Experts

The following description of Best disease (Vitelliform macular degeneration) has been reprinted from: Saul C Merin, Inherited Eye Diseases, Diagnosis and Management, chapter 8 (Inherited Macular Diseases), New York, Taylor and Francis, 2005 (in press), by courtesy of the publisher: Taylor and Francis Group, LLC.
This is the most recent publication on this subject.

BVMD AND THE VMD2 GENE

Description and Clinical Findings

BVMD refers to an autosomal dominant, congenital disorder, typically Affecting the macula by displaying yellow cysts, good visual acuity, and abnormally Low EOG responses. The disease is progressive and usually leads to decreased visual Acuity later in life. In addition, many atypical cases occur, as the expressivity of the Gene is variable. Monocular affection has been rarely reported. The macular lesions have been noted to be present as carly as early as I week after birth (88), or they may appear later.

The classic macular lesions are frequently observed between the ages of 3 and 15 years, peaking around age 6 (9). Patients with a normal macula, who developed their first lesions later in life or than 15 years have also been observed. For descriptive and practical purposes, it is therefore

Table 3: Clinical Stages of BVMD

Percentages refeer to the number of patients thus affected among 47 palients with BVMD studied by Godel et al. (86). Soures Refs 9,87, and 86 [From Deutman (9). Mohler (87), and Godel et al (86).] Feasible to divide the clinical appearance of the disease into stages (9,86,87) (Table 3; T3 Fig 14). The visual acuity is normal or near normal in stages 0,1 and 2. Almost 74% of all patients with BVMD are in are these stages (86). It is only in stage 4, when atrophic changes take place, usually after age 40, that visual acuity may drastically reduced. In some instances, extramacular or multiple lesions were described.

They may be temporal to the macula, or superior to the disk (89). In some patients, fluctuating vision with transient visual loss was reported (96). Incases of pseudohypopyon the fluid may be seen shifting when the head is turned Sideways, indicating that the fluid is located between the RPE and the sensory retina (91).

The Clinical and Genetic Types

Classic BVMD

This is the classic disease, as described in (BVMD description and clinical findings). It is typified by the characteristic macular lesions, a persistent subnortnal EOG, Autosomal dominant heredity with variable expressivity, and progression through life. Hitner et al. (92) suggested calling this disease BVMD to distinguish it from two other types: atypical vitelliform macular dystrophy (AVMD) and pseudovitelli- form macular dystrophy (PVMD).

The BVMD – causative gene was assigned in 1992 to chromosome 11 q 13 (93, 94). Initially, the ROMI gene seemed the most likely candidate, as it was found to be Located at the same site 11 q 13. (95) However, it was later excluded (96) and the gene VMD2 with Best disease causing mutations was identified (97,98). All 15 mutations initially reported were missense mutation, such as Tyr93Cys, Tyr85His, Gly299Glu. Tyr227Asp, Thr6Pro. Scientists found evidence that VMD2 mRNA is heavily and exclusively expressed in the RPE (97,98). The gene encodes a 585 amino acid Protein of 68 kd.

This protein was named bestrophin (99). It was found to be localize to the basolateral plasma membrane of the RPE (100). Its function is still unknown. A large number of mutations, predominantly missense mutations in the VMD2 gene, were identified and reported (101-103). By 2000, 40-48 mutations and several polymorphisms were identified (102,103).

In all affected individuals a heterozygous mutation was identified, thus Confirming the autosomal dominant nature of the disease. One patient, carrying the same disease bearing mutation as his affected family members members, was asympto- Maric and showed no objective sign of BVMD (104).

Atypical Vilelliform macular Dystrophy (Adult Onset Foveomacular Dystrophy)

Hittner et al. (92) described a large family with five generations affected by this condition. Initially, small yellow lesions are scen in the macular area, sometimes preceded by minimal fluorescein angiographic changes in the from of hypofluores- cent sport. The lesions may show a continuum of appcarances, from tiny dots to a (a) Figure 14 The yellow cyst stage of BVMD: (a) vitelliform stage: round smooth cyst filled With yellow matcrial; (b) beginning of scrambled agg appearance- uneven distribution of yellow material; and (c) pscudohypopyon –yellow material at bottom of cyst and atrophy of RPE in center (c). The same aya as (b), 1I year later. (Courtesy of GA. Fishman, MD, Illinois Eye and Ear Infirmary, Chicago). Single yellow lesion with a typical fluorescein angiographic finding (105). The single Lesion is smaller than the usually seen in BVMD (106) – The single lesion is Usually solitary, oval, slightly elevated, yellowish, and subretinal. Fluoredcein is Blocked in this area (107). This condition was first reported by Gass, under the mame of "peculiar foveo- Macular dystrophy" (106). Gass suggested that it is transmitted by the autosomal Dominant mode. Various terms were used, such as pseudovitelliform macular Degeneration, foveomacular dystrophy (105,106,108), and others.

