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Chapter 109 – Macular Dystrophies

Chapter 109 – Macular Dystrophies

 

KIMBERLY DRESNER

KENT W. SMALL

 

 

 

 

 

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.

 

KEY FEATURES

• Yellowish material within or beneath the retinal pigment epithelium.

• Loss of macular photoreceptors and retinal pigment epithelial cells.

• Loss of central vision.

 

ASSOCIATED FEATURES

• Neural retinal, retinal pigment epithelial, and choroidal atrophy commonly limited to the macula.

• Bull’s-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, form-following 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. 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. The difficulty is that many of the disorders exhibit histological abnormalities in all layers of the neural retina, retinal pigment epithelium (RPE), and choroids. 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. 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. It, therefore, is important to differentiate clinically among the disorders to be able to give the patient the best genetic counseling and advice on visual prognosis.

No treatment is available for any of the disorders discussed in this chapter. Laser therapy may be used in an attempt to halt the progression of choroidal neovascularization, when present. In this chapter the focus is specifically on macular dystrophies not associated with other systemic abnormalities.

STARGARDT’S DISEASE AND FUNDUS FLAVIMACULATUS

EPIDEMIOLOGY AND PATHOGENESIS

Usually, Stargardt’s disease is inherited as an autosomal recessive trait; however, affected families that have autosomal dominance have been described.[1] Stargardt’s 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] [3] An adenosine triphosphate–binding cassette, the ABCR gene (now called ABCA4), has been identified as the causative gene. Fundus flavimaculatus and Stargardt’s 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 and autosomal recessive retinitis pigmentosa.[2] A knock-out mouse model of Stargardt’s disease has been created.[3] The heterozygous mouse also has an accumulation of lipofuscin, supporting the role of ABCA4’s in age-related macular degeneration.

Autosomal dominant Stargardt’s disease originally was mapped to chromosome 13 as STGD2. More recently, this has been found to be in error, and dominant Stargardt’s disease maps to chromosome 6q16.6 in association with the mutation found on the ELOVL4 gene.[1] This finding lumps autosomal dominant Stargardt’s with several other retinal diseases mapping to chromosome 6.[4]

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 Stargardt’s 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. 109-1 ).[5] [6] The distribution

 

 

Figure 109-1 Stargardt’s disease

 

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of the flecks and the time of their appearance can vary, but the flecks seen in Stargardt’s 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 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 Stargardt’s disease.[7] The flecks, themselves, do not stain with fluorescein.

The electroretinogram findings are normal early but may be reduced moderately in more advanced cases. Also, the electro-oculogram (Arden ratio) may be reduced mildly when there are extensive RPE changes. Patients who have Stargardt’s disease can exhibit delayed dark adaptation.[8] The differential diagnosis of Stargardt’s disease and fundus flavimaculatus is given in Table 109-1 .

 

 

TABLE 109-1 — DIFFERENTIAL DIAGNOSIS OF MACULAR DYSTROPHIES

Disease

Differential Diagnosis

Stargardt’s disease and fundus flavimaculatus

Cone dystrophy

Neuronal ceroid lipofuscinosis

Pattern dystrophy

Best’s disease and vitelliform dystrophy

Age-related macular degeneration

Pattern dystrophy

Adult vitelliform degeneration

Best’s disease

Pattern dystrophy

Age-related macular degeneration

Familial (dominant) drusen

Flecked retinal syndromes

Sorsby’s fundus dystrophy

Age-related macular degeneration

Dominant cystoid macular edema

Dominantly inherited retinitis pigmentosa with cystoid macular edema

X-linked juvenile retinoschisis

Goldmann-Favre syndrome

North Carolina macular dystrophy

Toxoplasmosis

Age-related macular degeneration

Progressive bifocal chorioretinal atrophy

Atrophea areata

North Carolina macular dystrophy

Myopic macular degeneration

Atrophea areata

Serpiginous choroiditis

Peripapillary pigment epithelial dystrophy

Angioid streaks

Progressive bifocal chorioretinal atrophy

Myopic macular degeneration

Cone degeneration (dystrophy)

Stargardt’s disease

Hereditary optic atrophies

Toxic maculopathy

Central areolar choroidal dystrophy

Sorsby’s fundus dystrophy

North Carolina macular dystrophy

Angioid streaks

Stargardt’s disease

Cone dystrophy

Progressive bifocal chorioretinal atrophy

Serpiginous choroiditis

Acute multifocal placoid pigment epitheliopathy

 

 

PATHOLOGY

Pathological evaluation shows an accumulation of lipofuscin-like pigment throughout the RPE, although its origin and significance remain unknown[9] ( Fig. 109-2 ). 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.[3]

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 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. [6] [7] Less commonly, patients who have severe peripheral atrophy manifest visual field loss that may be difficult to differentiate from a rod–cone dystrophy. 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 authors do not recommend vitamins A or B-carotene vitamin supplements.

