19.1.1 Vitelliform Dystrophies (VMD2 Gene Dystrophy)

Bestrophin 1 (BEST1) gene has been implicated in autosomal dominant Best’s disease, autosomal dominant vitreoretinochoroidopathy (ADVIRC), autosomal dominant microcornea rod–cone degeneration syndrome (ADMRCS), and autosomal recessive bestrophinopathy (ARB).

Best’s Vitelliform Macular Dystrophy

Best’s disease (vitelliform macular dystrophy) is an autosomal dominantly inherited disorder with variable penetrance and expressivity. ^{1 ,​ 2 ,​ 3 ,​ 4 ,​ 5 ,​ 6 ,​ 7 ,​ 8 ,​ 9 ,​ 10 ,​ 11 ,​ 12 ,​ 13 ,​ 14 ,​ 15 ,​ 16 ,​ 17 ,​ 18 ,​ 19 ,​ 20 ,​ 21 ,​ 22 ,​ 23 ,​ 24 ,​ 25 ,​ 26 ,​ 27} The gene responsible for Best’s vitelliform macular dystrophy (BVMD) was cloned by Petrukhin and colleagues in 1998 and named the Bestrophin 1 (BEST1) gene. ²⁸ It consists of 11 exons and 585 amino acids, and spans 15 kilobases of genomic DNA. The gene is expressed predominantly in the retinal pigment epithelial (RPE) cells and the bestrophin protein is located mainly on the basolateral plasma membrane of the RPE and to a small extent within the RPE cells. The protein is believed to function as an intracellular Ca²⁺-dependent Cl^– channel and a HCO₃ ^– channel. ^{29 ,​ 30 ,​ 31 ,​ 32} Disruption of the ion conductance across the RPE by abnormal Bestrophin 1 is likely responsible for the absence of light peak response in the electro-oculogram (EOG) in both patients and unaffected carriers of Best’s disease. ^{14 ,​ 19 ,​ 26 ,​ 33 ,​ 34} The disease appears to affect primarily the RPE. The clinical appearance of the condition can be divided into five stages.

Previtelliform or Carrier Stage

Although vitelliform lesions have been observed as early as the first week of life, the fundi of most patients probably are normal during the first few months or years of life. Many carriers never manifest a change in the fundus and they are incidentally found when other family members with the typical vitelliform lesions are seen. They exhibit low Arden ratios on EOG testing.

Vitelliform Stage

In infancy or in early childhood, patients may develop a sharply circumscribed subretinal lesion that has been likened to the yolk of a sunny-side-up fried egg (Fig. 19-1). Visual acuity at this stage of the disease is usually normal. Early in the disease, little or no elevation of the retina occurs. Subsequently, the lesion appears elevated as the yellow material increases in amount and is found in the outer photoreceptor zone, subretinal space, and within the RPE layer. ^{29 ,​ 35} The color and pattern of the RPE surrounding the lesion are usually normal. Variations in size and stage of development of the lesion may be present in the eyes of the same patient. The lesion initially may be evident only in one eye. In some patients, the fellow eye may remain near-normal with 20/20 acuity throughout life. ³⁶ The vitelliform lesion may occasionally disappear spontaneously. The lesions may be eccentrically located and may be multiple. ³⁷ In a few patients, they may be unusually large and geographic in shape. Some patients may show a finely mottled pattern of yellowish change in the RPE throughout the fundus.

Pseudohypopyon Stage

Usually by the time the patient reaches puberty, the yellowish lesion shows evidence of disruption (Fig. 19-2). It appears that the yellow material is partly taken up by the RPE cells and the heavier material gravitates inferiorly in the subretinal space. There is thinning of the RPE and occasionally some clumping of pigment in the superior portion of these lesions.

With further disruption of the vitelliform lesion, multiple irregular yellowish subretinal deposits produce a picture likened to a scrambled egg (Fig. 19-3). Multifocal yellow deposits may occasionally be arranged in a more orderly ring distribution near the periphery of these lesions. The visual acuity is often decreased to the level of 20/30 to 20/40 in the presence of extensive scrambling of the vitelliform lesion.

Atrophic Stage

Eventually all of the yellow pigment may disappear and leave an oval area of atrophic RPE.

Cicatricial and Choroidal Neovascular Stage

Many patients develop evidence of one or more plaques of white subretinal fibrous tissue, and in some cases there is evidence of choroidal neovascularization and hemorrhagic detachment of the macula. ^{6 ,​ 12} These latter patients eventually develop a white or partly pigmented disciform scar. The central vision is generally 20/100 or less at this stage of the disease. Serous detachment of the retina may occur at any stage of the development of vitelliform lesions (Fig. 19-4). This “Best’s space” may never collapse even after the vitelliform material has been absorbed or broken down.

