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Leber congenital amaurosis type 4 (LCA4), caused by AIPL1 mutations, is characterized by severe sight impairment in infancy and rapidly progressing degeneration of photoreceptor cells. We generated retinal organoids using induced pluripotent stem cells (iPSCs) from renal epithelial cells obtained from four children with AIPL1 nonsense mutations. iPSC-derived photoreceptors exhibited the molecular hallmarks of LCA4, including undetectable AIPL1 and rod cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE6) compared with control or CRISPR-corrected organoids. Increased levels of cGMP were detected. The translational readthrough-inducing drug (TRID) PTC124 was investigated as a potential therapeutic agent. LCA4 retinal organoids exhibited low levels of rescue of full-length AIPL1. However, this was insufficient to fully restore PDE6 in photoreceptors and reduce cGMP. LCA4 retinal organoids are a valuable platform for in vitro investigation of novel therapeutic agents.

Objective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient selection for future therapeutic trials.Design: International, multicenter, retrospective cohort study.Subjects: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families.Methods: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral -domain OCT [SD-OCT], fundus autofluorescence).Main Outcomes Measures: Age of onset, evolution of BCVA, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging.Results: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (P = 0.798). At the age of 40 years, the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and that of the external limiting membrane (ELM) on SD-OCT correlated signifi-cantly with BCVA (Spearman r = 0.744, P = 0.001, and r = 0.712, P < 0.001, respectively) in those with CORD.Conclusions: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting long pres-ervation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence, with a progressive loss of vision, and culminated in severe visual impairment during mid-to-late adulthood. The integrity of the ELM and EZ may be suitable structural end points for therapeutic studies of GUCY2D-associated CORD. Ophthalmology Retina 2022;6:711-722 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Severe light sensitivity is a feature common to a range of ophthalmological and neurological diseases. In inherited retinal diseases (IRDs) particularly, this may be accompanied by significant visual disruption. These symptoms are extremely debilitating for affected individuals and have significant implications in terms of day-to-day activities. Underlying mechanisms remain to be fully elucidated. Currently, there are many assessments of photoaversion (PA), however, all have limitations, with quantitative measurement in particular needing further evaluation. To understand the complexities associated with photoaversion from different pathologies, qualitative and quantitative assessments of the light aversion response must be standardized. There is no treatment to date, and strategies to alleviate symptoms focus on light avoidance. With respect to IRDs, however, gene therapy is currently being investigated in clinical trials and promising and further treatments may be on the horizon. The better characterization of these symptoms is an important end point measure in IRD gene therapy trials.

Highlights • KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. • Disease course can be unpredictable and may severely affect children and young adults. • Findings suggest a potential window for intervention until 40 years of age, albeit with variability between patients due to macular atrophy., Purpose To describe the detailed retinal phenotype of KCNV2-associated retinopathy. Study design Multicenter international retrospective case series. Methods Review of retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), including qualitative and quantitative analyses. Results Three distinct macular FAF features were identified: (1) centrally increased signal (n = 35, 41.7%), (2) decreased autofluorescence (n = 27, 31.1%), and (3) ring of increased signal (n = 37, 44.0%). Five distinct FAF groups were identified based on combinations of those features, with 23.5% of patients changing the FAF group over a mean (range) follow-up of 5.9 years (1.9-13.1 years). Qualitative assessment was performed by grading OCT into 5 grades: (1) continuous ellipsoid zone (EZ) (20.5%); (2) EZ disruption (26.1%); (3) EZ absence, without optical gap and with preserved retinal pigment epithelium complex (21.6%); (4) loss of EZ and a hyporeflective zone at the foveola (6.8%); and (5) outer retina and retinal pigment epithelium complex loss (25.0%). Eighty-six patients had scans available from both eyes, with 83 (96.5%) having the same grade in both eyes, and 36.1% changed OCT grade over a mean follow-up of 5.5 years. The annual rate of outer nuclear layer thickness change was similar for right and left eyes. Conclusions KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. The identification of a single OCT or FAF measurement as an endpoint to determine progression that applies to all patients may be challenging, although outer nuclear layer thickness is a potential biomarker. Findings suggest a potential window for intervention until 40 years of age.

