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Best Vitelliform Macular Dystrophy

Synonyms: Best Macular Dystrophy, Vitelliform Macular Dystrophy Type 2

, MDCM and , MD, MSc.

Author Information
, MDCM
Department of Ophthalmology
University of Alberta
Edmonton, Alberta, Canada
, MD, MSc
Department of Ophthalmology
University of Ottawa
Ottawa, Ontario, Canada

Initial Posting: ; Last Update: December 12, 2013.

Summary

Disease characteristics. Best vitelliform macular dystrophy is a slowly progressive macular dystrophy with onset generally in childhood and sometimes in later teenage years. Affected individuals initially have normal vision followed by decreased central visual acuity and metamorphopsia. Individuals retain normal peripheral vision and dark adaptation. Age of onset and severity of vision loss show inter- and intrafamilial variability.

Diagnosis/testing. The diagnosis of Best vitelliform macular dystrophy is based on fundus appearance, electrooculogram (EOG), and family history. Affected individuals have a typical yellow yolk-like macular lesion on fundus examination. Lesions are usually bilateral, but can be unilateral. The EOG indirectly measures the standing potential of the eye. A normal light peak/dark trough ratio (Arden ratio) is greater than 1.8. In Best vitelliform macular dystrophy, the EOG is abnormal with a reduced light peak/dark trough ratio almost always less than 1.5, typically between 1.0 and 1.3. The Arden ratio stays constant with age for these individuals. BEST1 (VMD2) is the only gene in which mutations are known to cause Best vitelliform macular dystrophy.

Management. Treatment of manifestations: Low vision aids as needed. Direct laser photocoagulation and anti-vascular endothelial growth factors (anti-VEGF) for choroidal neovascularization and hemorrhage.

Surveillance: Annual ophthalmologic examination for persons of all ages.

Agents/circumstances to avoid: Smoking.

Genetic counseling. Best vitelliform macular dystrophy is most commonly inherited in an autosomal dominant manner; however, autosomal recessive inheritance has been reported in three families. For autosomal dominant Best vitelliform macular dystrophy:

  • Most individuals diagnosed with Best vitelliform macular dystrophy have an affected parent.
  • The proportion of cases caused by de novo mutations is unknown.
  • Each child of an individual with Best vitelliform macular dystrophy has a 50% chance of inheriting the mutation.
  • Prenatal testing is possible for families in which the disease-causing mutation is known.

Diagnosis

Clinical Diagnosis

The 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.

Figure 1

Figure

Figure 1. Vitelliform stage (Stage 2)

Figure 2

Figure

Figure 2. Pseudohypopyon (Stage 3)

Figure 3

Figure

Figure 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 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 optical coherence tomography (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.

Fundus autofluorescence (AF). This imaging modality has gained prominence over the past decade as it can detect metabolic changes in the retinal pigment epithelium (RPE) and photoreceptor layers that otherwise may not be detected in color fundus photos. Increased AF has been shown to correspond to the lesions seen in the fundus [Boon et al 2008].

Family history. Family history is consistent with autosomal dominant or autosomal recessive inheritance.

Molecular Genetic Testing

Gene. BEST1 is the only gene in which mutations are known to cause 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.

Clinical testing

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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
Family History
PositiveNegative
BEST1 Sequence analysisSequence variants 496% 550%-70% 6
Deletion/duplication analysis 7Partial or whole-gene deletions/duplicationsUnknown; none reported 8
Targeted mutation analysisc.383G>CMajority of affected individuals in an extended Swedish kindred 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Detects mutations in up to 96% of affected individuals with a positive family history [Krämer et al [2000]

6. 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]. Krämer et al [2000], White et al [2000].

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. No deletions or duplications in this gene have been reported to cause Best vitelliform macular dystrophy.

9. 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]

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Ramsden et al 2012 (full text)].

