Best vitelliform macular dystrophy (BVMD) is a genetic rare autosomal dominant form of macular degeneration (damage to a part of the eye called the macula) that occurs due to the mutation of BEST1 (or VMD2, TU15B) gene with incomplete penetrance and variable expression which typically presents in childhood. The physical cause of BVMD is a breakdown of the tissue in the retina called retinal pigment epithelium (RPE). The condition gets worse over time, starting with blurred central vision, and possibly leading to complete loss of central vision. Peripheral vision (vision from the sides of the eye) and the ability of the eye to adjust to dark are unaffected. The age of onset of BVMD can vary. Many individuals with BVMD have symptoms in childhood or early adulthood. BVMD is associated with a harmful genetic change (mutation) in the BEST1 gene. There is no cure for BVMD, although some treatments and medications exist that can minimize the damage caused by the breakdown of the RPE including anti-VEGF therapy (a medicine used to prevent the growth of new blood vessels in the eye), laser photocoagulation (laser treatment used to destroy leaky blood vessels), and photodynamic therapy (a combination of medicine and laser treatment used to get rid of bad eye cells).
Symptoms
BVMD has an average age of onset between age 5 and 10 but can vary from person to person. Affected individuals initially have normal vision and then experience blurred vision, reduced sharpness or clarity of vision, or the appearance of objects that have a distorted shape (metamorphopsia). BVMD affects central vision but usually not peripheral vision and varies in severity.
Some people with the disorder do not notice a decline in vision and may be diagnosed by passing a routine eye exam. Others experience a significant loss of vision, which can occur because of the formation of blood vessels under the macula and retina (choroidal neovascularization). The degree of visual loss can be different in each eye. Most individuals with BVMD have one eye more severely affected than the other and can continue to perform daily tasks such as driving well into the later decades of life.
Causes
The macula is the region of the retina that contains the light-sensing cells necessary for central vision. Individuals with BVMD develop a yellowish material under the macula that resembles an egg yolk (vitelliform means yolk-like). This material eventually breaks up and spreads throughout the macula, leading to a reduction in central vision. Lipofuscin, a chemical made by the body, makes up this yolk-like material.
BVMD is inherited as an autosomal dominant genetic condition and is usually associated with the mutations in the BEST1 gene. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent. It can also occur as a new gene change in the affected individual. Most individuals affected with BVMD have an affected parent. The chance of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
When working normally, the BEST1 gene acts as a gate to help move chemicals between cells in the retina. When this “gate” isn’t working properly, this can cause the build-up of fluid and lipofuscin in the retinal tissue. Because BVMD is a progressive condition, different stages are recognized.
- vitelliform stage (stage 1): The stage most commonly seen in new diagnoses of BVMD. In this stage, the macula has the characteristic pocket of yellow material that can be seen upon examination.
- pseudohypopyon stage (stage 2): The pocket of yellow material moves towards the bottom of the eye. This creates fluid layers where the bottom is the yellow yolk-like fluid and the top is a clear fluid.
- vitelliruptive stage (last stage): The common fluid layers become more spread out in the retina tissue. This spreading can lead to the formation of blood vessels under the macula (choroidal neovascularization) and can significantly impair central vision.
The BEST1 gene is one of two genes associated with this condition. This gene is linked to the early-onset form of this condition typically presenting in late childhood or early adolescence. BVMD-like symptoms diagnosed after age 20 with no gene abnormality in the BEST1 gene may be associated with mutations in the PRPH2 gene which is linked to adult-onset BVMD.
The mutation BEST1 causes multiple diseases, including:
- Vitelliform macular dystrophy 2 or BVMD (Phenotype MIM No. 153700)
- Autosomal recessive dystrophinopathy (Phenotype MIM No. 611809)
- Retinitis pigmentosa 50 (RP50)/concentric retinitis pigmentosa (Phenotype MIM No. 613194)
- Autosomal dominant microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 193220 (Phenotype MIM No. 193220)
- Autosomal dominant vitreoretinochoroidopathy (Phenotype MIM No. 193220)
- Adult-onset vitelliform macular dystrophy[7]
Diagnosis
Best vitelliform macular dystrophy is diagnosed by the appearance of a yellow mass on the macula during an eye exam. Different eye tests can detect or lead to a suspicion of BVMD including a test called an electrooculogram (EOG) which can measure how well the eye responds to light. The test measures how well the eye responds to light by looking at how the retina reacts to different amounts of light. A very low score on this test indicated as a number called an Arden ratio is a strong indicator for BVMD. Another test called a fundus exam can identify the yolk-like mass on the macula that is characteristic of BVMD.
