Best disease (vitelliform macular dystrophy)

Key Points at a Glance

Key Points of This Disease

• Best disease (BVMD) is a macular dystrophy known for its egg yolk-like (vitelliform) macular lesion, and is the representative subtype of hereditary retinal diseases (bestrophinopathies) caused by mutations in the BEST1 gene.
• Patients typically present with decreased vision around early elementary school age, but initial presentation in middle age or later is not uncommon.
• Initial visual acuity is around 0.1 to 0.5, often with asymmetry between eyes. Visual prognosis is relatively good, with many patients maintaining corrected visual acuity of 0.5 or better in at least one eye.
• A characteristic electrophysiological pattern across all subtypes is a reduced EOG Arden ratio (≤1.5) with essentially normal full-field ERG.
• In this disease, EOG abnormalities are present in nearly 100% of cases, making it a definitive diagnostic test.
• Approximately 20% of patients develop choroidal neovascularization (CNV), which causes rapid vision loss.
• Currently, there is no curative treatment, but anti-VEGF therapy is effective for CNV.

1. What is Best Disease (Vitelliform Macular Dystrophy)?

Best disease is a macular dystrophy known for its egg yolk-like (vitelliform) macular lesion. Bestrophinopathy is a group of hereditary retinal diseases caused by mutations in the BEST1 gene (formerly VMD2), and Best disease (BVMD) is the most common subtype. It primarily affects the retinal pigment epithelium (RPE) and is characterized by accumulation of vitelliform material in the macula.

First reported by J.E. Adams in 1883, Friedrich Best described it in detail in 1905 as an autosomal dominant familial disease.

The BEST1 gene is located on chromosome 11q12.3 and consists of 11 exons. It encodes a 585-amino acid transmembrane protein (Best1), which functions as a homopentameric Ca²⁺-activated chloride channel (CaCC) localized to the basolateral membrane of RPE cells ⁹⁾. Bestrophin is an ion channel protein involved in Cl⁻ ion transport in the cell membrane of retinal pigment epithelium (RPE) cells. Over 250 pathogenic mutations have been reported, and BEST1 mutations are detected in 3.9% to 7.8% of all inherited retinal dystrophy (IRD) patients, reaching 18% to 36% in pediatric IRD patients ¹⁰⁾.

Patients typically present with decreased vision around early elementary school age, but initial presentation in middle age or later is not uncommon. Initial visual acuity is around 0.1 to 0.5, and there is often asymmetry in visual acuity and fundus findings between eyes.

The major subtypes of bestrophinopathy are the following four.

BVMD

Best vitelliform macular dystrophy: The most common subtype. Autosomal dominant inheritance. Onset in childhood to adolescence (3–15 years). Prevalence 1/5,000 to 1/67,000. Characterized by classic “fried egg” macular lesions.

ARB

Autosomal recessive bestrophinopathy: Autosomal recessive inheritance. Onset at 4–40 years. Bilateral symmetric multifocal subretinal yellow deposits. Associated with hyperopia and short axial length, with risk of angle-closure glaucoma. Prevalence approximately 1/1,000,000.

AVMD

Adult-onset vitelliform macular dystrophy: Onset at 30–50 years. Lesions are smaller and progression is slower than BVMD.

ADVIRC

Autosomal dominant vitreoretinochoroidopathy: Lacks vitelliform lesions. Characterized by a pigment band from the equator to the ora serrata. Prevalence approximately 1/1,000,000.

Q Is Best disease hereditary? If one parent has Best disease, what is the effect on the child?

A

BVMD is autosomal dominant but shows incomplete penetrance and variable expressivity. Some individuals with the mutation may not develop the disease. In contrast, ARB is autosomal recessive; if both parents are carriers, the chance of a child developing the disease is 25%. In either case, genetic counseling is recommended.

2. Main symptoms and clinical findings

Subjective symptoms

BVMD typically presents in childhood to adolescence (3–15 years). In the early stages, visual acuity is minimally affected, and vision remains relatively good despite dramatic fundus findings. Visual acuity is generally good until the vitelliform stage, but often declines when the lesion begins to break down.

