing cataract surgery were compared. VA at 4 to 12 weeks postoperatively and rates of intraoperative and postoperative complications are reported. RESULTS: Seventy-two eyes had RP. The mean age in the RP group was 57 ± 15 compared to 75 ± 10 in controls (P < .001). Females represented 46% of RP cases and 60% of controls (P = .06). Preoperative VA (mean LogMAR = 1.03 vs 0.59, P < .001) and postoperative VA (0.71 vs 0.14, P < .001) were worse in RP group. The mean VA gain was 0.25 ± 0.60 LogMAR in RP vs 0.43 ± 0.48 LogMAR in controls (P < .001). There were no significant differences in the rate of intraoperative pupil expansion use, posterior capsular tears, or zonular dialysis. Postoperative cystoid macular edema developed in 6.9% of RP eyes and 1% of controls (P < .001). The need for IOL repositioning or exchange was not statistically different between the two groups. CONCLUSION: Cataract surgery can improve vision in eyes with RP and cataract. Intraoperative complications were similar to control eyes; however, RP eyes experienced more frequent postoperative cystoid macular edema.

Fractal Changes of the Retinal Microvasculature in Birdshot Chorioretinopathy.

BACKGROUND AND OBJECTIVE: Retinal vascular disorders are associated with lower fractal dimension (FD). We analyzed FD in birdshot chorioretinopathy (BSCR). PATIENTS AND METHODS: This was a retrospective cohort study. We performed optical coherence tomography angiography (OCTA) and analyzed FD of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) using ImageJ. For each vascular layer, we analyzed the presence of BSCR, subjects' age, sex, and presence of diabetes mellitus to determine which may predict lower FD. RESULTS: We compared 28 eyes (14 patients) with BSCR to 34 control eyes (17 patients). Mean FD of BSCR was lower in SCP (1.584 [± 0.126] vs 1.706 [± 0.118], P < 0.001), DCP (1.637 [± 0.134] vs 1.780 [± 0.096], P < 0.001), and CC (1.884 [± 0.063] vs 1.917 [± 0.047], P = 0.036). FD of SCP was lower per increasing year (0.005 [P = 0.014]). Male patients had lower FD-DCP (0.101 [P = 0.043]). CONCLUSION: In BSCR, fractal analysis showed significant involvement of the SCP, DCP, and to a lesser extent the CC. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Leveraging Programmatic Collaboration for a Radiopharmaceutical Clinic.

Radiation oncologists, radiopharmacists, nuclear medicine physicians, and medical oncologists have seen a renewed clinical interest in radiopharmaceuticals for the curative or the palliative treatment of cancer. To allow for the discovery and the clinical advancement of targeted radiopharmaceuticals, these stakeholders have reformed their trial efforts and remodeled their facilities to accommodate the obligations of a program centered upon radioactive investigational drug products. Now considered informally as drugs and not beam radiotherapy, radiopharmaceuticals can be more easily studied in the traditional clinical trial enterprise ranging from phase 0-I to phase III studies. Resources and physical facilities allocated to radiopharmaceuticals have brought forth new logistics and patient experience for safe and satisfactory drug delivery. The clinical use of theranostic agents-that is, diagnostic and therapeutic radionuclide pairs-has accelerated radiopharmaceutical development.

A patient with albinism and retinitis pigmentosa, a case report.

Purpose: To present a case of molecularly confirmed oculocutaneous albinism (OCA) and retinitis pigmentosa (RP). Observations: A 46-year-old male with a lifelong established diagnosis of OCA and baseline best corrected visual acuity (BCVA) of 20/200, presented for worsening visual acuity over the last few years. BCVA was light perception and hand motion at face for the right and left eye, respectively. Fundus exam showed hypopigmented fundi with visible choroidal vessels and blunted foveal reflexes in both eyes. Optical coherence tomography showed foveal hypoplasia and outer retinal degenerative changes not typical of OCA. Fundus autofluorescence (FAF) imaging showed focal areas of decreased signal at the fovea, similar to areas of atrophy in an age matched patient with PDE6A-RP. Genetic testing identified a homozygous disease-causing variant in TYR c.1467dup, p. (Ala490Cysfs*20) causing OCA, and a homozygous pathogenic variant c.304C > A, p. (Arg102Ser) in PDE6A causing autosomal recessive RP. Conclusions and importance: This is the first report of a patient with OCA and RP. The lack of pigmentary changes can make the diagnosis of RP challenging in patients with albinism. FAF can show features suggestive of RP and genetic testing can establish the diagnosis. The findings described herein may help physicians diagnose an extremely rare phenotype.

