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Vitelliform macular dystrophy

Vitelliform macular dystrophy is a rare genetic eye disorder that affects the retina, particularly the macula, leading to the buildup of lipofuscin—a yellow, fatty pigment—in the retinal pigment epithelium and subretinal space, which can cause progressive central vision loss.^[1] Also known as Best disease in its early-onset form, the condition typically presents with bilateral, egg-yolk-like lesions in the macula that are visible on eye examination, though symptoms such as blurred or distorted central vision may not appear until later stages.^[2] The disorder progresses through distinct stages, including previtelliform, vitelliform, pseudohypopyon, vitelliruptive, atrophic, and cicatricial, with potential complications like choroidal neovascularization.^[2] The primary cause of vitelliform macular dystrophy, especially Best disease, is mutations in the BEST1 gene on chromosome 11q12-q13, which encodes bestrophin-1, a protein essential for maintaining ion balance in retinal cells; these mutations disrupt retinal pigment epithelium function and lead to material accumulation.^[2] In adult-onset foveomacular vitelliform dystrophy—a related form—causes may involve BEST1 or PRPH2 gene mutations, though many cases have unidentified genetic origins.^[1] Inheritance is typically autosomal dominant with incomplete penetrance for Best disease, meaning affected individuals have a 50% chance of passing the mutation to offspring, but not all carriers develop symptoms; rare autosomal recessive cases have been reported.^[2] Prevalence is estimated at 1 in 16,500 to 1 in 21,000 in some populations, such as in Olmsted County, Minnesota, though estimates vary widely globally.^[2] Best disease often is detected in childhood or adolescence through routine eye exams, even if asymptomatic initially.^[2] Diagnosis relies on clinical findings, such as fundus examination revealing the characteristic lesions, alongside electrooculography showing a reduced Arden ratio (less than 1.5), optical coherence tomography for lesion characterization, and fundus autofluorescence imaging.^[2] There is no cure, but management focuses on monitoring progression and treating complications like neovascularization with anti-vascular endothelial growth factor injections, such as bevacizumab; as of 2025, gene therapy trials, such as a phase 1/2 study of OPGx-BEST1 by Opus Genetics, are underway to address the underlying genetic cause.^[2]^[3] Most patients retain functional vision (20/40 or better) in at least one eye long-term.^[2]

Overview

Synonyms and Classification

Vitelliform macular dystrophy, also known as Best disease, Best vitelliform macular dystrophy (BVMD), or vitelliform macular degeneration type 2 (VMD2), is recognized by several alternative names including Best macular dystrophy, early-onset vitelliform macular dystrophy, juvenile-onset vitelliform macular dystrophy, polymorphic vitelline macular degeneration, vitelline dystrophy, and vitelliruptive degeneration.^[4]^[2] The condition was first described in 1905 by German ophthalmologist Friedrich Best, who documented a familial form of macular degeneration in a detailed pedigree, leading to its eponymous naming.^[2]^[5] It is classified as an inherited retinal dystrophy primarily affecting the retinal pigment epithelium (RPE), characterized by progressive accumulation of lipofuscin-like material in the macula.^[2]^[5] Among juvenile-onset macular dystrophies, BVMD is one of the most common autosomal dominant forms, second only to Stargardt disease in prevalence, with an estimated incidence of 1 in 10,000 to 1 in 20,000 individuals.^[5]^[6] It is distinct from adult-onset foveomacular vitelliform dystrophy (AFVD), which typically manifests later in life (ages 30-60), often sporadically, and is associated with different genetic or environmental factors rather than early-onset BEST1 mutations.^[5]^[7] Rare autosomal recessive variants of the disease have been reported, arising from compound heterozygous mutations in the BEST1 gene, though these are far less common than the dominant form.^[7]^[2]

Epidemiology

Vitelliform macular dystrophy, commonly known as Best disease in its early-onset form, is a rare inherited retinal disorder with an estimated worldwide prevalence ranging from 1 in 5,000 to 1 in 67,000 individuals.^[4] A key population-based study in Olmsted County, Minnesota, United States, calculated the prevalence of Best disease specifically at 1 in 16,500 to 1 in 21,000, highlighting its rarity even in well-monitored communities.^[8] These figures underscore the condition's low overall occurrence, positioning it as one of the less common macular dystrophies despite being the most frequent autosomal dominant form.^[9] The disease shows no sex predilection, affecting males and females equally due to its autosomal dominant inheritance pattern.^[10] Onset typically occurs during childhood or adolescence, within the first two decades of life, though cases have been documented with presentation as late as age 75.^[4] There is no strong racial or ethnic predisposition, with reports spanning diverse populations including those of European, Middle Eastern, and North American descent.^[11] Geographic variations in detection are notable, with higher prevalence estimates in regions equipped with advanced screening capabilities, such as Europe and North America, where routine fundus examinations facilitate earlier identification.^[8] In contrast, underdiagnosis prevails in areas with limited access to ophthalmic imaging and genetic testing, potentially skewing global data toward lower reported rates.^[4] Incidence trends for vitelliform macular dystrophy have remained stable over time, consistently classifying it as a rare condition without evidence of increasing occurrence.^[10]

