Best Disease: Symptoms, Types, Causes and Treatment

Best disease, also known as Best vitelliform macular dystrophy (BVMD), is a rare, inherited eye disorder that affects the macula—the central part of the retina responsible for sharp, straight-ahead vision. This comprehensive article dives into the symptoms, types, causes, and current treatments for Best disease, synthesizing the latest research to provide clarity for patients, caregivers, and eye health enthusiasts.

Symptoms of Best Disease

Recognizing the symptoms of Best disease is key to early diagnosis and management. While many patients retain good vision for years, understanding the warning signs can help families and eye care professionals monitor progression and respond to complications.

Symptom	Description	Typical Age of Onset	Source(s)
Visual Loss	Gradual, central vision decline	Childhood to teens	5 6 8
"Egg-Yolk" Lesion	Yellow, round lesion at macula	3–15 years	5 6
Blurred Vision	Difficulty reading, recognizing faces	Variable	5 12
Metamorphopsia	Distorted central vision	Any	5 12
Choroidal Neovascularization	Abnormal blood vessel growth, sudden vision drop	Rare, can occur in childhood	10 12
Color Vision Changes	Reduced ability to distinguish colors	Variable	4 5

Table 1: Key Symptoms

Typical Presentation and Disease Stages

Best disease most often presents in childhood or early adolescence, usually between ages 3 and 15, but can occasionally be detected later in life. The hallmark clinical sign is a bright yellow, "egg-yolk"–like lesion in the macula, visible during an eye exam 5 6. This lesion represents the buildup of lipofuscin, a fatty pigment, beneath the retina. Symptoms can be subtle at first, and some individuals may not notice any vision loss until adulthood.

The Progression of Symptoms

The disease usually advances through several stages:

• Previtelliform Stage: No visible lesions, but subtle changes may be detected on special tests.
• Vitelliform Stage: Classic yellow "egg-yolk" lesion appears at the macula.
• Pseudohypopyon Stage: The lesion's material may settle, creating a layered appearance.
• Vitelliruptive Stage: The lesion breaks up, with vision possibly fluctuating.
• Atrophic Stage: The macula thins and scars, often leading to more permanent central vision loss 5.

Vision Loss and Complications

While most people with Best disease maintain relatively good vision for years, some experience gradual blurring or distortion of central vision (metamorphopsia). A smaller subset may develop sudden, more severe vision loss due to complications like choroidal neovascularization (CNV)—the growth of abnormal blood vessels beneath the retina. CNV can bleed or leak, causing rapid central vision loss if not treated promptly 10 12.

Color Vision and Other Findings

Color vision changes can occur, but are less common and usually mild 4 5. Some patients may notice increased difficulty with tasks like reading or recognizing faces, especially as the disease progresses. Notably, the peripheral (side) vision is typically preserved, which helps patients maintain independence.

Types of Best Disease

Best disease is not a one-size-fits-all diagnosis. It belongs to a broader family of retinal conditions known as bestrophinopathies, each with unique features and inheritance patterns.

Type	Inheritance	Key Features	Source(s)
Classic Best Disease	Autosomal dominant	"Egg-yolk" lesion, early onset	2 4 5
Autosomal Recessive Bestrophinopathy	Autosomal recessive	Early, severe onset; both eyes affected	2 4 12
Adult-Onset Vitelliform Macular Dystrophy	Autosomal dominant	Similar lesions, milder, late onset	1 2
Other Bestrophinopathies	Variable	Includes ADVIRC, retinitis pigmentosa	2

Table 2: Main Types of Best Disease and Related Bestrophinopathies

Classic Best Vitelliform Macular Dystrophy (BVMD)

This is the "classical" form most people refer to as Best disease. It is inherited in an autosomal dominant fashion, meaning only one mutated gene from either parent is sufficient to cause the condition. BVMD is characterized by the classic yellowish lesion at the macula and typically presents in childhood or early adolescence 5.

Autosomal Recessive Bestrophinopathy (ARB)

A rarer form, ARB is caused by inheriting two faulty copies of the gene—one from each parent. Patients often present with more severe, earlier-onset symptoms and may be prone to complications such as choroidal neovascularization 4 12. Interestingly, parents carrying one mutated gene are usually unaffected, with normal vision and electro-oculogram (EOG) test results 4 12.

Adult-Onset Vitelliform Macular Dystrophy (AVMD)

AVMD resembles Best disease but appears later, usually in adulthood, and tends to be milder. The lesions are smaller and less likely to cause significant vision loss. Some gene mutations are shared between AVMD and classic BVMD, suggesting overlapping mechanisms 1 2.

Other Bestrophinopathies

The BEST1 gene (formerly VMD2) is implicated in several other rare eye diseases, collectively called bestrophinopathies. These include:

• Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC)
• Retinitis Pigmentosa (RP) linked to BEST1 mutations

Each condition has distinct features and inheritance patterns, but all involve malfunction of the bestrophin-1 protein in the retinal pigment epithelium 2.

Causes of Best Disease

Understanding the root causes of Best disease helps demystify why it appears in families and how genetic changes disrupt vision.