Rare eye diseases such as inherited retinal diseases (IRDs) are challenging to diagnose genetically. IRDs are typically monogenic disorders and represent a leading cause of blindness in children and working-age adults worldwide. A growing number are now being targeted in clinical trials, with approved treatments increasingly available. However, access requires a genetic diagnosis to be established sufficiently early. Critically, the timely identification of a genetic cause remains challenging. We demonstrate that a deep-learning algorithm, Eye2Gene, trained on the largest imaging dataset of patients with IRDs currently available, provides expert-level accuracy for genetic diagnosis for the 36 most common molecular causes (top-5 accuracy = 85.6%). This algorithm has been deployed online (app.eye2gene.com) and externally validated on data provided by four different clinical centers. Eye2Gene can facilitate access to diagnostic expertise, only currently available in a limited number of specialist centers globally, and thereby dramatically accelerate the genetic diagnostic odyssey.

To review and describe in detail the clinical course, functional and anatomical characteristics of RP2-associated retinal degeneration.Retrospective case series.Males with disease-causing variants in the RP2 gene.Review of all case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT)) and electrophysiology assessment.Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), qualitative and quantitative retinal imaging analysis, and electrophysiology parameters.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, ±SD) was 9.6 years of age (1-57 years, ± 9.2 years). Forty-four patients (91.7%) had childhood-onset disease, with mean age of onset of 7.6 years. The commonest first symptom was night blindness (68.8%). Mean BCVA (range, ±SD) was 0.91 LogMAR (0-2.7, ±0.80) and 0.94 LogMAR (0-2.7, ±0.78) for right and left eyes respectively. Based on the WHO visual impairment criteria, 18 patients (34%) had low vision. The majority (17/22) showed 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 (EZ) width and outer nuclear layer (ONL) thickness. The mean annual rate of EZ width 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 identifiable EZ after the age of 26 years at baseline or follow-up. Four patients had adulthood-onset disease and a less severe phenotype.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 generalised (peripheral) cone system involvement of widely varying severity in the first two decades of life.

To analyze the clinical characteristics, natural history, and genetics of CRB1-associated retinal dystrophies.Multicenter international retrospective cohort study.Review of clinical notes, ophthalmic images, and genetic testing results of 104 patients (91 probands) with disease-causing CRB1 variants. Macular optical coherence tomography (OCT) parameters, visual function, fundus characteristics, and associations between variables were the main outcome measures.The mean age of the cohort at the first visit was 19.8 ± 16.1 (median 15) years, with a mean follow-up of 9.6 ± 10 years. Based on history, imaging, and clinical examination, 26 individuals were diagnosed with retinitis pigmentosa (RP; 25%), 54 with early-onset severe retinal dystrophy / Leber congenital amaurosis (EOSRD/LCA; 52%), and 24 with macular dystrophy (MD; 23%). Severe visual impairment was most frequent after 40 years of age for patients with RP and after 20 years of age for EOSRD/LCA. Longitudinal analysis revealed a significant difference between baseline and follow-up best-corrected visual acuity in the 3 subcohorts. Macular thickness decreased in most patients with EOSRD/LCA and MD, whereas the majority of patients with RP had increased perifoveal thickness.A subset of individuals with CRB1 variants present with mild, adult-onset RP. EOSRD/LCA phenotype was significantly associated with null variants, and 167_169 deletion was exclusively present in the MD cohort. The poor OCT lamination may have a degenerative component, as well as being congenital. Disease symmetry and reasonable window for intervention highlight CRB1 retinal dystrophies as a promising target for trials of novel therapeutics.

Purpose To investigate genetics, electrophysiology, and clinical course of KCNV2-associated retinopathy in a cohort of children and adults. Study design This was a multicenter international clinical cohort study. Methods Review of clinical notes and molecular genetic testing. Full-field electroretinography (ERG) recordings, incorporating the international standards, were reviewed and quantified and compared with age and recordings from control subjects. Results In total, 230 disease-associated alleles were identified from 117 patients, corresponding to 75 different KCNV2 variants, with 28 being novel. The mean age of onset was 3.9 years old. All patients were symptomatic before 12 years of age (range, 0-11 years). Decreased visual acuity was present in all patients, and 4 other symptoms were common: reduced color vision (78.6%), photophobia (53.5%), nyctalopia (43.6%), and nystagmus (38.6%). After a mean follow-up of 8.4 years, the mean best-corrected visual acuity (BCVA ± SD) decreased from 0.81 ± 0.27 to 0.90 ± 0.31 logarithm of minimal angle of resolution. Full-field ERGs showed pathognomonic waveform features. Quantitative assessment revealed a wide range of ERG amplitudes and peak times, with a mean rate of age-associated reduction indistinguishable from the control group. Mean amplitude reductions for the dark-adapted 0.01 ERG, dark-adapted 10 ERG a-wave, and LA 3.0 30 Hz and LA3 ERG b-waves were 55%, 21%, 48%, and 74%, respectively compared with control values. Peak times showed stability across 6 decades. Conclusion In KCNV2-associated retinopathy, full-field ERGs are diagnostic and consistent with largely stable peripheral retinal dysfunction. Report 1 highlights the severity of the clinical phenotype and established a large cohort of patients, emphasizing the unmet need for trials of novel therapeutics., Highlights • The current study established the largest and most characterized cohort of molecularly confirmed patients with KCNV2-associated retinopathy. • Report 1 highlights the genetic background, evidence of electroretinography stability over a broad age range, and the severe phenotype of the disease.

