DiagnosisClinical DiagnosisThe diagnosis of Best vitelliform macular dystrophy is based on fundus appearance, electrooculogram (EOG), and family history.Fundus appearance. Affected individuals may have a typical yellow yolk-like macular lesion on fundus examination. Lesions are usually bilateral, but can be unilateral. Multiple lesions and lesions outside the macula occur in at least one quarter of individuals See Figures 1, 2, and 3. FigureFigure 1. Vitelliform stage. Stage 2 FigureFigure 2. Pseudohypopyon. Stage 3 FigureFigure 3. Central scarring. Stage 4b The following clinical stages have been described, but it is important to note that the disease does not progress through each of these stages in every individual: Stage 0. Normal macula. Abnormal EOGStage 1. Retinal pigment epithelium (RPE) disruption in the macular region. Fluorescein angiogram (FA) shows window defects.Stage 2. Circular, well-circumscribed, yellow-opaque, homogenous 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 homogenous to develop a "scrambled-egg" appearance. FA shows partial blockage of fluorescence with a non-homogenous 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.ElectrophysiologyThe electrooculogram (EOG) measures indirectly the standing potential of the eye:A normal light peak/dark trough ratio (Arden ratio) is greater than 1.8. (Arden ratio decreases with age after the fourth decade; this value is not absolute.)In individuals with Best vitelliform macular dystrophy, the EOG is usually abnormal with a reduced light peak/dark trough ratio (Arden ratio) less than 1.5, most often between 1.0 and 1.3.
Note: Occasionally individuals with clinical findings of Best vitelliform macular dystrophy and a mutation in BEST1 have a normal EOG [Testa et al 2008].The full-field electroretinogram (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 OCT and retinal photography [Glybina & Frank 2006]. Scanning laser ophthalmoscope-evoked multifocal ERG (SLO-mfERG), used for topographic mapping of retinal function in individuals with Best vitelliform macular dystrophy [Rudolph & Kalpadakis 2003], reveals significantly reduced amplitudes in the macula.Color vision tests. A significant proportion of individuals have anomalous color discrimination particularly in the protan axis. Color vision changes are nonspecific and non-diagnostic.Optical coherence tomography (OCT). This imaging approach can reveal the cross-sectional anatomy of the retina in individuals with Best vitelliform macular dystrophy [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. Family history. Family history is consistent with autosomal dominant inheritance.Molecular Genetic TestingGene. BEST1 is the only gene known to be associated with Best vitelliform macular dystrophy [Marquardt et al 1998, Petrukhin et al 1998, Allikmets et al 1999, Krämer et al 2000, White et al 2000, Seddon et al 2001].Evidence for locus heterogeneity. Individuals with Best vitelliform macular dystrophy in whom no mutations in BEST1 could be found have been reported. This may result from the failure of sequence analysis to detect exonic deletions and mutations in introns or untranslated 5' and 3' regions of the gene [Petrukhin et al 1998, Bakall et al 1999, Caldwell et al 1999, Krämer et al 2000, White et al 2000]. It is possible that mutations in other genes can result in a similar phenotype. For example, Boon et al [2007] reported a patient in whom no mutation was found in BEST1 who had a sequence variant in the 5’ untranslated region of PRPH2 (RDS). A p.Pro210Arg mutation in PRPH2 has been found in adult-onset vitelliform macular dystrophy [Zhuk & Edwards 2006].Clinical testingSequence analysis of BEST1 detects mutations in up to 96% of affected individuals with a positive family history [Krämer et al 2000]. In individuals with no family history of Best vitelliform macular dystrophy the mutation detection rate ranges between 50% and 70% [Krämer et al 2000, White et al 2000]. Targeted mutation analysis for the BEST1 c.383G>C (p.Trp93Cys) mutation for individuals who can trace their ancestry to a large Swedish kindred ("pedigree S1") [Petrukhin et al 1998]Table 1. Summary of Molecular Genetic Testing Used in Best Vitelliform Macular DystrophyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityFamily HistoryPositiveNegativeBEST1 Sequence analysisSequence variants 296% 350%-70% 3, 4ClinicalTargeted mutation analysisc.383G>C Majority of affected individuals in an extended Swedish kindred ("pedigree S1")1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Krämer et al [2000]4. Krämer et al [2000], White et al [2000]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming/establishing the diagnosis in a proband. Targeted analysis for the c.383G>C mutation is recommended for individuals of Swedish ancestry who are suspected of having Best vitelliform macular dystrophy. If this mutation is not found, sequence analysis of the entire BEST1 gene may detect a mutation.Predictive testing for at-risk asymptomatic adult family members (for clarification of genetic status) requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersMutations in BEST1 have been found in: Eight individuals with bull's-eye maculopathy [Seddon et al 2001];Two individuals with adult vitelliform macular dystrophy (AVMD) [Krämer et al 2000] (see also Differential Diagnosis);Families with autosomal