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

Abstract

Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02–1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.

First Pediatric Case of Autosomal Recessive Homozygotic Bestrophinopathy due to Homozygous Mutation c.187G>C p. in Two Brothers

“…The BEST1 mutation spectrum underlying bestrophinopathies involves over 300 known mutations [ 1 - 6 ]. In BEST1 gene mutations, gain-of-function and loss-of-function mutations occur [ 1 , 5 , 7 ]. The prevalence of autosomal recessive pattern of BEST1 mutation is described as 1:1,000,000 [ 8 ].…”

“…To date, there is no effective treatment of bestrophinopathies [ 7 ]. Prognosis of the different BEST mutations and their clinical features are not clearly definable [ 1 , 5 , 7 , 8 ]. The pathology focuses on why BEST1 mutations disturb calcium-activated chloride channel activity with the result of retinal degeneration [ 2 , 5 , 9 - 12 ].…”

“…Prognosis of the different BEST mutations and their clinical features are not clearly definable [ 1 , 5 , 7 , 8 ]. The pathology focuses on why BEST1 mutations disturb calcium-activated chloride channel activity with the result of retinal degeneration [ 2 , 5 , 9 - 12 ]. BEST1 mutations are normally autosomal dominant, but sometimes autosomal recessive and therefore as recessive entity indicative for ARB [ 7 ].…”

“…This analysis failed to detect low-grade mosaics, larger delegations or duplications and rearrangements, and mutations outside the regions of the BEST1 gene examined. If a patient with a clinical picture of ARB has both parental alleles (gene copies) of BEST1 mutated, so-called bi-allelic mutation status, and there is no ocular symptomatology in the parents, the diagnosis of ARB is very likely [ 2 - 5 ]. The diagnosis should then be confirmed by a supplementary family analysis.…”

“…The diagnosis should then be confirmed by a supplementary family analysis. The clinical expression of identical genetic disposition can be quite variable, probably due to secondary developments in the wake of the gene mutation, such as neovascularization, glaucoma, extent of the macula, amblyopia in strabismus and glaucoma at least partially suitable to treat ARB [ 2 - 5 ]. The mutation in BEST1 found in the two brothers does not seem to have been described yet in world literature.…”