Suggestive Findings
A dystrophinopathy should be suspected in individuals with following the ophthalmologic findings and electrophysiologic studies by phenotype, and family history.
Ophthalmologic findings by phenotype
- Best vitelliform macular dystrophy (BVMD)
- Onset age three to 15 years
- Fundus examination. A typical yellow yolk-like macular lesion may be present, usually bilateral, but in some cases unilateral. Multiple lesions and lesions outside the macula occur in at least 25% of individuals.
- BEST1 adult-onset vitelliform macular dystrophy (AVMD)
- Onset age 30-50 years
- Fundus examination. Subretinal, small, circular, yellow vitelliform lesion; vitelliform lesion can become atrophic over time.
- Autosomal dominant vitreoretinochoroidopathy (ADVIRC)
- Onset in the first decade of life
- Fundus examination. Peripheral retinal pigmentation, white retinal opacities
- Other ocular findings. Nanophthalmos, hyperopia, microcornea, narrow-angle glaucoma
- Autosomal recessive dystrophinopathy (ARB)
- Onset in the first decade of life
- Fundus examination. White subretinal deposits with macular subretinal fluid
Electrophysiologic studies
- Electrooculogram (EOG) measures indirectly the standing potential of the eye. A normal light peak / dark trough ratio (Arden ratio) is >1.8. (As the Arden ratio decreases with age after the fourth decade, this value is not absolute.)
- BVMD. Usually abnormal with a reduced light peak / dark trough ratio (Arden ratio) <1.5, most often between 1.0 and 1.3.Note: Occasionally individuals with molecularly confirmed Best vitelliform macular dystrophy have a normal EOG [rx].
- AVMD. Normal or only slightly reduced
- ADVICE. Abnormal
- ARB. Abnormal
- Full-field electroretinogram (ERG)
- BVMD and AVMD. Normal
- ADVICE. Normal or reduced
- ARB. Reduced scotopic and photopic responses
- Spectral-domain optical coherence tomography (OCT)
- BVMD and AVMD. Splitting and elevation of the outer retina and retinal pigment epithelial layer with dome-like hyperreflective or hyperreflective material and subretinal fluid
- ADVICE. Retinal atrophy is usually present; possible cystoid macular edema
- ARB. Subretinal deposits with subretinal and/or intraretinal fluid
- Fundus autofluorescence (AF)
- BVMD and AVMD. Hyperautofluorescence at early stages progressing to hypofluorescence in late atrophic stages
- ADVICE. Typically normal centrally with blocked fluorescence in the periphery
- ARB. Diffuse, discrete small areas of hyper- and hypo autofluorescence
Only a few reports have investigated the histopathological features of Best vitelliform macular dystrophy.
Histopathology of a 69-year-old male with BVMD showed[rx]:
- Accumulation of lipofuscin within the RPE, particularly at the fovea. Lipofuscin was confirmed by staining, ultrastructural appearance, and autofluorescence properties.
- Other features included:
- Accumulation of heterogeneous material between RPE and Bruch’s membrane, which likely derived from degenerating RPE cells containing lipofuscin
- Loss of foveal photoreceptors above the lesion
- Photoreceptor outer segment debris and phagocytic cells in the subretinal space
Histology of another eye showed a ‘well-circumscribed area of RPE hyperplasia, accumulation of lipofuscin in the RPE, deposition of granular material in the photoreceptors, macrophages, and drusen.’[rx]
Mullin and colleagues reported a male who was noted to have small macular vitelliform lesions and extramacular subretinal flecks in both eyes for the first time at 75 years of age.[rx] On histopathology at 93 years, the eye showed attenuated outer nuclear layer (ONL) usually associated with normal RPE, degeneration of photoreceptors with loss of RPE at the central macula, and drusen and basal laminar deposits at the peripheral flecks. Bestrophin was noted to be present at the basolateral and apical membrane of RPE.
Histopathological evaluation of a 28-year-old male with vitelliruptive stage ‘with some features of a pseudo hypopyon revealed diffuse RPE abnormality with an accumulation of lipofuscin. Lipopigment was noted ‘within the RPE, within macrophages in the subretinal space, and within the choroid.’[rx]
Frangieh and colleagues suggested that the changes in the neurosensory retina were primary, and RPE changes were secondary.[rx] The choriocapillaris was normal, and they noted abnormal fibrillar material underneath RPE cells at the area of photoreceptor loss. Disruption in Bruch’s membrane with CNVM was also noted. They found lipofuscin and melanolipofuscin deposit in RPE, and ‘PAS-positive, acid-mucopolysaccharide-negative, electron-dense, finely granular material was deposited in the inner segments of the degenerating photoreceptors and the Mueller cells.’[rx] This material corresponds mainly to A2E.[rx]
Also, the brilliant autofluorescence of the vitelliform lesion might suggest the deposited material to be A2E or lipofuscin. However, angiographic evidence of generalized deposition of lipofuscin in RPE causing block fluorescence (dark choroid in fluorescein angiogram as seen in Stargardt disease) is not a feature in BVMD.