• Visual loss: Progressive bilateral visual loss occurs with disease progression. In the atrophic stage (stage V), visual acuity decreases to 20/30 to 20/200.
• Central scotoma: Appears as macular disease progresses.
• Metamorphopsia: A symptom where objects appear distorted, reflecting macular lesions.
• When CNV is present: Rapid vision loss occurs ⁶⁾, and in stage VI (CNV stage), visual acuity drops to 20/200 or worse.

Clinical Findings

BVMD has six clinical stages. The table below shows fundus findings and visual acuity by stage.

Stage	Fundus Findings	Visual Acuity
I Previtelliform	RPE changes only/normal	Normal
II Vitelliform	”Fried egg” lesion	Normal to mildly reduced
III Pseudohypopyon	Lipofuscin layer formation	Similar to stage II
IV Vitelliruptive (scrambled egg) stage	Scrambled egg appearance	Normal to mildly decreased
V Atrophic stage	RPE/retinal atrophy	20/30 to 20/200
VI CNV stage	Choroidal neovascularization	≤20/200

Stage I (previtelliform) shows normal visual acuity with only abnormal EOG. In stage II (vitelliform), a classic “fried egg”-shaped vitelliform lesion appears, and 30% of patients have ectopic lesions. In stage III (pseudohypopyon), the yellow material settles only inferiorly due to gravity, presenting a pseudohypopyon-like appearance. Stage IV (vitelliruptive) shows a disrupted “scrambled egg” appearance, also called the “scrambled egg stage.” In stage V (atrophic), central RPE and retinal atrophy occur. In stage VI (CNV stage), choroidal neovascularization develops in about 20% of patients. Visual loss often occurs in adulthood and rarely worsens to less than 0.1.

Not all cases go through all stages sequentially; the course varies greatly among individuals.

Additional findings from multimodal imaging include the following ¹⁾.

• OCT: Vitelliform lesions are located in the subretinal space, and lesion types are classified into vitelliform, mixed, SRF, and atrophic types. Disruption of the ellipsoid zone (EZ) is most strongly associated with visual loss. Outer nuclear layer (ONL) thickness is significantly lower than in healthy individuals across all stages.
• FAF (fundus autofluorescence): Changes from hyperautofluorescence in the vitelliform stage to hypoautofluorescence in the atrophic stage.
• AO-SLO (adaptive optics scanning laser ophthalmoscopy): Cone mosaic rarefaction is observed in all stages.
• Findings from canine models: It has been confirmed that the subretinal material is a gel-like matrix, not liquid²⁾.

Clinical findings of ARB⁹⁾: Bilateral symmetric multifocal subretinal yellow deposits, hyperautofluorescence on FAF, subretinal fluid/intraretinal cysts/elongation of photoreceptor outer segments on OCT, risk of angle-closure glaucoma due to shortened axial length, normal electroretinogram, and absent light peak on EOG.

Q Why is visual acuity good even when there are "fried egg"-like lesions?

A

In early BVMD, cone photoreceptors still maintain function. Visual acuity is preserved as long as ONL thickness and EZ integrity are maintained on OCT. The discrepancy between fundus findings and visual acuity is a clinical feature of BVMD and a diagnostic clue.

3. Causes and Risk Factors

The causative gene for bestrophinopathy is BEST1 (VMD2)⁹⁾. The inheritance pattern is basically autosomal dominant (BVMD), but in recent years, autosomal recessive forms (ARB) have also been identified. BVMD is autosomal dominant with incomplete penetrance and variable expressivity. ARB is autosomal recessive, caused by homozygous or compound heterozygous mutations⁹⁾.

Representative mutations reported include the following:

• Point mutation example in BVMD: c.851A>G (p.Tyr284Cys)⁶⁾
• Compound heterozygous mutation example in ARB: c.103G>A (p.Glu35Lys) + c.313C>A (p.Arg105Ser)⁹⁾
• Homozygous mutation example in arBVMD: c.695T>G (p.Ile232Ser)⁵⁾

Vitelliform patterns can also occur due to mutations in genes other than BEST1; genes requiring differentiation include PRPH2, IMPG1, IMPG2, and THRB^{3), 7)}. In particular, mutations in the THRB gene (thyroid hormone receptor beta) have been reported to cause vitelliform macular dystrophy, with high intrafamilial phenotypic variability³⁾.

