PART 6 RETINA AND VITREOUS

SECTION 4 Dystrophies

Macular Dystrophies

Steven N. Truong, Kimberly Dresner, David G. Telander, Lawrence S. Morse and Kent W. Small

6.11

Definition: The process of premature retinal cell aging and cell death,
generally confined to the macula, in which no clear demonstrable extrinsic cause is evident, and a heritable genetically determined enzymatic defect is implicated.

to give the patient the best genetic counseling and advice on visual prognosis. No treatment is available for the disorders discussed in this chapter. Treatments to halt the progression of choroidal neovascularization may be beneficial, including laser therapy and drugs that inhibit vascular endothelial growth factor (VEGF). In this chapter the focus is specifically on macular dystrophies not associated with other systemic abnormalities.

Key features
n n n

 ellowish material within or beneath the retinal pigment epithelium. Y Loss of macular photoreceptors and retinal pigment epithelial cells.  Loss of central vision. 

STARGARDTS DISEASE AND FUNDUS FLAVIMACULATIS EPIDEMIOLOGY AND PATHOGENESIS

Usually, Stargardts disease is inherited as an autosomal recessive trait; however, affected families that have autosomal dominance have been described.1 Stargardts disease is the most prevalent inherited macular dystrophy and accounts for roughly 7% of all retinal dystrophies. The autosomal recessive form of the disease was mapped to the short arm of chromosome 1.1, 2 An adenosine triphosphate-binding cassette, the ABCR gene (now called ABCA4), has been identified as the causative gene. This photoreceptor-specific gene is localized to chromosome 1p21-22.34 Fundus flavimaculatus and Stargardts disease are now known to be allelic. However, only about 60% of patients with these diseases have a detected mutation in this gene. This locus has also been implicated in age-related macular degeneration, autosomal recessive retinitis pigmentosa and autosomal recessive conerod dystrophy.4, 5 These ABCA4-related dystrophies may manifest as a spectrum of phenotypes, with overlapping or incomplete forms. In fact, autosomal recessive Stargardts disease itself exhibits great variability in clinical expression.68 A knock-out mouse model of Stargardts disease has been created.2 The heterozygous mouse also has an accumulation of lipofuscin, supporting the role of ABCA4s in age-related macular degeneration. Autosomal dominant Stargardts disease originally was mapped to chromosome 13 as STGD2. This was found to be in error, and dominant Stargardts disease maps to chromosome 6q16.6 in association with the mutation found on the ELOVL4 gene.1 Several different mutations in this gene, which codes for a photoreceptor-specific membrane-bound protein that plays a role in long chain fatty acid biosynthesis, have been implicated.9 Autosomal dominant Stargardts and several other retinal diseases map to chromosome 6, including recessive retinitis pigmentosa, Leber congenital amaurosis, dominant conerod dystrophy, North Carolina macular dystrophy, early onset dominant drusen, and progressive bifocal chorioretinal atrophy.10, 11

Associated features
n n n n

 eural retinal, retinal pigment epithelial, and choroidal atrophy N commonly limited to the macula. Bulls-eye appearance seen rarely.  Pigment clumps in the posterior pole, midperiphery, or far  periphery seen rarely. Optic atrophy, retinal vascular attenuation, macular edema,  and choroidal neovascularization seen rarely.

INTRODUCTION
The intricate anatomy of the retina is paralleled, perhaps, only by its complex physiology. Certainly, to have such a well-orchestrated, formfollowing function, many genes must be involved in the development of the macula. Modern genetics has helped to identify a few genetic defects implicated in some of the various macular dystrophies. This information can be found at several websites including the following: Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim) or the Laboratory for the Molecular Diagnosis of Inherited Eye Diseases (http://www.sph.uth.tmc.edu/RetNet). Unfortunately, until more information is available as to which genetic problem leads to a specific macular dystrophy, classification of the various disorders will not be perfect. Many of the disorders exhibit histological abnormalities in all layers of the neural retina, retinal pigment epithelium (RPE), and choroid. Different genetic disorders may have overlapping phenotypes and, in the end stages, many diseases can appear identical. Conversely, the same genetic abnormality may show different phenotypes, even within the same pedigree. Table 6-11-1 illustrates how molecular genetic approaches using candidate genes and positional mapping strategies has allowed us to better characterize various macular dystrophies and to better understand how specific gene defects can lead to a specific phenotype with variable expressivity. Table 6-11-2 emphasizes the retinal cellular localization of various macular dystrophies. Therefore, to determine a specific macular dystrophy, a constellation of clinical characteristics and ancillary tests must be relied upon. Most macular dystrophies share the clinical manifestation of accumulated yellowish material within the macular region. The course of each particular disease, however, can be quite different. Therefore, it is important to differentiate clinically among the disorders to be able

OCULAR MANIFESTATIONS AND DIAGNOSIS

The term fundus flavimaculatus is used when the characteristic flecks that accumulate at the level of the RPE are distributed throughout the fundus and onset is in adulthood. The term Stargardts disease is applied when the flecks are confined mostly to the posterior pole and are present early in life. An accumulation of discrete pisciform flecks at the level of the RPE is a hallmark of the disease (Fig. 6-11-1).12, 13 The distribution of the flecks and the time of their appearance can vary, but the flecks seen in Stargardts disease are found mostly at the posterior pole and macula. Patients often may have minimal ophthalmoscopic abnormalities early in the disease, but later many flecks, along with patches of central

560

 Table 6-11-1 Macular Dystrophy Candidate Genes

Cellular Location RPE specific Retinal Dystrophy AD Bests AD Sorsbys macular dystrophy Malattia leventinese (Doyne honeycomb macular dystrophy) Rod specific Cone specific Conerod specific AD Stargardts macular dystrophy AD Cone dystrophy AR Stargardts AD adult foveal macular dystrophy Chromosome 11q12.3 22q12.3 2p16 6q14 6p21.1 1p22.1 6p21.2 Gene VMD2, Bestrophin (chloride channel) TIMP-3 (tissue inhibitor of metalloproteinase) EFEMP1 (EGF-containing fibrillin-like extracellular matrix protein 1) ELOVL4 (photoreceptor-specific elongation of very long chain fatty acids) GUCA1A (guanylate cyclase activator 1A) ABC4 (ATP binding cassette protein found in rods and foveal cones) RDS/peripherin (cone and rod outer segment glyco-protein in disc membranes for structural integrity)

6.11
Macular Dystrophies

Table 6-11-2 Macular Dystrophies And Genes

Dystrophy Stargardts disease Stargardts disease (butterfly pattern dystrophy) Bests disease Adult vitelliform outer dystrophy Sorsby mascular dystrophy Malattia leventinese (Doynes dystrophy) North Carolina mascular dystrophy Cone dystrophy
(Modified from Voo & Small. Retina. 2004.)