Genetics and Etiology

Vitelliform macular dystrophy encompasses several related conditions, primarily Best vitelliform macular dystrophy (BVMD, also known as Best disease) and adult-onset foveomacular vitelliform dystrophy (AFVMD). BVMD is mainly caused by mutations in the BEST1 gene, while AFVMD can result from BEST1 mutations, as well as variants in PRPH2, IMPG1, or IMPG2 genes, or remain genetically unidentified in some cases.^[1]^[2]

BEST1 Gene and Mutations

The BEST1 gene, also known as VMD2, is located on the long arm of chromosome 11 at position 11q12.3 and spans approximately 15 kb with 11 exons.^[12] It encodes bestrophin-1, a 585-amino-acid transmembrane protein belonging to the chloride channel family, primarily expressed in the basolateral membrane of retinal pigment epithelium (RPE) cells, where it functions as a calcium-activated chloride channel regulating ion and fluid transport across the RPE.^[7] This protein is crucial for maintaining RPE homeostasis and supporting photoreceptor function.^[11] Over 350 distinct mutations in BEST1 have been identified worldwide in association with Best vitelliform macular dystrophy (BVMD), an autosomal dominant disorder.^[11] The vast majority (approximately 90%) are missense mutations, which typically alter a single amino acid in the protein sequence, though nonsense, frameshift, splicing, and small deletions/insertions also occur.^[11] Common examples include p.Ala243Val, often linked to adult-onset or pattern dystrophy-like phenotypes, and p.Asp323Asn, which has been reported in diverse populations.^[13]^[11] These mutations cluster in conserved domains, such as transmembrane helices and intracellular loops, disrupting the protein's structure and function.^[11] Functionally, BEST1 mutations lead to protein misfolding, reduced stability, or trafficking defects, resulting in loss of chloride channel activity and impaired calcium-dependent conductance.^[11] This dysfunction causes accumulation of lipofuscin in RPE cells and progressive RPE instability, contributing to the characteristic vitelliform lesions observed in BVMD.^[7] Genetic testing, typically involving targeted sequencing or panel analysis of BEST1, plays a key role in confirming the diagnosis, particularly in atypical or early-onset cases where clinical findings are ambiguous.^[7] BEST1 pathogenic variants exhibit complete penetrance for electrooculogram (EOG) abnormalities (reduced Arden ratio), with high but incomplete clinical penetrance (approximately 95%), such that a small proportion (around 5%) of carriers remain asymptomatic despite molecular confirmation.^[2]^[10]

Inheritance and Penetrance

Vitelliform macular dystrophy, also known as Best disease, is primarily inherited in an autosomal dominant manner due to heterozygous pathogenic variants in the BEST1 gene.^[7] This pattern results in vertical transmission through multiple generations within families, where each child of an affected individual has a 50% chance of inheriting the variant and thus the risk of developing the condition.^[7] Rare cases of autosomal recessive inheritance have been reported, typically arising from compound heterozygous BEST1 mutations, leading to affected siblings when both parents are carriers, though parental phenotypes are usually unaffected.^[7] The disease exhibits high but incomplete clinical penetrance, estimated at approximately 95%, with variable expressivity that causes differing severity and age of onset among affected family members.^[2] All carriers of BEST1 pathogenic variants demonstrate electro-oculogram (EOG) abnormalities, characterized by a reduced Arden ratio, by adulthood, even in those with normal fundus appearance, reflecting age-dependent expression where subclinical changes precede visible retinal alterations.^[10] This variability underscores the importance of comprehensive family screening beyond overt symptoms.^[14] Genetic counseling is strongly recommended for affected families to discuss inheritance risks, variable expressivity, and options such as prenatal or preimplantation genetic testing, enabling informed reproductive decisions and early monitoring for at-risk relatives.^[7]

