Best Vitelliform Macular Dystrophy

[Best Macular Dystrophy, Vitelliform Macular Dystrophy Type 2]

Clinical Diagnosis

The diagnosis of Best vitelliform macular dystrophy is based on fundus appearance, electrooculogram (EOG), and family history.

Figure 1. Vitelliform stage. Stage 2

Figure 1. Vitelliform stage. Stage 2

Figure 2. Pseudohypopyon. Stage 3

Figure 2. Pseudohypopyon. Stage 3

Figure 3. Central scarring. Stage 4b

Figure 3. Central scarring. Stage 4b

Figures 1

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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 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, 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.

Electrophysiology

• The 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 Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. 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].

Other loci. 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 the RDS/peripherin gene. A Pro210Arg mutation in the RDS/peripherin gene has been found in adult-onset vitelliform macular dystrophy [Zhuk & Edwards 2006].

Clinical testing

• Sequence analysis. Sequence 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. Targeted mutation analysis for the BEST1 c.383G>C (p.Trp93Cys) mutation is available to individuals who can trace their ancestry to a large Swedish kindred ("pedigree S1") [Petrukhin et al 1998].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Best Vitelliform Macular Dystrophy

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method		Test Availability
			Family History
			Positive	Negative
BEST1	Sequence analysis	Sequence variants	96% 1	50%-70% 1,2	Clinical
	Targeted mutation analysis	c.383G>C	Majority of affected individuals in an extended Swedish kindred ("pedigree S1")

1. Krämer et al [2000]

2. 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 Strategy

Confirming/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) Disorders

Mutations in the BEST1 gene 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 History

Best 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.

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 Correlations

Heterozygotes. 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 Val89Ala mutation in the BEST1 gene and a phenotype of late-onset visual failure (age 40-50 years).

Mullins et al [2005] describe a family with a Tyr227Asn mutation in BEST1 gene and a phenotype of late-onset small vitelliform lesions.

Penetrance

Best vitelliform macular dystrophy shows generally complete penetrance, especially when the EOG is used as evidence of clinical expression. Evidence for non-penetrance has been reported.

Anticipation

Genetic anticipation has not been reported in Best vitelliform macular dystrophy.

Nomenclature

The following terms are in use:

• Best disease

• Vitelliform macular dystrophy, early onset

• Vitelliform macular dystrophy, juvenile onset

• Vitelliform macular dystrophy, adult onset

• Macular degeneration, polymorphic vitelline

Prevalence

Best vitelliform macular dystrophy is a rare disorder. The prevalence is unknown.

Evaluations Following Initial Diagnosis

To determine the stage of disease in an individual diagnosed with Best vitelliform macular dystrophy, ophthalmologic examination should be performed.

Treatment of Manifestations

Low 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.

Surveillance

Ophthalmologic 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 Avoid

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

Testing of Relatives at Risk

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

Therapies Under Investigation

Search 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.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

Best vitelliform macular dystrophy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with Best vitelliform macular dystrophy have an affected parent.

• A proband with Best vitelliform macular dystrophy may have the disorder as the result of a de novo mutation [Apushkin et al 2006, Li et al 2006, Marchant et al 2007, Atchaneeyasakul et al 2008, Testa et al 2008]. The proportion of cases caused by a de novo mutation is unknown.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include funduscopic examination. Given that the fundus may appear normal in affected individuals, an EOG or molecular genetic testing (if the disease-causing mutation in the family has been identified) can be definitive in the diagnosis of the disease [White et al 2000]. The disease may occur in simplex cases (i.e., a single occurrence in a family) [Palomba et al 2000].

Note: Although most individuals diagnosed with Best vitelliform macular dystrophy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

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 or has the disease-causing mutation, the risk to the sibs is 50%.

• When the parents are clinically unaffected and do not have the disease-causing mutation, the risk to the sibs of a proband appears to be low.

• If the proband's disease-causing mutation cannot be detected in DNA extracted from the leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with Best vitelliform macular dystrophy has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.

Specific risk issues. The age of onset, clinical manifestations of the disease and degree of functional impairment in an affected individual cannot be predicted.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Requests for prenatal testing for conditions such as Best vitelliform macular dystrophy that do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

Sun 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. The BEST1 gene 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 C.)

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].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Author History

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

Revision History

• 7 April 2009 (me) Comprehensive update posted live

• 8 December 2005 (me) Comprehensive update posted to live Web site

• 27 October 2003 (imd) Revision: sequence analysis clinically available

• 30 September 2003 (me) Review posted to live Web site

• 14 July 2003 (imd) Original submission