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

Giuseppe Casalino,Kamron N Khan,Monica Armengol,Genevieve Wright,Nikolas Pontikos,Michalis Georgiou,Andrew R Webster,Anthony G Robson,Parampal S Grewal,Michel Michaelides

doi:10.1016/j.ophtha.2020.10.006

Abstract

PurposeTo investigate the clinical course, genetic findings, and phenotypic spectrum of autosomal recessive bestrophinopathy (ARB) in a large cohort of children and adults.DesignRetrospective case series.ParticipantsPatients 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.MethodsReview of case notes, retinal imaging (color fundus photography, fundus autofluorescence, OCT), electrophysiologic assessment, and molecular genetic testing.Main Outcome MeasuresVisual acuity (VA), retinal imaging, and electrophysiologic changes over time.ResultsFifty-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.ConclusionsAlthough 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.

Highlights

The current study provides a detailed characterization of the clinical phenotype, genetic findings, and the natural history of autosomal recessive bestrophinopathy (ARB) in a large number of patients from a single institution, aiming to assist the design of anticipated clinical therapeutic trials for this disease and to help inform advice on prognosis
Near infrared reflectance (NIR) imaging, OCT, and fundus autofluorescence (FAF) imaging were reviewed for all patients
Comparing the pathogenicity score (Combined Annotation Dependent Deletion; Table S1) of our reported ARB missense variants (n 1⁄4 18) with those reported in gnomAD (n 1⁄4 397), we found it to be significantly higher in our ARB variants (P < 0.001), as expected

Summary

Methods

Clinical records and multimodal retinal imaging of patients with ARB attending a tertiary referral center, Moorfields Eye Hospital in London, United Kingdom, were reviewed.[12]. Near infrared reflectance (NIR) imaging, OCT, and fundus autofluorescence (FAF) imaging were reviewed for all patients. Multimodal imaging, including NIR, OCT, FAF, and color fundus photography, at presentation and most recent follow-up visit were reviewed. Fibrosis was said to be present if well-delineated areas of yellow-white tissue with corresponding increased reflectivity were present on NIR and well-defined hyperreflective material was present on the accompanying OCT images.[19] Central retinal thickness (CRT) from the central 1-mm subfield was determined using the Heidelberg software, after manual inspection to ensure correct centration and segmentation. Subretinal deposit was defined as subretinal yellowish material on color fundus photography, with corresponding hyperreflective material on OCT and increased autofluorescence on FAF and was classified as either unifocal or multifocal; subfoveal involvement was assessed. The chosen level of statistical significance was P < 0.05

Results

Molecular Genetic Findings

Imaging Findings

Electrophysiologic Findings

Discussion