Imaging
The disease usually involves the eye only with no systemic manifestations.
Refractive error (usually hypermetropia) – The fundus appearance is drastic and shows a single egg-yolk-like symmetrical subretinal deposit at the macula bilaterally, but the visual acuity is usually normal. However, there are reports of unilateral cases in patients with BEST1 mutation and bilateral reduced EOG Arden ratio with normal electroretinogram.[rx] Best vitelliform macular dystrophy with affected EOG may have multifocal vitelliform lesions.[rx] Typically, the optic nerve and retinal vessels are normal, and bony spicules are not seen. The vitelliform macular lesion may progress through the typical stages, may regress with time, or may be associated with newer extramacular lesions.
Visual field – Usually, there is no peripheral visual field defect. Central scotoma may be present.
Autofluorescence – The vitelliform material is typically brilliantly autofluorescent and has a round or oval shape in the vitelliform stage. In the pseudohypopyon stage, the autofluorescence is visible in the inferiorly deposited yellow material. Vitelliruptive disease shows speckled autofluorescence. The atrophic stage shows hypo-autofluorescence. Peripheral ring/small circumferential dots of hyper-autofluorescence may be noted in the vitelliruptive stage.[rx] Late stages characteristically show central hypo autofluorescence and peripheral hyper-autofluorescence.[rx] Retinal dysfunction and autofluorescence revealed a centrifugal pattern of loss from center to periphery in a study.[rx] The central area of atrophy correlates with low visual acuity, reduced autofluorescence, central scotoma, reduced color vision, and reduced pattern ERG (PERG) response.[rx]
Fundus fluorescein angiogram (FFA)- FFA is crucial to rule out choroidal neovascular membrane (CNVM), which shows fluorescence that increases in size and intensity with time. The vitelliform deposit usually causes hypofluorescence secondary to blocked fluorescence. The atrophic stage reveals a window defect. There is no ‘black choroid’ appearance on FFA, as seen in Stargardt disease.
Optical coherence tomography (OCT) – In the vitelliform stage, the OCT reveals the deposit of homogenous hyperreflective material.[rx] In the pseudohypopyon stage, the vertical OCT scan shows clear fluid superiorly and a sharp margin of the deposited vitelliform material. In the atrophic phase, retinal thinning may be noted similar to geographic atrophy in age-related macular degeneration. Subretinal/intraretinal fluid, and/or subretinal hemorrhage may characterize the CNVM stage. The location of vitelliform material has undergone study with both time-domain and spectral-domain OCT.
EOG – The normal light peak to dark trough ratio (Arden ratio) is at least 1.85. In BVMD (all stages, even with no apparent fundus lesion, all patients, and carriers with normal fundus), the light peak is universally reduced, resulting in an Arden ratio of 1.50 or less usually.
The diagnosis of BVMD needs the following criteria
- Presence of one of the typical lesions of BVMD
- Abnormal EOG
- The dominant mode of inheritance
- Typical natural course and onset of the disease as in BVMD
ERG – Typically, the ERG is normal. Dark adaptometry is normal.
Color vision and contrast sensitivity may be affected.
Other family members like siblings or parents with similar symptoms may help in diagnosing BVMD in an individual. Molecular genetic testing for the BEST1 gene is available to confirm the diagnosis. Sequencing of BEST1 (reading every letter of the gene from start to finish) can detect more than 96% of harmful genetic changes if there is a family history of BVMD. This means that only 4% of harmful changes in the BEST1 gene are not detected in an individual with BVMD. If there is no family history, sequencing can detect 50 – 70% of harmful genetic changes known to cause BVMD.
Treatment
There is no cure for BVMD but there are treatment options available that can help reduce the effects of vision loss. For individuals with BVMD who have choroidal neovascularization, anti-VEGF therapy is available to help limit the formation of blood vessels in the macula.
