The BEST1 (alternatively VMD2, RP50, BMD) gene located on chromosome 11q12.3 (genomic coordinates: 11:61,946,721-61,965,514) encodes a transmembrane pentameric protein consisting of 585 amino acids that is predominantly expressed in the basolateral plasma membrane of the retinal pigment epithelium (RPE).[1–4] It functions as a calcium-activated chloride channel (CaCC) which regulates the flow of chloride and other monovalent anions across cellular membranes in response to intracellular calcium levels.[4–6] Mutation of this gene has been associated with a wide range of ocular phenotypes that may be influenced by age, gender, environment, epigenetic factors, and presence of modifier genes and are collectively termed as bestrophinopathies.[1,7,8] ARB may result from a total absence (null phenotype) of functional BEST1 protein in the RPE, [9,10] improper localization to the cell membrane with intact anion channel activity[11] or lack of channel activity specifically.[12]
Schatz et al. [13], in 2006, were the first to report two related patients with multifocal vitelliform dystrophy with compound BEST1 heterozygous variants. Two years later, Burgess et al. [9] coined the term autosomal recessive bestrophinopathy (ARB) and concluded that this condition was the fourth phenotype associated with BEST1 gene mutations. Phenotypes associated with pathogenic variants of BEST1 include (1) conditions that predominantly affect the macula, including autosomal recessive bestrophinopathy (ARB, OMIM 611809)[9,12]; Best disease (OMIM, 153700) [14,15] and adult vitelliform macular dystrophy (OMIM 153840); (2) those with generalized retinal involvement, including autosomal dominant vitreoretinochoroidopathy (OMIM 193220)[16,17]; rod-cone dystrophy and retinitis pigmentosa (OMIM 613194)[1,18]; and (3) diseases with retinal and anterior segment involvement, including autosomal dominant microcornea, rod-cone dystrophy, early-onset cataract, and posterior staphyloma.[1] In contrast to Best vitelliform macular dystrophy (BVMD), which is results from autosomal dominant BEST1 mutations[19][20,21], autosomal recessive bestrophinopathy (ARB) is associated with biallelic mutations in the BEST1 gene[9].
The clinical features of ARB include a gradual and progressive visual loss, hyperopia, predominantly peri-macular sub-retinal vitelliform deposits of lipofuscin in the retinal pigment epithelium (RPE), evident as hyperautofluorescent areas at the posterior pole, accumulation of subretinal and/or intraretinal fluid, absence of light peak in EOG, normal or reduced ERG, and in some, shallow anterior chambers, predisposing the affected patients to angle-closure glaucoma. [9,22,23] The reduction in electrooculogram light peak-to-dark trough ratio can be explained by the severe generalized RPE dysfunction. Full-field electroretinography typically normal early on in the disease and shows abnormal results from late childhood or adolescence, indicating generalized rod and cone dysfunction. In addition, pattern electroretinography evidence of macular dysfunction is also seen.[9] ARB usually manifests in the first two decades of life but may remain asymptomatic as late as the fifth decade.[9,12,24] In this article, we present the results of a clinical, electrophysiological, and genetic investigation of two siblings with ARB.