Pathophysiology

Molecular Mechanisms

Bestrophin-1, the protein product of the BEST1 gene, is an integral membrane protein predominantly localized to the basolateral membrane of retinal pigment epithelial (RPE) cells. It operates as a calcium-activated chloride channel, facilitating chloride ion conductance and contributing to the regulation of ion and fluid transport across the RPE monolayer. This transport activity is critical for maintaining the ionic balance and fluid homeostasis between the subretinal space and the choroid, thereby supporting overall retinal function and preventing fluid imbalances that could disrupt photoreceptor health.^[15]^[16]^[17] Pathogenic mutations in BEST1 produce defective bestrophin-1 variants that impair chloride channel activity, leading to reduced anion conductance and abnormal repolarization of the RPE basolateral membrane potential following physiological stimuli. This functional deficit disrupts the RPE's ability to manage trans-epithelial fluid resorption, resulting in progressive accumulation of extracellular fluid in the subretinal space. Concurrently, the impaired phagocytosis and metabolic processing in mutant RPE cells promote the buildup of lipofuscin, an autofluorescent aggregate of oxidized lipids and proteins, within RPE lysosomes, exacerbating cellular stress.^[18]^[19]^[20]^[21] These molecular disruptions culminate in the secondary accumulation of vitelliform material—yellowish deposits composed of lipid-protein complexes derived from incompletely degraded photoreceptor outer segments—in the subretinal space, forming the characteristic egg-yolk-like lesions. The chronic fluid dysregulation and lipofuscin overload may further compromise RPE barrier integrity by altering tight junction stability and paracellular permeability, potentially amplifying subretinal pathology.^[22]^[23]^[24]

Histopathology

Histopathological examination of eyes affected by vitelliform macular dystrophy reveals a primary disorder of the retinal pigment epithelium (RPE), characterized by abnormal accumulation of lipofuscin granules within RPE cells, particularly in the macula. This material, which appears as PAS-positive, autofluorescent deposits, consists of lipofuscin-like substances rich in phospholipids and other lipids derived from photoreceptor outer segments. The deposits are often located between the photoreceptors and the RPE, as well as subretinally, leading to focal RPE hypertrophy, hyperplasia, and depigmentation in early stages. Fewer melanosomes are observed in the affected RPE cells, contributing to the yellowish appearance of the vitelliform lesion.^[25]^[2] In advanced stages, progressive degeneration manifests as photoreceptor atrophy, with focal dropout of outer segments and disruption of the outer retinal layers. RPE cells show atrophic changes, including cell loss and migration, accompanied by clumps of pigment and drusen formation containing PAS-positive material. Fibrosis may develop in the choriocapillaris and subretinal space, forming chorioretinal scars, while occasional choroidal neovascularization (CNV) arises from breaches in the RPE-Bruch's membrane complex, introducing fibrovascular tissue. Macrophages containing lipofuscin are present in the subretinal space, indicating mild phagocytic activity without significant inflammation. These changes correlate with the transition from vitelliform to atrophic phases of the disease.^[25]^[2] Post-mortem analyses from rare autopsy cases confirm subretinal deposits of heterogeneous, electron-dense material without evidence of widespread inflammation, underscoring the RPE's role in material accumulation. In the atrophic phase, extensive RPE cell loss is evident at the central macula, with secondary photoreceptor degeneration and thinning of the neurosensory retina. These observations highlight a generalized RPE dysfunction that secondarily impacts overlying retinal layers.^[25] Histological findings definitively confirm the vitelliform nature of the dystrophy through identification of characteristic lipofuscin-laden deposits and RPE alterations, though such examinations are rarely performed in vivo due to reliance on non-invasive imaging modalities.^[2]

Clinical Features

Signs and Symptoms

Vitelliform macular dystrophy, also known as Best disease, is frequently asymptomatic in its early stages, with many affected individuals showing no noticeable visual complaints until later in the disease course.^[2] As the condition progresses, common symptoms emerge, including central vision blurring, metamorphopsia (distorted vision), central scotoma, and difficulties with reading or fine visual tasks.^[26] These manifestations are typically bilateral but can be asymmetric, with one eye often more severely affected than the other.^[27] The disorder is often first detected in childhood through family screening or routine examinations, though overt symptoms may not appear until adolescence or early adulthood, with an average onset around ages 5 to 10 years.^[28] Visual complaints tend to develop gradually, and photopsia (flashes of light) is uncommon.^[5] On fundoscopic examination, the hallmark sign is a yellow, dome-shaped lesion at the macula resembling an "egg yolk," typically measuring 1 to 2 disc diameters in size, with a preserved foveal reflex in early presentations.^[2] This appearance arises from the accumulation of vitelliform deposits in the subretinal space.^[26] Associated features include minimal involvement of the peripheral retina, with central vision predominantly affected while peripheral vision remains largely intact.^[27] Nyctalopia (night blindness) and significant color vision defects are rare in this condition.^[28]

