RPGR-Related Retinopathy: Clinical Features, Molecular Genetics, and Gene Replacement Therapy

Retinitis pigmentosa GTPase regulator (RPGR) gene variants are the predominant cause of X-linked retinitis pigmentosa (XLRP) and a common cause of cone-rod dystrophy (CORD). XLRP presents as early as the first decade of life, with impaired night vision and constriction of peripheral visual field and rapid progression, eventually leading to blindness. In this review, we present RPGR gene structure and function, molecular genetics, animal models, RPGR-associated phenotypes and highlight emerging potential treatments such as gene-replacement therapy

Prognostication in Stargardt disease using Fundus Autofluorescence: Improving Patient Care

PURPOSE: To explore fundus autofluorescence (FAF) imaging as an alternative to electroretinogram (ERG), as a non-invasive, quick, and readily interpretable method to predict disease progression in Stargardt disease (STGD). DESIGN: Retrospective case series of patients who attended Moorfields Eye Hospital (London, UK). SUBJECTS: Patients with STGD who met the following criteria were included: (i) biallelic disease-causing variants in ABCA4, (ii) ERG testing performed inhouse with an unequivocal ERG group classification, and (iii) ultra-widefield (UWF) FAF imaging performed up to 2 years before or after the ERG. METHODS: Patients were divided into three ERG groups based on retinal function and three FAF groups according to the extent of the hypoautofluorescence and their retinal background appearance. FAF imaging of 30 and 55° were also subsequently reviewed. MAIN OUTCOME MEASURES: ERG/FAF concordance and its association with baseline visual acuity and genetics. RESULTS: 234 patients were included in the cohort. 170 patients (73%) had the same ERG and FAF group, 33 (14%) had a milder FAF than ERG group, and 31 (13%) had a more severe FAF than ERG group. Children under the age of 10 (n=23) had the lowest ERG/FAF concordance, 57% (9 out of the 10 with discordant ERG/FAF had milder FAF than ERG), and adults with adult onset had the highest (80%). Missense genotypes were more commonly seen in the mildest phenotypes. In 97% and 98% of the cases, respectively, 30° and 55° FAF imaging matched with the group defined by UWF FAF. CONCLUSIONS: We demonstrate that FAF imaging is an effective modality to determine the extent of retinal involvement and thereby inform prognostication, by comparing FAF to the current gold standard of ERG testing to determine retinal involvement and thereby prognosis. In 80% of patients in our large molecularly proven cohort we were able to predict if the disease was confined to the macula or also affected the peripheral retina. Children assessed at a young age, with at least one null variant, early disease onset, and/or poor initial VA may have wider retinal involvement than predicted by FAF alone and/or progress to a more severe FAF phenotype over time

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 MEASUREMENTS: Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), choroidal neovascularization (CNV) rates, and electrophysiology parameters. RESULTS: 222 patients (127 males and 95 females) from 141 families were identified, harboring 69 BEST1 variants, including 22 novel variants. Mean age at presentation was 26.8 years (range 1.3-84.8 years) and most patients (61.5%) presented with a deterioration of central vision. Major funduscopic findings at presentation 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 LogMAR (20/47) for the right eye and 0.33 LogMAR (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 9.6 years. 37 patients (17.3%) were diagnosed with CNV over a mean follow-up period of 8.0 years (range 0-55 years). Eyes with CNV that received treatment with anti-VEGF had a better mean VA compared to eyes that were not treated with anti-VEGF (0.28 LogMAR (20/38) versus 0.62 LogMAR (20/83). The majority of eyes exhibited a hyperopic refractive error (185/235, 78.7%) and 13 patients (6.1%) were diagnosed with amblyopia. Among the three most common variants, p.A243V was associated with a later age of onset, a better age-adjusted VA and less advanced Gass stages compared to p.R218C and p.R218H. 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