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.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The identification of the central role of vascular endothelial growth factor (VEGF) in the pathogenesis of neovascular AMD and the introduction of anti-VEGF agents as gold-standard treatment, have drastically changed its prognosis—something yet to be seen in dry AMD. Several therapeutic avenues with a wide variability of targets are currently being investigated in dry AMD. The approaches being investigated to reduce the rate of disease progression include, (1) drugs with antioxidative properties, (2) inhibitors of the complement cascade, (3) neuroprotective agents, (4) visual cycle inhibitors, (5) gene therapy and (6) cell-based therapies. A number of early phase clinical trials have provided promising results, with many more ongoing and anticipated in the near future. In this review, we aim to provide an update of the interventional trials to date and future prospects for the treatment of dry AMD.

Purpose To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. Methods Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). Results The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. Conclusions The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.

Purpose To determine the genetic background of sector retinitis pigmentosa (RP) natural history to better inform patient counseling. Design Retrospective case series. Methods Review of clinical notes, retinal imaging including color fundus photography (CFP), fundus autofluorescence (FAF), optical coherence tomography (OCT), electrophysiological assessment (ERG), and molecular genetic testing were performed in patients with sector RP from a single tertiary referral center. Main outcomes measured were demographic data, signs and symptoms, visual acuity, molecular genetics; and ERG, FAF, and OCT findings. Results Twenty-six molecularly confirmed patients from 23 different families were identified harboring likely disease-causing variants in 9 genes. The modes of inheritance were autosomal recessive (AR, n=6: USH1C, n=2; MYO7A, n=2; CDH3, n=1; EYS, n=1), X-linked (XL, n=4: PRPS1, n=1; RPGR, n=3), and autosomal dominant (AD, n=16: IMPDH1, n=3; RP1, n=3; RHO, n=10), with a mean age of disease onset of 38.5, 30.5, and 39.0 years old, respectively. Five of these genes have not previously been reported to cause sector RP (PRPS1, MYO7A, EYS, IMPDH1, and RP1). Inferior and nasal predilection was common across the different genotypes, and patients tended to maintain good central vision. Progression on serial FAF was observed in RPGR, MYO7A, CDH23, EYS, IMPDH1, RP1, and RHO-associated sector RP. Conclusions The genotypic spectrum of the disease is broader than previously reported. The longitudinal data provided will help to make accurate patient prognoses and counseling as well as inform patients' potential participation in the increasing numbers of trials of novel therapeutics and access to future treatments., Highlights • This is the largest series and longitudinal study in sector retinitis pigmentosa. • The genotypic spectrum of the disease is broader than previously reported. • The longitudinal data provided more accurate patient prognosis and counseling. • The study informed patients' potential participation in the increasing numbers of trials of novel therapeutics and access to future treatments.

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.

Disease-causing sequence variants in the highly polymorphic AIPL1 gene are associated with a broad spectrum of inherited retinal diseases ranging from severe autosomal recessive Leber congenital amaurosis to later onset retinitis pigmentosa. AIPL1 is a photoreceptor-specific co-chaperone that interacts with HSP90 to facilitate the stable assembly of retinal cGMP phosphodiesterase, PDE6. In this report, we establish unequivocal correlations between patient clinical phenotypes and in vitro functional assays of uncharacterized AIPL1 variants. We confirm that missense and nonsense variants in the FKBP-like and tetratricopeptide repeat domains of AIPL1 lead to the loss of both HSP90 interaction and PDE6 activity, confirming these variants cause LCA. In contrast, we report the association of p.G122R with milder forms of retinal degeneration, and show that while p.G122R had no effect on HSP90 binding, the modulation of PDE6 cGMP levels was impaired. The clinical history of these patients together with our functional assays suggest that the p.G122R variant is a rare hypomorphic allele with a later disease onset, amenable to therapeutic intervention. Finally, we report the primate-specific proline-rich domain to be dispensable for both HSP90 interaction and PDE6 activity. We conclude that variants investigated in this domain do not cause disease, with the exception of p.A352_P355del associated with autosomal dominant cone-rod dystrophy.

