Best vitelliform macular dystrophy (VMD) is an autosomal dominant (AD) macular dystrophy defined by the early central macular egg yolk–like (vitelliform) lesions, which then progress over time (▶ Fig. 24.1). Lesions are typically bilateral, but can be unilateral. Deposits outside the macula may also occur. It typically progresses slowly. Generally, VMD has an onset in childhood, but occasionally can appear in later teenage years. The lesions may be initially asymptomatic with remarkably preserved vision despite the obvious macular lesion. Initial symptoms may include decreased visual acuity or metamorphopsias. Peripheral vision and dark adaptation should be normal. Clinical stages are listed in ▶ Table 24.1, but the condition does not necessarily progress through each of these stages in every patient. Up to 75% of patients retain a visual acuity of 20/40 or better in their better eye.

There is also an AD adult-onset form of the disease in which symptoms and retinal changes begin later, usually after the age of 40 years, and causes vision loss that tends to worsen over time. This condition is also characterized by subretinal yellowish flecks in the posterior pole. Electro-oculogram (EOG) is normal or mildly reduced, but Arden’s ratio is always above 1.5.

Because of the distinctive presentation, the diagnosis of VMD is clinical, based on macular appearance, EOG, and, when present, AD family history. VMD may show incomplete penetrance although those with the gene mutation almost invariably have an abnormal EOG even when the clinical examination is normal. Variable expression is a hallmark of the disease and given that patients may be asymptomatic, examination and testing of family members who may report themselves as unaffected is essential. The prevalence is unknown.

Individuals with VMD are at risk for subretinal neovascularization, especially for those in stage 4. Either laser or anti-VEGF (vascular endothelial growth factor) agents may be helpful. Smoking should be discouraged.

24.2 Molecular Genetics

BEST1 (formerly known as VMD2; 11q12.3) is the gene that when mutated is most commonly the cause of Best disease. Its protein product is bestrophin-1, and it is expressed in the basolateral membrane of the retinal pigment epithelium (RPE) cells. Disruption of bestrophin-1 function may produce an abnormal ion and fluid transport by the RPE, disrupting the interaction with photoreceptors. Patients with VMD have lipofuscin deposits within the RPE, predominantly in the macula. This explains the characteristic electrophysiologic finding of an abnormal EOG. The BEST1 gene has 11 exons. The majority of pathogenic variants are in the first five exons, whereas most of the polymorphisms occur in noncoding regions.

Pathogenic mutations in the PRPH2 gene can also cause the adult-onset form of VMD; however, it has been classically said that less than 25% of all affected patients have mutations in BEST1 or PRPH2 genes. In patients with adult-onset vitelliform dystrophy, IMPG1 and IMPG2 genes are causal genes in 8% of patients who were negative for BEST1 and PRPH2 mutations. These individuals usually have moderate visual impairment, drusen like lesions, and, on optical coherence tomography (OCT), normal reflectivity of the RPE line and vitelliform deposits located between ellipsoid and interdigitation lines.

Individuals with VMD may have no pathogenic variants in BEST1 due to incomplete exon sequencing, deep intronic mutations, or genetic heterogeneity (e.g., pathogenic variants in PRPH2 for adult-onset VMD). In VMD, the proportion of patients who present as a de novo mutation is unknown. If a proband has an apparent de novo pathogenic variant, and fundus examination of parents is normal, EOG on the parents is still recommended for ruling out variable expressivity.

Sequence analysis of BEST1 exons and intron–exon boundaries has approximately a 95% detection rate. To the best of our knowledge, there are no reported pathogenic deletions or duplications of the BEST1 gene. There is a specific Swedish mutation (c.383G>C); targeted analysis could be tried first with proper counseling in that group as a cost-saving measure. Evidence of genotype–phenotype correlation is scarce. p.Val89Ala is associated with late-onset VMD. p.Tyr227Asn has been seen with late-onset small vitelliform lesions.

24.3 Differential Diagnosis

The differential diagnosis of Stargardt disease (SGD) applies to VMD. In addition, the following disorders also deserve consideration.

24.3.1 Central Serous Retinopathy

Central serous retinopathy (CSR) is characterized by leakage of fluid under the neurosensory retina. It is typically seen in young males, and it is exacerbated by stress or corticosteroid use. It causes a circular macular elevated lesion similar to that seen in VMD but without lipofuscin, although exudates may be seen. Intravenous fluorescein angiography (IVFA) will usually show a typical “smoke stack” focus of leakage CSR that is usually unilateral. EOG is normal.