Disease Stages

Vitelliform macular dystrophy, also known as Best disease, progresses through distinct stages characterized by evolving retinal changes, primarily observed in the macula. These stages, originally described by Gass, reflect the accumulation and subsequent resorption of lipofuscin-laden material in the subretinal space due to retinal pigment epithelium (RPE) dysfunction.^[2] Progression is typically slow, spanning decades, with variability influenced by genotype and age of onset.^[29] Stage 1: Previtelliform. This initial subclinical phase features a normal fundus appearance in asymptomatic individuals, often children or infants at risk due to family history. Detection occurs through screening via electrooculography (EOG), which reveals an abnormal Arden ratio (≤1.50), indicating early RPE impairment despite preserved visual acuity.^[2] Stage 2: Vitelliform. The hallmark stage presents with a classic yellow, egg-yolk-like lesion (0.5–2 disc diameters) centered at the macula, typically emerging in early childhood (ages 3–15 years, though often infancy). Visual acuity remains near-normal (20/20–20/60), and the lesion corresponds to a solid hyperreflective dome on optical coherence tomography (OCT), with hyperautofluorescence on fundus autofluorescence (FAF).^[2]^[30] Stage 3: Pseudohypopyon. Partial resorption of the vitelliform material leads to inferior layering of yellow deposits beneath a clear superior fluid space, resembling a hypopyon. This stage usually develops around puberty, with vision remaining stable and good. OCT shows subretinal fluid with settled hyperreflective material.^[2] Stage 4: Vitelliruptive. The lesion breaks down into a nonhomogeneous, "scrambled egg" appearance with RPE mottling and pigment clumping. Vision begins to decline (20/20–20/120), and multimodal imaging reveals disrupted material with intraretinal or subretinal fluid.^[2]^[30] Stage 5: Atrophic. Advanced RPE and photoreceptor loss results in geographic atrophy and pigmentation changes, typically after age 40 years. Visual acuity deteriorates markedly (<20/200), with OCT demonstrating outer retinal thinning and FAF showing hypoautofluorescence.^[2] Stage 6: Cicatricial or Choroidal Neovascularization (CNV). Fibrosis or subretinal neovascularization causes scarring or hemorrhage, leading to severe vision loss (<20/200). This stage occurs in approximately 17% of patients over an 8-year follow-up period.^[2]^[29] Recent natural history studies highlight a wide phenotypic spectrum across stages, with OCT revealing patterns like vitelliform lesions with subretinal fluid (42%) or focal choroidal excavation (3%), and FAF showing hyperautofluorescent areas that decrease over time (from 36% to 31% in 6 years). Progression shows an annual central retinal thickness loss of about 5–6 μm, with advanced stages (4–5) increasing from 49% to 67% over 8 years.^[29]^[30]

Diagnosis

Clinical Examination

Clinical examination of patients with vitelliform macular dystrophy, also known as Best disease, typically begins with visual acuity testing using Snellen charts under best-corrected conditions. In early stages, such as the previtelliform or vitelliform phases, visual acuity is frequently preserved at 20/40 or better, particularly in individuals under 40 years of age, with approximately 76% achieving this level in the better-seeing eye.^[31] As the disease progresses to vitelliruptive, atrophic, or cicatricial stages, acuity often declines, with mean values around 20/50 at presentation and potential reduction to 20/120 or worse in advanced cases.^[9]^[32] Fundus examination via dilated slit-lamp biomicroscopy is essential for identifying hallmark macular abnormalities. It reveals bilateral, symmetric yellow subretinal lesions resembling an egg yolk in the central macula during the vitelliform stage, with stereoscopic ophthalmoscopy highlighting the elevated, well-circumscribed nature of these deposits, often 2-5 disc diameters in size.^[2]^[33] The peripheral retina, optic disc, and retinal vessels remain normal, without signs of inflammation or vascular abnormalities.^[33] Pupillary examination shows normal brisk responses to light with no relative afferent pupillary defect, and refraction typically uncovers no disease-specific errors, though mild hypermetropia may coexist independently.^[2]^[33] A thorough family history review is integral to the clinical assessment, given the autosomal dominant inheritance pattern with incomplete penetrance. Pedigree analysis often uncovers affected relatives, with about 12% of cases initially suspected through familial screening.^[2]^[9] Incidental detection occurs frequently during routine eye examinations, especially in asymptomatic children, accounting for approximately 12% of diagnoses in prospective cohorts.^[9]