ARB is often associated with hyperopia and shortened axial length, and attention should be paid to the risk of developing angle-closure glaucoma⁹⁾.

What to know about hereditary diseases

• Best disease is hereditary, so we recommend that family members (siblings, parents, children) also undergo ophthalmic examination.
• Even if a person carries the mutated gene, they may not necessarily develop the disease (incomplete penetrance).
• Genetic counseling provides professional advice on genetic risks and future family planning.
• Regular eye examinations enable early detection of CNV complications, which helps protect vision.

4. Diagnosis and Examination Methods

The diagnosis of Bestrophinopathy combines electrophysiological tests, morphological tests, and genetic testing.

EOG

Arden ratio: Uniformly decreased (≤1.5) in all Bestrophinopathies. In this disease, EOG abnormalities are seen in nearly 100% of cases, making it a definitive diagnostic test. The combination with normal electroretinogram is characteristic. In ARB, the light peak of EOG disappears.

OCT/FAF

OCT: Evaluates the location and composition of lesions. Useful for lesion type classification (vitelliform/mixed/SRF/atrophy). EZ disruption correlates most strongly with visual acuity decline. FAF: Confirms changes in autofluorescence according to disease stage.

OCTA

MNV detection: Superior to FA and ICGA in detecting MNV. Quiescent (nonexudative) NV can also be detected only by OCTA. After the introduction of OCTA, the prevalence of MNV was revised upward to up to 65%.

Details of each examination are described below.

• EOG: Abnormal uniformly in all Bestrophinopathies, with an Arden ratio (light peak/dark trough ratio) ≤1.5 ^{5), 9)}. In arBVMD, Arden ratios of 1.52/1.59 have been reported ⁵⁾, and in cases with MNV, an Arden ratio of 1.1 has been reported ⁸⁾. In ARB, the light peak itself disappears ⁹⁾.
• Electroretinogram (ERG): Basically normal in BVMD ⁹⁾. Normal full-field ERG reflects RPE-specific functional impairment (peripheral retina is not affected). In ARB, normal to mildly abnormal ⁹⁾. The dissociation between abnormal EOG and normal ERG is a characteristic electrophysiological pattern of Bestrophinopathy.
• Genetic testing: Definitive diagnosis can be made by genetic analysis of the BEST1 gene ^{6), 9)}. Performed together with genetic counseling. Searching for genes other than BEST1 (PRPH2, IMPG1, IMPG2, THRB) is also useful for differential diagnosis.
• OCTA: Superior to FA and ICGA in detecting MNV (macular neovascularization) ⁴⁾, and useful for differentiating exudative MNV from nonexudative (quiescent) NV ⁴⁾. With the widespread use of OCTA, the estimated prevalence of MNV has been revised upward to up to 65% ¹⁾.

Q What is the most important test for diagnosis?

A

Throughout all bestrophinopathies, a reduced EOG Arden ratio (≤1.5) is uniformly observed, and the combination with a normal full-field ERG is characteristic. Since EOG abnormalities are present in nearly 100% of cases, this test is decisive for diagnosis. Definitive diagnosis requires BEST1 genetic testing. OCTA is most useful for detecting MNV, including quiescent NV.

5. Standard Treatment

Currently, there is no curative treatment for BVMD and bestrophinopathies. Symptomatic treatment and low vision care are the mainstays. The primary goal of treatment is early detection and management of complications (especially CNV) and preservation of visual function.

Anti-VEGF Therapy for CNV

When exudative MNV (choroidal neovascularization) is confirmed, anti-VEGF therapy is indicated. Anti-VEGF therapy is an option for CNV that appears in the atrophic stage. Treatment of non-exudative MNV may accelerate atrophic changes, so observation without treatment is recommended ¹⁾.

The results of anti-VEGF treatment are shown in the table below.