To describe the clinical, electrophysiological, and molecular features of an unusual macula-predominant retinopathy in two unrelated probands with biallelic variants in RDH12. Retrospective case se...

Oliver McFarlane syndrome (OMS) is a rare autosomal recessive disorder characterised by pigmentary chorioretinal atrophy with no previous reports of choroidal neovascularisation (CNV).We describe the history, findings of clinical examination, retinal imaging and electrodiagnostic studies, and the treatment of a patient with CNV secondary to OMS.CNV secondary to OMS was diagnosed in a ten-year-old white female who presented with reduced visual acuity and a macular haemorrhage in her right eye. CNV was confirmed on optical coherence tomography. She was initially treated with a single injection of intravitreal bevacizumab and 2 years later with an injection of intravitreal ranibizumab for a recurrence. Although macular scarring secondary to the CNV was observed, her vision has stabilised and she continues to be closely monitored.We report the first case of CNV secondary to OMS and its successful treatment with intravitreal anti-vascular endothelial growth factor injections.

KCNV2 -associated retinopathy or “cone dystrophy with supernormal rod responses” is an autosomal recessive cone-rod dystrophy with pathognomonic ERG findings. This gene encodes Kv8.2, a voltage-gated potassium channel subunit that acts as a modulator by shifting the activation range of the K+ channels in photoreceptor inner segments. Currently, no treatment is available for the condition. However, there is a lack of prospective long-term data in large molecularly confirmed cohorts, which is a prerequisite for accurate patient counselling/prognostication, to identify an optimal window for intervention and outcome measures, and ultimately to design future therapy trials. Herein we provide a detailed review of the clinical features, retinal imaging, electrophysiology and psychophysical studies, molecular genetics, and briefly discuss future prospects for therapy trials.

Purpose To determine the reliability and repeatability of quantitative evaluation of areas of decreased autofluorescence (DAF) from fundus autofluorescence (FAF) images and track disease progression in children with Stargardt disease (STGD1), and to investigate clinical and genotype correlations, disease symmetry, and intrafamilial variability. Design Prospective cohort study. Methods Children and adults with molecularly confirmed STGD1 (n = 90) underwent longitudinal FAF imaging with subsequent semiautomated measurement of the area of DAF and calculation of the annual rate of progression. The age of disease onset was recorded for all subjects, as well as the electroretinography (ERG) group at baseline (n = 86). Patients were grouped for analysis based on the age at baseline and age of onset, into children (n = 56), adults with childhood-onset STGD1 (n = 15), and adults with adult-onset (n = 19). Fifty FAF images were selected randomly and analyzed by 2 observers to evaluate repeatability and reproducibility. Differences between groups, interocular symmetry, genotype–phenotype correlations, and intrafamilial variability were also investigated both for baseline measurements as well as progression rates. We measured visual acuity, molecular genetics, ERG group, FAF metrics, and their correlations. Results The mean age of onset ± SD was 9.6 ± 3.4 years for childhood-onset (n = 71) and 28.3 ± 7.8 years for adult-onset STGD1 (n = 19). The intra- and interobserver reliability of DAF quantification was excellent (intraclass correlation coefficients 0.995 and 0.987, respectively). DAF area was symmetric between eyes and the mean rate of progression (SD) was 0.69 (0.72), 0.78 (0.48), and 0.40 (0.36) mm2/year for children, adults with childhood-onset, and adults with adult-onset disease, respectively. Patients belonging to a group 3 ERG phenotype (generalized cone and rod dysfunction) had a significantly greater progression rate. Limited intrafamilial variability was observed. Conclusions This is the first large prospective study of FAF in a cohort of molecularly confirmed children with STGD1. DAF area quantification was highly reliable and may thereby serve as a robust structural endpoint. A high rate of progression was observed in childhood-onset disease, making this subtype of STGD1 ideally suited to be considered for prioritization in clinical trials., Highlights • First large prospective study of fundus autofluorescence in a cohort of molecularly confirmed children with STGD1. • Fundus autofluorescence is a robust structural outcome measure in children with Stargardt disease. • A high rate of progression was observed in childhood-onset disease, making this subtype of STGD1 ideally suited to be considered for prioritization in clinical trials.