Diagnostic Tests

The diagnosis of vitelliform macular dystrophy, also known as Best disease, is confirmed through specialized electrophysiological and imaging tests that assess retinal pigment epithelium (RPE) function and macular structure.^[2] These investigations are essential for distinguishing the condition from mimics such as central serous chorioretinopathy or age-related macular degeneration, particularly when clinical findings are subtle.^[34] The electro-oculogram (EOG) serves as a hallmark diagnostic tool, revealing an abnormal light-peak to dark-trough ratio, known as the Arden ratio, typically less than 1.5 in affected individuals, compared to a normal value of at least 1.85.^[2] This abnormality reflects impaired RPE depolarization and is present across all disease stages, even in previtelliform phases with normal fundus appearance, providing high sensitivity for early detection.^[34] In contrast, the full-field electroretinogram (ERG) remains normal, as the disorder primarily affects the RPE rather than the photoreceptors.^[2] Optical coherence tomography (OCT), particularly spectral-domain OCT, demonstrates subretinal hyperreflective material in the vitelliform stage, with early RPE thickening and progressive outer nuclear layer thinning in later phases.^[2] Fundus autofluorescence (FAF) imaging reveals speckled patterns of hyper- and hypoautofluorescence, corresponding to lipofuscin accumulation and RPE mottling, which evolve from central hyperautofluorescence in early stages to surrounding hypoautofluorescence in atrophic phases.^[35] Fluorescein angiography (FFA) typically shows early hypofluorescence due to blockage by the vitelliform material, followed by late staining, without evidence of leakage, thereby helping to exclude choroidal neovascularization (CNV).^[36] Genetic testing via sequencing of the BEST1 gene can confirm the diagnosis in equivocal cases by identifying heterozygous mutations responsible for the condition in many families.^[34] In advanced stages, visual field testing discloses central scotomas, correlating with macular atrophy and visual acuity loss.^[2]

Management

Supportive Care

Supportive care for vitelliform macular dystrophy focuses on regular monitoring to track disease progression and early detection of complications, alongside strategies to optimize quality of life. Patients typically undergo annual or semi-annual ophthalmologic examinations, tailored to the disease stage, which include assessments of visual acuity, fundus evaluation, and optical coherence tomography (OCT) imaging to monitor macular structural changes.^[37]^[38] Electro-oculography (EOG), while primarily diagnostic, may be referenced in follow-up to confirm retinal pigment epithelium (RPE) dysfunction stability.^[34] For individuals experiencing moderate vision loss, low-vision aids such as magnifiers and reading devices are prescribed to assist with daily tasks like reading and navigation.^[39]^[27] Lifestyle modifications play a key role in supportive management by potentially mitigating factors that exacerbate RPE damage. Smoking cessation is strongly recommended, as tobacco use can accelerate progression in macular conditions, including vitelliform dystrophy.^[40] Wearing ultraviolet (UV)-protective sunglasses and avoiding excessive sun exposure are advised to protect the retina from additional oxidative stress, a general precaution for hereditary macular dystrophies.^[41] Nutritional supplements, such as the AREDS formula containing antioxidants and minerals, are sometimes considered for overall eye health despite lacking proven efficacy specifically for vitelliform macular dystrophy.^[40]^[42] Patient education emphasizes understanding the hereditary nature of the condition to facilitate family screening and informed decision-making. Genetic counseling is provided to discuss inheritance risks—typically autosomal dominant—and options for testing relatives, with detection rates exceeding 99% using sequence analysis of the BEST1 gene.^[7]^[27] Psychological support, including counseling for vision-related anxiety, helps address emotional challenges associated with progressive sight loss.^[40] Rehabilitation services support adaptation to vision impairment through targeted interventions. Occupational therapy assists with modifying daily activities, such as home adaptations and mobility training, to maintain independence as vision declines.^[37] Access to support groups, such as those offered by the Macular Society, provides peer connection and resources for individuals and families affected by macular dystrophies.^[40]