In the vitelliform stage, the early phases of angiography demonstrate complete obstruction of the choroidal fluorescence by the lesion. ^{12 ,​ 18} There is no generalized obscuration of the choroidal fluorescence such as occurs in Stargardt’s disease. During the later stages of angiography, the vitelliform lesion may appear nonfluorescent or may appear to fluoresce slightly. As the yellow pigment gravitates inferiorly, angiography in the area vacated by the yellow material reveals evidence of early fluorescence secondary to depigmentation and late staining of the altered RPE (Fig. 19-5). Angiography permits detection of choroidal neovascularization and shows evidence of staining of fibrous tissue if present in the subretinal space. It is probable that occult choroidal neovascularization is present within some of the subretinal plaques of fibrous tissue. The vitelliform lesions are brightly hyperautofluorescent (Fig. 19-6).

Peripheral visual fields, electroretinographic findings, and dark adaptation in these patients are normal. Color vision in the late stages of the disease may be mildly disturbed. The EOG is markedly abnormal, with the light-to-dark ratio (Arden ratio) usually being below 1.50. ^{8 ,​ 14 ,​ 19} EOGs of carriers of the disease usually yield a subnormal result. Patients who are both homozygous and heterozygous for the BEST1 gene show low Arden ratio, thus making this feature most characteristic of the condition. The disease is inherited as an autosomal dominant trait. Best’s disease usually occurs in Caucasian patients but may occur occasionally in Africans and Asians. ³⁸

Visual prognosis is moderate to good for at least the first six decades of life. ⁵ Most patients retain reading vision in at least one eye throughout life. The progression of visual loss is slow and occurs for the most part beyond the age of 40 years. ¹⁶ Acute and permanent loss of central vision may occur in association with bleeding from subretinal new vessels. A macular hole may occasionally occur in patients with Best’s disease.

Histopathologic findings in Best’s disease included a periodic acid–Schiff (PAS)-positive, acid mucopolysaccharide–negative, electron-dense, finely granular material in the inner segments of the degenerating photoreceptors and Müller cells recently identified predominantly as A2E ³⁹ ; an abnormal fibrillar material beneath the RPE cells in the region of photoreceptor cell loss; and normal choriocapillaris. ¹³ Breaks in Bruch’s membrane and choroidal neovascularization have been demonstrated. ^{1 ,​ 13} These studies, together with the in vivo demonstration of autofluorescence of vitelliform lesions in Best’s disease by Miller, ^{7 ,​ 29 ,​ 35 ,​ 40} suggest that the yellow pigment may at least in part be caused by lipofuscin. Histopathologic examination of an 86-year-old homozygous for BEST1 gene showed accumulation of lipofuscin, a large component of it made up of A2E, within the RPE cells. Other RPE granules were melanoliposomes. Extraction of the granules in this eye and another 81-year-old’s eye heterozygous for the gene showed the lipofuscin to be mostly made up of A2E similar to that found in diseases caused by the ABCR transport gene abnormality. ³⁹

The vitelliform stage of Best’s disease should be differentiated from other diseases that cause solitary yellowish macular lesions—for example, dominantly inherited adult-onset vitelliform foveomacular dystrophy (pattern dystrophy), basal laminar drusen with vitelliform detachment, acute polymorphous exudative vitelliform maculopathy, paraneoplastic vitelliform maculopathy in metastatic melanoma, and fundus flavimaculatus (Stargardt’s disease) with large central flecks. The early age of development of the yellow lesion and the progressive vitelliruptiform changes are essential findings to differentiate patients with Best’s disease from those with adult-onset vitelliform foveomacular dystrophy (pattern dystrophy), because the latter disease may be associated with subnormal EOGs in one-third of cases and because both are dominantly inherited. Four other yellow lesions that simulate Best’s disease include vitelliform detachment in some patients with basal laminar drusen, focal serous RPE detachments containing dehemoglobinized blood pigment, some cases of central serous retinopathy with subretinal fibrin, and resolving subretinal hematomas. Gene testing for the BEST1 gene with the presence of these features confirms the diagnosis. Future identification of specific gene defects and the nature of the vitelliform material will help elucidate the pathogenic relationship of the various disorders that demonstrate similar yellow lesions in the macula. ^{41 ,​ 42}

Multifocal vitelliform lesions may occur in patients with Best’s disease (Fig. 19-7). The lesions may vary in size and may be several disc diameters or larger in size and often have some irregularity to their contour. These larger lesions frequently demonstrate partial resolution or disruption of the yellow material.

Pearls

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  Atypical presentations of Best’s disease include multifocal vitelliform lesions, normal fundus and reduced EOG in family members manifesting incomplete penetrance, and unilateral vitelliform lesion with bilateral reduced EOG.

