Clinical characteristics.

Bestrophinopathies, the spectrum of ophthalmic disorders caused by pathogenic variants in BEST1, are typically characterized by retinal degeneration. The four recognized phenotypes are the three autosomal dominant disorders: Best vitelliform macular dystrophy (BVMD), BEST1 adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC); and autosomal recessive bestrophinopathy (ARB). Onset is usually in the first decade (except AVMD in which onset is age 30 to 50 years). Slow visual deterioration is the usual course. Choroidal neovascularization can occur in rare cases. ADVIRC is also associated with panophthalmic involvement including nanophthalmos, microcornea, hyperopia, and narrow anterior chamber angle with angle closure glaucoma.

Diagnosis/testing.

The diagnosis of autosomal dominant bestrophinopathy is established in a proband with suggestive findings and a heterozygous BEST1 pathogenic (or likely pathogenic) variant identified by molecular genetic testing. The diagnosis of autosomal recessive bestrophinopathy is established in a proband with suggestive findings and biallelic BEST1 pathogenic variants.

Management.

Treatment of manifestations: For individuals with significant visual impairment, referral to a low vision clinic; attention to special education needs for children with visual impairment; and occupational counseling. Regarding advanced BVMD fundus lesions, no clinical trials have compared conservative treatment vs laser photocoagulation for choroidal neovascularization (CNV) and hemorrhage. Also, there are no ongoing clinical trials regarding the effectiveness of treatment with anti-VEGF (vascular endothelial growth factor) agents.

Surveillance: Annual ophthalmologic examination (including best corrected visual acuity, visual fields, and spectral domain optical coherence tomography) to monitor progression of fundus lesions and to evaluate for coincidental development of CNV; in childhood, perform annual ophthalmologic examinations to help prevent the development of amblyopia.

Agents/circumstances to avoid: Cessation of smoking to help prevent neovascularization of the retina.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt ophthalmologic evaluation and routine follow up.

Genetic counseling.

BVMD, AVMD, and ADVIRC are inherited in an autosomal dominant (AD) manner. By definition, autosomal recessive bestrophinopathy (ARB) is inherited in an autosomal recessive (AR) manner.

• AD bestrophinopathy. Each child of an affected individual has a 50% chance of inheriting the BEST1 pathogenic variant.
• AR bestrophinopathy. If both parents are known to be heterozygous for a BEST1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Once the BEST1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a bestrophinopathy are possible.

Suggestive Findings

A bestrophinopathy should be suspected in individuals with following the ophthalmologic findings and electrophysiologic studies by phenotype, and family history.

Ophthalmologic findings by phenotype

• Best vitelliform macular dystrophy (BVMD)
  • Onset age three to 15 years
  • Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals. See Figure 1, Figure 2, Figure 3.
• BEST1 adult-onset vitelliform macular dystrophy (AVMD)
  • Onset age 30-50 years
  • Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
• Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
  • Onset in the first decade of life
  • Fundus examination. Peripheral retinal pigmentation, white retinal opacities
  • Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
• Autosomal recessive bestrophinopathy (ARB)
  • Onset in the first decade of life
  • Fundus examination. White subretinal deposits with macular subretinal fluid

Figure 1.

Best vitelliform macular dystrophy: Vitelliform stage (Stage 2)

Figure 2.

Best vitelliform macular dystrophy: Pseudohypopyon (Stage 3)

Figure 3.

Best vitelliform macular dystrophy: Central scarring (Stage 4b)

Electrophysiologic studies

• Electrooculogram (EOG) measures indirectly the standing potential of the eye. A normal light peak / dark trough ratio (Arden ratio) is >1.8. (As the Arden ratio decreases with age after the fourth decade, this value is not absolute.)
  • BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.
    Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [Testa et al 2008].
  • AVMD. Normal or only slightly reduced
  • ADVIRC. Abnormal
  • ARB. Abnormal
• Full-field electroretinogram (ERG)
  • BVMD and AVMD. Normal
  • ADVIRC. Normal or reduced
  • ARB. Reduced scotopic and photopic responses
• Spectral-domain optical coherence tomography (OCT)
  • BVMD and AVMD. Splitting and elevation of outer retina and retinal pigment epithelial layer with dome-like hyporeflective or hyperreflective material and subretinal fluid
  • ADVIRC. Retinal atrophy usually present; possible cystoid macular edema
  • ARB. Subretinal deposits with subretinal and/or intraretinal fluid
• Fundus autofluorescence (AF)
  • BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
  • ADVIRC. Typically normal centrally with blocked fluorescence in the periphery
  • ARB. Diffuse, discrete small areas of hyper- and hypoautofluorescence