Therapeutic Interventions

Vitelliform macular dystrophy, also known as Best disease, currently lacks an approved curative treatment, with management for uncomplicated cases primarily involving observation due to the typically slow progression of the condition.^[37]^[7] In cases complicated by choroidal neovascularization (CNV), which affects approximately 15-17% of eyes in affected individuals, intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections represent the standard intervention to stabilize or improve visual acuity. Agents such as bevacizumab and ranibizumab have demonstrated efficacy, with studies showing visual stabilization or gains in best-corrected visual acuity following 1-3 injections in most patients, often requiring only maintenance dosing thereafter.^[43]^[44]^[45]^[46]^[47]^[48] Surgical interventions, such as pars plana vitrectomy, are rarely indicated and reserved for specific complications like pseudohypopyon or subretinal fibrosis causing significant mechanical issues or vision impairment. These procedures aim to remove subretinal material but carry risks including retinal detachment and are not routinely recommended due to limited long-term benefits.^[37]^[49] Photodynamic therapy (PDT) with verteporfin was historically employed for CNV in Best disease, particularly in pediatric cases, yielding anatomical resolution of neovascular lesions and visual stabilization in small series; however, its use has declined in favor of anti-VEGF therapy due to comparable or superior outcomes with fewer sessions.^[50]^[51]^[37] Emerging therapies focus on addressing the underlying BEST1 gene mutation. Gene therapy trials using adeno-associated virus (AAV) vectors to deliver wild-type bestrophin-1, such as OPGx-BEST1, have advanced to phase 1/2 clinical testing, with the first participant dosed in November 2025, aiming to restore retinal pigment epithelium function in patients with BEST1-related diseases including Best vitelliform macular dystrophy.^[52]^[53]^[54]^[55]^[56] Stem cell-based retinal pigment epithelium (RPE) replacement remains in preclinical stages, with animal models demonstrating potential for repopulating dysfunctional RPE layers. Laser photocoagulation is generally contraindicated due to the risk of exacerbating RPE damage in this inherited dystrophy.^[57]^[58]^[37]

Prognosis and Complications

Visual Outcomes

Vitelliform macular dystrophy, also known as Best disease, exhibits a generally favorable prognosis characterized by slow progression and long-term preservation of functional vision in the majority of patients. Approximately 88% of patients retain 20/40 or better visual acuity in the better eye long-term.^[10] Most patients experience stability until approximately age 40, after which gradual central vision decline may occur, though severe impairment remains uncommon without complications.^[32] The impact of disease stages on visual outcomes is pronounced, with early stages (1-3, including previtelliform, vitelliform, and pseudohypopyon) typically preserving normal or near-normal vision (20/20 to 20/60). Progression to advanced stages, such as vitelliruptive or atrophic, correlates with greater acuity loss; in the atrophic stage, visual acuity is often worse than 20/200. Longitudinal data indicate that over 8-10 years, approximately 19% of eyes in atrophic or cicatricial stages showed loss of vision.^[32] Several factors influence prognosis, including age of onset, where early childhood presentation often demonstrates slower overall progression despite earlier symptom emergence. Interocular asymmetry is common, resulting in discrepant visual acuity between eyes and unpredictable unilateral decline. Recent 2024 natural history analyses further reveal that variable optical coherence tomography (OCT) phenotypes—such as solid vitelliform lesions with subretinal fluid (associated with better acuity around 0.3 logMAR) versus intraretinal fluid or atrophic/fibrotic patterns (worse acuity up to 0.9 logMAR)—play a key role in modulating outcomes, with annual central retinal thickness loss averaging 5-6 μm.^[59]^[30]^[5] Quality of life is affected primarily by central vision impairment, which hinders tasks requiring fine detail like reading and driving, though preserved peripheral vision supports overall mobility and orientation.^[28] As of November 2025, a phase 1/2 clinical trial for gene therapy targeting BEST1 mutations (OPGx-BEST1) has dosed its first patient, offering potential for improved long-term outcomes.^[3]

Associated Risks

One of the primary associated risks in vitelliform macular dystrophy (VMD), also known as Best disease, is the development of choroidal neovascularization (CNV), which occurs in approximately 17% of cases over an average follow-up period of 8 years.^[44] CNV typically arises as a late complication due to damage to the retinal pigment epithelium (RPE) and Bruch's membrane, leading to subretinal hemorrhage and potentially rapid vision loss if untreated.^[60] The risk is notably higher in childhood-onset VMD (around 53%) compared to adult-onset variants (about 17%), with CNV often presenting earlier in younger patients.^[44] Other complications include subretinal fibrosis, observed in roughly 12% of affected eyes during advanced stages, which contributes to scarring and further visual impairment.^[61] Macular holes are a rare occurrence, reported primarily in case studies and associated with both juvenile and adult-onset forms, potentially leading to macular hole-associated retinal detachment in isolated instances.^[49] RPE tears or apertures, manifesting as disruptions in the RPE layer, have also been documented sporadically, particularly in adult-onset foveomacular vitelliform dystrophy, though they do not confer an increased risk of retinal detachment overall.^[62]^[63] VMD remains isolated to the retina with no established systemic associations, though rare extramacular involvement, such as bilateral solitary peripheral retinal lesions, has been reported in atypical cases.^[28]^[64] To mitigate these risks, particularly CNV, annual monitoring with fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) is recommended to enable early detection and intervention.^[65]^[66] Recent studies, including those from 2024 and 2025, emphasize the utility of OCT angiography in identifying CNV in adult-onset variants, where progression may be subtler but still warrants vigilant surveillance.^[44]^[67]