24.3.2 Toxoplasmosis Retinochoroiditis

White focal retinitis with overlying vitritis (“headlight in the fog”), accompanied by adjacent pigmented retinochoroidal scars, can help distinguish from VMD. Lipofuscin accumulation is not seen.

24.3.3 Solar Retinopathy

This condition is caused by photochemical toxicity, usually occurring at the fovea. It is associated with sun-gazing or eclipse viewing, and results in visual acuity deficit or paracentral scotomas. At examination, a very small foveal yellowish spot is seen in the fovea without elevation. EOG would be normal.

24.3.4 Autosomal Recessive Bestrophinopathy (OMIM 611809)

Autosomal Recessive Bestrophinopathy (ARB) is an AR disorder that differs from VMD in that it is multifocal and involves the retina more widely. Patients have multiple yellowish subretinal lesions (▶ Fig. 24.2), which show hyperfluorescence on fundus autofluorescence (FAF) as well as subretinal fluid or fibrosis. EOG is characterized by significant reduction or absence of light rise. Patients have patchy deep hyperfluorescent areas on IVFA, which usually extend beyond the retinal arcades. Intraretinal cystoid spaces or subretinal neovascularization may also be seen. Although the full-field electroretinogram (ffERG) is usually normal in the early stages of the condition, it has been reported that some ARB patients have severe photoreceptor dysfunction, characterized by prolonged latencies of the photopic responses. The multifocal ERG shows mild to markedly abnormal responses throughout the macula. OCT can reveal subretinal yellowish lesions and scars corresponding to hyper-reflective accumulations within or just above the RPE layer. Serous subretinal fluid or intraretinal cystoid spaces can also be observed. Color vision tests are usually normal.

ARB is usually diagnosed in the first two decades of life. Other associated abnormalities include hyperopia, amblyopia, narrow angles, and/or short axial length. In individuals with biallelic mutations in the BEST1 gene, subretinal neovascular lesions with hemorrhage may occur. Up to 50% of patients with ARB may develop angle closure glaucoma. Carbonic anhydrase inhibitors have been used to reduce intraretinal cystoid spaces in this condition.

The main differential diagnoses for ARB are SGD, drusen disorders, chronic CSR, North Carolina macular dystrophy (caused by dysregulation of the retinal transcription factor PRDM13) and age-related macular degeneration. These were described in the SGD and VMD sections earlier. Subretinal lipofuscin in SGD is not associated with subretinal fluid, a finding that can be seen in ARB. Factors that help differentiate atypical multifocal VMD from ARB include AD rather than AR inheritance, degree of EOG abnormality being worse in ARB, and larger clumps of lipofuscin in ARB. Some ARB patients have been misdiagnosed as having posterior uveitis (e.g., birdshot chorioretinitis), and treated mistakenly with systemic immunosuppressants. Patients with chorioretinitis often have vitreous cells, contrary to ARB patients.

ARB is due to biallelic mutation in the BEST1 gene. Both mutations are found in nearly 85% of patients. The c.422G>A mutation is one of the most frequent pathogenic variants in ARB. BEST1 full sequencing is crucial to diagnose ARB, especially in challenging cases in which clinical findings are atypical. Depending on cost and availability, for some cases the best strategy will be a macular dystrophy panel.

24.3.5 Autosomal Dominant Vitreoretinochoroidopathy (OMIM 193220)

Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is an AD condition characterized by a discreet band of chorioretinal hypo- and hyperpigmentation, usually from the midperiphery to the ora serrata for 360 degrees (▶ Fig. 24.3). In addition, posterior to this ring, preretinal punctate white opacities, retinal arteriolar narrowing and occlusion, and choroidal atrophy can be seen. ADVIRC patients may have cystoid macular edema, vitreous changes (fibrillar degeneration, liquefaction, peripheral vitreal condensations), and cataract. Generally, patients present with only mild visual impairment, and rarely develop severe visual loss. In some cases, progressive central macular atrophy and cone dysfunction lead to visual impairment. Other rare manifestations include microcornea, retinal dystrophy, cataract, and posterior staphyloma, which can be seen together as a syndrome in patients who have ADVIRC. Nanophthalmos and microphthalmia have also been described. Characteristically, EOG is abnormal. Patients with ADVIRC may also have glaucoma, neovascularization, retinal detachment, vitreous hemorrhage, dyschromatopsia, or nystagmus. Progressive foveal atrophy may be seen as well.

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