Purpose To describe the natural history of Leber congenital amaurosis (LCA) associated with GUCY2D variants (GUCY2D-LCA) in a cohort of children and adults, in preparation for trials of novel therapies. Design Retrospective case series. Methods Participants: Patients with GUCY2D-LCA at a single referral center. Procedures: Review of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), electroretinography (ERG), and molecular genetic testing. Main Outcome Measures: Demographic data, symptoms at presentation, visual acuity, evidence of progression, OCT and FAF findings, ERG assessment, and molecular genetics. Results Twenty-one subjects with GUCY2D-LCA were included, with a mean follow-up ± standard deviation (SD) of 10 ± 11.85 years. Marked reduction in visual acuity (VA) and nystagmus was documented in all patients within the first 3 years of life. Fifty-seven percent (n = 12) exhibited photophobia and 38% (n = 8) had nyctalopia. VA was worse than hand motion in 71% of the patients (n = 15). Longitudinal assessment of VA showed stability in all patients, except 1 patient who experienced deterioration over a follow-up of 44 years. Hyperopia was reported in 13 of the 17 subjects (71%) with available refraction data. Eighteen subjects had either normal fundus appearance (n = 14) or a blond fundus (n = 3), while only 4 of the eldest subjects had mild retinal pigment epithelium (RPE) atrophy (mean, 49 years; range 40-54 years). OCT data were available for 11 subjects and 4 different grades of ellipsoid zone (EZ) integrity were identified: (1) continuous/intact EZ (n = 6), (2) focally disrupted EZ (n = 2), (3) focally disrupted with RPE changes (n = 2), and (4) diffuse EZ disruption with RPE changes (n = 1). All examined subjects had stable OCT findings over the long follow-up period. Full-field ERGs showed evidence of a severe cone-rod dystrophy in 5 of 6 patients and undetectable ERGs in 1 subject. Novel genotype-phenotype correlations are also reported. Conclusion GUCY2D-LCA is a severe early-onset retinal dystrophy associated with very poor VA from birth. Despite the severely affected photoreceptor function, the relatively preserved photoreceptor structure based on EZ integrity until late in the disease in the majority of subjects suggests a wide therapeutic window for gene therapy trials., Highlights • GUCY2D-associated Leber congenital amaurosis is a severe early-onset retinal dystrophy. • There is severe cone and rod dysfunction but with preserved photoreceptor structure evident on optical coherence tomography. • Stable natural history suggests a wide therapeutic window for intervention.

© 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), 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.

Purpose To characterize the retinal phenotype of juvenile neuronal ceroid lipofuscinosis (JNCL), highlight delayed and mistaken diagnosis, and propose an algorithm for early identification. Design Retrospective case series. Subjects Eight children (5 females) with JNCL. Methods Review of clinical notes, retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), electroretinography (ERG), and both microscopy and molecular genetic testing. Main Outcome Measurements Demographic data, signs and symptoms, visual acuity, FAF and OCT findings, ERG phenotype, and microscopy/molecular genetics. Results Subjects presented with rapid bilateral vision loss over one to eighteen months, with mean visual acuity deteriorating from 0.44 LogMAR (range: 0.20 - 1.78 LogMAR) at baseline, to 1.34 LogMAR (0.30 LogMAR - light perception) at last follow-up. Age of onset ranged from 3 to 7 years (mean 5.3 years). The age at diagnosis of JNCL ranged from 7 to 10 years (mean 8.3 years). Six children displayed eccentric fixation, and six had cognitive or neurological signs at time of diagnosis (75%). Seven patients had bilateral bull’s-eye maculopathy at presentation. Coats-like exudative vasculopathy, not previously reported in JNCL, was observed in one patient. OCT imaging revealed near complete loss of outer retinal layers, and marked atrophy of the nerve fibre and ganglion cell layers, at the central macula. An ‘electronegative’ ERG was present in four patients (50%), but with additional a-wave reduction; there was an undetectable ERG in the remaining four. Blood film microscopy revealed vacuolated lymphocytes and electron microscopy showed lysosomal (fingerprint) inclusions, in all eight patients. Conclusions In a young child with bilateral rapidly progressive vision loss and macular disturbance, blood film microscopy to detect vacuolated lymphocytes is a rapid, readily accessible, and sensitive screening test for JNCL. Early suspicion of JNCL can be aided by detailed directed history and high-resolution retinal imaging, with subsequent targeted microscopy/genetic testing. Early diagnosis is critical to ensure appropriate management, counselling, support and social care for children and their families. Furthermore, although potential therapies for this group of disorders are in early phase clinical trial, realistic expectations are that successful intervention will be most effective when initiated at the earliest stage of disease.