BEST1 gene has also been implicated in ADVIRC, ADMRCS, and ARB, all with extraretinal features implicating that the gene may be involved in ocular development. ²⁹

19.1.2 Autosomal Dominant Vitreoretinochoroidopathy

Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is an autosomal dominantly inherited pigmentary retinopathy described by Kaufman et al in 1982. ⁴³ It is characterized by an annular peripheral pigmentary retinopathy for 360 degrees with a distinct posterior boundary near the equator (Fig. 19-8) associated with punctate whitish opacities in the superficial retina along with vitreous cells and fibrillary condensation. Peripheral retinal arteriolar narrowing and occlusion, evidence of retinal neovascularization, choroidal atrophy, and presenile cataracts can be present. Evidence of blood–retinal barrier breakdown is seen by cystoid macular edema.

These patients usually do not have symptoms of night blindness. The electroretinogram (ERG) is normal or only slightly reduced. The EOG is variably affected, with Arden ratio ranging from normal to subnormal. There have been a few cases with late cone dystrophy. ⁴⁴ The gene defect has been localized to the BEST1 gene with missense mutations and exon skipping on the long arm of chromosome 11. ^{29 ,​ 45 ,​ 46}

19.1.3 Autosomal Dominant Microcornea Rod–Cone Dystrophy, Cataract with Staphyloma

A subgroup of patients who have all or some features of ADVIRC may also have microcornea and shallow anterior chamber with evidence of subacute or acute angle-closure glaucoma. Some of these patients show posterior staphyloma and some are myopic. ⁴⁷ The inheritance pattern is autosomal dominant, with a mutation in the BEST1 gene. ^{29 ,​ 45} The EOG is abnormal in all patients with ADMRCS syndrome. A full-field ERG may show subnormal photopic and scotopic responses. With time, these patients show progressive ERG changes with severe rod and cone photoreceptor dysfunction, unlike ADVIRC that is relatively stable. The ADMRCS syndrome is generally more severe than ADVIRC. However, there are family members who have overlapping findings of the two conditions. ²⁹

19.1.4 Autosomal Recessive Bestrophinopathy

Autosomal Recessive Bestrophinopathy (ARB), first described by Burgess et al in 2008, ⁴⁸ usually starts with central visual loss, with an age of onset ranging from 4 to 40 years (mean, 25 years). The visual acuity often deteriorates to less than 20/60 in both eyes within a few years. Patients are generally hyperopic with shallow anterior chambers and may present with subacute or acute angle-closure glaucoma. Fundus examination shows irregular RPE alterations with yellow-white subretinal deposits that are seen throughout the retina, preferentially in the macula and midperiphery (Fig. 19-9). They resemble multifocal Best’s disease. Intraretinal and subretinal fluid may be observed in the macula that can be confirmed by optical coherence tomography (OCT). The macular lesions may evolve into atrophic scars, causing a further decline in vision. ⁴⁸ The EOG is severely reduced or absent to light rise. The macular focal pattern ERG and multifocal ERG are markedly abnormal, indicating severe macular dysfunction. The full-field ERG shows reduced and delayed rod and cone responses indicating panretinal photoreceptor dysfunction. On angiography, there is widespread patchy hyperfluorescence due to RPE atrophy and retinal edema. These areas correspond to areas of increased fundus autofluorescence (Fig. 19-10), suggesting lipofuscin accumulation in the pigment epithelium. The areas of RPE loss show decreased fundus autofluorescence. High-resolution OCT of the macula shows photoreceptor detachment from the pigment epithelium, disruption of the photoreceptor layer, and intraretinal cysts but persevered inner retinal layers (Fig. 19-11). ^{29 ,​ 48} Those patients who are heterozygous to the mutation are entirely normal clinically and electrophysiologically.

All three conditions described earlier are caused by mutations in the BEST1 gene, the same gene that causes BVMD. Whereas Best’s, ADVIRC, and ADMRCS syndromes are autosomal dominant, ARB occurs in the presence of homozygous or compound heterozygous BEST1 mutation.

Nearly all mutations identified in BVMD and adult-onset foveal macular vitelliform dystrophy, a type of pattern dystrophy, are missense mutations. Those mutations causing ADVIRC and the MRCS syndrome are splice mutations, ^{29 ,​ 46 ,​ 48} leading to in-frame deletions or duplications. The null phenotype of ARB is caused by homozygous or compound heterozygous nonsense or missense BEST1 mutation. ^{29 ,​ 49} The variable expressivity and penetrance probably account for the wide variation in the phenotype of these conditions. It is likely they are also dependent on other genetic or environmental modifiers to manifest all features of the condition.