Inheritance AR AD AD AD AD AD AD AD, AR, mitochondrial, X

Chromosome 1p22.1 6q14 (STGD3) 11q12.3 (VMD2) 6p 22q12.3 2p16 6q (MCDR1) Multiple genes (CORD1-8), multiple chromosomes

Gene ABCR or ABCR4 (ATP-binding cassette transporter in rod and cone outer segments) ELOVL4 (photoreceptor-specific membrane-bound protein for elongation of very-long-chain fatty acid) Bestrophin (chloride channel) Peripherin/RDS (cone and rod segment glycoprotein in disc membranes for structural integrity) TIMP-3 (tissue inhibitor of metalloproteinases) EFEMP1 (EGF-containing fibrillin-like extracellular matrix protein 1) Not identified

The electroretinogram findings are normal early but may be reduced moderately in more advanced cases. However, these ERG findings are varied and do not directly correlate with clinical findings.16 Also, the electro-oculogram (Arden ratio) may be reduced mildly when there are extensive RPE changes. Patients who have Stargardts disease can exhibit delayed dark adaptation. The differential diagnosis of Stargardts disease and fundus flavimaculatus is given in Table 6-11-3. Atrophic changes in the photoreceptors and disruption of foveal retinal pigment epithelium are demonstrated on ultrahigh resolution optical coherence tomography. Lipofuscin deposits could be detected within the parafoveal retinal pigment epithelium.17 Determining the status of the photoreceptor layer on OCT may provide an assessment of central visual function.18

PATHOLOGY
Fig. 6-11-1 Stargardts disease.

atrophy, can develop. In other patients, particularly those who have fundus flavimaculatus, peripheral flecks only may be seen with a macula of a reasonably normal appearance. Geographical, atrophic RPE patches often coalesce to give the macula a beaten bronze appearance. The most characteristic finding on fluorescein angiography is the phenomenon known as the dark or silent choroids, which appears as a prominent retinal circulation against hypofluorescent choroids. Although this finding helps to make the diagnosis, it is not seen in up to one fourth of the cases of Stargardts disease.14 The flecks, themselves, do not stain with fluorescein. Stargardts disease also exhibits autofluorescence, an index of lipofuscin content in the retinal pigment epithelium. The autofluorescence patterns may relate to photoreceptor functional abnormalities.15

Pathological evaluation shows an accumulation of lipofuscin-like pigment throughout the RPE, although its origin and significance remain unknown19 (Fig. 6-11-2). The mouse model (abcr/) also has accumulation of a lipofuscin material, the toxic bis-retinoid, N-retinylidene-N retinylethanolamine (A2E) suggesting a significant role in the pathophysiology of the disease.2

TREATMENT, COURSE, AND OUTCOME

Tremendous variability occurs in course and outcome among the various pedigrees and even within individual families. Decreased visual acuity is the main symptom and may appear as early as the first decade or much later in middle age. The visual acuity ranges between 20/50 and 20/200, depending on the degree of macular atrophy. Most patients retain a visual acuity of

561

6
RETINA AND VITREOUS

between 20/70 and 20/100 in at least one eye. The prognosis is worse for patients with fundus flavimaculatus, and the duration predicts the severity more accurately.13, 14, 20 Less commonly, patients who have severe peripheral atrophy manifest visual field loss that may be difficult to differentiate from a rod-cone dystrophy. Rare cases of late-onset fundus flavimaculatus and choroidal neovascularization have been reported.21

Table 6-11-3 Differential Diagnosis Of Macular Dystrophies

Disease Stargardts disease and fundus flavimaculatus Bests disease and vitelliform dystrophy Adult vitelliform degeneration Differential Diagnosis Cone dystrophy Neuronal ceroid lipofuscinosis Pattern dystrophy Age-related macular degeneration Pattern dystrophy Bests disease Pattern dystrophy Age-related macular degeneration Flecked retinal syndromes Sorsbys fundus dystrophy Age-related macular degeneration Dominantly inherited retinitis pigmentosa with cystoid macular edema X-linked juvenile retinoschisis Goldmann-Favre syndrome Toxoplasmosis Age-related macular degeneration Atrophea areata North Carolina macular dystrophy Myopic macular degeneration Serpiginous choroiditis Peripapillary pigment epithelial dystrophy Angioid streaks Progressive bifocal chorioretinal atrophy Myopic macular degeneration Stargardts disease hereditary optic atrophies Toxic maculopathy Sorsbys fundus dystrophy North Carolina macular dystrophy Angioid streaks Stargardts disease Cone dystrophy Progressive bifocal chorioretinal atrophy Serpiginous choroiditis Acute multifocal placoid pigment epitheliopathy

As with all the retinal dystrophies, no known treatment exists for the disease. Because ABCA4 is involved in vitamin A processing within the photoreceptors, it is suspected that vitamin A supplements might make the disease worse. Therefore, the author does not recommend vitamin A or B-carotene supplements.22 A recent study by Hubbard et al. revealed that dietary factors could influence phenotypic expressions of ELOVL4associated macular dystrophies. Patients with the autosomal dominant form could potentially benefit from supplemental polyunsaturated fatty acids such as decosahexanoic acid and eicosapentaenoic acid. Lastly, a report by Radu et al. suggested that accutane treatment may reduce the A2E toxic by-product that accumulates in this disorder. However, the doses are likely too toxic for human use but are potentially therapeutic in the mouse model.

BESTS DISEASE AND VITELLIFORM DYSTROPHY EPIDEMIOLOGY AND PATHOGENESIS

Bests disease is extremely rare the actual incidence is unknown. The disease is autosomal dominantly inherited and shows highly variable clinical expression and penetrance. Furthermore, some individuals who carry the defective gene have completely normal vision and fundus examination findings.23 Such individuals have been referred to as carriers of Bests disease, but this is a misnomer. The gene for Bests disease was mapped to chromosome 11q13 and mutations found in the bestrophin (VMD2) gene. This gene encodes for a transmembrane protein that acts as a putative ion exchanger.2426 The protein, expressed in the RPE, modulates voltage-dependent calcium channels. Several mutations within the bestrophin gene have been identified and are associated with both Bests and adult vitelliform diseases.27 In fact, Bests disease probably represents a spectrum of diseases with great variability in expression, even among single families.

Familial (dominant) drusen

Dominant cystoid macular edema

North Carolina macular dystrophy Progressive bifocal chorioretinal atrophy

Atrophea areata

OCULAR MANIFESTATIONS AND DIAGNOSIS

Bests disease is typified by a large, yellow, yolk-like (vitelliform) lesion (Fig. 6-11-3) that is bilateral and symmetrical in the central macula and appears during childhood. The diameter of the lesion is in the range 15mm. Later in life, the lesion breaks down, with resultant scarring and atrophy. Late lesions often are difficult to diagnose correctly on the basis of their clinical appearance alone. Less commonly, the lesions may be multifocal.28 Choroidal neovascularization can arise adjacent to old vitelliform scars.29 Early in the disease process, vitelliform dystrophy has such a characteristic egg yolk appearance that the diagnosis is not difficult to make. In longstanding cases, or when a fundus of normal appearance is seen, the definitive diagnosis is made on the basis of abnormal electrooculogram findings. Specifically, a severe loss of the light response of the standing potential occurs. All affected individuals, whether they have funduscopic manifestations or not, have a light-to-dark (or Arden) ratio of less than 1.5 and frequently near 1.1. For this reason, the electrooculogram is used to evaluate individuals who have a poorly defined macular lesion.