Family history is typically consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations); however, autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity) has been reported in some families. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of bestrophinopathy is established in a proband with suggestive findings and a heterozygous BEST1 pathogenic (or likely pathogenic) variant or biallelic BEST1 pathogenic (or likely pathogenic) variants identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a variant(s) of uncertain significance does not establish or rule out the diagnosis of bestrophinopathy.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing and genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of a bestrophinopathy has not been considered may be more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Bestrophinopathies, the spectrum of ophthalmic disorders caused by pathogenic variants in BEST1, are typically characterized by retinal degeneration but may also be pan ophthalmic. The four recognized phenotypes are the three autosomal dominant disorders: Best vitelliform macular dystrophy (BVMD), BEST1 adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC); and autosomal recessive bestrophinopathy (ARB).

Best Vitelliform Macular Dystrophy (BVMD)

BVMD is a slowly progressive macular dystrophy typically with juvenile onset. The characteristic "egg yolk"-like lesion can be either unilateral or bilateral, single or multiple, and macular or eccentric. Retinal lesions progress from the "egg yolk" or vitelliform stage to a vitelliruptive form and finally to an end-stage form with macular scarring or neovascularization [MacDonald et al 2012, Boon et al 2013]. Inter- as well as intrafamilial variability is observed.

Although the following clinical stages have been described, it is important to note that the disease does not progress through each of these stages in every individual:

• Stage 0. Normal macula. Abnormal electrooculogram (EOG)
• Stage 1. Retinal pigment epithelium (RPE) disruption in the macular region. Fluorescein angiogram (FA) shows window defects.
• Stage 2. Circular well-circumscribed yellow-opaque homogeneous yolk-like macular lesion (vitelliform lesion) (see Figure 1). FA reveals marked hypofluorescence in the zone covered by the lesion.
• Stage 2a. Vitelliform lesion contents become less homogeneous to develop a "scrambled-egg" appearance. FA shows partial blockage of fluorescence with a non-homogeneous hyperfluorescence.
• Stage 3. Pseudohypopyon phase (see Figure 2). The lesion develops a fluid level of a yellow-colored vitelline substance. FA shows inferior hypofluorescence from the blockage by the vitelline material, along with superior hyperfluorescent defects.
• Stage 4a. Orange-red lesion with atrophic RPE and visibility of the choroid. FA shows hyperfluorescence without leakage.
• Stage 4b. Fibrous scarring of the macula (see Figure 3). FA shows hyperfluorescence without leakage.
• Stage 4c. Choroidal neovascularization with new vessels on the fibrous scar or appearance of subretinal hemorrhage. FA shows hyperfluorescence as a result of neovascularization and leakage.

Other findings

• Electroretinogram (ERG). While the full-field ERG is normal, foveal ERG or multifocal ERG reveals reduced central amplitudes [Scholl et al 2002, Palmowski et al 2003]. Abnormal multifocal ERG (mfERG) recordings match areas defined as clinically abnormal by optical coherence tomography (OCT) and retinal photography [Glybina & Frank 2006]. Scanning laser ophthalmoscope-evoked multifocal ERG, used for topographic mapping of retinal function in individuals with BVMD, reveals significantly reduced amplitudes in the macula [Rudolph & Kalpadakis 2003].
• Color vision tests. While a significant proportion of individuals with BVMD have anomalous color discrimination particularly in the protan axis, color vision changes are nonspecific and not diagnostic.
• OCT can reveal the cross-sectional anatomy of the retina in BVMD [Pianta et al 2003, Querques et al 2008]. OCT has defined normal retinal architecture or subtle changes in the outer retina in previtelliform clinical stages, splitting and elevation at the outer retina – retinal pigment epithelium complex in intermediate clinical stages, and thinning of the retina and retinal pigment epithelium in the atrophic clinical stage.
• Pathology. See Figure 4 and Figure 5.

Figure 4.

Right eye of a male age 72 years with molecularly confirmed Best disease A. Macula shows loss of photoreceptor cells and an attenuated outer plexiform layer (OPL).

Figure 5.

Left eye of the same individual A. Macula shows loss of photoreceptor cells and attenuated OPL.