Cause	Description	Genetic Basis	Source(s)
BEST1 Gene Mutation	Alters bestrophin-1 protein function	Chromosome 11q12-q13	2 6 7 9
Inheritance	Mostly autosomal dominant; sometimes recessive	Variable	4 5 6
Channel Dysfunction	Impaired Ca2+-activated Cl− channel in RPE cells	Protein dysfunction	2 9 11
Lipofuscin Build-Up	Abnormal pigment accumulation in macula	Secondary to BEST1 defect	5 7 8

Table 3: Causes of Best Disease

The Role of the BEST1 (VMD2) Gene

Best disease is primarily caused by mutations in the BEST1 gene (previously known as VMD2) located on chromosome 11q12-q13 6 7. This gene encodes bestrophin-1, a protein that acts as a calcium-activated chloride ion channel in the retinal pigment epithelium (RPE) 2 9. When BEST1 is mutated, the resulting protein may not function properly, disturbing ion and fluid transport in the retina and leading to the characteristic buildup of lipofuscin pigment 5 7 8.

Inheritance Patterns

• Autosomal dominant: Most cases result from inheriting a single mutated gene from one parent. The condition can skip generations due to incomplete penetrance—some carriers show no symptoms 5.
• Autosomal recessive: Rarely, individuals inherit two defective copies, causing more severe, early-onset disease, while parents who carry just one copy remain unaffected 4 12.

Mechanisms of Disease

Channel Dysfunction

Bestrophin-1 acts as a channel that helps regulate chloride ions and calcium signaling in RPE cells 2 9. Mutations can:

• Disrupt the channel's ability to transport ions
• Alter protein folding or trafficking to the cell membrane
• Exert a dominant negative effect, where the mutated protein interferes with the function of normal protein 9 11

Lipofuscin Accumulation

Impaired bestrophin-1 function leads to the accumulation of lipofuscin—a yellowish pigment—under the retina. This buildup causes the classic "egg-yolk" lesion and, ultimately, damages retinal cells, resulting in vision loss 5 7 8.

Genetic Variability and Penetrance

Not everyone with a BEST1 mutation develops symptoms. Variable expressivity means the severity and age of onset can differ even within the same family 5 9. Some individuals may never develop vision problems, while others are affected in childhood.

Treatment of Best Disease

While there is no cure for Best disease, advances in research are providing hope for more effective therapies. Management currently focuses on monitoring, treating complications, and exploring emerging treatments.

Treatment	Approach	Purpose/Effect	Source(s)
Observation	Regular eye exams, imaging, EOG tests	Monitor progression	5 12
Bevacizumab Injection	Intravitreal anti-VEGF therapy	Treats choroidal neovascularization	10 12
Amblyopia Therapy	Eye patching, vision training	Improves vision in children	12
Gene Therapy	BEST1 gene supplementation (AAV)	Restores channel function	11
Small Molecules	4PBA, 2-NOAA restore bestrophin-1 function	Rescue defective protein	14
DHA Supplements	Docosahexaenoic acid (omega-3)	Unproven, under study	13

Table 4: Treatments and Management Options

Monitoring and Supportive Care

Most patients require periodic eye exams, including retinal imaging and electro-oculography (EOG), to monitor the macula's health and detect complications early 5 12. Because peripheral vision is usually preserved, many people adapt well, but low vision aids may be helpful for those with central vision loss.

Managing Complications

Choroidal Neovascularization

A small percentage of patients develop choroidal neovascularization (CNV)—abnormal blood vessel growth under the retina—which can cause rapid vision loss. Intravitreal injections of anti-VEGF drugs like bevacizumab have been shown to effectively treat CNV in both children and adults, often restoring vision 10 12.

Amblyopia Therapy

For children whose vision is reduced in one eye (amblyopia), patching the stronger eye and vision training can improve visual outcomes if started early 12.

Emerging Therapies

Gene Therapy

Recent studies demonstrate that supplementing the BEST1 gene using viral vectors (adeno-associated virus, AAV) can restore chloride channel function in patient-derived retinal cells. Both dominant and recessive mutations may be treatable using this approach, offering proof-of-concept for gene therapy as a future cure 11.

Small Molecule Treatments

FDA-approved small molecules like sodium phenylbutyrate (4PBA) and investigational compounds (e.g., 2-NOAA) have been shown to rescue the function of mutant bestrophin-1 in laboratory models. These drugs can restore protein expression and ion channel activity in cells from patients with both dominant and recessive forms of the disease, suggesting they may be promising treatments for bestrophinopathies 14.

Nutritional Supplements

Docosahexaenoic acid (DHA), an omega-3 fatty acid, has been studied for its potential to support macular health. However, a controlled clinical trial did not show significant improvement in vision or retinal function in Best disease patients taking DHA supplements 13. More research is needed in this area.

Genetic Counseling and Family Support

Given the hereditary nature of Best disease, genetic counseling is recommended for affected families. Understanding inheritance patterns helps inform reproductive decisions and enables early detection in at-risk relatives 4 5.

Conclusion

Best disease is a complex but fascinating retinal disorder that blends clinical intrigue with genetic discovery. The journey from symptoms to diagnosis, understanding causation, and exploring treatment options highlights the power of modern medicine and research.

Key Points:

• Best disease usually presents in childhood with a characteristic "egg-yolk" macular lesion and gradual central vision loss, but symptoms and severity vary widely 5.
• It is caused by mutations in the BEST1 gene, inherited mainly in an autosomal dominant manner, though recessive cases exist 2 4 6.
• Types include classic BVMD, adult-onset forms, and related bestrophinopathies, each with unique features 2 5.
• Management focuses on monitoring, treating complications like CNV (often with anti-VEGF injections), and emerging therapies such as gene therapy and small molecule treatments 10 11 14.
• Genetic counseling is vital for patients and families to understand risks and inheritance patterns 4 5.

With ongoing advances in genetics and treatment research, the outlook for individuals with Best disease continues to improve, offering hope for future therapies and better quality of life.