19.2.1 Group 1: Adult-Onset Foveomacular Vitelliform Dystrophy

Patients with adult-onset foveomacular vitelliform dystrophy are visually asymptomatic or suffer mild visual blurring and metamorphopsia in one or both eyes, usually with the onset between ages 30 and 50 years. Symmetric, solitary, usually 1/3 to 1 disc diameter size, round or oval, slightly elevated, yellow subretinal lesions, often with a central pigmented area in each eye are characteristic of the condition (Fig. 19-12). Additional small yellow flecks may sometimes be present in the paracentral region. ^{12 ,​ 51 ,​ 52 ,​ 53 ,​ 55 ,​ 57 ,​ 59 ,​ 60 ,​ 61 ,​ 67 ,​ 69 ,​ 70 ,​ 72 ,​ 73 ,​ 74 ,​ 79 ,​ 84} Initially, the yellow lesion may be present in only one eye. Although most of the foveal lesions are approximately 1/3 disc diameter in size, occasionally they may be larger and misdiagnosed as the “sunny-side-up” stage of BVMD or as bilateral serous detachment of the RPE. Later, the foveal lesions may fade and leave an irregular oval or round area of depigmentation of the RPE (Fig. 19-13). Some patients eventually develop additional paracentral yellow deposits, often in a triradiate pattern. Fluorescein angiography during the early stages of the disease shows either a nonfluorescent lesion or, more typically, a small irregular ring (halo) of hyperfluorescence surrounding a central nonfluorescent spot (Fig. 19-14). Some of the extrafoveal small yellow lesions show discrete staining, similar to drusen, and others are either nonfluorescent or have a halo of fluorescence surrounding them. The yellow and gray components of the lesions are brightly autofluorescent and the depigmented RPE in late lesions are hypoautofluorescent.

This form of pattern dystrophy was first observed in female patients in three successive generations in one family at the Bascom Palmer Eye Institute and reported by Gass. ⁷² Recently, a mutation of the peripherin RDS gene has been demonstrated in two of these patients. ⁹¹

Unlike those in BVMD, the vitelliform lesions in patients with pattern dystrophy usually first appear in the fourth decade or beyond, are generally smaller, and do not show disruption and layering of the yellow pigment in the dependent portion of the lesions. In some families, there is an overlap in the features of Best’s disease and pattern dystrophy. ¹⁰²

19.2.2 Group 2: Butterfly-Shaped Pigment Dystrophy

Gray-brown or yellow pigment is arranged in a well-organized triradiate pattern confined to the center of the macula in a symmetric fashion, likened to the shape of a butterfly (Fig. 19-15). ^{62 ,​ 71 ,​ 78} A zone of depigmentation occurs around this pigment figure. The optic disc and vessels are normal. Some patients have a reticular pigmentary pattern of drusen in the periphery. The early phases of angiography show hypofluorescence of the central pigment lines with hyperfluorescent borders. The shapes of the central yellow lesions in pattern dystrophies vary considerably and may simulate a variety of inanimate or animate objects.

19.2.3 Group 3: Reticular Dystrophy of the RPE

In patients with reticular dystrophy, the pattern of yellow pigment extends into the periphery of the macula and resembles coarse, knotted fishnet or chicken wire. ^{56 ,​ 63 ,​ 66 ,​ 76 ,​ 77 ,​ 82} It begins in the foveal area and gradually extends 4 or 5 disc diameters from the macula in all directions. The midperiphery and the periphery of the fundus are unaffected early in the disease. The network may be more apparent angiographically than ophthalmoscopically. It usually fades with age and may be replaced by extensive atrophic changes in the RPE in later life. Patients with reticular dystrophy may show an autosomal recessive as well as autosomal dominant inheritance.

19.2.4 Group 4: Multifocal Pattern Dystrophy Simulating Fundus Flavimaculatus

Some patients develop multiple irregular or triradiate yellow lesions centrally or eccentrically, and in some cases these are widely scattered and partly interconnected in a triradiate fashion that may simulate those in fundus flavimaculatus (Stargardt’s disease) (Fig. 19-16). ^{103 ,​ 104 ,​ 105} These patients, who do not show fluorescein angiographic evidence of a dark choroid suggesting lipofuscin storage, have been recently reported as examples of dominantly inherited fundus flavimaculatus. Unlike most patients with fundus flavimaculatus, these patients have good visual acuity and a more favorable visual prognosis. However, some of these patients with an exaggerated phenotype can show progressive loss of the yellow material and RPE/photoreceptor thinning and atrophy resulting in islands of, or confluent, geographic atrophy (Fig. 19-17). Choroidal neovascular membranes can rarely occur. Histopathologic and electron microscopic studies of the eye of a patient with this type of pattern dystrophy have demonstrated that the flecks are not caused by abnormal lipofuscin storage. ¹⁰⁵