Surgical intervention in patients with severe glaucoma remains controversial, especially in unilateral cases with a minimally affected fellow eye. Many question the benefit of trabeculectomy in such cases due to high complication rates and prolonged recovery. In this retrospective, non-comparative, interventional case series we aimed to determine the effect of trabeculectomy or combined phaco-trabeculectomy on the visual function of advanced glaucoma patients. Consecutive cases with perimetric mean deviation loss worse than −20 dB were included. Survival of visual function according to five predetermined visual acuity and perimetric criteria was set as the primary outcome. Qualified surgical success utilizing two different sets of criteria commonly used in the literature constituted secondary outcomes. Forty eyes with average baseline visual field mean deviation −26.3 ± 4.1 dB were identified. The average pre-operative intraocular pressure was 26.5 ± 11.4 mmHg and decreased to 11.4 ± 4.0 mmHg (p < 0.001) after an average follow-up of 23.3 ± 15.5 months. Visual function was preserved at two years in 77% or 66% of eyes respectively according to two different sets of visual acuity and perimetric criteria. Qualified surgical success was 89%, 72% at 1 and 3 years respectively. Trabeculectomy and/or phaco-trabeculectomy is associated with meaningful visual outcomes in patients with uncontrolled advanced glaucoma.

SummaryLeber Congenital Amaurosis type 4 (LCA4), caused by AIPL1 mutations, is characterised by severe sight impairment in infancy and rapidly progressive degeneration of photoreceptor cells. We generated retinal organoids using induced pluripotent stem cells (iPSCs) from renal epithelial cells obtained from four children with AIPL1 nonsense mutations. iPSC-derived photoreceptors exhibited the molecular hallmarks of LCA4, including undetectable AIPL1 and rod cGMP phosphodiesterase (PDE6) compared to control or CRISPR corrected organoids. Moreover, increased levels of cGMP were detected. The translational readthrough inducing drug (TRID) PTC124 was investigated as a potential therapeutic. LCA4 retinal organoids exhibited rescue of AIPL1 and PDE6; however, the level of full-length, functional AIPL1 induced through PTC124 treatment was insufficient to reduce cGMP levels and fully rescue the LCA4 phenotype. LCA4 retinal organoids are a valuable platform for the in vitro investigation of the molecular mechanisms that drive photoreceptor loss and for the evaluation of novel therapeutics.

BACKGROUND: Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here we characterize the clinical phenotypic of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12. MATERIALS AND METHODS: Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease causing variants in CEP78, CEP250, ARSG, or ABHD12. RESULTS: CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12 related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe. CONCLUSIONS: This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients that have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.

This study investigated the phenotypic spectrum of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and early-onset cataract) syndrome caused by biallelic variants in the ABHD12 gene. A total of 15 patients from 12 different families were included, with a mean age of 36.7 years (standard deviation [SD] ± 11.0, range from 17.5 to 53.9) at the most recent examination. The presence and onset of neurological, audiological and ophthalmic symptoms were variable, with no evident order of symptom appearance. The mean best-corrected visual acuity was 1.1 logMAR (SD ± 0.9, range from 0.1 to 2.8, equivalent to 20/250 Snellen) and showed a trend of progressive decline. Different types of cataract were observed in 13 out of 15 patients (87%), which also included congenital forms of cataract. Fundus examination revealed macular involvement in all patients, ranging from alterations of the retinal pigment epithelium to macular atrophy. Intraretinal spicular hyperpigmentation was observed in 7 out of 15 patients (47%). From an ophthalmic perspective, clinical manifestations in patients with PHARC demonstrate variability with regard to their onset and severity. Given the variable nature of PHARC, an early multidisciplinary assessment is recommended to assess disease severity.

PURPOSE: To compare foveal hypoplasia and the appearance of the ellipsoid zone (EZ) at the fovea in patients with genetically confirmed achromatopsia (ACHM) and blue cone monochromacy (BCM). DESIGN: Retrospective, multi-center observational study. SUBJECTS: Molecularly confirmed patients with ACHM (n = 89) and BCM (n = 33). METHODS: We analyzed high-resolution spectral domain optical coherence tomography (SD-OCT) images of the macula from aforementioned patients with BCM. Three observers independently graded SD-OCT images for foveal hypoplasia (i.e. retention of one or more inner retinal layers at the fovea) and four observers judged the integrity of the EZ at the fovea, based on an established grading scheme. These measures were compared with previously published data from the ACHM patients. MAIN OUTCOME MEASURES: Presence of foveal hypoplasia and EZ grade. RESULTS: Foveal hypoplasia was significantly more prevalent in ACHM than in BCM (p

Combined vision and hearing loss, also known as dual sensory impairment, can occur in several genetic conditions, including ciliopathies such as Usher and Bardet-Biedl syndrome, mitochondrial DNA disorders and systemic diseases, such as CHARGE, Stickler, Waardenburg, Alport and Alstrom syndrome. The retinal phenotype may point to the diagnosis of such disorders. Herein, we aim to provide a comprehensive review of the molecular genetics and clinical features of the most common non-chromosomal inherited disorders to cause dual sensory impairment.