Genotype-Phenotype Correlations

For most BEST1 variants, genotype-phenotype correlations have not been demonstrated. However, a few missense variants have been associated with a milder phenotype:

• A family with a p.Val89Ala substitution had late-onset visual failure (age 40-50 years) [Eksandh et al 2001].
• A family with p.Tyr227Asn had late-onset small vitelliform lesions [Mullins et al 2005].
• Khan et al [2018] described affected individuals and families with the p.Ala243Val variant and late-onset disease with a distinct pattern of fundus autofluorescence. This variant was previously associated with mild disease [Boon et al 2009, Querques et al 2011].

Other observations:

• Six children from three different families had biallelic pathogenic variants in BEST1 [Bitner et al 2011, Iannaccone et al 2011, Zhao et al 2012]. Three of the six were compound heterozygotes for the variants p.Leu41Pro and p.Ile201Thr; two of the six were homozygous for the c.1415delT variant; and one of the six was a compound heterozygote for p.Arg141Ser and p.Arg141His. Heterozygotes (i.e., carriers) did not develop disease.
• BEST1 variants that affect splicing cause ADVIRC [Yardley et al 2004].

Penetrance

BVMD shows high but reduced (>70%) penetrance, especially when electrooculogram is used as evidence of clinical expression.

Individuals heterozygous for a BEST1 variant associated with ARB are generally clinically unaffected [Zhao et al 2012].

Nomenclature

Other terms used to refer to BVMD include Best disease, early-onset vitelliform macular dystrophy, juvenile-onset vitelliform macular dystrophy, and polymorphic vitelline macular degeneration.

Prevalence

BVMD is a rare disorder. The prevalence has been estimated at 1:5,500 in a North American population [Dalvin et al 2017].

The BEST1 founder variant c.383G>C (p.Trp93Cys) has been identified in individuals who can trace their ancestry to a large Swedish kindred ("pedigree S1" in Petrukhin et al [1998]).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a bestrophinopathy, the evaluations summarized below (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Ophthalmologic examination, including best-corrected visual acuity, fundus examination, fundus photographs, and spectral-domain optical coherence tomography (SD-OCT) to determine the stage of disease
• Consultation with a low vision specialist/clinic as needed
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of bestrophinopathies in order to facilitate medical and personal decision making

Treatment of Manifestations

Low vision aids benefit those individuals with significantly reduced visual acuity.

In the United States (US), educational issues for children with visual impairment can be addressed in the following:

• Individualized education plan (IEP) services:
  • An IEP provides specially designed instruction and related services to children who qualify.
  • IEP services will be reviewed annually to determine whether any changes are needed.
  • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
  • Vision consultants should be a part of the child's IEP team to support access to academic material.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.

Occupational counseling, often available through state agencies, patient advocacy groups, and health plans, should be offered.

Best vitelliform macular dystrophy (BVMD) stage 4c fundus lesions (see Clinical Description) or choroidal neovascularization and hemorrhage can be managed by direct laser photocoagulation. Marano et al [2000] suggested a conservative approach in the treatment of choroidal neovascularization based on two individuals with BVMD whose visual acuity improved. No clinical trials comparing the efficacy of laser photocoagulation to conservative treatment have been conducted.

Anti-VEGF (vascular endothelial growth factor) agents are the standard treatment for individuals with subfoveal choroidal neovascularization (CNV). Leu et al [2007] injected intravitreal bevacizumab in a boy age 13 years with BVMD and CNV, hastening visual recovery and regression of the CNV. Intravitreal ranibizumab has also been used with success [Querques et al 2009]. There are no reports on the use of aflibercept. Long-term follow up of these affected individuals is unknown. Currently there are no clinical trials to demonstrate the effectiveness of anti-VEGF agents on CNV in BVMD.

Andrade et al [2003] performed photodynamic therapy (PDT) using verteporfin for CNV on one person with BVMD. The CNV regressed and the subretinal hemorrhage resolved. The authors suggested that PDT may be an option for treatment of CNV in BVMD.

Surveillance

Ophthalmologic examination (including best-corrected visual acuity, visual fields, and SD-OCT) should be performed annually to monitor the progression of the fundus lesions and to evaluate for coincident development of choroidal neovascularization (CNV).

In children, annual examinations are important in preventing the development of amblyopia, especially if there is a significant difference in the best-corrected visual acuity of one eye. A trial of conventional patching therapy of the better-seeing eye may be able to determine if amblyopia is present.

Affected individuals should be advised to see their ophthalmologist in the event of decreased vision or metamorphopsia (straight lines appearing wavy), which could be signs of CNV. In some cases, affected individuals can be advised to use an Amsler grid for self-evaluation.

