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

Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options

Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4 Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored

Clinical course of focal choroidal excavation in Vogt-Koyanagi-Harada disease

We describe focal choroidal excavation (FCE) in a case of Vogt–Koyanagi–Harada (VKH) disease and compare the findings with different chorioretinal conditions. A 55-year-old man was diagnosed with VKH based on panuveitis and exudative retinal detachments. Spectral-domain optical coherence tomography demonstrated a dome-shaped protrusion with a nonconforming pattern at the fovea, which had been detected as a conforming pattern 1 year before the onset. The FCE pattern returned into a conforming pattern following corticosteroid therapy. These findings suggest that the natively existent FCE could be affected by pathophysiological changes of VKH as well as other chorioretinal conditions

Prediction of causative genes in inherited retinal disorder from fundus photography and autofluorescence imaging using deep learning techniques

Background/Aims: To investigate the utility of a data-driven deep learning approach in patients with inherited retinal disorder (IRD) and to predict the causative genes based on fundus photography and fundus autofluorescence (FAF) imaging. / Methods: Clinical and genetic data from 1302 subjects from 729 genetically confirmed families with IRD registered with the Japan Eye Genetics Consortium were reviewed. Three categories of genetic diagnosis were selected, based on the high prevalence of their causative genes: Stargardt disease (ABCA4), retinitis pigmentosa (EYS) and occult macular dystrophy (RP1L1). Fundus photographs and FAF images were cropped in a standardised manner with a macro algorithm. Images for training/testing were selected using a randomised, fourfold cross-validation method. The application program interface was established to reach the learning accuracy of concordance (target: >80%) between the genetic diagnosis and the machine diagnosis (ABCA4, EYS, RP1L1 and normal). / Results: A total of 417 images from 156 Japanese subjects were examined, including 115 genetically confirmed patients caused by the three prevalent causative genes and 41 normal subjects. The mean overall test accuracy for fundus photographs and FAF images was 88.2% and 81.3%, respectively. The mean overall sensitivity/specificity values for fundus photographs and FAF images were 88.3%/97.4% and 81.8%/95.5%, respectively. / Conclusion: A novel application of deep neural networks in the prediction of the causative IRD genes from fundus photographs and FAF, with a high prediction accuracy of over 80%, was highlighted. These achievements will extensively promote the quality of medical care by facilitating early diagnosis, especially by non-specialists, access to care, reducing the cost of referrals, and preventing unnecessary clinical and genetic testing

Ca-substitution and O-doping effects in superconducting Cu(Ba0.8Sr0.2)2(Yb1-xCax)Cu2O6+z obtained from neutron diffraction refinements

Distinct calcium and oxygen doping effects were studied in the Cu(Ba0.8Sr0.2)2(Yb1−xCax)Cu2O6+z (Cu−1212:P) system by means of neutron diffraction and superconducting quantum interference device experiments in the wide substitution ranges of 0<~x<~0.35 and 0<z<1. The effectiveness of the two different ways to introduce holes into the CuO2 planes was compared both in respect to the capability to increase Tc and in terms of the hole production as estimated from neutron-diffraction data via bond-valence-sum calculation. Oxygen doping was found to increase the hole concentration less efficiently, and further, at a certain hole concentration value higher Tc values were obtained with calcium substitution than with oxygen doping. The two different hole-doping methods exhibited also different Tc vs Cu-O bond length relations. As a conclusion, the possible roles of the hole distribution in the in-plane Cu-O bond and the flatness of the CuO2 planes in determining the superconducting properties were recognized.Peer reviewe

Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

Cataract is the most common cause of blindness in the world; during infancy and early childhood, it frequently results in visual impairment. Congenital cataracts are phenotypically and genotypically heterogeneous and can occur in isolation or in association with other systemic disorders. Significant progress has been made in identifying the molecular genetic basis of cataract; 115 genes to date have been found to be associated with syndromic and non-syndromic cataract and 38 disease-causing genes have been identified to date to be associated with isolated cataract. In this review, we briefly discuss lens development and cataractogenesis, detail the variable cataract phenotypes and molecular mechanisms, including genotype-phenotype correlations, and explore future novel therapeutic avenues including cellular therapies and pharmacological treatments

Prediction of Causative Genes in Inherited Retinal Disorders from Spectral-Domain Optical Coherence Tomography Utilizing Deep Learning Techniques