Congenital Stationary Night Blindness: Structure, Function and Genotype-Phenotype Correlations in a Cohort of 122 Patients.

OBJECTIVE: To examine the molecular causes of Schubert-Bornschein (S-B) congenital stationary night blindness (CSNB), clinically characterize in detail, and assess genotype-phenotype correlations for retinal function and structure. DESIGN: Retrospective, longitudinal, single-center case series. PARTICIPANTS: One hundred twenty-two patients with S-B CSNB attending Moorfields Eye Hospital, United Kingdom. METHODS: All case notes, results of molecular genetic testing, and OCT were reviewed. MAIN OUTCOME MEASURES: Molecular genetics, presenting complaints, rates of nystagmus, nyctalopia, photophobia, strabismus, color vision defects and spherical equivalent refraction (SER). Retinal thickness, outer nuclear layer (ONL) thickness, and ganglion cell layer + inner plexiform layer (GCL+IPL) thickness from OCT imaging. RESULTS: X-linked (CACNA1F and NYX) and autosomal recessive (TRPM1, GRM6, GPR179 and CABP4) genotypes were identified. The mean (± standard deviation) reported age of onset was 4.94 ± 8.99 years. Over the follow-up period, 95.9% of patients reported reduced visual acuity (VA), half had nystagmus, and 64.7% reported nyctalopia. Incomplete CSNB (iCSNB) patients more frequently had nystagmus and photophobia. Nyctalopia was similar for iCSNB and complete CSNB (cCSNB). Color vision data were limited but more defects were found in iCSNB. None of these clinical differences met statistical significance. There was no significant difference between groups in VA, with a mean of 0.46 logarithm of the minimum angle of resolution, and VA remained stable over the course of follow-up. Complete congenital stationary night blindness patients, specifically those with NYX and TRPM1 variants, were more myopic. CACNA1F patients showed the largest refractive variability, and the CABP4 patient was hyperopic. No significant differences were found in OCT structural analysis during the follow-up period. CONCLUSIONS: Retinal structure in CSNB is stationary and no specific genotype-structure correlates were identified. Visual acuity seems to be relatively stable, with rare instances of progression. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

IQCB1 (NPHP5)-Retinopathy: Clinical and Genetic Characterization and Natural History.

PURPOSE: To describe the clinical and genetic features, and explore the natural history of retinopathy associated with IQCB1 variants in children and adults with retinopathy. DESIGN: Retrospective cohort study at a single tertiary care referral center. METHODS: The study recruited 19 patients with retinopathy, harboring likely disease-causing variants in IQCB1. Demographic data and clinical presentation, best corrected visual acuity (BCVA), fundus appearance, optical coherence tomography (OCT) and autofluorescence features, electroretinography (ERG) and molecular genetics are reported. RESULTS: Ten patients had best corrected visual acuity better than 1.0 LogMAR, and BCVA remained stable till the last review. Seven patients had a vision of hand movements or worse in at least one eye at presentation. There was no correlation found between age of onset and severity of vision loss. Nine patients (47.4%) had a diagnosis of end-stage renal failure at presentation. The other 10 patients (52.6%) had a diagnosis of non-syndromic IQCB1-retinopathy and maintained normal renal function until the last follow-up. The mean age at diagnosis of renal failure was 26.3 ±19.8 years. OCT showed ellipsoid zone (EZ) disruption with foveal sparing in 8/13 patients. All patients had stable OCT findings. Full-field ERGs in four adults revealed a severe cone-rod dystrophy and three children had extinguished ERGs. We identified 17 IQCB1 variants, all predicted to cause loss of function. CONCLUSION: IQCB1-retinopathy is a severe early-onset cone-rod dystrophy. The dissociation between severely decreased retinal function and relative preservation of retinal structure over a wide age window makes the disease a candidate for gene therapy.

Fractal Changes of the Retinal Microvasculature in Syphilitic Uveitis.