Agents/Circumstances to Avoid

Cessation of smoking helps prevent neovascularization of the retina [Clemons et al 2005].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt ophthalmologic evaluation and routine follow up.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Best vitelliform macular dystrophy (BVMD), BEST1 adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC) are inherited in an autosomal dominant manner.

By definition, autosomal recessive bestrophinopathy (ARB) is inherited in an autosomal recessive manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with BVMD, AVMD, or ADVIRC have an affected parent.
• A proband with BVMD, AVMD, or ADVIRC may have the disorder as the result of a de novo pathogenic variant [Apushkin et al 2006, Li et al 2006, Marchant et al 2007, Atchaneeyasakul et al 2008, Testa et al 2008]. The proportion of individuals with bestrophinopathy caused by a de novo pathogenic variant is unknown.
• Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling. Note: Fundoscopic examination may be unreliable for the evaluation of the parents because the fundus may appear normal in affected individuals.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with BVMD, AVMD, or ADVIRC may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Note: The age of onset, clinical manifestations, and degree of functional impairment is highly variable among heterozygous family members.
• If the BEST1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the BEST1 pathogenic variant but are clinically unaffected based on electrooculogram (EOG), the risk to sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still at increased risk for BVMD, AVMD, or ADVIRC because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with an autosomal dominant bestrophinopathy has a 50% chance of inheriting the BEST1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is heterozygous for the BEST1 pathogenic variant, the parent's family members are also at risk of having the pathogenic variant.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are typically heterozygotes (i.e., carriers of one BEST1 pathogenic variant).
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a BEST1 pathogenic variant. If carrier testing detects the variant in only one parent:
  • And the child appears to have homozygous BEST1 pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy for chromosome 11;
  • And the child has compound heterozygous BEST1 pathogenic variants, the child may theoretically have one inherited variant and one de novo pathogenic variant. De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].
• Individuals who are heterozygous for a BEST1 variant associated with ARB are generally clinically unaffected [Zhao et al 2012]. However, mildly diminished responses on multifocal ERG and/or mild symptoms of maculopathy have been reported in several individuals with heterozygous ARB-related BEST1 pathogenic variants [MacDonald et al 2012, Wivestad Jansson et al 2016].

Sibs of a proband

• If both parents are known to be heterozygous for a BEST1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Individuals who are heterozygous for a BEST1 variant associated with ARB are generally clinically unaffected [Zhao et al 2012]. However, mildly diminished responses on multifocal ERG and/or mild symptoms of maculopathy have been reported in several individuals with heterozygous ARB-related BEST1 pathogenic variants [MacDonald et al 2012, Wivestad Jansson et al 2016].

Offspring of a proband. The offspring of an individual with ARB are obligate heterozygotes for a pathogenic variant in BEST1.

Other family members. Each sib of the proband's parents has a 50% chance of being heterozygous for a BEST1 pathogenic variant.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the BEST1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Note: Because intrafamilial clinical variability is observed in the bestrophinopathies, expression and age of onset cannot be predicted on the basis of prenatal molecular genetic test results.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

BEST1 encodes bestrophin, a chloride ion channel that is sensitive to intracellular calcium [Petrukhin et al 1998, Sun et al 2002]. Bestrophin is highly expressed by the retinal pigment epithelium (RPE) and localizes to the basolateral plasma membrane [Marmorstein et al 2000]. Bestrophin functions either as a chloride channel or as a regulator of voltage-gated calcium channels in the RPE [Hartzell et al 2008, Yu et al 2008].

Expression of disease-associated missense variants causes reduced or abolished membrane current. Bestrophin undergoes dephosphorylation by a protein phosphatase, suggesting that bestrophin participates in a signal transduction pathway that may be related to the modulation of the light peak on electrooculogram [Marmorstein et al 2002].

Mechanism of disease causation. Loss of function. Pathogenic variants in BEST1 alter ion transport by the RPE, resulting in the accumulation of fluid between the RPE and the photoreceptors [Qu et al 2006, Yu et al 2007, Hartzell et al 2008].

Author History

Jessica Lawrence, MSc (2020-present)
Thomas Lee, MD (2003-present)
Ian M MacDonald, MD, CM (2003-present)
Dean Y Mah, MSc, MD; University of Alberta (2003-2009)

Revision History

• 16 July 2020 (bp) Comprehensive update posted live
• 12 December 2013 (me) Comprehensive update posted live
• 7 April 2009 (me) Comprehensive update posted live
• 8 December 2005 (me) Comprehensive update posted live
• 27 October 2003 (imd) Revision: sequence analysis clinically available
• 30 September 2003 (me) Review posted live
• 14 July 2003 (imd) Original submission

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