Autosomal Recessive Bestrophinopathy Research Articles

Mutant Best1 Expression and Impaired Phagocytosis in an iPSC Model of Autosomal Recessive Bestrophinopathy

Autosomal recessive bestrophinopathy (ARB) is caused by mutations in the gene BEST1 which encodes bestrophin 1 (Best1), an anion channel expressed in retinal pigment epithelial (RPE) cells. It has been hypothesized that ARB represents the human null phenotype for BEST1 and that this occurs due to nonsense mediated decay (NMD). To test this hypothesis, we generated induced pluripotent stem cells (iPSCs) from a patient with ARB and her parents. After differentiation to retinal pigment epithelial (iPSC-RPE) cells, both BEST1 mRNA and Best1 protein expression were compared to controls. BEST1 mRNA expression levels, determined by quantitative PCR, were similar in ARB iPSC-RPE, parental cells, and genetically unrelated controls. Western blotting revealed that CRALBP and RPE65 were expressed within the range delineated by unrelated controls in iPSC-RPE from the ARB donor and her parents. Best1 protein was detected in different clones of ARB iPSC-RPE, but at reduced levels compared to all controls. When tested for the ability to phagocytose photoreceptor outer segments, ARB iPSC-RPE exhibited impaired internalization. These data suggest that impaired phagocytosis is a trait common to the bestrophinopathies. Furthermore, ARB is not universally the result of NMD and ARB, in this patient, is not due to the absence of Best1.

BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes.

Mutations in bestrophin-1 (BEST1) are associated with distinct retinopathies, notably three forms with autosomal dominant inheritance and one condition with an autosomal recessive mode of transmission. The molecular mechanisms underlying their distinct retinal phenotypes are mostly unknown. Although heterozygous missense mutations in BEST1 reveal dominant-negative effects in patients with autosomal dominant Best disease (BD), heterozygous mutations associated with autosomal recessive bestrophinopathy (ARB) display no disease phenotype. Here we show that the recessive mutations trigger a strong and fast protein degradation process in the endoplasmic reticulum (ER), thereby favoring a decreased stoichiometry of mutant versus normal BEST1 subunits in the assembly of the homo-pentameric BEST1 chloride channel. In contrast, dominant mutations escape ER-associated degradation and are subjected to a slightly delayed post-ER degradation via the endo-lysosomal degradation pathway. As a result, increased formation of a non-functional BEST1 channel occurs due to a roughly equimolar incorporation of normal and mutant BEST1 subunits into the channel complex. Taken together, our data provide insight into the molecular pathways of dominantly and recessively acting BEST1 missense mutations suggesting that the site of subcellular protein quality control as well as the rate and degree of mutant protein degradation are ultimately responsible for the distinct retinal disease phenotypes in BD and ARB.

Best Vitelliform Macular Dystrophy.

Autosomal recessive bestrophinopathy (ARB) results from a total absence of functional bestrophin-1 protein owing to two BEST1 mutations, one on each of the chromosomes. If present at an early age, the presenting feature could be decreased vision due to amblyopia. Refractive error is hyperopia, predisposing these eyes for acute angle-closure glaucoma. The yellowish lesions are larger and more extensive-extending beyond the arcades-than in the typical autosomal dominant Best disease. Some of the eyes also show numerous yellowish subretinal dots. Lesions are multifocal (Fig. 29.1). Subretinal fibrosis in the macular area is a common feature. Optical coherence tomography (OCT) may show cystoid changes in the neurosensory retina. Fundus autofluorescence (FAF): Increased AF reflects lipofuscin accumulation in the RPE; decreased AF reflects RPE atrophy. Electroretinography (ERG): As panretinal photoreceptor dysfunction progresses with advancing age, full-field (FF) ERG shows delayed rod and cone responses. Electrooculography (EOG): Abnormal Arden ratio.