This study investigated the phenotypic spectrum of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and early-onset cataract) syndrome caused by biallelic variants in the ABHD12 gene. A total of 15 patients from 12 different families were included, with a mean age of 36.7 years (standard deviation [SD] ± 11.0; range from 17.5 to 53.9) at the most recent examination. The presence and onset of neurological, audiological and ophthalmic symptoms were variable, with no evident order of symptom appearance. The mean best-corrected visual acuity was 1.1 logMAR (SD ± 0.9; range from 0.1 to 2.8; equivalent to 20/250 Snellen) and showed a trend of progressive decline. Different types of cataract were observed in 13 out of 15 patients (87%), which also included congenital forms of cataract. Fundus examination revealed macular involvement in all patients, ranging from alterations of the retinal pigment epithelium to macular atrophy. Intraretinal spicular hyperpigmentation was observed in 7 out of 15 patients (47%). From an ophthalmic perspective, clinical manifestations in patients with PHARC demonstrate variability with regard to their onset and severity. Given the variable nature of PHARC, an early multidisciplinary assessment is recommended to assess disease severity.

Functional assessments are a fundamental part of the clinical evaluation of patients with inherited retinal diseases (IRDs). Their importance and impact have become increasingly notable, given the significant breadth and number of clinical trials and studies investigating multiple avenues of intervention across a wide range of IRDs, including gene, pharmacological and cellular therapies. Moreover, the fact that many clinical trials are reportingimprovementsin vision, rather than the previously anticipated structural stability/slowing of degeneration, makes functional evaluation of primary relevance. In this review, we will describe a range of methods employed to characterise retinal function and functional vision, beginning with tests variably included in the clinic, such as visual acuity, electrophysiological assessment and colour discrimination, and then discussing assessments often reserved for clinical trials/research studies such as photoaversion testing, full-field static perimetry and microperimetry, and vision-guided mobility testing; addressing perimetry in greatest detail, given it is commonly a primary outcome metric. We will focus on how these tests can help diagnose and monitor particular genotypes, also noting their limitations/challenges and exploring analytical methodologies for better exploiting functional measurements, as well as how they facilitate patient inclusion and stratification in clinical trials and serve as outcome measures.

Joubert syndrome is a genetically heterogeneous multisystem disorder typically diagnosed in childhood. Nephronophthisis is the most common renal pathology in Joubert syndrome, and renal failure usually occurs in childhood or in young adults. We report a 61-year-old female diagnosed with AHI1-related oculorenal Joubert syndrome, who presented initially with decline in renal function in her 50s. Our report describes exceptionally late presentation of renal disease in Joubert syndrome and highlights the importance of continued renal function monitoring in older adults with Joubert syndrome.

Macular dystrophies (MDs) consist of a heterogeneous group of disorders that are characterised by bilateral symmetrical central visual loss. Advances in genetic testing over the last decade have led to improved knowledge of the underlying molecular basis. The developments in high-resolution multimodal retinal imaging have also transformed our ability to make accurate and more timely diagnoses and more sensitive quantitative assessment of disease progression, and allowed the design of optimised clinical trial endpoints for novel therapeutic interventions. The aim of this review was to provide an update on MDs, including Stargardt disease, Best disease, X-linked r etinoschisis, pattern dystrophy, Sorsby fundus dystrophy and autosomal dominant drusen. It highlights the range of innovations in retinal imaging, genotype–phenotype and structure–function associations, animal models of disease and the multiple treatment strategies that are currently in clinical trial or planned in the near future, which are anticipated to lead to significant changes in the management of patients with MDs.