BEST’S DISEASE AND VITELLIFORM DYSTROPHY

EPIDEMIOLOGY AND PATHOGENESIS

Best’s disease is extremely rare—the actual incidence is unknown. The disease is autosomal dominantly inherited and shows highly variable clinical expression. Furthermore, some individuals who carry the defective gene have completely normal vision and fundus examination findings.[10] Such individuals have been referred to as carriers of Best’s disease, but this is a misnomer. The gene for Best’s disease was mapped to chromosome 11q13 and mutations found in the bestrophin (VMD2) gene. This is a transmembrane protein of undetermined function.[11] [12] The protein is expressed in the RPE. Several mutations within the bestrophin gene have been identified and are associated with both Best’s and adult vitelliform diseases.[13]

 

 

Figure 109-2 Stargardt’s disease (fundus flavimaculatus). Note the fluorescein effect caused by enlarged lipofuscin-containing retinal pigment epithelial cells, which act as a fluorescent filter. (Case reported by Eagle RC Jr, et al. Ophthalmology. 1980;7:1189.)

 

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Figure 109-3 Best’s disease. Typical vitelliform lesion from an 11-year-old girl. (Courtesy of Ola Sandgren, University Hospital of Umeå, Sweden.)

OCULAR MANIFESTATIONS AND DIAGNOSIS

Best’s disease is typified by a large, yellow, yolk-like (vitelliform) lesion ( Fig. 109-3 ) that is bilateral and symmetrical in the central macula and appears during childhood. The diameter is in the range 1–5?mm. 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.[14] [15] Choroidal neovascularization can arise adjacent to old vitelliform scars.[15] [16]

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 electro-oculogram 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 electro-oculogram is used to evaluate individuals who have a poorly defined macular lesion.

Electroretinographic studies show a reduced “C” wave but are otherwise normal. This is the only disease with relatively normal electroretinographic results associated with abnormal electro-oculographic findings. The differential diagnosis is shown in Table 109-1 .

PATHOLOGY

Histopathological studies show an accumulation of lipofuscin-like material throughout the RPE. [17] [18] [19] [20] Unfortunately, no histological studies describe the yolk-like lesion seen early in the disease. Interestingly, despite the accumulation of lipofuscin-like material in the RPE, no dark choroid 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.

TREATMENT, COURSE, AND OUTCOME

The age of onset and expression of Best’s disease is variable. For most individuals, manifestation of the disease occurs in childhood; however, occasionally onset is in adulthood. The visual acuity usually is good when the “yolk” remains intact. The vision drops, however, once scarring begins.[14] 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 formation is infrequent but may arise from an old scar.[14]

 

 

Figure 109-4 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;118:259–60.)

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.[21] Mutations in the bestrophin gene, VMD2, have also been associated with adult vitelliform degeneration.[11] Some authors consider the foveomacular dystrophy to be a variant of the pattern dystrophies (see later).

OCULAR MANIFESTATIONS AND DIAGNOSIS

Affected individuals show symmetrical, yellowish foveal deposits that resemble the lesions of Best’s disease but are smaller ( Fig. 109-4 ). 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.[22]

These disorders usually are distinguished from Best’s disease on the basis of a normal or only minimally reduced electro-oculogram. The full-field electroretinogram is normal, but the foveal electroretinogram may be reduced (Arden ratio <1.7). Also, 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 109-1 .

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 recently been shown to be excluded by newer, more informative genetic markers.[23]

PATHOLOGY

Histopathological analyses of these patients’ eyes have demonstrated damage at the level of the RPE. Focal loss of the photoreceptors overlie atrophic RPE cells in the fovea. Pigmented material is seen to lie between the retina and Bruch’s membrane. Gass[22] found no abnormal accumulation of lipofuscin in RPE cells. Patrinely et al.[17] on the other hand, found high concentrations of lipofuscin in RPE cells and postulated that this accumulation is responsible for the foveal lesion.