Idiopathic Acute Exudative Polymorphous Vitelliform Maculopathy: Clinical Spectrum and Multimodal Imaging Characteristics

To describe clinical findings in patients with acute exudative polymorphous vitelliform maculopathy (AEPVM). Retrospective, observational, multicenter case series review. Consecutive patients diagnosed with idiopathic AEPVM. Review of clinical charts, multimodal imaging, electrophysiologic findings, and genetic findings in previously unpublished patients and review of the literature. Clinical features of idiopathic AEPVM and differential diagnosis. Eighteen patients (age range, 21-74 years) with typical features of AEPVM, including initial localized, serous detachments followed by the development of characteristic yellow-white deposits in the vitelliform space. Over time, this hyperautofluorescent material gravitated within the larger lesions, resulting in typical curvilinear deposits characteristic of later stages. Symptoms and clinical findings lasted from weeks to several years. Some patients showed previously undescribed features such as fluorescein-negative intraretinal cystic changes, choroidal neovascularization, serous retinal elevations mimicking retinal folds, increased choroidal thickness, lack of rapid visual recovery, and recurrence years after complete resolution of initial manifestations. Acute exudative polymorphous vitelliform maculopathy can present with a more variable natural course than previously described. Paraneoplastic retinopathy and autosomal recessive bestrophinopathy closely resemble AEPVM, necessitating medical and hereditary evaluation to exclude these clinical possibilities. This series of patients with AEPVM expands the clinical spectrum of the disorder, including demographics, clinical manifestations, imaging features, natural course, and visual prognosis.

Adult-Onset Vitelliform Macular Dystrophy caused by BEST1 p.Ile38Ser Mutation is a Mild Form of Best Vitelliform Macular Dystrophy

Adult-onset vitelliform macular dystrophy (AVMD) is a common and benign macular degeneration which can be caused by BEST1 mutation. Here, we investigated the clinical characteristics associated with a newly identified BEST1 mutation, p.Ile38Ser and confirmed the associated physiological functional defects. The 51-year-old patient presented bilateral small subretinal yellow deposits. Consistent with AVMD, the corresponding lesions showed hyperautofluorescence, late staining in fluorescein angiography, and subretinal hyper-reflective materials in spectral-domain optical coherence tomography. Genetic analysis demonstrated that the patient presented with a heterozygous p.Ile38Ser BEST1 mutation. Surface biotinylation and patch clamp experiments were performed in transfected HEK293T cells. Although, the identified BEST1 mutant maintains normal membrane expression, p.Ile38Ser mutant showed significantly smaller currents than wild type (WT). However, it showed larger currents than other BEST1 mutants, p.Trp93Cys, causing autosomal dominant best vitelliform macular dystrophy (BVMD), and p.Ala195Val, causing autosomal recessive bestrophinopathy (ARB). The cells expressing both WT and each BEST1 mutant showed that the functional defect of p.Ile38ser was milder than that of p.Trp93Cys, whereas combination of p.Ala195Val with WT showed good current. We identified and described the phenotype and in vitro functions of a novel BEST1 mutation causing AVMD. AVMD induced by p.Ile38Ser BEST1 mutation is a mild form of BVMD.

Screening of BEST1 Gene in a Chinese Cohort With Best Vitelliform Macular Dystrophy or Autosomal Recessive Bestrophinopathy.

Mutations in the BEST1 gene can cause Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB). The aim of the current study was to establish the BEST1 mutation spectrum in Chinese patients with BVMD and ARB and to describe the phenotypic characteristics of patients carrying BEST1 mutations. A total of 37 probands with a clinical diagnosis of BVMD (17 patients) or ARB (20 patients) were recruited for genetic analysis; of these, only 5 probands had a family history. All probands underwent detailed ophthalmic examinations. All coding exons and exon-intron boundaries of the BEST1 gene were screened by PCR-based DNA sequencing. In silico programs were used to analyze the pathogenicity of all the variants. Genomic DNA rearrangements of the BEST1 gene were identified by real-time quantitative PCR (RQ-PCR). For patients with BVMD, single heterozygous BEST1 mutations were identified in 13 patients and compound heterozygous mutations were found in 3 patients. For patients with ARB, biallelic mutations were found in 13 probands and single mutant alleles in six patients. Overall, 36 disease-causing variants (20 novel mutations) of the BEST1 gene were identified, including 28 (77.8%) missense, 3 (8.3%) nonsense, 4 (11.1%) splicing effect, and 1 (2.8%) frameshift small duplication mutations. The mutation spectrum of the BEST1 gene in Chinese patients differed from those of Caucasian patients. Mutations that cause ARB differ from those that cause BVMD. BEST1 screening is important for precise diagnosis of BVMD or ARB.