PURPOSE: To quantify chorioretinal microvascular damage and recovery post-treatment in patients with acute syphilitic posterior placoid chorioretinitis (ASPPC) using fractal dimension (FD). METHODS: Retrospective cohort study of patients with serologically confirmed syphilitic uveitis. We obtained optical coherence tomography angiography (OCTA) scans at baseline and follow-up after intravenous penicillin treatment and computed FD of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) using ImageJ. RESULTS: We enrolled seven patients with ASPPC (11 eyes), and 17 control subjects (34 eyes). Pre-treatment averages of FD-SCP, FD-DCP, and FD-CC were: 1.672 (±0.115), 1.638 (±0.097), and 1.72 (±0.137); post-treatment: 1.760 (±0.071), 1.764 (±0.043), and 1.898 (±0.047). After treatment FD-CC increased in all 11 eyes with an average of 0.163 (p = 0.003); FD-DCP increased in 10 (91%) eyes with an average of 0.126 (p = 0.003); and FD-SCP increased in seven (64%) eyes with an average of 0.089 (p = 0.059). Compared to the post-treatment FD values in the syphilitic group, controls had similar FD-SCP (p = 0.266), FD-DCP (p = 0.078), and FD-CC (p = 0.449). CONCLUSIONS: CC and DCP are mostly affected in ASPPC with minimal changes in the SCP. All vascular layers FD recovered after completing antibiotic treatment.

RBP3-Retinopathy-Inherited High Myopia and Retinal Dystrophy: Genetic Characterization, Natural History, and Deep Phenotyping.

PURPOSE: To examine the genetic and clinical features and the natural history of RBP3-associated retinopathy. DESIGN: Multi-center international, retrospective, case series of adults and children, with moleculraly confirmed RBP3-asociated retinopathy. METHODS: The genetic, clinical, and retinal imaging findings, including optical coherence tomography (OCT) and fundus autofluorescence (FAF), were investigated both cross-sectionally and longitudinally. The results of international standard full-field electroretinography (ERG) and pattern electroretinography (PERG) were reviewed. RESULTS: We ascertained 12 patients (5 female and 7 male) from 10 families (4 patients previously reported). Ten novel disease-causing RBP3 variants were identified. Ten patients were homozygous. The mean age (±SD, range) of the group was 21.4 years (±19.1, 2.9-60.5 years) at baseline evaluation. All 12 patients were highly myopic, with a mean spherical equivalent of -16.0D (range, -7.0D to -33.0D). Visual acuity was not significantly different between eyes, and no significant anisometropia was observed. Mean best-corrected visual acuity (BCVA) was 0.48 logMAR (SD, ±0.29; range, 0.2-1.35 logMAR); at baseline. Eleven patients had longitudinal BCVA assessment, with a mean BCVA of 0.46 logMAR after a mean follow-up of 12.6 years. All patients were symptomatic with reduced VA and myopia by the age of 7 years old. All patients had myopic fundi and features in keeping with high myopia on OCT, including choroidal thinning. The 4 youngest patients had no fundus pigmentary changes, with the rest of the patients presenting with a variable degree of mid-peripheral pigmentation and macular changes. FAF showed variable phenotypes, ranging from areas of increased signal to advanced atrophy in older patients. OCT showed cystoid macular edema at presentation in 3 patients, which persisted during follow-up in 2 patients and resolved to atrophy in the third patient. The ERGs were abnormal in 9 of 9 cases, revealing variable relative involvement of rod and cone photoreceptors with additional milder dysfunction post-phototransduction in some. All but 1 patient had PERG evidence of macular dysfunction, which was severe in most cases. CONCLUSIONS: This study details the clinical and functional phenotype of RBP3-retinopathy in the largest cohort reported to date. RBP3-retinopathy is a disease characterized by early onset, slow progression over decades, and high myopia. The phenotypic spectrum and natural history as described herein has prognostic and counseling implications. RBP3-related disease should be considered in children with high myopia and retinal dystrophy.

RP2-Associated X-linked Retinopathy: Clinical Findings, Molecular Genetics, and Natural History in a Large Cohort of Female Carriers.