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### Summary of Vitelliform Macular Dystrophy
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https://www.aaojournal.org/article/S0161-6420(24)00086-1/fulltext
[30]
https://www.ophthalmologyretina.org/article/S2468-6530(25)00103-4/fulltext
[31]
Visual acuity in patients with best vitelliform macular dystrophy
In the eyes with the best visual acuity, the majority of patients younger than 40 years of age (76%) had a visual acuity of 20/40 or better. In patients older ...
[32]
Long-term evaluation of patients with Best's vitelliform dystrophy
Visual acuity decreased after age 40 and was worse for patients with atrophic maculas and fibrous scars. Nineteen percent of patients with atrophic maculas or ...
[33]
Best's Vitelliform Macular Dystrophy - PMC - PubMed Central - NIH
It results in typical vitelliform lesions that are bilateral though asymmetrical and cause only moderate diminution of vision for a long time.
[34]
https://emedicine.medscape.com/article/1227128-workup
[35]
Adult-onset foveomacular vitelliform dystrophy - Frontiers
Aug 9, 2023 · Total incidence of CNV has been reported as being 2.1% (17), 7.7% (64), and 11.7% (65). Among papers which report rates of CNV, two describe the ...Abstract · Epidemiology and... · Clinical diagnosis, staging... · Differential diagnoses
[36]
Fundus autofluorescence patterns in Best vitelliform macular dystrophy
Abstract. Purpose: To provide a systematic classification of fundus autofluorescence (FAF) patterns in patients affected by Best vitelliform macular dystrophy.
[37]
Recognizing Best's Disease - Review of Optometry
Dec 2, 2010 · Best's disease is a rare, incurable, autosomal dominant, slowly developing vitelliform (yolk-like) macular dystrophy associated with central visual disturbance ...
[38]
Best Disease Treatment & Management: Medical Care, Consultations, Long-Term Monitoring
### Summary of Non-Treatment Aspects for Best Disease
[39]
Detecting and Managing Multifocal Vitelliform Dystrophy
Jun 15, 2022 · Patients need to be monitored every four to six months with dilated fundus exams and OCT scans, and doctors also need to be attentive for ...
[40]
Best Disease (Vitelliform Macular Dystrophy): Stages & Symptoms
Best disease is an inherited condition that affects the macula of your eyes. You may lose central vision but keep side vision.
[41]
Best disease (Best vitelliform macular dystrophy) - RNIB
Best disease is a type of macular dystrophy and is also called “Best vitelliform macular dystrophy”. Macular dystrophies are inherited eye conditions.Best Disease (best... · Looking After Your Sight · CopingMissing: synonyms classification
[42]
Nutrition and lifestyle - Macular Disease Foundation Australia
The link between macular diseases and sunlight exposure is not strong but protecting the eyes from UV light is recommended. This also makes going outside more ...Missing: cessation | Show results with:cessation
[43]
AREDS 2 Supplements for Age-Related Macular Degeneration (AMD)
Jun 22, 2021 · AREDS 2 are dietary supplements that can help stop intermediate age-related macular degeneration (AMD) from turning into late AMD.
[44]
Choroidal Neovascularization Is Common in Best Vitelliform Macular ...
Dec 13, 2022 · Clinical data, including age, gender, best-corrected visual acuity (BCVA), and treatment with intravitreal anti-VEGF injections were recorded.
[45]
Best Vitelliform Macular Dystrophy Natural History Study Report 1
Jan 24, 2024 · The disease is very slowly progressive, and the observed phenotype–genotype correlations allow for more accurate prognostication and counselling ...Visual Acuity And Refraction · Funduscopic Findings And... · Refractive Error And...Missing: signs | Show results with:signs
[46]
Intravitreal bevacizumab for choroidal neovascular membrane ... - NIH
Intravitreal bevacizumab appears to be a promising, cost-effective modality of treatment with a potential for improvement in visual acuity.
[47]
Intravitreal Anti-VEGF Therapy for Choroidal Neovascularization ...
Purpose : To report on the effect of intravitreal anti-VEGF therapy for choroidal neovascularization (CNV) due to Best vitelliform macular dystrophy (BVMD) ...
[48]
Intravitreal Ranibizumab for the Treatment of Choroidal ...
In Best's vitelliform macular dystrophy, usually a gradual loss of visual acuity occurs over a period of years. During the disruptive phase, subretinal ...
[49]