FUNCTIONAL AND ANATOMICAL OUTCOMES OF CHOROIDAL NEOVASCULARIZATION COMPLICATING BEST1-RELATED RETINOPATHY.

To describe the presenting features and functional outcomes in a series of patients with choroidal neovascular membrane complicating BEST1-related retinopathy (Best disease and autosomal recessive bestrophinopathy). Retrospective review of consecutive cases at a tertiary care eye hospital. Patients were identified retrospectively over an 11-year period. Records were reviewed to extract demographic as well as functional and anatomical outcome data. Fourteen eyes of 12 patients were identified (11 Best disease and 1 autosomal recessive bestrophinopathy). Median follow-up was 2.8 years (range 0.8-6). The median age at choroidal neovascular membrane discovery was 15.5 years (range 6-72). Choroidal neovascular membranes were active early in the disease course before vitelliruption. Seven eyes were treated with intravitreal bevacizumab, 7 eyes were monitored by observation alone. On average, patients required a single treatment (median = 1, range 1-10). The median gain in visual acuity was greater in the treated versus the observed group-0.46 versus 0.17 decimalized units of Snellen acuity, respectively (P < 0.05 Mann-Whitney U test). Although a significant reduction in central macular thickness was evident in both groups, 150 μm (treated) and 104 μm (observed), active treatment was not associated with greater thinning than observation (P > 0.05 Mann-Whitney U test). There is a high rate of spontaneous recovery of BEST1-related choroidal neovascular membrane, and overall the authors observed a gain in visual acuity associated with a reduction in central macular thickness. Active treatment, here with intravitreal bevacizumab, is associated with better functional outcomes than observation alone.

Bestrophin 1 and retinal disease.

Mutations in the gene BEST1 are causally associated with as many as five clinically distinct retinal degenerative diseases, which are collectively referred to as the "bestrophinopathies". These five associated diseases are: Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, adult-onset vitelliform macular dystrophy, autosomal dominant vitreoretinochoroidopathy, and retinitis pigmentosa. The most common of these is Best vitelliform macular dystrophy. Bestrophin 1 (Best1), the protein encoded by the gene BEST1, has been the subject of a great deal of research since it was first identified nearly two decades ago. Today we know that Best1 functions as both a pentameric anion channel and a regulator of intracellular Ca2+ signaling. Best1 is an integral membrane protein which, within the eye, is uniquely expressed in the retinal pigment epithelium where it predominantly localizes to the basolateral plasma membrane. Within the brain, Best1 expression has been documented in both glial cells and astrocytes where it functions in both tonic GABA release and glutamate transport. The crystal structure of Best1 has revealed critical information about how Best1 functions as an ion channel and how Ca2+ regulates that function. Studies using animal models have led to critical insights into the physiological roles of Best1 and advances in stem cell technology have allowed for the development of patient-derived, "disease in a dish" models. In this article we review our knowledge of Best1 and discuss prospects for near-term clinical trials to test therapies for the bestrophinopathies, a currently incurable and untreatable set of diseases.

Flat Anterior Chamber after Trabeculectomy in Secondary Angle-Closure Glaucoma with BEST1 Gene Mutation: Case Series.