dominant vitreoretinochoroidopathy (ADVIRC) associated with nanophthalmos [Yardley et al 2004]. Patients with ADVIRC have nanophthalmos, microcornea, angle closure glaucoma, congenital cataract (posterior subcapsular), and a retinal dystrophy. The retinal dystrophy is characterized by peripheral retina pigment, white preretinal opacities, apparent cystoid macular edema, retinal neovascularization, choroid atrophy, and a fibrillar condensation of the vitreous. The ERG and EOG are abnormal. Individuals with autosomal recessive bestrophinopathy (ARB): Mutations in both alleles of BEST1 (biallelic mutation) that result in a more severe retinopathy than Best vitelliform macular dystrophy have been seen in individuals of Swedish ancestry who have two missense mutations [Schatz et al 2006].Similarly, an autosomal recessive bestrophinopathy [Burgess et al 2008] has been identified in individuals with a cone-rod dystrophy, an abnormal ERG, and a markedly reduced Arden ratio of the EOG. Affected individuals have white subretinal deposits and macular subretinal fluid which may suggest the diagnosis. Heterozygotes, who have either a deletion in one allele or a nonsense mutation, do not have clinical signs or electrophysiological abnormalities.}

Natural HistoryBest vitelliform macular dystrophy is a slowly progressive macular dystrophy with onset in childhood and sometimes in later teenage years. Retinal findings are not generally present at birth and typically do not manifest until ages five to ten years. Best vitelliform macular dystrophy is characterized by normal vision followed by decreased central visual acuity and metamorphopsia (Table 2). Expression and age of onset are variable (Table 3). Some affected individuals remain asymptomatic, while others have significant visual impairment. Peripheral vision and dark adaptation remain normal.The genetic or environmental factors that influence severity of disease are unknown.Table 2. Stages of Disease Progression in Best Vitelliform Macular DystrophyView in own windowStageSigns0 & 1 No change in stage in 10 yrs
Visual acuity of 20/20 in 75%2 & 3 For a large portion, advance in stage within 5-10 yrs
Visual acuity of 20/40 or better in majority4No change in stage over 5 yrs for majority
10% of 4a and 16% of 4b progress to stage 4c
Visual acuity of 20/20 in 10%; 19% lose 2 lines or more in visual acuity over 8-10 yrsTable 3. Age and Disease Progression in Best Vitelliform Macular DystrophyView in own windowAgeVisual Acuity≤40 yrs In ~75%, ≥20/40 in better eye
In ~66%, <20/40 in worse eye≥50 yrs In ~50%, 20/70 in better eye
In 100%, ≤20/100 in worse eyeFrom Miller et al [1976], Mohler & Fine [1981], Fishman et al [1993], Marano et al [2000]Histopathology. Light and electron microscopy show abnormal accumulation of lipofuscin granules within the RPE throughout the macula and also in the remainder of the retina.

Genotype-Phenotype CorrelationsHeterozygotes. Genotype-phenotype correlations have not been demonstrated. Minimal information correlates individual mutations to a specific stage of disease or degree of visual impairment. However, Eksandh et al [2001] describe a family with a p.Val89Ala mutation in BEST1 and a phenotype of late-onset visual failure (age 40-50 years).Mullins et al [2005] describe a family with a p.Tyr227Asn mutation in BEST1 and a phenotype of late-onset small vitelliform lesions.

Differential DiagnosisBest vitelliform macular dystrophy is readily recognized by its distinct macular lesion. The following retinopathies may be confused with Best vitelliform macular dystrophy [Allikmets et al 1999, Krämer et al 2000, White et al 2000, Seddon et al 2001]:Adult vitelliform macular dystrophy (AVMD). This autosomal dominant disorder, characterized by the presence of bilateral, small, circular, yellow, symmetrical, subretinal lesions with drusen-like deposits, affects mainly middle-aged individuals. The funduscopic findings can easily be mistaken for Best vitelliform macular dystrophy, but the EOG is normal or only slightly reduced in these individuals. Mutations in PRPH2 (RDS) (which encodes the protein peripherin) and BEST1 have been found in a small number of individuals with AVMD, demonstrating the genetic heterogeneity of the disorder [Renner et al 2004, Yu et al 2006, Zhuk & Edwards 2006]. There is significant overlap of this phenotype with Best vitelliform macular dystrophy. Using OCT, Hayami et al [2003] found that the structure of the vitelliform lesions in AVMD and BVMD were similar.Age-related macular degeneration (AMD). This common disorder is characterized by drusen, RPE disruption, and choroidal neovascularization. Multiple lines of evidence indicate that AMD has a familial component. Mutations in a number of genes have been associated with AMD including CFH, CFB, ABCA4, TIMP3, and EFEMP1 [Patel et al 2008]. Mutations in BEST1 are rare in cases of AMD [Allikmets et al 1999, Krämer et al 2000, Lotery et al 2000, Seddon et al 2001]. Bull's-eye maculopathy. This descriptive clinical diagnosis is typified by an annular region with depigmentation of central RPE in the macula [Seddon et al 2001]. The phenotype can be seen in individuals with cone dystrophy, cone-rod dystrophy, Stargardt disease, chloroquine maculopathy, and other maculopathies. Seddon et al [2001] found one individual with a bull's-eye maculopathy who had a mutation in BEST1.