Case	Drug / Number of injections	Outcome
12-year-old girl, choroidal neovascularization	Bevacizumab	20/125 → 20/206)
12-year-old boy, MNV	Ranibizumab 2 injections	MNV regression for 2 years8)
28-year-old female, CME	Aflibercept 3 injections	20/20, maintained for 15 months5)

Notably, there is a case report of MNV regression after two injections of ranibizumab (0.5 mg/0.05 mL), with stability maintained for two years⁸⁾. In the same case, temporary resolution of vitelliform deposits was observed after ranibizumab injection. This is the first such report⁸⁾.

For cystoid macular edema (CME) associated with ARB, three injections of aflibercept 2.0 mg/0.05 mL resulted in recovery of visual acuity to 20/20, maintained for 15 months⁵⁾.

Other Treatments and Management

• Carbonic anhydrase inhibitors: One year of topical treatment for subretinal fluid in ARB was attempted but did not result in improvement⁹⁾.
• Regular follow-up: Regular ophthalmic examinations including OCTA are important for early detection of non-exudative MNV or CNV.
• Low vision care: For patients with progressive visual impairment, use of magnifiers, tinted glasses, visual aids, and social support are important.

Treatment Considerations

• Anti-VEGF treatment for non-exudative (quiescent) MNV may accelerate atrophic changes and requires careful judgment¹⁾.
• To avoid missing CNV, continue regular ophthalmic follow-up including OCTA.
• ARB carries a risk of angle-closure glaucoma due to shortened axial length, so regular assessment of intraocular pressure and angle is necessary⁹⁾.

Prognosis

Visual prognosis is not poor. Many patients maintain corrected visual acuity of 0.5 or better in at least one eye, and even in the atrophic stage, many retain social visual function. However, when CNV is complicated, rapid visual decline can occur, so early detection of CNV through regular ophthalmic examinations is important.

Q Is there a treatment? Is gene therapy possible?

A

Currently, there is no curative treatment, and management focuses on addressing complications. When CNV is present, anti-VEGF therapy is effective and has been reported to improve vision. Regarding gene therapy, treatment using AAV vectors has shown dramatic effects in canine models, and Phase 1/2 clinical trials are planned. For details, see the section “Latest Research and Future Prospects”.

6. Pathophysiology and Detailed Mechanisms

Structure and Function of BEST1 Protein

Best1 is a homopentamer located on the basolateral cell membrane of the RPE, forming an ion pore in the center ⁹⁾. It functions as a Ca²⁺-activated chloride channel (CaCC) and is involved in ion transport and fluid homeostasis of the RPE ⁹⁾.

Mechanisms of Mutation

• Mutation mechanism in BVMD: Dominant-negative mechanism. The mutant protein inhibits the function of wild-type Best1, leading to disease onset ⁹⁾.
• Mutation mechanism in ARB: Null phenotype (loss of function). Loss of function in both alleles results in a phenotype different from BVMD ⁹⁾.

Disruption of the RPE-Photoreceptor Interface

Studies in canine models have revealed that underdevelopment of RPE apical microvilli leads to incomplete ensheathment of cone outer segments, causing microdetachments ²⁾. These microdetachments dynamically change in response to light, expanding in bright conditions and shrinking in dark conditions ²⁾.

Mechanism of Lipofuscin Accumulation

Lipofuscin accumulation is not a primary effect of BEST1 gene abnormality but occurs as a result of loss of adhesion between photoreceptors and the RPE ¹⁾. Loss of RPE pump function is the main driving force promoting the accumulation of yolk-like material ¹⁾.

Mechanism of MNV (Macular Neovascularization)

It is thought that continuous mechanical, ischemic, and oxidative stress on Bruch’s membrane leads to VEGF production and the development of MNV ⁸⁾. Exudative MNV grows rapidly, whereas non-exudative MNV follows a slow course ¹⁾.