More recently, The terms used include AOFMD (109), adult- onset foveomacular pigment epithelial Dystrophy (110), and adult- onset foveomacular vitelliform dystrophy (107). The EOG of this atypical disease in contrast to that of BVMD , is normal or Moderately reduced (111). The age of onset is variable, but much later than in BVMD, usually between 30 and 40 (106,108). The prognosis of final visual acuity Seems poor (108), although the progression of the disease is variable. In one patient, This condition was in one eye and a butterfiy- shaped epithelial dystrophy was Seen in the other aya (112).

It was suggested that this condition may be more related To the pattern dystrophies than to BVMD (105,112). Studies by optical coherence tomography showed thickening of the RPE layer and accumulation of hyperreflective material located between the RPE and the neural retina. The autosomal dominant VMD or AOFMD was initially found to be Linked to the glutamate pyruvate transaminase locus (113), later localized to chromo some 8q24.3 and given the locus name of VMD-1. Later, such linkage was excluded (114). In some families and in sporadic cases of a typical VMD, a mutated gene Cannot be detected. In some families, mutations in the VMD2 gene were Identified (115).

More frequently mutations were identified within the RDS /peripherin gene (109). It was suggested that this condition may be more related the pattetn dystrophies than to BVMD (105,109,112). However, currently investigation exists to Distinguish between the two genotypes, and the only available method is to identify the existing mutation.

Pseudovitelliform Macular Dystrophy

The term PVMD should be used for one of two conditions: (1) a disease similar to Atypical vitelliform macular dystrophy, but sporadic and nonhereditary in nature, And (2) a macular degeneration from different causes, which clinically mimics vitelli Form macular dystrophy. Cases of vitelliform dystrophy with normal EOGs were described as separate entities in sporadic cases (115,116), and rarely even in inherited cases (192,105,106,108).

The clinical manifestation may be similar to those of typical BVMD. AOFMD is a term used for a heterogcnous group of diseases caused by one of two or three mutated genes. In other cases, it is associated with age-related macular degeneration (ARMD). Several maculopathies may mimic vitelliform dystrophy. The most frequent are Macular drusen (117): serous detachment of RPE with lipid or protein deposition] (117,118):sub retinal neovascularization, especially in young persons (119) who tend to respond with a yellow deposit (Fig.15): and basal laminar drusen, a recently defined clinical entity (120).

As with AVMD, the resemblance to the pattern dystrophies is often striking (121,122). Figure 15 Pseudovitelliform macular dystrophy in a 1/2 year-old girl with congenital Rubella syndrome: (a) clinical photograph of a macular cyst filled by a yellow materialand: (b) fluorescein angio showing subrelinal ncovasclarization.

The VMD2 Gene

Diagnosis and Laboratory Tests

The diagnosis of BVMD of BVMD is readily made by the combination of the typical ophthal Moscopic findings and an abnormally low EOG result. The diagnosis is confirmed by Familial occurrence, with ceal autosomal dominant transmission. Fluorescein angiography is characteristic.

The yellow material blocks choroidal Fluorescence. When atrophy occurs, as in the stage of pseudohypopyon, defects in the RPE cause sport of hypofluorscence, with a mottling appearance (91). With Progression of the disease, fluorescein angiography shows a sequence of changes that Parallel the clinical developments. Initially, tiny sports of hypofluorescence (transmission defects) are seen. In the vitelliform cyst stage, blockage of the choroidal fluorescence is noted: later, with the atropllic changes occurring in the RPE, more and More transmission defects are seen. In the final stage of secondary changes, the typimore transmission defects are seen. In the final stage of secondary changes, the typical appearance of a subretinal membrane of sub retinal neovascularization with Leakage is seen. ERG was reported as normal.

The foveal ficker fusion thresholds (foveal cone ERG) are abnormally elevated, even in patients with normal or near normal vision (125). EOG is the most important single test for BVMD, as it can distinguish between Disease and the atypical or pseudovitelliform variants. In the hereditary cases, the Light peak/dark trough ratio ( Arden ratio) is abnormally low, usually less than 1.55 (87). The Arden ration ia low before any morphologic changes take place and in carriers of the gene who never develop the clinical signs of the disease (126)- In AVMD, the results of the tests are different. The EOG is usually normal but sometimes moderately subnormal.

Fluorescein angiography shows a characteristic picture described as sports of hyperfluorescence (transmission defects) with a ring of hypofluorescence at the lesions (92) or spots of leakage from perifoveal capillaries around the macula, as in cystoid macular edema (108). In PVMD, the results of the various tests vary with the cause of the disease, Showing fot instance, a strong leakage (”hot sport") in cases of sub retinal neovascu Larization (see Fig. 15).

Pathology and Pathogenesis

Several histopathologic studies were performed in BVMD and related diseases. These attempted to answer the three questions as outlined by Cavender (127): What Is the yellow material? Where is it located? Where dies it originate? Kobrin et al. (128) examined an eye with relatively early BVMD and found that the RPE cells. Were engorged with cytosomes containing an abnormal unidentified substance. Such RPE cells may involute and become atrophic, with loss of central retinal function Resulting later.

Capillaries may invade the subretinal space through breaks in Bruch's membrane. Light and electron microscopic of an eye with The "scrambled-egg" lesion of a 28-year-old patient with BVMD, by Wcingeist Et al, (129), showed a heavy accumulation of lipofuscin granules within RPE cells (Fig.16), within macrophages in the subretonal space, and within the choeoid.