Cone degeneration (dystrophy)

Central areolar choroidal dystrophy

562

Fig. 6-11-2 Stargardts disease (fundus flavimaculatus). Note the fluorescein effect caused by enlarged lipofuscin-containing retinal pigment epithelial cells, which act as a fluorescent filter.

Fig. 6-11-3 Bests disease. Typical vitelliform lesion from an 11-year-old girl. (Courtesy of Ola Sandgren, University Hospital of Ume, Sweden.)

Electroretinographic studies show a reduced C wave but are therwise normal. This is the only disease with relatively normal o electroretinographic results associated with abnormal electro-oculo graphic findings. The differential diagnosis is shown in Table 6-11-3.

PATHOLOGY
Histopathological studies show an accumulation of lipofuscin-like material throughout the RPE.3032 Unfortunately, no histological stud ies describe the yolk-like lesion seen early in the disease. Interestingly, despite the accumulation of lipofuscin-like material in the RPE, no dark choroids effect is seen on fluorescein angiography. Furthermore, decreased visual acuity results from atrophy and scarring in the macula, not from accumulated material in the RPE.

be reduced. By definition, adult vitelliform macular dystrophies have a presumed adult onset, although this has not been well documented in most reports. The differential diagnosis is given in Table 6-11-3. In addition, recent studies using optical coherence tomography (OCT) have suggested that the absence of subretinal fluid differentiates adult vitelliform dystrophy from Bests disease.35 It should be noted that VMD1 (also called atypical vitelliform macular dystrophy) no longer exists as a genetic locus and probably as a disease entity. The original mapping of VMD1 to a chromosome 8 locus has been shown to be excluded by newer, more informative genetic markers.36

6.11
Macular Dystrophies

PATHOLOGY
Histopathological analyses of these patients eyes have demonstrated damage at the level of the RPE. Focal loss of the photoreceptors overlies atrophic RPE cells in the fovea. Pigmented material is seen to lie between the retina and Bruchs membrane. OCT images localize the vitelliform lesion to the highly reflective photoreceptorRPE complex.36 Gass34 found no abnormal accumulation of lipofuscin in RPE cells. Patrinely et al.,30 on the other hand, found high concentrations of lipofuscin in RPE cells and postulated that this accumulation is responsible for the foveal lesion. This is further supported by findings of high levels of fundus autofluorescence seen with this dystrophy.37

TREATMENT, COURSE, AND OUTCOME

The age of onset and expression of Bests disease is variable. For most individuals, manifestation of the disease occurs in childhood; however, occasionally onset is in adulthood. Adult Bests disease represents one manifestation in a spectrum of diseases with variable expressivity. The visual acuity usually is good when the yolk remains intact. The vision drops, however, once scarring begins.28 Although acuity can decrease to the 20/200 range, most patients retain enough vision in at least one eye to read and drive. Choroidal neovascular membrane (CNVM) formation is infrequent but may arise from an old scar.28

TREATMENT, COURSE, AND OUTCOME

The onset of these disorders usually is during the fourth to sixth decade, with visual symptoms generally limited to metamorphopsia or mildly blurred vision. However, rare cases of CNVM complicating the disease course have been reported.38 The overall prognosis of adult vitelliform dystrophy is similar to that of Bests disease, in that as the yolk-like accumulations break down, atrophy and gliotic scarring occur, leading to decreased visual acuity. It is important to distinguish adult vitelliform dystrophy from Bests disease because of the potential genetic implications and need for appropriate genetic counseling.

ADULT VITELLIFORM DEGENERATION EPIDEMIOLOGY AND PATHOGENESIS

This rare dystrophy usually does not have a discernible inheritance pattern. Some patients with adult foveomacular dystrophies, however, have an autosomal dominant trait with mutations in the peripherin/ RDS gene.33 Mutations in the bestrophin gene, VMD2, have also been associated with adult vitelliform degeneration.24 Some authors consider the foveomacular dystrophy to be a variant of the pattern dystrophies (see later).

FAMILIAL DRUSEN EPIDEMIOLOGY AND PATHOGENESIS

Familial (dominant) drusen is a rare autosomal dominant disease with variable expression and age-dependent penetrance.39 A mutation from an arginine to a tryptophan at amino acid 345 in the EFEMP1 gene, mapped to chromosome 2p16-21, has been associated with both Doynes and malattia leventinese, which are, therefore, the same disease.40 The function of the EMEMP1 gene has not been determined; however, it has been shown to accumulate in beneath the RPE in drusen associated with these dystrophies, but not in those associated with agerelated macular degeneration.41 Another locus on chromosome 6q14 adjacent to the conerod dystrophy gene (CORD7) and the North Carolina dystrophy gene (MCDR1) has been identified, also, in those with dominant drusen.4244 However, these cases are more consistent with North Carolina macular dystrophy with only drusen present and were misdiagnosed as dominant drusen. The various phenotypic patterns have resulted in a number of different names in the older literature, such as Doynes honeycomb dystrophy, malattia leventinese, and guttate choroiditis. This disease is thought to arise from an inborn error of metabolism localized to the RPE. One hypothesis is that the defect is in an intercellular matrix protein or a structural protein, which leads to the development of abnormal basement membranes. Although diffuse drusen often are described as being inherited dominantly, to identify a significant family history is difficult because affected individuals usually are not recognized until middle age, when other potentially affected family members are very old or deceased.

OCULAR MANIFESTATIONS AND DIAGNOSIS

Affected individuals show symmetrical, yellowish foveal deposits that resemble the lesions of Bests disease but are smaller (Fig. 6-11-4). The phenotype can vary from small yolks as seen in adults who have widespread, fine, cuticular drusen, to only subtle accumulations of yellowish material in the central fovea. Examples of the adult vitelliform degenerations include foveomacular dystrophy of Gass, and adults who have coalescent, widespread, cuticular drusen that form vitelliform lesions in the macula.34 These disorders usually are distinguished from Bests disease on the basis of a normal or only minimally reduced electro-oculogram (Arden ratio <1.7). The fullfield electroretinogram is normal, but the foveal electroretinogram may

OCULAR MANIFESTATIONS AND DIAGNOSIS

Fig. 6-11-4 Adult vitelliform degeneration. (Reproduced with permission from Feist RM, White MF Jr, Skalka H, Stone BM. Choroidal neovascularization in a patient with adult foveomacular dystrophy. Am J Ophthalmol. 1994;118:25960.)

Patients exhibit widespread drusen that extend beyond the macula, in a pattern distinct from age-related drusen (Fig. 6-11-5).45 Typically, diffuse drusen extend peripherally to the macula and involve retina nasal to theoptic disc. The drusen, themselves, may be large and sparse or form a constellation of tiny dots, called cuticular or basal laminar

563

6
RETINA AND VITREOUS

Fig. 6-11-5 Familial drusen. (Reproduced with permission from Evans K, Gregory CY, Wijesuriya SD, et al. Assessment of the phenotypic range seen in Doyne honeycomb retinal dystrophy. Arch Ophthalmol. 1997;115:90410.)