Other Morphological Changes

• Choroidal thickness: Increases during the vitelliform stage and thins during the atrophic/fibrotic stage¹⁾.
• Deep capillary plexus (DCP): Decreased vascular density is associated with rapid progression¹⁾.
• Choriocapillaris (CC): Damage begins from the subclinical stage¹⁾.
• Full-thickness macular hole: Reported as a rare complication¹⁾.
• RPE vs photoreceptors: Studies using AO-ICG showed that RPE cells are more severely damaged than cones¹⁾.

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7. Latest Research and Future Perspectives (Investigational Reports)

For patients: Please read this

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Gene Therapy Using AAV Vectors

Gene therapy research using a canine model of Best disease has made significant progress.

In a study where gene therapy using the AAV2/2-hVMD2-cBEST1 vector was administered to a canine model of BVMD, lesions in the pseudohypopyon stage regressed within two weeks, and restoration of RPE-photoreceptor contact and interface repair were confirmed²⁾. The therapeutic effect was stably maintained for over 33 months²⁾.

Based on these results, a Phase 1/2 human clinical trial is planned²⁾. Gene therapy is currently at the preclinical stage, and application to humans awaits the results of future clinical trials.

Advances in OCTA Technology and Reassessment of MNV Prevalence

With the widespread use of OCTA (optical coherence tomography angiography), quiescent (non-exudative) MNV, which was difficult to detect with conventional fluorescein angiography (FA) or ICGA, can now be detected⁴⁾. As a result, the estimated prevalence of MNV in Best disease patients has been revised upward to up to 65%¹⁾, and the understanding of the natural course of the disease is changing significantly.

Discovery of New Causative Genes

Mutations in the THRB gene (thyroid hormone receptor beta) have been reported to cause vitelliform macular dystrophy, providing new insights that may explain some patients who are negative for BEST1 mutations ³⁾. In addition, it has been clarified that IMPG2 mutations can cause both ARB and AVMD phenotypes ⁷⁾, revealing the diversity of genetic causes.

Establishment of OCT Lesion Classification

OCT-based lesion classification (vitelliform type, mixed type, SRF type, atrophy type) has been systematized ¹⁾, providing a foundation for predicting disease progression and determining treatment indications. The integrity of the EZ (ellipsoid zone) has been identified as the most important predictor of visual prognosis ¹⁾.

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8. References

1. Bianco L, Arrigo A, Antropoli A, et al. Multimodal imaging in Best Vitelliform Macular Dystrophy: Literature review and novel insights. Eur J Ophthalmol. 2024;34(1):39-51.
2. Aguirre GD, Beltran WA. Canine Best disease as a translational model. Eye (Lond). 2025;39:412-417.
3. Mahler EA, Moeller LC, Wall K, et al. Mutation of the Thyroid Hormone Receptor Beta Gene (THRB) Causes Vitelliform Macular Dystrophy with High Intrafamilial Variability. Genes. 2025;16:1240.
4. Mente J, Bari ME. Multimodal Imaging Characteristics of Quiescent Type 1 Neovascularization in Best Vitelliform Macular Dystrophy. Turk J Ophthalmol. 2021;51:188-191.
5. Albuainain A, Alhatlan HM, Alkhars W. A novel variant of autosomal recessive best vitelliform macular dystrophy and management of early-onset complications. Saudi J Ophthalmol. 2021;35:159-163.
6. Hoyek S, Lin LY, Klofas Kozek L, et al. Bilateral consecutive choroidal neovascularization in Best vitelliform macular dystrophy. Proc (Bayl Univ Med Cent). 2022;35(4):562-564.
7. Georgiou M, Chauhan MZ, Michaelides M, et al. IMPG2-associated unilateral adult onset vitelliform macular dystrophy. Am J Ophthalmol Case Rep. 2022;28:101699.
8. Fayed A. Temporary Vitelliform Regression After Intravitreal Ranibizumab Injection for Macular Neovascularization Complicating Best Disease. Int Med Case Rep J. 2022;15:593-598.
9. Haque OI, Chandrasekaran A, Nabi F, et al. A novel compound heterozygous BEST1 gene mutation in two siblings causing autosomal recessive bestrophinopathy. BMC Ophthalmol. 2022;22:493.
10. Morda D, et al. Prog Retin Eye Res. 2025;109:101405.