 

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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. The overall prognosis of adult vitelliform dystrophy is similar to that of Best’s 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 Best’s disease because of the potential genetic implications and need for appropriate genetic counseling.

FAMILIAL DRUSEN

EPIDEMIOLOGY AND PATHOGENESIS

Familial (dominant) drusen is a rare autosomal dominant disease with variable expression and age-dependent penetrance.[24] A mutation from an arginine to a tryptophan at amino acid 345 in the EFEMP1 locus has been associated with both Doyne’s and malattia leventinese, which are, therefore, the same disease.[25] Another locus on chromosome 6q14 adjacent to the cone–rod dystrophy gene (CORD7) and the North Carolina dystrophy gene (NCMD) has also been identified in those with dominant drusen. [26] [27] [28] [29] 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 Doyne’s 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

Patients exhibit widespread drusen that extend beyond the macula, in a pattern distinct from age-related drusen ( Fig. 109-5 ).[30] [31] Typically, diffuse drusen extend peripherally to the macula and involve retina nasal to the optic disc. The drusen, themselves, may be large and sparse or form a constellation of tiny dots, called cuticular or basal laminar drusen. Sometimes, basal laminar drusen coalesce to form a vitelliform lesion.[32] 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. Dark adaptation is usually normal, as are the electroretinographic findings. The electro-oculographic findings are normal in the initial stages, but they become subnormal depending on the degree of macular involvement. The differential diagnosis is shown in Table 109-1 .

PATHOLOGY

Histopathological examinations show round accumulations of hyaline in the pigment epithelium that are continuous with the inner layer of Bruch’s membrane.[33] The choroids and neural

 

 

Figure 109-5 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;115:904–10.)

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 choroidal neovascularization 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. Choroidal neovascularization may occur occasionally.

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 mutations in peripherin, a retinal protein encoded by a gene located on chromosome 6p.[34] Interestingly, some forms of retinitis pigmentosa, as well as other macular dystrophies (such as the adult foveomacular dystrophy of Gass), are attributed to mutations in this same protein.[35] [36] Within a family, some affected patients may manifest retinitis pigmentosa, while others phenotypically appear to have a macular dystrophy. Some patients with butterfly dystrophy have a mutation located at the peripherin/RDS gene, although most patients who have pattern dystrophy do not have mutations in the peripherin gene.[37] [38]

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.[39] [40] Yellow flecks and drusen typically are not found. The clinical phenotypes often take on a characteristic pattern ( Fig. 109-6 ) 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. Sjögren’s 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

 

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Figure 109-6 Pattern dystrophy.

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 Stargardt’s 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 electro-oculogram 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

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.[40]

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.[41] Interestingly, autosomal dominant retinitis pigmentosa, known as RP9, also maps to this region.

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. Müller’s cells are the specific cellular constituents thought to be involved, based on histopathological evidence.[42]

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. Electrophysiology 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. [42] The differential diagnosis is given in Table 109-1 .

PATHOLOGY

Histopathological studies demonstrate macular cysts, disorganized and gliotic inner nuclear layer, focal Müller’s 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.[43] Histopathological features seen in dominantly inherited cystoid macular edema, namely the involvement of Müller’s cells, are quite different from those features seen in cystoid macular edema secondary to other causes.

TREATMENT, COURSE, AND OUTCOME

Patients first begin to notice decreasing visual acuity at about 30 years 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.

SORSBY’S 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 Sorsby’s dystrophy that codes for a tissue inhibitor metalloproteinase, TIMP-3, has been identified.[44] TIMP-3 has been cloned and linked to chromosome 22. [45] [46] Several mutations of TIMP-3 have been identified in patients with Sorsby’s dystrophy. 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. This enzyme is expressed in the RPE.[47] No association exists between TIMP-3 mutations and age-related macular degeneration.

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 40 years of age, patients develop bilateral exudative maculopathy, which leaves heavily pigmented macular scars and areas of geographical atrophy.[48]

The electroretinogram and electro-oculogram results usually are normal, but decreased photopic and scotopic electroretinographic amplitudes can be seen late in the disease.