These authors that in the previtelliform stage the storage of lipofuscin In the RPE cells causes the decrease in the EOG, in the vitelliform stage, lipofuscin Accumulates heavily in the RPE cells and partially in the subretinal space. In later Stages, the disease may be predominately affected by alterations in the RPE, Disruption of the "egg yolks", scar formation, and breaks in Bruch's membrane. Frangieh et al. (130), examining an eye of an 80-year-old woman with BVMD, similarly concluded that the most pronounced abnormality is the accumula, Tion of an abnormal lipofuscin. In the macular area, RPE cells were flat Tened, with an average height of 10 nm (normal range, 10-14 nm), and average Figure 16 Electron micrograph of an eye a 28-year-old patient with the scrambled-egg Lesion diagnosed as BVMD: multiple lipofuscin granules are seen within the RPE cell (18,000) [From Weingeust et al. (129)].

Lnherited Macular Diseases

Diameter of 21.5 nm (normal 14 nm), and they contained a heavy deposition of an Abnormal lipofuscin and melanolipofuscin granules. Abnormal granular material Accumulated between neuroepithelium and RPE cells. An abnormal fibrillar material of unknown origin or nature wes found underneath the RPE in the most affected areas. Bruch's membrane had breaks, with blood vessels crossing through them.

The neural retina was severely affected, with most photoreceplor outer segments lost or degenerated and accumulation of acid mucopolysaccharides in the inner segments of the photoreceptors in the most affected areas. These studies seem to indicate that the yellow material is mainly formed by Lipofuscin or its products, that it accumulates mainly within the RPE cells and later In the subretinal space. It did not answer the question of the origin of the disease, Believed to be a malfunction of the RPE in one study (129) and a primary abnormality of the neuroepithelium in the other (130).

One study study confirmed the excessive amounts of lipofuscin accumulated in the RPE cells, a combination of regenerating RPE cells and lipofuscin granules producing the previtelliform lesion, and indicated the RPE layer as the primary sute of the disorder (131). In fact, both clinical and pathologic studies cinfirmed the nature of the deposits between RPE cells and neuroepithelium to be lipofuscin (97,98,110). Lipofuscin accumulates the RPE cells.

Different results were obtained in histopathologic studies of AVMD and PVMD. Gass, in the first reported such study (106), found that yellow zone Surrounding the central pigmented lesion corresponds to an area of thin and degg Nerated RPE cells separated from Bruch's membrane by an eosinophilic material. There was on intracellular deposit of any abnormal. In contrast, in a later Study of a condition they called "foveomacular vitelliform dystrophy, adult type," Patiently and coauthors (132) found intracellular deposition of lipofuscin pigment, Both in RPE cells and in intraetinal migratory macrophages.

The size of RPE cells was abnormal, and these flat pigmented epithelial cells were surrounded by tall hypertrophied cells. These findings were closer to the description of BVMD that those in the study by Gass (106). The variability of the pathologic findings in atypical vitelliform dystrophy stresses the heterogeneity of this condition.

Epidemiology and Genetics

The prevalence of B VMD is different in various popularions, according to the Prevalence of the gene. In Sweden 250 cases of BVMD were detected and traced to a single gene source in the 17 th century (133). These authors present the clinical findings in a homozygous father whose 11 children were heterozygous and affected. There were great variations in the phenotypic presentation of the gene.

The homozygous did not seem different the heterozygous state (133). BVMD is transmitted by a single by a single autosornal dominant gene, with high Pene trance and very variable expressivity for age of onset, clinical findings, progression of the disease, and final outcome. This statement is true for both BVMD and AVMD. It was shown in the large family described by Nordstrom as the Villbelmina Type (134) and in many publications on smaller families.

The locus for AVMD was tentatively assigned to the short arm of chromo Some 16 when linkage to the soluble glutamate pyruvate (GP) transaminase was Suggested (113) A later study demonstrated tight linkage between VMD-1, the Gene for AVMD and GPD, and a possible loose linkage between BVMD and GPD (135). The authors concluded that BVMD and atypical vitelliform dystrophy could be either allelic mutations separate genetic, and that atypical viteliform dystrophy should provisionally be assigned to chromosome 16-pter-p11 (135). As mentioned earlier, both the locations and linkages not confimed and Were, in fact, excluded. However, VMD2 mutations are the cause of classic BVMD and of some or many or many of cases of AVMD or adult onset foveomacular dystrophy

Management

Surgical and Medical Management

Genetic Counseling

Genetic counseling should be based on the assumption that BVMD and AVMD are Caused by an autosomal dominant gene, whereas PVMD is sporadic. If the transmis Sion is in doubt, all available first- degree should be examined and have an EOG test, as sometimes minor macular abnormalities or subnormal EOG will be the proof for the dominant transmission.

The variable expressivity and the prolcaged course should be mentioned to the patient. Identification of the causative gene and its mutation is important as VMD2 is not the only gene which may cause the disease. Prenatal Diagnosis Prenatal diagnosis is possible for vitelliform dystrophies once the mutated gene of The family is identified.

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