Purpose. To illustrate a data-driven deep learning approach to predicting the gene responsible for the inherited retinal disorder (IRD) in macular dystrophy caused by ABCA4 and RP1L1 gene aberration in comparison with retinitis pigmentosa caused by EYS gene aberration and normal subjects. Methods. Seventy-five subjects with IRD or no ocular diseases have been ascertained from the database of Japan Eye Genetics Consortium; 10 ABCA4 retinopathy, 20 RP1L1 retinopathy, 28 EYS retinopathy, and 17 normal patients/subjects. Horizontal/vertical cross-sectional scans of optical coherence tomography (SD-OCT) at the central fovea were cropped/adjusted to a resolution of 400 pixels/inch with a size of 750 × 500 pix2 for learning. Subjects were randomly split following a 3 : 1 ratio into training and test sets. The commercially available learning tool, Medic mind was applied to this four-class classification program. The classification accuracy, sensitivity, and specificity were calculated during the learning process. This process was repeated four times with random assignment to training and test sets to control for selection bias. For each training/testing process, the classification accuracy was calculated per gene category. Results. A total of 178 images from 75 subjects were included in this study. The mean training accuracy was 98.5%, ranging from 90.6 to 100.0. The mean overall test accuracy was 90.9% (82.0–97.6). The mean test accuracy per gene category was 100% for ABCA4, 78.0% for RP1L1, 89.8% for EYS, and 93.4% for Normal. Test accuracy of RP1L1 and EYS was not high relative to the training accuracy which suggests overfitting. Conclusion. This study highlighted a novel application of deep neural networks in the prediction of the causative gene in IRD retinopathies from SD-OCT, with a high prediction accuracy. It is anticipated that deep neural networks will be integrated into general screening to support clinical/genetic diagnosis, as well as enrich the clinical education

The Effect on Retinal Structure and Function of 15 Specific ABCA4 Mutations: A Detailed Examination of 82 Hemizygous Patients

Purpose: To determine the effect of 15 individual ABCA4 mutations on disease severity. Methods: Eighty-two patients harboring 15 distinct ABCA4 mutations in trans with null (hemizygous), 10 homozygous, and 20 nullizygous patients were recruited. Age of onset was determined from medical histories. Electroretinography (ERG) responses were classified into three groups (normal; cone dysfunction; cone and rod dysfunction). The dark-adapted bright-flash (DA 10.0) a-wave amplitudes and the light-adapted flicker ERG (LA 3.0 30 Hz) amplitudes were plotted against age and compared with the nullizygous patients. Fundus autofluorescence imaging (FAF) was assessed when available. Results: Patients hemizygous for p.G1961E and p.R2030Q had normal ERGs. Patients harboring p.R24H, p.R212C, p.G863A/delG, p.R1108C, p.P1380L, p.L2027F, and c.5714+5G>A had abnormal ERGs (ERG group 2 or 3) at older ages, in most cases with significantly higher amplitudes than nullizygous patients. Mutations p.L541P+A1038V, p.E1022K, p.C1490Y, p.E1087K, p.T1526M, and p.C2150Y were associated with abnormal ERGs (group 2 or 3) and amplitudes comparable to those of nullizygous patients. The majority of patients, including those harboring p.G1961E, had foveal atrophy; while both patients harboring p.R2030Q had foveal sparing. Most patients harboring intermediate and null-like mutations displayed FAF abnormalities extending beyond the vascular arcades. Conclusions: In the hemizygous state, 2/15 ABCA4 alleles retain preserved peripheral retinal function; 7/15 are associated with either preserved or only mildly abnormal retinal function, worse in older patients; 6/15 behave like null mutations. These data help characterize the degree of dysfunction conferred by specific mutant ABCA4 proteins in the human retina

Clinical and genetic characteristics of 10 Japanese patients with PROM1-associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population

Variants in the PROM1 gene are associated with cone (-rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (-rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p.Gly53Asp). Characteristic features of macular atrophy with generalized cone-dominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population

Sector Retinitis Pigmentosa: Extending the Molecular Genetics Basis and Elucidating the Natural History

PURPOSE: To determine the genetic background of sector retinitis pigmentosa (RP), natural history, in order to better inform patient counselling. DESIGN: Retrospective case series. METHODS: Review of clinical notes, retinal imaging including color fundus photography (CFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT), electrophysiological assessment (ERG), and molecular genetic testing was performed in patients with sector RP from a single tertiary referral center. MAIN OUTCOME: Measures: Reporting demographic data, signs and symptoms, visual acuity, molecular genetics, ERG, FAF and OCT findings. RESULTS: Twenty-six molecularly confirmed patients from 23 different families were identified, harboring likely disease-causing variants in nine genes. The mode of inheritance was 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 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 provided longitudinal data will help to provide more accurate patient prognosis and counselling, as well as inform patients' potential participation in the increasing numbers of trials of novel therapeutics and access to future treatments