Fig. 6-11-6 Pattern dystrophy.

rusen. Sometimes, basal laminar drusen coalesce to form a vitelliform d lesion.46 The drusen usually first appear around the third or fourth decade of life and become quite numerous by middle age. In the late stages, pigmentations occur, along with atrophy of the RPE, choriocapillaris, and large choroidal vessels. Flecks in this disorder are whiter and more sharply delineated than those in fundus flavimaculatus. Fluorescein angiography often highlights atrophy of the RPE, and the drusen appear more extensive than seen clinically. In advanced cases, a central scotoma is seen on visual field examination. Optical coherence tomography reveals a thickening and occasional elevation of the RPE Bruchs membrane complex.47 Dark adaptation is usually normal, as are the electroretinographic findings.48 The electro-oculographic findings are normal in the initial stages, but they become subnormal depending on the degree of macular involvement. Familial drusen also exhibit fundus autofluorescence.49 The differential diagnosis is shown in Table 6-11-3.

most patients who have pattern dystrophy do not have mutations in the peripherin gene. Current hypotheses as to how mutations in the peripherin protein result in the disease suggest that the abnormal peripherin molecules, which normally are present in photoreceptor outer segments, interfere with RPE metabolism after phagocytosis of the outdated outer-segment material.

OCULAR MANIFESTATIONS AND DIAGNOSIS

This heterogeneous group of disorders is characterized by reticular pigmentation at the level of the RPE.55, 56 Yellow flecks and drusen typically are not found. The clinical phenotypes often take on a characteristic pattern (Fig. 6-11-6) and, thus, some of these disorders have acquired descriptive names such as butterfly dystrophy. Often, no specific pattern exists, and many individuals within affected families have different patterns of pigmentation. Sjgrens reticular dystrophy, an autosomal recessive-pattern dystrophy, is characterized by a network of pigmented lines that surround the macula. Butterfly dystrophy, on the other hand, can be autosomal dominant and demonstrates pigment deposits that radiate from the fovea in the pattern of butterfly wings. However, we now recognize the error of splitting these diseases based on such findings as a butterfly shape of pigment in a single individual when findings in other family members have a different appearance. Less commonly, yellowish deposits similar to those found in foveomacular dystrophy or Stargardts disease are seen. The diagnosis often is based on the characteristic findings discovered on ophthalmoscopy or angiography, as described above. Electrophysiological testing results usually are normal, but a borderline electrooculogram result is consistent with a diffuse RPE disorder. Late in the disease, the electroretinogram result may be mildly subnormal as a result of diffuse damage to the photoreceptors.

PATHOLOGY
Histopathological examinations show round accumulations of hyaline in the pigment epithelium that are continuous with the inner layer of Bruchs membrane. The choroids and neural retina may show atrophy later on, although they appear normal in the earlier stages of the disease.

TREATMENT, COURSE, AND OUTCOME

No known effective treatment exists for diseases in this category. If CNVM ensues, laser treatment may stabilize vision, but rarely. As long as the drusen are relatively discrete and do not affect the fovea markedly, central vision usually is good. Some suggestions exist that affected patients may be at greater risk for degenerative changes in the macula as a result of aging. When basal laminar drusen coalesce to form a vitelliform cyst, a marked degradation in visual acuity can occur if the yolk degenerates into an atrophic scar. CNVM may occur occasionally.

PATHOLOGY
To the authors knowledge, a histological study has not been performed for this disease, but it is thought to be a primary abnormality of the RPE in the macula.56

PATTERN DYSTROPHY EPIDEMIOLOGY AND PATHOGENESIS

The incidence of the pattern dystrophies is unknown; however, they are fairly rare. A number of hereditary patterns are documented. Some autosomal dominant forms of the disease are associated with several different mutations in peripherin, a retinal protein encoded by a gene located on chromosome 6p.5052 This peripherin/RDS is a transmembrane glycoprotein localized to the rim region of outer segment disks, and play a role in the structural integrity of the photoreceptors. Most of the reported mutations involve coding regions; however, splice site mutations have recently been implicated in pattern dystrophy as well.51 Interestingly, some forms of retinitis pigmentosa (RP), as well as other macular dystrophies (such as the adult foveomacular dystrophy of Gass), are attributed to mutations in this same protein.53, 54 Within a family, some affected patients may manifest RP , while others phenotypically appear to have a macular dystrophy. Some patients with butterfly dystrophy have a mutation located at the peripherin/RDS gene, although

TREATMENT, COURSE AND OUTCOME

The usual initial symptom is slightly diminished visual acuity or mild metamorphopsia. However, many patients who have the disorder are asymptomatic and disease is discovered during routine ophthalmoscopy. Visual acuity usually is good through the first five or six decades of life. The prognosis for maintaining good visual acuity is excellent, except in those patients who develop geographical macular atrophy, which mimics age-related macular degeneration, in old age. A small risk exists of developing choroidal neovascularization later in life.

DOMINANT CYSTOID MACULAR EDEMA EPIDEMIOLOGY AND PATHOGENESIS

This is an extremely rare autosomal dominant disease that was mapped to chromosome 7q using linkage analysis.57 Interestingly, autosomal dominant RP , known as RP9, also maps to this region.

564

In contrast to other diseases that affect the macula, this disorder appears to be unique in that the inner nuclear layer of the retina is the site primarily affected. Mllers cells are the specific cellular constituents thought to be involved, based on histopathological evidence.

6.11
Macular Dystrophies

OCULAR MANIFESTATIONS AND DIAGNOSIS

Ophthalmoscopy reveals multilobulated cysts in the macula. Later in the course of the disease, macular disease of an atrophic appearance develops. Peripheral pigmentary changes may be present. Ancillary testing with fluorescein angiography shows capillary leakage, with petaloid dye accumulation in the macula. Electrophysi ology shows normal electroretinographic findings, but subnormal electro-oculographic light peak-to-dark trough ratios have been found, and abnormal dark-adaptation studies have been documented. The differential diagnosis is given in Table 6-11-3.

Fig. 6-11-7 North Carolina macular dystrophy. Macular coloboma in an 18-year-old woman with visual acuity of 20/40 (6/12).

PATHOLOGY
Histopathological studies demonstrate macular cysts, disorganized and gliotic inner nuclear layer, focal Mllers cell necrosis, epiretinal membrane formation, and abnormal deposition of basement membrane in the perivascular space. Degenerative changes also have been seen in the RPE and photoreceptors of the macula.58 Histopathological features seen in dominantly inherited cystoid macular edema, namely the involvement of Mllers cells, are quite different from those features seen in cystoid macular edema secondary to other causes.