We investigated axial length (AL) distributions in inherited retinal diseases (IRDs), comparing them with reference cohorts.AL measurements from IRD natural history study participants were included and compared with reference cohorts (TwinsUK, Raine Study Gen2-20, and published studies). Comparing with the Raine Study cohort, formal odds ratios (ORs) for AL ≥ 26 mm or AL ≤ 22 mm were derived for each IRD (Firth's logistic regression model, adjusted for age and sex).Measurements were available for 435 patients (median age, 19.5 years). Of 19 diseases, 10 had10 participants: ABCA4 retinopathy; CNGB3- and CNGA3-associated achromatopsia; RPGR-associated disease; RPE65-associated disease; blue cone monochromacy (BCM); Bornholm eye disease (BED); TYR- and OCA2-associated oculocutaneous albinism; and GPR143-associated ocular albinism. Compared with the TwinsUK cohort (n = 322; median age, 65.1 years) and Raine Study cohort (n = 1335; median age, 19.9 years), AL distributions were wider in the IRD groups. Increased odds for longer ALs were observed for BCM, BED, RPGR, RPE65, OCA2, and TYR; increased odds for short AL were observed for RPE65, TYR, and GPR143. In subanalysis of RPGR-associated disease, longer average ALs occurred in cone-rod dystrophy (n = 5) than rod-cone dystrophy (P = 0.002).Several diseases showed increased odds for longer AL (highest OR with BCM); some showed increased odds for shorter AL (highest OR with GPR143). Patients with RPE65- and TYR-associated disease showed increased odds for longer and for shorter eyes. Albinism genes were associated with different effects on AL. These findings add to the phenotype of IRDs and may yield insights into mechanisms of refractive error development.

PURPOSE To investigate microperimetry testing of retinitis pigmentosa GTPase regulator gene (RPGR)-associated retinopathy in a cohort of children and adults. DESIGN Prospective observational case series. METHODS The coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated for mesopic microperimetry. Best-corrected visual acuity (BCVA), contrast sensitivity (CS), MS, total volume (VTOT), and central 3-degree field volume (V3) from volumetric and topographic analyses were acquired. RESULTS The study recruited 76 individuals with RPGR (53 adults, 23 children). The mean follow-up period was 2.8 years. The ICC values for MS, VTOT, and V3 were 0.982 dB (95% CI, 0.969-0.989 dB), 0.970 dB-steradian (sr) (95% CI, -0.02658 to 0.03691 dB-sr), and 0.986 dB-sr (95% CI, 0.978-0.991), respectively. The r values for interocular MS, VTOT, and V3 were 0.97 (P < .01), 0.97 (P < .01), and 0.98 (P < .01), respectively, indicating strong interocular correlation. The interocular correlation of progression for MS, VTOT, and V3 was 0.81 (P < .01), 0.64 (P < .01), and 0.81 (P < .01), respectively. There was no statistically significant difference in the interocular progression rates for MS or VTOT. V3 did show a statistically significant difference. Most patients lost retinal sensitivity rapidly during their second and third decades of life. CONCLUSIONS The high degree of reproducibility of results and the good interocular correlation lends this method to accurately monitoring disease progression, as well as supporting validation of the use of MP in assessing the outcomes of gene therapy clinical treatment trials.

Purpose: To determine whether artifacts in optical coherence tomography (OCT) images are associated with the success or failure of adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in subjects with achromatopsia (ACHM). / Methods: Previously acquired OCT and non-confocal, split-detector AOSLO images from one eye of 66 subjects with genetically confirmed achromatopsia (15 CNGA3 and 51 CNGB3) were reviewed along with best-corrected visual acuity (BCVA) and axial length. OCT artifacts in interpolated vertical volumes from CIRRUS macular cubes were divided into four categories: (1) none or minimal, (2) clear and low frequency, (3) low amplitude and high frequency, and (4) high amplitude and high frequency. Each vertical volume was assessed once by two observers. AOSLO success was defined as sufficient image quality in split-detector images at the fovea to assess cone quantity. / Results: There was excellent agreement between the two observers for assessing OCT artifact severity category (weighted kappa = 0.88). Overall, AOSLO success was 47%. For subjects with OCT artifact severity category 1, AOSLO success was 65%; for category 2, 47%; for category 3, 11%; and for category 4, 0%. There was a significant association between OCT artifact severity category and AOSLO success (P = 0.0002). Neither BCVA nor axial length was associated with AOSLO success (P = 0.07 and P = 0.75, respectively). / Conclusions: Artifacts in OCT volumes are associated with AOSLO success in ACHM. Subjects with less severe OCT artifacts are more likely to be good candidates for AOSLO imaging, whereas AOSLO was successful in only 7% of subjects with category 3 or 4 OCT artifacts. These results may be useful in guiding patient selection for AOSLO imaging. / Translational Relevance: Using OCT to prescreen patients could be a valuable tool for clinical trials that utilize AOSLO to reduce costs and decrease patient testing burden.