The CNVM may respond favorably to anti-vascular endothelial growth factor agents (anti-VEGF agents like bevacizumab, ranibizumab, or aflibercept).[rx] Other options include laser and photodynamic therapy.[rx] The CNVM may regress spontaneously also, but the visual outcome may be better with anti-VEGF agents.[rx] On average, one bevacizumab injection was necessary for BVMD with CNVM in the study by Khan and colleagues.[rx]
Affected individuals should have regular eye examinations to monitor the progression of the disease. Devices or aids to help with poor vision are beneficial for those who experience significant vision loss.
If the eye lesions are large enough, sudden injury to the eye or head may lead to the bursting of the lesions. People with BVMD should avoid strenuous exercise or high contact activity that may lead to head trauma.
Genetic counseling is beneficial for affected individuals and their families. These specialists can provide information on the genetic causes of certain inherited conditions, counsel on the chance of genetic disease reoccurring in the family, discuss the availability of different genetic testing options, and provide resources related to genetic disease
Differential Diagnosis
The differential diagnoses include:
- Central serous chorioretinopathy with fibrin
- There is the presence of serious pigment epithelial detachment and an area of subretinal lucency at the location of the leak[26]
- FFA features are typical and show leaks (ink-blot, smoke-stack, or diffuse) and pigment epithelial detachment
- Adult-onset vitelliform macular dystrophy (a variant of pattern dystrophy)
- The patients present in late-middle or old age with visual decline
- The lesion is smaller and may not pass through the typical stages of BVMD
- There may be a mutation of the BEST1 or PRPH2 (RDS) gene. Up to one-third of patients have abnormal EOG and the disease is dominantly inherited
- Subretinal granuloma due to choroidal tuberculosis/sarcoidosis
- There is clinical or angiographic evidence of inflammation
- Wet age-related macular degeneration
- Distinguishing features are old age and irregular lesion
- Disciform scar has a whitish appearance rather than the typical yellow, smooth appearance of BVMD
- Acute exudative vitelliform maculopathy
- Fundus flavimaculatus with large flecks
- Large dehemoglobinized subretinal hemorrhage
- Basal laminar drusen
Staging
The disease usually goes through several stages:
- Previtelliform/subclinical stage – The fundus is normal in an asymptomatic infant or child. However, EOG is abnormal.
- Vitelliform stage or egg yolk stage – Best vitelliform macular dystrophy gets its name from this stage, and this stage typically presents in infancy or early childhood. An egg-yolk-like round or oval yellow smooth elevated lesion with a well-defined margin is seen at the macula. The size is 0.5 to 2 disc diameters, and the lesion usually centers on the fovea but not in every case. The size/size/shape/stage of the lesion may not be very symmetrical. Vision is usually normal or minimally affected despite the drastic fundus appearance. The lesion(s) may be multiple and extramacular and be very large with a geographic shape.
- Pseudohypopyon stage – The vitelliform deposits gravitate down in the subretinal space with a horizontal upper level, usually at puberty. The fluid above this deposit is clear. One hypothesis is that the retinal pigment epithelium takes up the yellow deposit, and heavier material gravitates down. Vision is usually good at this stage. After a change of head position for 60 to 90 minutes, the pseudohypopyon may shift.
- The vitelliruptive stage or scrambled egg stage – is due to the breakup of the smooth and uniform vitelliform material giving a nonhomogenous look. Visual acuity starts to deteriorate at this stage. A small area or areas of pigmentation/atrophy may be noted.
- Atrophic stage – The vitelliform material is no longer visible, and there is an area of atrophy and pigmentation which may simulate geographic atrophy due to age-related macular degeneration. Marked visual deterioration is present. This stage usually occurs after 40 years of age.
- Cicatricial and choroidal neovascularization – Subretinal bleed may be present due to CNVM. This stage is associated with poor vision and may lead to subretinal fibrosis.
or
- Stage 0. Normal macula. The abnormal electrooculogram (EOG)
- Stage 1. Retinal pigment epithelium (RPE) disruption in the macular region. A fluorescein angiogram (FA) shows window defects.
- Stage 2. Circular well-circumscribed yellow-opaque homogeneous yolk-like macular lesion (vitelliform lesion). FA reveals marked hypofluorescence in the zone covered by the lesion.
- Stage 2a. Vitelliform lesion contents become less homogeneous to develop a “scrambled-egg” appearance. FA shows partial blockage of fluorescence with a non-homogeneous hyperfluorescence.
- Stage 3. Pseudohypopyon phase. 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. An orange-red lesion with atrophic RPE and visibility of the choroid. FA shows hyperfluorescence without leakage.
- Stage 4b. Fibrous scarring of the macula. 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.
References