PATHOLOGY
Light and electron microscopic studies show lipid-containing deposits between the basement membrane and the pigment epithelium and the inner collagenous layers of Bruchs membrane.67

TREATMENT, COURSE, AND OUTCOME

Patients typically develop bilateral CNVM at an early age. Severe loss of central visual acuity results from extensive macular scarring related to the CNVM. Attempts at laser treatment have had poor results. Peiretti et al.68 reported a single case successfully treated with combined photodynamic therapy with Visudyne and intravitreal triamcinolone acetonide. Later, vision can decrease to light perception only. Nyctalopia also is a symptom late in the course of disease.66

TREATMENT, COURSE, AND OUTCOME

Patients first begin to notice decreasing visual acuity at about 30years of age, with slowly progressive worsening to a moderate or severe level years later. Advanced cases have maculae of atrophic appearance, with window defects seen on fluorescein angiography. As in all the macular dystrophies, no known effective treatment exists.

NORTH CAROLINA MACULAR DYSTROPHY EPIDEMIOLOGY AND PATHOGENESIS

North Carolina macular dystrophy is an autosomal dominant macular degeneration first discovered in a large family in North Carolina, after which the disease was inappropriately named. It has a rare incidence but is found worldwide in over 25 families (Small, personal communication). Several separate affected families have been discovered in the United States, Europe, and Central America. This disorder is now known as MCDR1 (macular dystrophy, retinal subtype, first one mapped). Linkage analysis of the large family from North Carolina mapped the diseased gene to chromosome 6q16.69 Further genetic analysis reveals that families reported to have central areolar pigment epithelial dystrophy and central pigment and choroidal degeneration are branches of the same family from North Carolina.70 Indeed, reports of various branches of the single family from North Carolina have resulted in this one disease being given seven different names during the last 25years. Again, lumping diseases has proven to be more accurate than splitting. Recently, two phenotypes resembling North Carolina macular dystrophies have been described whose linkage analyses mapped the disorders to chromosomes 5 and 14.71 In the latter phenotype, the ocular findings were associated with progressive sensorineural hearing loss.

SORSBYS MACULAR DYSTROPHY EPIDEMIOLOGY AND PATHOGENESIS

This is an extremely rare, dominantly inherited disorder, with many clinical similarities to age-related macular degeneration. A gene for Sorsbys dystrophy that codes for a tissue inhibitor metalloproteinase, TIMP-3, has been identified. TIMP-3 has been cloned and linked to chromosome 22.59, 60 Several mutations of TIMP-3 have been identified in patients with Sorsbys dystrophy.61, 62 The gene product is an important enzyme in the regulation and composition of the extracellular matrix and is critical for wound healing, bone adaptation, and organ hypertrophy. TIMP3 has a second function, one independent of its MMP-inhibitory activity. TIMP3 encodes a potent angiogenesis inhibitor by blocking the binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2. Studies have shown that TIMP3 overexpression suppresses primary tumor growth and metastasis.63 This enzyme is expressed in the RPE.64 EFEMP1, whose mutated gene is responsible for malattia leventinese, was discovered as a strong interacting protein with TIMP3. Both these dystrophies have similarities to age-related macular degeneration. This suggests the possibility of a common pathogenetic mechanism for these different forms of macular diseases. A knock-out mouse model of Sorsbys has been created.65 The model features changes in Bruchs membrane and the RPE that may represent the primary clinical manifestations of Sorsby.

OCULAR MANIFESTATIONS AND DIAGNOSIS

The most striking feature in about one third of affected individuals is a macular coloboma (Fig. 6-11-7), with well-demarcated atrophy of the RPE and choriocapillaris. A highly variable phenotypic expression occurs from family member to family member. Some individuals express only a few drusen, while others have disciform scars of the cen tral macular area. CNVM can occur. The electroretinogram and electrooculogram results are normal, as is color vision. As expected, multifocal ERG recordings revealed significant amplitude reductions in the central retina.72 The differential diagnosis is given in Table 6-11-3.

OCULAR MANIFESTATIONS AND DIAGNOSIS

Early in the disease process, several very fine drusen or a large confluent plaque of yellowish material may be noted beneath the central RPE. Then, typically at around 40years of age, patients develop bilateral exudative maculopathy, which leaves heavily pigmented macular scars and areas of geographical atrophy.66 The electroretinogram and electro-oculogram results usually are normal, but decreased photopic and scotopic electroretinographic amplitudes can be seen late in the disease.

PATHOLOGY
Recently, Small et al.73 have studied the histopathology of a mildly affected family member who had bilaterally symmetrical confluent drusen in the central macula. Light microscopy demonstrated a discrete

565

6
RETINA AND VITREOUS

Fig. 6-11-8 Progressive bifocal chorioretinal atrophy. (Reproduced with permission from Godley BF, Tiffin PA, Evans K, et al. Clinical features of progressive bifocal chorioretinal atrophy: a retinal dystrophy linked to chromosome 6q. Ophthalmology. 1996;103:8938.)

Fig. 6-11-9 Atrophia areata in a 37-year-old man. (Courtesy of Fridbert Jonasson, University Department of Ophthalmology, Landsptalinn, Iceland.)

macular lesion characterized by focal absence of photoreceptor cells and RPE. Bruchs membrane was attenuated in the center of the lesion and associated with marked atrophy of the choriocapillaris. Adjacent to the central lesion, some lipofuscin was identified in the RPE.

TEAD1, may alter the expression of genes responsible for the structural and metabolic support of photoreceptors.77 This is in concordance with electrophysiological testing, which demonstrates normal photoreceptor, but abnormal RPE, function.

TREATMENT, COURSE, AND OUTCOME

The onset is congenital and nonprogressive. Visual acuity is usually much better than the appearance of the macula suggests. In general, vision is in the 20/20 to 20/200 range, with a median of 20/60. Some individuals may develop progressive worsening of vision secondary to CNVM.

OCULAR MANIFESTATIONS AND DIAGNOSIS

As with most inherited retinal diseases, atrophia areata is a bilateral, symmetrical maculopathy and has an early onset.76 Marked choroidal atrophy radiates from the optic disc, with two or more ring-shaped extensions that do not follow the major retinal vessels (Fig. 6-11-9). The choroidal vessels drop out in areas of atrophy. This disorder often is associated with high myopic astigmatism. Anterior polar cataracts sometimes are seen in affected persons. The funduscopic appearance is quite characteristic, particularly in advanced cases. Color vision usually is normal, and high myopia is a consistent feature. The differential diagnosis is given in Table 6-11-3.

PROGRESSIVE BIFOCAL CHORIORETINAL ATROPHY EPIDEMIOLOGY AND PATHOGENESIS

Progressive bifocal chorioretinal atrophy is a rare (reported only in the United Kingdom) degeneration that is inherited in an autosomal dominant fashion with complete penetrance. The pigment epithelium is thought to be the primary site of involvement. This disease has been mapped to a region overlapping MCDR1 on chromosome 6.74

TREATMENT, COURSE, AND OUTCOME

Chorioretinal atrophy begins in childhood and is slowly progressive throughout life. Young patients usually have good visual acuity, but a gradual decline occurs in central vision as macular atrophy ensues.