PATHOLOGY

Light and electron microscopic studies show lipid-containing deposits between the basement membrane and the pigment epithelium and the inner collagenous layers of Bruch’s membrane.[49]

TREATMENT, COURSE, AND OUTCOME

Patients typically develop bilateral choroidal neovascularization at an early age. Severe loss of central visual acuity results from extensive macular scarring related to the choroidal neovascular membranes. Attempts at laser treatment have had poor results.[50]

 

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Later, vision can decrease to light perception only. Nyctalopia also is a symptom late in the course of disease.[48]

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.[51] [52] 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.[53] Indeed, reports of various branches of the single family from North Carolina have resulted in this one disease being given 7 different names during the last 25 years. Again, “lumping” diseases has proven to be more accurate than “splitting.”

OCULAR MANIFESTATIONS AND DIAGNOSIS

The most striking feature in about one third of affected individuals is a macular coloboma ( Fig. 109-7 ), 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 central macular area. Choroidal neovascularization can occur. The electroretinogram and electro-oculogram results are normal, as is color vision. The differential diagnosis is given in Table 109-1 .

PATHOLOGY

Recently Small et al.[54] 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 macular lesion characterized by focal absence of photoreceptor cells and RPE. Bruch’s 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.

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 choroidal neovascularization.

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.[55] [56]

 

 

Figure 109-7 North Carolina macular dystrophy. Macular coloboma in an 18-year-old woman with visual acuity of 20/40 (6/12).

 

 

Figure 109-8 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;103:893–8.)

OCULAR MANIFESTATIONS AND DIAGNOSIS

An initial focus of atrophic retina and choroids 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. 109-8 ). The diagnosis is made chiefly on the basis of the unusual clinical appearance.[57]

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.

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, has been mapped to chromosome 11p15.[58] Although no histological studies exist, it appears that the RPE and choroid are the primary sites affected.

OCULAR MANIFESTATIONS AND DIAGNOSIS

As with most inherited retinal diseases, atrophia areata is a bilateral, symmetrical maculopathy and has an early onset.[58] Marked choroidal atrophy radiates from the optic disc, with two or more

 

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Figure 109-9 Atrophia areata in a 37-year-old man. (Courtesy of Fridbert Jonasson, University Department of Ophthalmology, Landspítalinn, Iceland.)

ring-shaped extensions that do not follow the major retinal vessels ( Fig. 109-9 ). 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 109-1 .

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 DEGENERATION

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.[59] [60] found a single large family from eastern Tennessee with autosomal dominant cone degeneration (designated CORD 5 by 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).[61] [62] Again, “lumping” is better than “splitting.” Mutations in the cone–rod homeobox (CRX) as well as the ABCR gene have also been associated with cone degeneration. [2]

OCULAR MANIFESTATIONS AND DIAGNOSIS

Hallmarks of cone degeneration include the triad of progressive central acuity loss, color vision disturbances, and photophobia.[55] [56] 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 region[55] ( Fig. 109-10 ).

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. [55] Full-field electroretinographic studies show selective diminution of the photopic “B” wave and decreased amplitudes of the 30?Hz flicker. The dark-adapted rod responses, on the other hand, are usually normal or mildly attenuated. Focal macular electroretinograms

 

 

Figure 109-10 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;121:1–12.)

 

 

Figure 109-11 Central areolar choroidal dystrophy. (Courtesy of Giuliani Silvestri.

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 109-1 .

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.[58] [59] 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, ß-arrestin 2, pigment epithelium–derived factor, and recoverin. Interestingly, several other inherited retinal diseases have been mapped to chromosome 17p, including autosomal dominant cone dystrophy, Leber’s congenital amaurosis, and autosomal dominant retinitis pigmentosa.[63] 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. [34] [64] This disease appears to be a

 

831

primary dystrophy of either the choroidal vessels or of the pigment epithelium, with secondary involvement of the choroids.

OCULAR MANIFESTATIONS AND DIAGNOSIS

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 intermediate and large choroidal vessels visible ( Fig. 109-11 ). 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 usually are normal.

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.[65] The rest of the retina and choroid is normal outside of the atrophic zone. The differential diagnosis is shown in Table 109-1 .

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.

 

 

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