Value of anti-VEGF treatment in choroidal neovascularization ...
Dec 30, 2013 · In 2008 Burgess et al described an autosomal recessive condition associated with biallelic mutations in the BEST1 gene, with either homozygous ...
[50]
Macular hole-associated retinal detachment in Best vitelliform ...
Surgical intervention led to Type 1 closure of macular hole, resolution of retinal detachment, and improvement in vision in both patients. Keywords: Best ...Missing: options | Show results with:options
[51]
Photodynamic therapy for best disease complicated by choroidal ...
Purpose: To describe the results of photodynamic therapy (PDT) with verteporfin for the treatment of choroidal neovascularization (CNV) associated with Best ...
[52]
Full article: Long-Term Results of Photodynamic Therapy for ...
Purpose: To report long-term results of photodynamic therapy (PDT) in young patients affected by Best vitelliform macular dystrophy (VMD) complicated by ...
[53]
Opus Genetics Announces FDA Clearance of IND Application for ...
Aug 18, 2025 · Phase 1/2 trial expected to initiate in 2H 2025 in patients with BEST1 inherited retinal disease. RESEARCH TRIANGLE PARK, N.C., Aug.Missing: 2023-2025 | Show results with:2023-2025
[54]
Gene Therapy Trial for BEST Disease Planned - Retinal Physician
Aug 18, 2025 · Opus Genetics reports that a phase 1/2 trial of its investigational gene therapy OPGx-BEST1 will begin by the end of 2025.Missing: 2023-2025 | Show results with:2023-2025
[55]
Opus Genetics Receives FDA Clearance to Launch Clinical Trial for ...
Aug 22, 2025 · OPGx-BEST1 uses an adeno-associated virus (AAV), which works like a container system, to deliver healthy copies of Best1 into retinal cells to ...Missing: 2023-2025 | Show results with:2023-2025
[56]
Safety and Tolerability of Subretinally Injected OPGx-BEST1 in ...
Sep 30, 2025 · The goal of this clinical trial is to learn if drug OPGx-BEST1 works to treat BVMD and ARB Bestrophinopathy. It will also learn about the ...Missing: 2023-2025 | Show results with:2023-2025
[57]
BEST1: the Best Target for Gene and Cell Therapies - PMC
Oct 27, 2015 · A retinal pigmented epithelial (RPE) disorder, bestrophinopathy has recently been proven to be amenable to gene and cell-based therapies in preclinical models.
[58]
BEST1: the Best Target for Gene and Cell Therapies - ScienceDirect
Oct 27, 2015 · Although the mechanism is still unclear, mutations in BEST1 alter the CaCC conductance of the bestrophin-1 protein, which hinders the RPE from ...Missing: transport | Show results with:transport
[59]
https://doi.org/10.1016/j.ophtha.2024.01.027
[60]
Choroidal Neovascularization Associated with Best Vitelliform ... - NIH
The most serious complication of the disease is choroidal neovascularization (CNV), which is seen in 20%. CNV occurs as a late complication as a result of ...
[61]
Best Vitelliform Macular Dystrophy Natural History Study Report 1
The occurrence of stage 3 rose from 10.7% to 17.9%, that of stage 4 declined from 17.8% to 10.7%, and that of stage 5 increased from 35.7% to 46.4%. Patients ...
[62]
Adult-onset foveomacular vitelliform dystrophy - PubMed Central - NIH
Aug 10, 2023 · Adult-onset foveomacular dystrophy (AOFVD) is a retinal pattern dystrophy that may affect up to 1 in 7400 individuals.
[63]
Retinal pigment epithelium aperture: A late-onset... - LWW
The purpose of the study was to report aperture of retinal pigment epithelium (RPE) as a late complication and an unreported finding during the natural course ...
[64]
Bilateral, Solitary, Extramacular Vitelliform Retinal Lesions in a ...
This work describes the first published case of Best vitelliform macular dystrophy (BVMD) with bilateral, solitary, extramacular retinal lesions.
[65]
Trends in application of fundus fluorescein angiography in fundus ...
FFA is used to identify and document the activity of CNV in various retinal diseases, including AMD, myopia, angioid streaks, Best vitelliform macular dystrophy ...
[66]
Role of OCT Angiography OCTA in the Diagnosis of Macular Diseases
Sep 6, 2023 · Therefore, OCTA can be very useful to detect the CNV complication of vitelliform dystrophy which is mostly undetectable by either FFA or B-scan ...<|control11|><|separator|>
[67]
Cataract surgery in eyes with adult-onset foveomacular-vitelliform ...
Nov 3, 2025 · Purpose. To assess the outcomes and safety of cataract surgery in Adult-Onset Foveomacular-Vitelliform dystrophy (AFVD) patients.