PurposeTrabeculectomy has been regarded as a mainstay of initial treatment in eyes of angle closure glaucoma (ACG) with peripheral anterior synechia > 180° in the Chinese population while its efficacy in secondary ACG with BEST1 gene mutation remains unclear. We set out to investigate the treatment outcome of trabeculectomy for secondary ACG in a group of patients with autosomal recessive bestrophinopathy (ARB).MethodsIn this retrospective case series study, 8 secondary ACG patients with ARB and their 4 recruited family members underwent a thorough ophthalmic examination including best-corrected visual acuity, Goldmann applanation tonometry, gonioscopy, and fundus examinations. Ultrasound biomicroscopy, optical coherence tomography (OCT), ultrasound A-scan, B-scan, electro-oculography (EOG), Humphrey perimetry, fundus photography, fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were also performed. Blood samples were obtained in the patients and their available family members to analyze the variants of the BEST1 gene. Trabeculectomy was performed in the 8 patients (15 eyes).ResultsThe age of onset varied from 13 to 38 years. The average axial length (AL) of the affected eyes was 21.82 ± 0.92 mm and the average anterior chamber depth (ACD) was 2.19 ± 0.29 mm. There was marked axial shallowing of the anterior chamber in all 15 eyes after trabeculectomy, and was not improved with potent mydriatics. The IOP was elevated in 3 eyes. Variable degree of yellowish subretinal deposits was observed in the posterior retina. The FFA showed punctuate or patched hyperfluorescence suggesting retinal pigment epithelium impairment. The ICGA demonstrated dilatation of choroidal vessels. The OCT revealed diffused neuroretinal detachment in the posterior and midperipheral retina, with intraretinal fluid collections, and hyperreflective subretinal accumulations. The average subfoveal choroidal thickness of the patients was 382.36 ± 80.09 μm. All the patients and enrolled family members carried mutation in BEST1 gene.ConclusionsARB is a rare condition with fundus manifestations mimicking various diseases. Careful discrimination should be taken to exclude any secondary causes for ACG before treatment. Concerning the high incidence of postoperative shallow anterior chamber, selection of filtering surgery should be very careful in these patients.

EVER Past president lecture: lessons from the Fascinating World of Bestrophinopathies

SummaryPurposeTo describe the genotypes and phenotypes in patients with bestrophinopathies.MethodsExamples of Best vitelliform macular dystrophy will be compared with the phenotype of patients with autosomal recessive bestrophinopathy and autosomal dominant vitreoretinochoroidopathy.ResultsPhenotypes of BVMD range from asymptomatic, normal fundi in heterozygous BEST1 mutation carriers, to classic macular egg yolk‐like lesions. Biallelic BEST1 mutations cause ARB, characterized by shallow retinal detachments in the posterior pole, with hyperautofluorescent deposits in the watershed zone and superonasal to the optic disc. In addition, there are small, inner retinal, cystoid changes. Rod‐cone dystrophy (RCD) develops later. Subacute angle closure glaucoma is frequent. ADVIRC patients show a 360° peripheral hyperpigmented band, peripapillary staphylomata, RCD and microcornea. Unique mutations in one BEST1 allele cause ADVIRC. Electro‐oculography is abnormal in all bestrophinopathies first.ConclusionsBestrophinopathies are a diverse group of conditions caused by either mono‐ or biallelic mutations in BEST1. Whereas ADVIRC is very different, BVMD and ARB show considerable overlap. This suggests that a threshold of bestrophin protein production, blurring the differences between dominant or recessive mechanisms of disease, may be the main determinant of the phenotype. Abnormal EOGs indicate primary RPE involvement.

Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy in Japanese Cohort

To report the clinical and genetic findings of 9 Japanese patients with autosomal recessive bestrophinopathy (ARB). Retrospective, multicenter observational case series. Nine ARB patients from 7 unrelated Japanese families that were examined in 3 institutions in Japan were studied. A series of ophthalmic examinations including fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, electrooculography (EOG), electroretinography, and the results of genetic analysis were reviewed. Genetic analyses identified 7 pathogenic variants in BEST1 including 2 novel variants, c.478G>C (p.A160P) and c.948+1delG. Homozygous variants were found in 4 families and compound heterozygous variants were found in 3 families. Two patients were diagnosed as ARB only after the whole exome sequencing analyses. The Arden ratio of the EOG was less than 1.5 in all 7 patients tested. Vitelliform lesions typical for Best vitelliform macular dystrophy were not seen in any of the patients. Seven patients shared some of the previously described features of ARB: subretinal deposits, extensive subretinal fluid, and cystoid macular edema (CME). However, the other 2 patients with severe retinal degeneration lacked these features. Focal choroidal excavations were present bilaterally in 2 patients. One case had a marked reduction of the CME and expansion of subretinal deposits over an 8-year of follow-up period. Japanese ARB patients had some butnot all of the previously described features. Geneticanalyses are essential to diagnose ARB correctly in consequence of considerable phenotypic variations.