CONE DYSTROPHY EPIDEMIOLOGY AND PATHOGENESIS

Cone degenerations are a heterogeneous group of disorders characterized by an inherited selective degeneration of cone photoreceptor cells. The mode of inheritance is autosomal dominant in most described cases, but sporadic, sex-linked, and autosomal recessive forms occur as well. Small et al.78, 79 found a single large family from eastern Tennessee with autosomal dominant cone degeneration (designated CORD 5 by the Human Genome Organization) and mapped it to chromosome 17p12-13. A similar disease, CORD 6, was subsequently mapped nearby. Eventually, both CORD 5 and CORD 6 were found to be caused by the same mutations in retinal guanylate cyclase 1 (GUCY2D). Again, lumping is better than splitting. Mutations in the conerod homeobox (CRX) as well as the ABCR gene have also been associated with cone degeneration.6

OCULAR MANIFESTATIONS AND DIAGNOSIS

An initial focus of atrophic retina and choroid is seen temporal to the disc. The focus enlarges in all directions, and the temporal border typically has a serrated edge. Although the atrophy extends to the equator, it does not cross the vertical midline. Later in the disease process, a second nasal atrophic site appears that also slowly and progressively enlarges in all directions, but it also does not cross the vertical midline. The end-stage funduscopic appearance has the unusual image of two separate foci of chorioretinal atrophy, with an intervening segment of normal retina (Fig. 6-11-8). The diagnosis is made chiefly on the basis of the unusual clinical appearance.75

TREATMENT, COURSE, AND OUTCOME

Progressive bifocal chorioretinal atrophy usually is already present at birth and is progressive. Visual acuity loss corresponds to the level and proximity of chorioretinal atrophy of the fovea. Visual loss is usually severe and frequently nystagmus is found. No treatment is effective.

OCULAR MANIFESTATIONS AND DIAGNOSIS

Hallmarks of cone degeneration include the triad of progressive central acuity loss, color vision disturbances, and photophobia.74 Ophthalmoscopic findings can be highly variable. Fundus findings can range from a subtle, diffuse macular granularity only, to a well-demarcated, circular atrophic area in the macular region74 (Fig. 6-11-10). Special color vision testing with the Farnsworth-Munswell 100-Hue test or Hardy-Rand-Rittler plates almost always reveals variable degrees of dyschromatopsia. The electroretinogram is most useful for the definitive diagnosis.74 Full-field electroretinographic studies show selective diminution of the photopic B wave and decreased amplitudes of the 30Hz flicker. The dark-adapted rod responses, on the other hand, are

ATROPHIA AREATA EPIDEMIOLOGY AND PATHOGENESIS

Atrophia areata is a rare autosomal dominant disease reported only in Icelandic families. This disorder, also referred to as helicoid peripapillary chorioretinal degeneration or Sveinssons chorioretinal atrophy, has been mapped to chromosome 11p15.76 The encoded protein,

566

6.11
Macular Dystrophies

Fig. 6-11-10 Cone degeneration. (Reproduced with permission from Small KW, Gehrs K. Clinical study of a large family with autosomal dominant progressive cone degeneration. Am J Ophthalmol. 1996;121:112.)

Fig. 6-11-11 Central areolar choroidal dystrophy. (Courtesy of Giuliani Silvestri.)

usually normal or mildly attenuated. Focal macular electroretinograms show abnormally low amplitudes or an abnormal foveal-to-parafoveal ratio, which supports disease involvement of the cone photoreceptors. The electro-oculogram shows abnormalities in severe cases. Perimetry reveals full peripheral fields with bilateral central scotomata. The differential diagnosis is given in Table 6-11-3.

OCULAR MANIFESTATIONS AND DIAGNOSIS

The disease is characterized by late-onset of the phenotypic manifestations (midlife) with progression occurring over a 310-year period. It shows variable expressivity among family members.82 Fundus examination early in the course of the disease reveals nonspecific granular hyperpigmentation of the fovea, which is indicative of pigment epithelial dystrophy. Gradually, a sharply demarcated area of RPE atrophy with underlying loss of choriocapillaris leaves inter mediate and large choroidal vessels visible (Fig. 6-11-11). As the disease progresses, the macular atrophic area expands in a slow, centrifugal manner. This can appear clinically similar to CORD 5 findings. Fluorescein angiography early in the course of the disease shows background hyperfluorescence from RPE atrophy. When the choriocapillaris becomes lost, this hyperfluorescence disappears, and the intermediate and large choroidal vessels are outlined sharply. The margins of the lesion show hyperfluorescence because of leakage from choriocapillaris at the edges. The electroretinogram and electro-oculogram findings range from normal to severely abnormal.82 Multifocal ERG recordings show significant macular dysfunction that extends beyond the atrophic areas seen clinically.83, 84

TREATMENT, COURSE, AND OUTCOME

Typically, cone degenerations begin to manifest symptoms during the first or second decades of life. In contrast to other macular dystrophies, patients with cone degeneration experience color vision problems early in the course of the disease. Individuals with early symptoms tend to have a more severe manifestation of the disease. Visual acuity can range from 20/20 to hand movements. Patients experience progressive worsening of their disease with age.

CENTRAL AREOLAR CHOROIDAL DYSTROPHY EPIDEMIOLOGY AND PATHOGENESIS

Central areolar choroidal dystrophy is a rare autosomal dominant macular disease that has been mapped to chromosome 17p13.76, 78 Several genes map to this same region and may be potential candidates in the development of the disease; they include phosphatidylinositol transfer protein, retinal guanylate cyclase, -arrestin 2, pigment epithelium-derived factor, and recoverin. Several mutations to various loci in this region have been implicated in central areolar dystrophy.80 Interestingly, several other inherited retinal diseases have been mapped to chromosome 17p, including autosomal dominant cone dystrophy, Lebers congenital amaurosis, and autosomal dominant retinitis pigmentosa. A mutation in the peripherin gene on chromosome 6 also has been associated with central areolar choroidal dystrophy, linking it with the chromosome 6 retinopathies, as well.50, 80, 81 This disease appears to be a primary dystrophy of either the choroidal vessels or of the pigment epithelium, with secondary involvement of the choriocapillaris.

PATHOLOGY
Histological analysis of the affected area shows an atrophic, fibrosed area, with loss of RPE as well as photoreceptor cells and the underlying choriocapillaris.85 The rest of the retina and choroid is normal outside of the atrophic zone. The differential diagnosis is shown in Table 6-11-3.

TREATMENT, COURSE, AND OUTCOME

Patients begin to complain of symptoms of central vision loss during the third to fourth decades of life. Progressive atrophy leads to severe visual dysfunction and absolute scotoma formation by the seventh decade. Atrophy and fibrosis is noted in the avascular zone, although no arteriosclerosis is present. Some patients, however, may exhibit macular sparing with 20/20 visual acuity.