ManagementEvaluations Following Initial DiagnosisTo determine the stage of disease in an individual diagnosed with Best vitelliform macular dystrophy, ophthalmologic examination should be performed.Treatment of ManifestationsLow vision aids provide benefit for those individuals with significant deterioration in visual acuity.Stage 4c fundus lesions 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 Best vitelliform macular dystrophy whose visual acuity improved. No clinical trials comparing the efficacy of laser photocoagulation to conservative treatment have been conducted. Andrade et al [2003] performed photodynamic therapy (PDT) using verteporfin for subfoveal choroidal neovascularization (CNV) on one person with Best vitelliform macular dystrophy. The CNV regressed and the subretinal hemorrhage resolved. The authors suggested that PDT may be an option for treatment of CNV in Best vitelliform macular dystrophy. Anti-VEGF (vascular endothelial growth factor) agents such as bevacizumab are used increasingly to treat individuals with CNV. Leu et al [2007] injected intravitreal bevacizumab in a 13 year-old with Best vitelliform macular dystrophy and CNV, hastening visual recovery and regression of the CNV. Long-term follow-up of this patient is unknown. There are currently no clinical trials to demonstrate the effectiveness of anti-VEGF agents on CNV in Best vitelliform macular dystrophy.Genetic counseling and occupational counseling should be offered.SurveillanceOphthalmologic examination should be performed annually to monitor the progression of the fundus lesions; in childhood, annual examinations are important in preventing the development of amblyopia.Agents/Circumstances to AvoidCessation of smoking helps prevent neovascularization of the retina [Clemons et al 2005].Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Best Vitelliform Macular Dystrophy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDBEST111q12​.3Bestrophin-1VMD2 Mutation Database @ Institute of Human Genetics, University of Regensburg
Retina International Mutations of the Bestrophin GeneBEST1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Best Vitelliform Macular Dystrophy (View All in OMIM) View in own window 153700MACULAR DYSTROPHY, VITELLIFORM; VMD 607854BESTROPHIN 1; BEST1Molecular Genetic PathogenesisSun et al [2002] showed the existence of a new chloride channel family that includes Best vitelliform macular dystrophy. They used heterologous expression studies to demonstrate that human, Drosophila, and C. elegans bestrophin homologs form oligomeric chloride channels. Human bestrophin was sensitive to intracellular calcium. Fifteen missense mutations were associated with reduced or abolished membrane current. Marmorstein et al [2002] demonstrated that bestrophin undergoes dephosphorylation by a protein phosphatase. This finding suggests that bestrophin participates in a signal transduction pathway that may be related to the modulation of the light peak on the EOG. Despite the current genetic and molecular information of Best vitelliform macular dystrophy, the pathology remains unexplained.Normal allelic variants. BEST1 has 11 exons. Most of the frequent polymorphisms and rare variants occur within non-coding regions or do not result in an amino acid substitution [White et al 2000]. Allikmets et al [1999] also described three rare amino acid substitutions of unknown significance located at the C-terminus (p.Glu525Ala, p.Glu557Lys, and p.Thr561Ala).Pathologic allelic variants. A spectrum of missense mutations have been identified [Marquardt et al 1998, Petrukhin et al 1998, Allikmets et al 1999, Bakall et al 1999, Krämer et al 2000, White et al 2000, Seddon et al 2001, Krämer et al 2003]. White et al [2000] reviewed 48 reported mutations in BEST1: 45 missense mutations, two deletions, and one splice site mutation. The majority of the mutations occur in the first 50% of the protein and occurs in four unique clusters (exon 2, 4, 6, and 8), suggesting possible regions of functional importance [White et al 2000]. (For more information, see Table A. Genes and Databases.)One deletion was reported by Caldwell et al [1999] involving two base pairs that led to a shift in the reading frame and truncation of the protein at amino acid 513. A splice mutation affecting the donor site of exon 5 was reported by Krämer et al [2000].Normal gene product. Bestrophin has 585 amino acids and a size of 68 kd [Petrukhin et al 1998]. The hydropathy profile predicts at least four putative transmembrane domains. Bestrophin has been found to be highly expressed by the RPE and was localized 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].Abnormal gene product. Mutations in BEST1 alter the function of bestrophin and 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].