Detailed analysis of family with autosomal recessive bestrophinopathy associated with new BEST1 mutation.

PurposeTo describe the clinical and genetic findings in a patient with autosomal recessive bestrophinopathy (ARB) and his healthy parents.MethodsThe patient and his healthy non-consanguineous parents underwent detailed ophthalmic evaluations including electro-oculography (EOG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Mutation analysis of the BEST1 gene was performed by Sanger sequencing.ResultsThe FAF images showed multiple spots of increased autofluorescence, and the sites of these spots corresponded to the yellowish deposits detected by ophthalmoscopy. SD-OCT showed cystoid macular changes and a shallow serous macular detachment. The Arden ratio of the EOG was markedly reduced to 1.1 in both eyes. Genetic analysis of the proband detected two sequence variants of the BEST1 gene in the heterozygous state: a novel variant c.717delG, p.V239VfsX2 and an already described c.763C>T, p.R255W variant associated with Best vitelliform macular dystrophy and ARB. The proband’s father carried the c.717delG, p.V239VfsX2 variant in the heterozygous state, and the mother carried the c.763C>T, p.R255W variant in the heterozygous state. The parents who were heterozygous for the BEST1 variants had normal visual acuity, EOG, SD-OCT, and FAF images.ConclusionsIn a truncating BEST1 mutation, the phenotype associated with ARB is most likely due to a marked decrease in the expression of BEST1 promoted by the nonsense-mediated decay surveillance mechanism, and it may depend on the position of the premature termination of the codon created.

BESTROPHINOPATHY: A Spectrum of Ocular Abnormalities Caused by the c.614T>C Mutation in the BEST1 Gene.

To describe the variable ocular phenotype associated with a heterozygous mutation in the BEST1 gene. Clinical and genetic assessment was performed in five members of the same family. Molecular genetic analysis of the BEST1 gene was performed by direct sequencing. Extensive ophthalmic examination included color fundus imaging, spectral domain optical coherence tomography, fundus autofluorescence, electro-oculography (EOG), and full-field electroretinography (ERG). The main outcome measures were BEST1 mutations, imaging, and electroretinography findings. All affected family members carried a single heterozygous c.614T>C (p.I205T) mutation in exon 5 of the BEST1 gene. The 46-year-old proband showed nanophthalmos with chorioretinal atrophy in the macula, extensive coarse hyperpigmentation in the (mid) peripheral retina with tractional vitreous strands. Full-field ERG revealed nonrecordable cone and rod responses, and EOG showed an absent light rise. The daughter and son of the proband showed a phenotype resembling autosomal recessive bestrophinopathy, including short axial lengths, cystoid fluid collections, and shallow serous subretinal fluid accumulation on spectral domain optical coherence tomography throughout the macula in combination with mild retinal pigment epithelium changes. The son of the proband also showed subretinal yellowish deposits inferiorly in the macula as well as outside the temporal vascular arcade, that were hyperfluorescent on fundus autofluorescence, similar to those seen in autosomal recessive bestrophinopathy. Full-field ERG revealed a reduced rod and cone response and a markedly reduced or absent EOG light peak in both brother and sister of the proband. The clinical spectrum of bestrophinopathy may encompass severe ocular phenotypes that affect the development and function of the entire eye. A clinical picture similar to autosomal recessive bestrophinopathy can also be caused by a single heterozygous mutation in the BEST1 gene, such as the c.614T>C (p.I205T) variant in this family.

Restoration of mutant bestrophin-1 expression, localisation and function in a polarised epithelial cell model.

ABSTRACTAutosomal recessive bestrophinopathy (ARB) is a retinopathy caused by mutations in the bestrophin-1 protein, which is thought to function as a Ca2+-gated Cl− channel in the basolateral surface of the retinal pigment epithelium (RPE). Using a stably transfected polarised epithelial cell model, we show that four ARB mutant bestrophin-1 proteins were mislocalised and subjected to proteasomal degradation. In contrast to the wild-type bestrophin-1, each of the four mutant proteins also failed to conduct Cl− ions in transiently transfected cells as determined by whole-cell patch clamp. We demonstrate that a combination of two clinically approved drugs, bortezomib and 4-phenylbutyrate (4PBA), successfully restored the expression and localisation of all four ARB mutant bestrophin-1 proteins. Importantly, the Cl− conductance function of each of the mutant bestrophin-1 proteins was fully restored to that of wild-type bestrophin-1 by treatment of cells with 4PBA alone. The functional rescue achieved with 4PBA is significant because it suggests that this drug, which is already approved for long-term use in infants and adults, might represent a promising therapy for the treatment of ARB and other bestrophinopathies resulting from missense mutations in BEST1.