REFERENCES
1.  Donoso LA, Frost AT, Stone EM, et al. Autosomal dominant Stargardt-like macular dystrophy: founder effect and reassessment of genetic heterogeneity. Arch Ophthalmol. 2001;119:56470. 2.  Mata NL, Weng J, Travis GH. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCRmediated retinal and macular degeneration. Proc Natl Acad Sci U S A. 2000;97:71549. 3.  Allikmets R, Sing N, Sun H, et al. A photoreceptor cellspecific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15:23646. 4.  Maugeri A, Klevering BJ, Rohrschneider K, et al. Mutation in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. Am J Hum Genet. 2000;67:9606. 5.  Koenekoop R. The gene for Stargardt disease, ABCA4, is a major retinal gene: a mini review. Ophthalmic Genet. 2003;24:7580. 6.  Fishman GA, Stone EM, Grover S, et al. Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Arch Ophthalmol. 1999;117:50410. 7.  Papaioannou M, Ocaka L, Bessant D, et al. An analysis of ABCR mutations in British patients with recessive retinal dystrophies. Invest Ophthalmol Vis Sci. 2000;41:169. 8.  Gerth C, Andrassi-Darida M, Bock M, et al. Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation. Graefes Arch Clin Exp Ophthalmol. 2002;240:62838. 9.  Edwards AO, Donoso LA, Ritter R, III. A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family. Invest Ophthalmol Vis Sci. 2001;42: 265263. 10.  Kaplan J, Gerber S, Larget-Piet D, et al. A gene for Stargardts disease maps to the short arm of chromosome 1. Nat Genet. 1993;5:30811. 11.  Donoso LA, Edwards AO, Frost A, et al. Autosomal dominant Stargardt-like macular dystrophy. Surv Ophthalmol. 2001;46:14963. 12.  Welber RG. Stargardts macular dystrophy. Arch Ophthalmol. 1994;112:7524. 13.  Noble KG, Carr RE. Stargardts disease and fundus flavimaculatus. Arch Ophthalmol. 1979;97: 12815.

567

6
RETINA AND VITREOUS

14.  Fishman GA, Farber M, Patel S, Derlacki DJ. Visual acuity loss in patients with Stargardts macular dystrophy. Ophthalmology. 1987;94:80914. 15.  Lois N, Halfyard AS, Bird AC, et al. Fundus autofluorescence in Stargardt macular dystrophy-fundus flavimaculatus. Am J Ophthalmol. 2004;138:5563. 16.  Oh KT, Weleber RG, Stone EM, et al. Electroretinographic findings in patients with Stargardt disease and fundus flavimaculatus. Retina. 2004;24:9208. 17.  Wirtitsch MG, Ergun E, Hermann B, et al. Ultrahigh resolution optical coherence tomography in macular dystrophy. Am J Ophthalmol. 2005;140:97683. 18.  Ergun E, Hermann B, Wirtitsch MG, et al. Assessment of central visual function in Stargardts disease/fundus flavimaculatus with ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci. 2005;46:3106. 19.  Eagle RC Jr, Lucier AC, Bernardino VB Jr, Yanoff M. Retinal pigment abnormalities in fundus flavimaculatus: a light and electron microscope study. Ophthalmology. 1980;87:1189200. 20.  Oh KT, Weleber RG, Oh DM, et al. Clinical phenotype as a prognostic factor in Stargardt disease. Retina. 2004;24:25462. 21.  Souied EH, Pawlak D, Algan M, et al. Photodynamic therapy for choroidal neovascularization on late-onset fundus flavimaculatus. Am J Ophthalmol. 2005;140:3124. 22.  Voo I, Small KW. Update on the genetics of macular dystrophies. Retina. 2004;24:592601. 23.  Maloney WF, Robertson DM, Duboff SM. Hereditary vitelliform macular degeneration. Arch Ophthalmol. 1977;95:97983. 24.  Bakall B, Marknell T, Ingvast S, et al. The mutation spectrum of the bestrophin protein: functional implications. Hum Genet. 1999;104:3839. 25.  Stone EM, Nichols BE, Stre LM, et al. Genetic linkage of vitelliform macular degeneration (Bests disease) to chromosome 11q13. Nat Genet. 1992;1:24650. 26.  Stohr H, Milenkovwic V, Weber BH. VMD2 and its role in Bests disease and other retinopathies. Ophthalmologe. 2005;102:11621. 27.  White K, Marquardt A, Weber BH. VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies. Hum Mutat. 2000;15:3018. 28.  Mohler CW, Fine SL. Long-term evaluation of patients with Bests vitelliform dystrophy. Ophthalmology. 1981;88:68892. 29.  Feist RM, White MF Jr, Skalka H, Stone BM. Choroidal neovascularization in a patient with adult foveomacular dystrophy. Am J Ophthalmol. 1994;118:25960. 30.  Patrinely JR, Lewis RA, Foni RL. Foveomacular vitelliform dystrophy, adult type. A clinicopathologic study, including electron microscopic observations. Ophthalmology. 1985;92:17128. 31.  Weingeist TA, Kobrin JL, Watzke RC. Histopathology of Bests macular dystrophy. Arch Ophthalmol. 1982;100:110814. 32.  Frangich GT, Green WR, Fine SL. A histopathologic study of Bests macular dystrophy. Arch Ophthalmol. 1982;100:111521. 33.  Felbor U, Schilling H, Weber BH. Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene. Hum Mutat. 1997;10:3019. 34.  Gass JD Clinicopathologic study of a peculiar foveomacular dystrophy. Trans Am Ophthalmol Soc. 1974; 72:13956. 35.  Pierro L, Tremolada G, Introini U, et al. Optical coherence tomography findings in adult-onset foveomacular vitelliform dystrophy. Am J Ophthalmol. 2002;134:67580. 36.  Wirtitsch MG, Ergun E, Hermann B, et al. Ultrahigh resolution optical coherence tomography in macular dystrophy. Am J Ophthalmol. 2006;140:97683. 37.  Renner AB, Tillack H, Kraus H, et al. Morphology and functional characteristics in adult vitelliform macular dystrophy. Retina. 2004;24:92939. 38.  Ergun E, Costa D, Slakter J, et al. Photodynamic therapy and vitelliform lesions. Retina. 2004;24:399406. 39.  Evans K, Gregory CY, Wijesuriya SD, et al. Assessment of the phenotypic range seen in Doyne honeycomb retinal dystrophy. Arch Ophthalmol. 1997;115:90410.