Testing Strategy

To confirm/establish 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 gene may detect a mutation.
  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having Best vitelliform macular dystrophy is sequence analysis of BEST1.
  • Multi-gene panel. For some probands, it may be appropriate to consider using an eye disorders multi-gene panel that includes BEST1. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual also varies.

Predictive testing for at-risk asymptomatic adult family members (for clarification of genetic status) requires prior identification of the disease-causing mutation(s) in the family.

Carrier testing for at-risk relatives (in those rare cases where inheritance is autosomal recessive) 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(s) in the family.

Clinical Description

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.

Atypical phenotypic presentations in individuals with biallelic mutations in BEST1 have been described. Affected individuals may show multiple vitelliform lesions, lesions with fibrosis, or variable presentations within families. All affected individuals have had an abnormal EOG; some have had an abnormal ERG [MacDonald et al 2012, Boon et al 2013].

The genetic or environmental factors that influence severity of disease are unknown.

Table 2. Stages of Disease Progression in Best Vitelliform Macular Dystrophy

StageSigns
0 & 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 majority
4No 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 yrs

Table 3. Age and Disease Progression in Best Vitelliform Macular Dystrophy

AgeVisual 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 eye

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

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 substitution and a phenotype of late-onset visual failure (age 40-50 years).

Mullins et al [2005] describe a family with a p.Tyr227Asn substitution and a phenotype of late-onset small vitelliform lesions.

Three families with compound heterozygous mutations and autosomal recessive inheritance of Best vitelliform macular dystrophy were reported [Bitner et al 2011, Iannaccone et al 2011, Zhao et al 2012]. Six children from three different families have been found to have biallelic pathogenic variants in BEST1. Four of the affected individuals had multiple vitelliform lesions. Two individuals were homozygous for the c.1415delT variant, one individual was a compound heterozygote for p.Arg141Ser and p.Arg141His, and three individuals were compound heterozygotes for p.Leu41Pro and p.Ile201Thr variants. Heterozygous carriers did not develop disease.

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.

Differential Diagnosis

Best 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]. AVMD shows significant phenotypic overlap with Best vitelliform macular dystrophy. Using OCT, Hayami et al [2003] found that the structure of the vitelliform lesions in the two disorders 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 (including CFH, CFB, ABCA4, TIMP3, and EFEMP1) have been associated with AMD [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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To determine the stage of disease and needs in an individual diagnosed with Best vitelliform macular dystrophy, ophthalmologic examination should be performed. Medical genetics consultation may also be considered.

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.

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 13 year-old with Best vitelliform macular dystrophy 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. There are currently no clinical trials to demonstrate the effectiveness of anti-VEGF agents on CNV in Best vitelliform macular dystrophy.

Andrade et al [2003] performed photodynamic therapy (PDT) using verteporfin for 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.

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. Affected individuals should be advised to see their ophthalmologist in the event of decreased vision or metamorphopsia, which could be signs of CNV.

Agents/Circumstances to Avoid

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

Evaluation 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Best vitelliform macular dystrophy is most commonly inherited in an autosomal dominant manner. However, three families with compound heterozygous mutations and autosomal recessive inheritance have been described [Bitner et al 2011, Iannaccone et al 2011, Zhao et al 2012].

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

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

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 affected, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual has 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 an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) of mutations known to be associated with autosomal recessive Best vitelliform macular dystrophy are asymptomatic.

Offspring of a proband

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.

Related Genetic Counseling Issues

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

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, clarification of carrier status, 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, are carriers, 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.