Phenotypes of bestrophinopathies

AbstractPurpose: To describe the phenotypes of conditions due to mutations in BEST1, the gene encoding bestrophin‐1. Methods: A case presentation format will be used to illustrate the phenotypes and genotypes of the different bestrophinopathies, with special attention to both the clinical and electrophysiological features that distinguish one phenotype from the other, and those they have in common. In addition, the different BEST1 genotypes will be discussed. Results: The phenotypes of Best vitelliform macular dystrophy (BVMD), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and autosomal recessive bestrophinopathy (ARB) are very different. Nevertheless, they share an abnormal electro‐oculography (EOG) as a common feature. Electroretinography is normal in BVMD, whereas a rod‐cone dystrophy is evident in the later stages of ADVIRC and ARB. BVMD is due to a heterozygous missense mutation in BEST1, ADVIRC is due to interaction of several bestrophin protein isoforms, and ARB is probably the null phenotype. Conclusions: The phenotypes of the bestrophinopathies are diverse, although they share an abnormal EOG as the common feature. The specific genotypes are also different, leading to different molecular pathogenetic mechanisms.

Disease-causing mutations associated with four bestrophinopathies exhibit disparate effects on the localization, but not the oligomerization, of Bestrophin-1

BEST1 encodes Bestrophin-1 (Best1), a homo-oligomeric, integral membrane protein localized to the basolateral plasma membrane of the retinal pigment epithelium. Mutations in BEST1 cause five distinct retinal degenerative diseases, including adult vitelliform macular dystrophy (AVMD), autosomal recessive bestrophinopathy (ARB), autosomal dominant vitreoretinochoroidopathy (ADVIRC), and retinitis pigmentosa (RP). The mechanisms underlying these diseases and why mutations cause one disease over another are, for the most part, unknown. To gain insights into these four diseases, we expressed 28 Best1 mutants fused to YFP in polarized MDCK monolayers and, via confocal microscopy and immunofluorescence, live-cell FRET, and reciprocal co-immunoprecipitation experiments, screened these mutants for defects in localization and oligomerization. All 28 mutants exhibited comparable FRET efficiencies to and co-immunoprecipitated with WT Best1, indicating unimpaired oligomerization. RP- and ADVIRC-associated mutants were properly localized to the basolateral plasma membrane of cells, while two AVMD and most ARB mutants were mislocalized. When co-expressed, all mislocalized mutants caused mislocalization of WT Best1 to intracellular compartments. Our current and past results indicate that mislocalization of Best1 is not an absolute feature of any individual bestrophinopathy, occurring in AVMD, BVMD, and ARB. Furthermore, some ARB mutants that do not also cause dominant disease cause mislocalization of Best1, indicating that mislocalization is not a cause of disease, and that absence of Best1 activity from the plasma membrane is tolerated. Lastly, we find that the ARB truncation mutants L174Qfs*57 and R200X can form oligomers with WT Best1, indicating that the first ∼174 amino acids of Best1 are sufficient for oligomerization to occur.

Value of anti-VEGF treatment in choroidal neovascularization associated with autosomal recessive bestrophinopathy

A 26-year-old white woman presented with a 1-year history of reduced vision in both eyes, bilateral yellowish deposits in the central macula, and pale yellow retinal flecks extending to midretinal periphery. Choroidal neovascularization (CNV) was confirmed in her left eye. On optical coherence tomography, both eyes showed diffuse intraretinal cystic spaces, thickening and separation of the photoreceptor layer from the retinal pigment epithelium (RPE), subretinal fluid, and focal thickening at the level of the RPE at the fovea. A diagnosis of autosomal recessive bestrophinopathy was confirmed by electrodiagnostic and molecular genetics testing. The CNV responded well to intravitreal ranibizumab therapy, and visual acuity in the left eye improved and stabilized; however, retinoschisis due to fluctuations in intraretinal fluid persisted. This case highlights the fact that current optical coherence tomography-driven protocols used widely to treat neovascular age-related macular degeneration may not be appropriate for CNV associated with other retinal diseases.