40.  Matsumoto M, Traboulsi EI. Dominant radial drusen and Arg345Trp EFEMP1 mutation. Am J Ophthalmol. 2001;131:8102. 41.  Narendran N, Guymer RH, Cain M, Baird PN. Analysis of the EFEMP1 gene in individuals and families with early onset drusen. Eye. 2005;19:115. 42.  Kniazeva M, Traboulsi EI, Yu Z. A new locus for dominant drusen and macular degeneration maps to chromosome 6q14. Am J Ophthalmol. 2000;130:197202. 43.  Heon E, Piguet B, Munier F. Linkage of autosomal dominant radial drusen (malattia leventinese) to chromosome 2p16-21. Arch Ophthalmol. 1996;114:1938. 44.  Pearce WC. Genetic aspects of Doynes honeycomb degeneration of the retina. Ann Hum Genet. 1967;31:17380. 45.  Deutman AF, Hansen LMAA. Dominantly inherited drusen of Bruchs membrane. Br J Ophthalmol. 1970;34:37382. 46.  Gass JD, Jallow S, Davis B. Adult vitelliform macular detachment occurring in patients with basal laminar drusen. Am J Ophthalmol. 1985;99:44559. 47.  Souied EH, Leveziel N, Letien V, et al. Optical coherence tomography features of mallatia leventinese. Am J Ophthalmol. 2006;141:4047. 48.  Gerber DM, Munier FL, Niemeyer G. Cross-sectional study of visual acuity and electroretinogram in 2 types of dominant drusen. Invest Ophthalmol Vis Sci. 2003;44:4936. 49.  vonRuckmann A, Schmidt KG, Fitzke FW, et al. Fundus autofluorescence in patients with hereditary macular dystrophies, mallatia leventinese, familial dominant and agerelated drusen. Klin Monatsbl Augenheilkd. 1998;213:816. 50.  Small KW. High tech meets low tech on chromosome 6. Arch Ophthalmol. 2001;119:5735. 51.  Khoubian FJ, Shakin EP, Tantri A, et al. Autosomal dominant pattern dystrophy: identification of a novel splice site mutation in the peripherin/RDS gene. Retina. 2005;25:9991004. 52.  Francis PJ, Schultz DW, Gregory AM, et al. Genetic and phenotypic heterogeneity in pattern dystrophy. Br J Ophthalmol. 2005;89:11159. 53.  Sohocki MM, Daiger SP, Bowne SJ, et al. Prevalence of mutations causing retinitis pigmentosa and other inherited retinopathies. Hum Mutat. 2001;17:4251. 54.  Wells J, Wroblewski KJ, et al. Mutations in the human retinal degenerations slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nat Genet. 1993;3:2138. 55.  Marmor MF, Byers B. Pattern dystrophy of the pigment epithelium. Am J Ophthalmol. 1977;84:3244. 56.  Hsieh RC, Fine BS, Lyons JS. Pattern dystrophies of the retinal pigment epithelium. Arch Ophthalmol. 1977;95:42935. 57.  Kremer H, Pinkers A, van den Helm B, et al. Localization of the gene for dominant cystoid macular dystrophy on chromosome 7p. Hum Mol Genet. 1994;3:299302. 58.  Loeffler KU, Li ZL, Fishman GA, Tso MO. Dominantly inherited macular edema. A histopathologic study. Ophthalmology. 1992;99:138592. 59.  Weber BH, Vogt G, Wolz W, et al. Sorsbys fundus dystrophy is genetically linked to chromosome 22q13-d. Nat Genet. 1994;7:15861. 60.  Della NG, Campochiaro PA, Zack DJ. Localization of TIMP-3 mRNA expression to the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 1996;37:19214. 61.  Jacobson SG, Cideciyan AV, Bennett J, et al. Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. Arch Ophthalmol. 2002;120:3769. 62.  Carrero-Valenzuela RD, Klein ML, Welber RG, et al. Sorsby fundus dystrophy. A family with the Ser181Cys mutation of the tissue inhibitor of metalloproteinases 3. Arch Ophthalmol. 1996;114:7378. 63.  Qi JH, Ebrahem Q, Moore N, et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med. 2003;9:40715. 64.  Felbor U, Doepner D, Schneider U, et al. Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 in various maculopathies. Invest Ophthalmol Vis Sci. 1997;38:10549.

65.  Weber BH, Lin B, White K, et al. A mouse model for Sorsby fundus dystrophy. Invest Ophthalmol Vis Sci. 2002;43:273240. 66.  Hamilton WK, Ewing CC, Ives EJ, et al. Sorsbys fundus dystrophy. Ophthalmology. 1989;96:175562. 67.  Capon MR, Marshall J, Krafft JI, et al. Sorsbys fundus dystrophy. A light and electron microscopic study. Ophthalmology. 1989;96:176977. 68.  Peiretti E, Klancnik JMJ, Spaide RF, Yannuzzi LA. Choroidal neovascularization in Sorsby fundus dystrophy treated with photodynamic therapy and intravitreal triamcinolone acetonide. Retina. 2005;25:3779. 69.  Small KW, Weber JL, Roses A, et al. North Carolina macular dystrophy is assigned to chromosome 6. Genomics. 1992;13:6815. 70.  Small KW, Hermsen V, Gurney N, et al. North Carolina macular dystrophy and central areolar pigment epithelial dystrophy: one family, one disease. Arch Ophthalmol. 1992;110:5158. 71.  Francis PJ, Johnson S, Edmunds B, et al. Genetic linkage analysis of a novel syndrome comprising North Carolinalike macular dystrophy and progressive sensorineural hearing loss. Br J Ophthalmol. 2003;87:8938. 72.  Szlyk JP, Paliga J, Seiple W, Rabb MF. Comprehensive functional vision assessment of patients with North Carolina macular dystrophy (MCDR1). Retina. 2005;25:48997. 73.  Small KW, Voo I, Glasgow B, et al. Clinicopathologic correlation of North Carolina macular dystrophy. Trans Am Ophthalmol Soc. 2001;99:2338. 74.  Kelsell RE, Godley BF, Evans K, et al. Localization of the gene for progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 6q. 1995;4:16536. 75.  Godley BF, Tiffin PA, Evans K, et al. Clinical features of progressive bifocal chorioretinal atrophy: a retinal dystrophy linked to chromosome 6q. Ophthalmology. 1996;103:8938. 76.  Fossdal R, Manusson L, Weber JL, Jensson O. The locus of atrophia areata, a helicoids peripapillary chorioretinal degeneration with autosomal dominant inheritance, to chromosome 11p15. Hum Mol Genet. 1995;4:47983. 77.  Fossdal R, Jonasson F, Kristjansdottir GT, et al. A novel TEAD1 mutation is the causative allele in Sveinssons chorioretinal atrophy (helicoid peripapillary chorioretinal degeneration). Hum Mol Genet. 2004;13:97581. 78.  Small KW, Gehrs K. Clinical study of a large family with autosomal dominant progressive cone degeneration. Am J Ophthalmol. 1996;121:112. 79.  Small KW, Syrquin M, Mullen Y, Gehrs K. Mapping of autosomal dominant progressive cone degeneration to chromosome 17p. Am J Ophthalmol. 1996;121:138. 80.  Castori M, Valente EM, Clementi M, et al. A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies. Invest Ophthalmol Vis Sci. 2005;46:353944. 81.  Hoyng CB, Heutink P, Testers L, et al. Autosomal dominant central areolar choroidal dystrophy caused by a mutation in codon 142 in the peripherin/RDS gene. Am J Ophthalmol. 1996;121:6239. 82.  Keithahn MAZ, Huang M, Keltner JL, et al. The variable expressivity of a family with central areolar pigment epithelial dystrophy. Ophthalmology. 1996;103:40615. 83.  Hartley KL, Blodi BA, VerHoeve JN. Use of the multifocal electroretinogram in the evaluation of a patient with central areolar choroidal dystrophy. Am J Ophthalmol. 2002;133:8524. 84.  Nagasaki K, Horiguchi M, Shimada Y, Yuzawa M. Multifocal electroretinograms in cases of central areolar choroidal dystrophy. Invest Ophthalmol Vis Sci. 2003;44:16739. 85.  Ashton N. Central areolar choroidal sclerosis: a histopathologic study. Br J Ophthalmol. 1953;37:1407.

568