Prenatal Testing

If the disease-causing mutation(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like Best vitelliform macular dystrophy) 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) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Macular Diseases
    210 East 64th Street
    8th Floor
    New York NY 10065
    Phone: 212-605-3719
    Fax: 212-605-3795
    Email: association@retinal-research.org
  • Macular Degeneration Foundation
    PO Box 531313
    Henderson NV 89053
    Phone: 888-633-3937 (toll-free); 702-450-2908
    Fax: 702-450-3396
    Email: liz@eyesight.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Foundation Fighting Blindness
    11435 Cronhill Drive
    Owings Mills MD 21117-2220
    Phone: 800-683-5555 (toll-free); 800-683-5551 (toll-free TDD); 410-568-0150
    Email: info@fightblindness.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Molecular Genetics

Information 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 Databases

Data 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)

153700MACULAR DYSTROPHY, VITELLIFORM; VMD
607854BESTROPHIN 1; BEST1

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 pathogenesis 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).

Pathogenic 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].

Note that carriers of mutations found to cause AR disease are asymptomatic [Zhao et al 2012]. This is postulated to be due to the fact that the causative mutations, when heterozygous, allow the protein to retain a sufficient level of functioning as an ion channel or an ion channel regulator.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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  2. Andrade RE, Farah ME, Costa RA. Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization in best disease. Am J Ophthalmol. 2003;136:1179–81. [PubMed: 14644242]
  3. Apushkin MA, Fishman GA, Taylor CM, Stone EM. Novel de novo mutation in a patient with Best macular dystrophy. Arch Ophthalmol. 2006;124:887–9. [PubMed: 16769844]
  4. Atchaneeyasakul LO, Jinda W, Sakolsatayadorn N, Trinavarat A, Ruangvoravate N, Thanasombatskul N, Thongnoppakhun W, Limwongse C. Mutation analysis of the VMD2 gene in Thai families with Best macular dystrophy. Ophthalmic Genet. 2008;29:139–44. [PubMed: 18766995]
  5. Bakall B, Marknell T, Ingvast S, Koisti MJ, Sandgren O, Li W, Bergen AA, Andreasson S, Rosenberg T, Petrukhin K, Wadelius C. The mutation spectrum of the bestrophin protein — functional implications. Hum Genet. 1999;104:383–9. [PubMed: 10394929]
  6. Bitner H, Mizrahi-Meissonnier L, Griefner G, Erdinest I, Sharon D, Banin E. A homozygous frameshift mutation in BEST1 causes the classical form of Best disease in an autosomal recessive mode. Invest Ophthalmol Vis Sci. 2011;52:5332–8. [PubMed: 21467170]
  7. Boon CJ, Klevering BJ, den Hollander AI, Zonneveld MN, Theelen T, Cremers FP, Hoyng CB. Clinical and genetic heterogeneity in multifocal vitelliform dystrophy. Arch Ophthalmol. 2007;125:1100–6. [PubMed: 17698758]
  8. Boon CJ, Klevering BJ, Keunen JE, Hoyng CB, Theelen T. Fundus fluorescence imaging of retinal dystrophies. Vision Res. 2008;48:2569–77. [PubMed: 18289629]
  9. Burgess R, MacLaren RE, Davidson AE, Urquhart JE, Holder GE, Robson AG, Moore AT, Keefe RO, Black GC, Manson FD. ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. J Med Genet. 2009;46:620–5. [PubMed: 18611979]
  10. Boon CJ, van den Born LI, Visser L, Keunen JE, Bergen AA, Booij JC, Riemslag FC, Florijn RJ, van Schooneveld MJ. Autosomal recessive bestrophinopathy: differential diagnosis and treatment options. Ophthalmology. 2013;120:809–20. [PubMed: 23290749]
  11. Burgess R, Millar ID, Leroy BP, Urquhart JE, Fearon IM, De Baere E, Brown PD, Robson AG, Wright GA, Kestelyn P, Holder GE, Webster AR, Manson FD, Black GC. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet. 2008;82:19–31. [PMC free article: PMC2253971] [PubMed: 18179881]
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  13. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL. Age-Related Eye Disease Study Research Group; Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology. 2005;112:533–9. [PMC free article: PMC1513667] [PubMed: 15808240]
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Chapter Notes

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

  • 12 December 2013 (me) Comprehensive update posted live
  • 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
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