Autosomal Recessive Bestrophinopathy

Abstract

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 ¼ 4 patients). Mean presenting VA was 0.52 AE 0.36 logarithm of the minimum angle of resolution (logMAR), and final VA was 0.81 AE 0.75 logMAR (P ¼ 0.06). The mean rate of change in VA was 0.05 AE 0.13 logMAR/year. A significant change in VA was detected in patients with a follow-up of 5 years or more (n ¼ 18) compared with patients with a follow-up of 5 years or less (n ¼ 10; P ¼ 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 ¼ 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.

Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene

“…Especially, we extend on a previous report of focal choroidal excavation in two ARB patients [14]. Focal or large choroidal excavation was observed in 11 eyes of nine patients or 30.6% of all eyes in the present study, which is much higher compared to 14.3% in a recent study [18]. In contrast to the latter study, especially small focal choroidal excavation, as seen in most of our patients, was neither associated with choroidal neovascularization, pigment epithelial detachment or subretinal hyperreflective material ( Figure 4B).…”

“…In the latter four patients and patient #2, mfERG amplitudes were centrally reduced as well. The decline of electrophysiologic responses with increasing age has been observed previously [18]. The OCT image shows a very large choroidal excavation (white arrows), associated marked thinning of the inner retinal layers and in between a large cystoid space with highly reflective material.…”

“…Recently, peripapillary sparing has been described as a characteristic feature of ARB [18,33]. This was not a homogeneous finding in the present series, but most typical for phenotype II.…”

“…Since then, clinical and/or genetic findings from about 310 ARB patients with confirmed mutations in the BEST1 gene were described in over 65 publications. Most of the reports included only one or few patients or families, only few included more than 10 families [15,18,21,22]. In the present study, we add extensive clinical and genetic findings from a further 15 ARB families with a total of 18 ARB patients.…”

“…Multiple single case reports, few families, and some larger Asian and European cohorts with ARB were reported [14][15][16][17][18]. Here we present a large European study comprising the clinical and functional features of 18 individuals with ARB from 15 unrelated families.…”