Ocular Phenotype Analysis of a Family With Biallelic Mutations in the BEST1 Gene

To investigate the genetic cause and perform a comprehensive clinical analysis of a Danish family with autosomal recessive bestrophinopathy; to investigate whether Bestrophin may be expressed in normal human retina. Retrospective clinical and molecular genetic analysis and immunohistochemical observational study. setting: National referral center. participants: A family with 5 individuals and biallelic BEST1 mutations, and enucleated eyes from 2 individuals with nonaffected retinas. observation procedures: Molecular genetic analysis included sequencing of BEST1 and co-segregation analysis. Clinical investigations included electro-oculography, full-field electroretinography, multifocal electroretinography, spectral-domain optical coherence tomography, and fundus autofluorescence imaging. Immunohistochemical analysis was performed. main outcome measures: BEST1 mutations, imaging findings, electroretinography amplitudes, and implicit times. The index case was compound heterozygous for p.A195V and a novel 15 base pair deletion leading to p.Q238L. The index case at age 10 demonstrated multifocal vitelliform changes that were hyperautofluorescent, cystoid macular edema in the inner nuclear layer, no light rise in the electro-oculography, and a reduced central but preserved peripheral retinal function by multifocal electroretinography. Full-field electroretinography demonstrated a reduced rod response and inner retina dysfunction. Retinal structure was normal in all 3 family members who carried a sequence change in BEST1. Electro-oculography light peak was reduced in both the mother and sister (heterozygous for p.Q238L). Immunohistochemistry could not confirm the presence of Bestrophin in normal human retina. Because of a relatively well preserved retinal function, autosomal recessive bestrophinopathy may be a suitable first candidate, among the BEST1-related ocular conditions, for gene replacement therapy.

Clinical and Genetic Misdiagnosis of Autosomal Recessive Bestrophinopathy

Clinical and Genetic Misdiagnosis of Autosomal Recessive Bestrophinopathy

Autosomal Recessive Bestrophinopathy: Differential Diagnosis and Treatment Options

To describe the clinical and genetic characteristics of patients with autosomal recessive bestrophinopathy (ARB).Retrospective case series.Ten patients with ARB from 7 different families.All patients underwent a complete ophthalmic examination, including dilated fundus examination, fundus photography, and fluorescein angiography (FA). In all probands, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), electro-oculography (EOG), and Goldmann perimetry were performed. In selected patients, multifocal ERG was performed. Blood samples were obtained to analyze the BEST1 gene for biallelic mutations that confirmed the diagnosis of ARB.Age at onset; visual acuity; fundus appearance; characteristics on FA, FAF, OCT, full-field ERG, and EOG; BEST1 gene mutations; and genotype-phenotype correlation.The age at onset varied widely, from 2 to 54 years. A spectrum of fundus abnormalities was observed, such as multifocal yellowish subretinal deposits, subretinal fibrous scars, and cystoid intraretinal fluid collections in the macula. All ARB patients were hyperopic, and some had shallow anterior chamber angles that predisposed them to angle-closure glaucoma. The EOG results were abnormal in all patients. The full-field ERG results were abnormal in 8 ARB patients, whereas 2 patients demonstrated normal cone and rod responses on full-field ERG. Nine ARB patients carried biallelic mutations in the BEST1 gene, and in 1 patient with a characteristic ARB phenotype, only 1 mutation could be identified. Seven different mutations were detected, including 4 novel mutations.Autosomal recessive bestrophinopathy is a recognizable phenotype caused by autosomal recessively inherited mutations in the BEST1 gene. A differential diagnosis with other conditions can be made on the basis of marked autofluorescence changes in combination with an absent light rise on the EOG that outweighs the full-field ERG abnormalities, which point to the BEST1-related hereditary nature of the disease. A number of currently available therapeutic options should be considered in ARB, a disease that seems to be a suitable candidate for future gene therapy.