PURPOSE: RP2-associated retinopathy typically causes severe early onset retinitis pigmentosa (RP) in affected males. However, there is a scarcity of reports describing the clinical phenotype of female carriers. We tested the hypothesis that RP2 variants manifest in female carriers with a range of functional and anatomic characteristics. DESIGN: Retrospective case series. METHODS: Females with disease-causing variants in RP2 were identified from investigation of pedigrees affected by RP2 retinopathy. All case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence imaging, optical coherence tomography (OCT)), and electrophysiology were reviewed. RESULTS: Forty pedigrees were investigated. Twenty-nine pedigrees had obligate carriers or molecularly confirmed female members with recorded relevant history and/or examination. For 8 pedigrees, data were available only from history, with patients reporting affected female relatives with RP in 4 cases and unaffected female relatives in the other 4 cases. Twenty-seven females from 21 pedigrees were examined by a retinal genetics specialist. Twenty-three patients (85%) reported no complaints and had normal vision and 4 patients had RP-associated complaints (15%). Eight patients had normal fundus examination (30%), 10 had a tapetal-like reflex (TLR; 37%), 5 had scattered peripheral pigmentation (19%), and the 4 symptomatic patients had fundus findings compatible with RP (15%). All asymptomatic patients with normal fundus, TLR, or asymptomatic pigmentary changes had a continuous ellipsoid zone on OCT when available. The electroretinograms revealed mild to severe photoreceptor dysfunction in 9 of 11 subjects, often asymmetrical, including 5 with pattern electroretinogram evidence of symmetrical (n = 4) or unilateral (n = 1 subject) macular dysfunction. CONCLUSIONS: Most carriers were asymptomatic, exhibiting subclinical characteristics such as TLR and pigmentary changes. However, female carriers of RP2 variants can manifest RP. Family history of affected females with RP does not exclude X-linked disease. The phenotypic spectrum as described herein has prognostic and counselling implications for RP2 carriers and patients.

Clinical, Genetic, and Histopathological Characteristics of CRX-associated Retinal Dystrophies.

PURPOSE: To describe phenotypic, genotypic, and histopathological features of inherited retinal dystrophies associated with the CRX gene (CRX-RDs). DESIGN: Retrospective multicenter cohort study including histopathology. SUBJECTS: Thirty-nine patients from 31 families with pathogenic variants in the CRX gene. METHODS: Clinical data of 152 visits were collected from medical records. The median follow-up time was 9.1 years (interquartile range (IQR), 3.3-15.3 years; range, 0.0-48.8 years). Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset CRX-RD was performed. MAIN OUTCOME MEASURES: Visual acuity, retinal imaging, electroretinography, genotype-phenotype correlation, and histopathological examination were evaluated. RESULTS: The age at onset ranged from birth to the eighth decade of life. Median visual acuity was 1.00 logarithm of the minimum angle of resolution (logMAR) (IQR, 0.69-1.48 logMAR; range, 0.06-3.00 logMAR) at a mean age of 52.0 ± 19.9 years (range, 4.6-81.9 years). Sufficient imaging was available for 36 out of 39 patients (92.3%), and all showed degeneration of at least the macula. Of these 36 patients, 22 (61.1%) had only macular dystrophy. Another 10 patients (27.8%) had additional degeneration beyond the vascular arcades, and 4 patients (11.1%) panretinal degeneration. Two patients (5.1%) had Leber congenital amaurosis. In total, 21 different disease-associated heterozygous CRX variants were identified (10 frameshift, 7 missense, 2 deletion, 1 nonsense, 1 deletion-insertion variants). Missense variants in the CRX homeodomain and 2 variants deleting all functional domains, thus causing haploinsufficiency, generally tended to cause milder late-onset phenotypes. Histopathologic examination of the eye of a 17-year-old patient with advanced early-onset retinal dystrophy due to a heterozygous deletion of exons 3 and 4 of the CRX gene revealed loss of laminar integrity and widespread photoreceptor degeneration especially in the central retina, with extensive loss of photoreceptor nuclei and outer segments. CONCLUSIONS: This study illustrates the large clinical and genetic heterogenic spectrum of CRX-RDs, ranging from Leber congenital amaurosis to mild late-onset maculopathy resembling occult macular dystrophy. Haploinsufficiency and missense variants tended to be associated with milder phenotypes. Patients showed degeneration predominantly affecting the central retina on imaging. The histopathological findings also mirror these clinical findings and features similar to previously reported animal models of CRX-RDs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.