Autosomal Recessive Bestrophinopathy: Clinical and Genetic Characteristics of Twenty-Four Cases

Abstract

Background. To describe ocular manifestations, imaging characteristics, and genetic test results of autosomal recessive bestrophinopathy (ARB). The study design is an observational case series. Methods. Forty-eight eyes of 24 patients diagnosed with ARB underwent complete ophthalmic examinations including refraction, anterior and posterior segment examination, enhanced depth imaging optical coherence tomography (EDI-OCT), fluorescein angiography (FA), electroretinography (ERG), and electrooculography (EOG). Optical coherence tomography angiography (OCTA) and BEST1 gene sequencing were performed in selected patients. Results. The age at onset was 4–35 years (mean: 18.6 years). The male-to-female ratio was 0.45. All patients were hyperopic, except one with less than one diopter myopia. EOG was abnormal in 18 cases with near-normal ERGs. Six patients did not undergo EOG due to their young age. Eighteen patients (75%) had a thick choroid on EDI-OCT, of which three had advanced angle-closure glaucoma, 15 patients were hyperopic, and eight of them had more than four diopters hyperopia in both eyes. Macular retinoschisis was observed in 46 eyes of 23 patients (95%) with cysts mostly located in the inner nuclear layer (INL) to the outer nuclear layer (ONL). Of the 18 patients who underwent FA, mild peripheral leakage was seen in eight eyes of four patients (22%). Subfoveal choroidal neovascularization (CNV) was seen in three eyes of two patients (6%) that responded well to intravitreal bevacizumab (IVB). Seven mutations of the bestrophin-1 (BEST1) gene were found in this study; however, only two of them (p.Gly34 = and p.Leu319Pro) had been previously reported as the cause of ARB based on ClinVar and other literature studies. Conclusions. ARB can be presented with a wide spectrum of ocular abnormalities that may not be easily diagnosed. Pachychoroid can occur alongside retinal schisis and may be the underlying cause of angle-closure glaucoma in ARB. Our study also expands the pathogenic mutation spectrum of the BEST1 gene associated with ARB.

Biallelic Heterozygous Mutations in Crumbs Homolog-1 Gene Associated With Macular Retinoschisis and Angle-Closure Glaucoma: A Case Report and Literature Review

“…Bujakowska et al (9) analyzed published phenotypes of CRB1 mutants and showed that the presence/absence of Coats-like vasculopathy did not reveal a particular mutation pattern, which suggests the involvement of additional genetic and/or environmental modifying factors. Notably, similar signatures, including retinoschisis, mild peripheral angiographic leakage, and ACG, could also be found in autosomal recessive bestrophinopathy (ARB) caused by mutations in both alleles of the BEST1 gene (27,28). Therefore, genetic testing is essential for differential diagnosis.…”

Case report: Autosomal recessive bestrophinopathy with macular cysts and MNV over 13-year follow-up

“…In fact, misdiagnosis of ARB as XLRS has been reported in previous literature (Nakanishi et al, 2016;Habibi et al, 2019;Khojasteh et al, 2021). Definite diagnosis is usually based on genetic analysis, whereas clinical features such as early onset bilateral vitelliform depositions, cystic changes in retinal layers, abnormal hyperfluorescence as well as aberrant EOG could give some hint for ophthalmologists to make a differential diagnosis (Khojasteh et al, 2021). SRF and MNV are very rare in XLRS for differential diagnosis.…”

“…The bestrophin-1 ( BEST1 ) gene (formerly known as VMD2 ) is located on the long arm of chromosome 11 (11q12) and encodes the bestrophin-1 protein located mainly in the retinal pigment epithelium (RPE). Its mutation may lead to a variety of ocular phenotypes known as “bestrophinopathies” ( Khojasteh et al, 2021 ). Autosomal recessive bestrophinopathy (ARB) is caused by mutations in both alleles of the BEST1 gene with either homozygous or compound heterozygous mutations.…”

Autosomal recessive bestrophinopathy combined with neurofibromatosis type 1 in a patient

“…Compound heterozygous or homozygous mutations of the BEST1 gene is responsible for the ARB, which is usually inherited in an autosomal recessive pattern [16] . Unlike other early onset retinal dystrophies, children with ARB typically present good central vision in the rst decade of life [17] . However, progressive deterioration of visual function was identi ed in older patients (> 18 years of age) and in those with longer follow-up (≥ 5 years).…”

“…However, progressive deterioration of visual function was identi ed in older patients (> 18 years of age) and in those with longer follow-up (≥ 5 years). In addition to the retinopathy, ARB is strongly associated with abnormal iridocorneal anatomic features, shallow anterior chamber depth, and reduced axial length and increased susceptibility to angle-closure glaucoma [17] . Xuan et al [18] claimed that about 50% of ARB patients had angle closure glaucoma, which was based on the study of the clinical and genetic characteristics of a large cohort of Chinese patients with vitelliform macular dystrophies.…”