Hereditary Maculopathies

Stargardt disease, initially described by Stargardt in 1909, has an autosomal recessive pattern of inheritance. It is the most common hereditary macular dystrophy, with a prevalence of 1 in 10,000, and it accounts for approximately 7% of all retinal dystrophies. It presents with gradual bilateral central vision loss during the first or second decade of life and carries a poor prognosis, with visual acuities ranging from 20/200 to 20/400. Classic fundus changes include bilateral, typically symmetric areas of macular atrophy with prominent yellow-white flecks at the level of the RPE in the posterior pole (Figure 1). Macular lesions may have a characteristic "beaten-bronze" appearance or "bull's-eye" pattern of atrophy.

The "flavimaculatus" flecks initially led Franceschetti in the 1960s to describe a disease entity, fundus flavimaculatus, as being separate from Stargardt disease. However, linkage studies have demonstrated a variable phenotype within Stargardt disease. Fundus flavimaculatus is simply Stargardt disease that presents in adulthood, typically with retinal flecks but without macular atrophy.

Fluorescein angiography (FA) classically demonstrates a dark choroid. This FA finding is thought to be due to focal lipofuscin deposits in the RPE that block choroidal fluorescence by absorbing the blue excitatory light used during FA. Macular hyperfluorescence, or window defects, are also seen on FA, corresponding to areas of RPE atrophy. Fundus autofluorescence imaging gives additional information about lipofuscin distribution and RPE metabolic activity. Areas of increased autofluorescence correspond to groups of RPE cells with increased lipofuscin quantities and likely are areas at increased risk for photoreceptor cell death. Electroretinography (ERG) and electro-oculography (EOG) studies are rarely diagnostic and are abnormal only in advanced disease.

Inheritance in Stargardt disease is usually autosomal recessive. The locus for the autosomal recessive form (STGD1) was mapped to chromosome 1p and the disease gene was identified as ABCA4 (formerly ABCR). This gene encodes a protein expressed in rod outer segments that is involved in ATP-dependent transportation and recycling of retinoids between photoreceptors and RPE. Mutations in the ABCA4 gene result in accumulation of lipofuscin in the RPE, which likely causes secondary photoreceptor death. Predicting the phenotype of patients based on mutation screening is complicated by the large, polymorphic nature of the gene. Genetic screening of the ABCA4 gene extends beyond those with Stargardt disease, as this gene has also been associated with cone-rod dystrophy and autosomal recessive retinitis pigmentosa. Additionally, alterations in the ABCA4 gene may be associated with an increased risk for age-related macular degeneration (AMD).

Autosomal dominant Stargardt-like macular dystrophy shares many features with the autosomal recessive form and, ophthalmoscopically, the two diseases are difficult to distinguish (Figures 2a, b). Autosomal dominant Stargardt-like macular dystrophy is a form of juvenile macular degeneration causing decreased visual acuity. It is characterized by bilateral macular atrophy and prominent flecks in the posterior pole. Color vision is mostly preserved, and ERG and EOG findings are usually normal. However, FA rarely demonstrates a dark choroid, as is classically observed in the autosomal recessive form.

Chromosomal loci for the autosomal dominant disease have been mapped to 6q14 (STGD3) and 4p (STGD4). ELOVL4, the gene involved in STGD3, encodes a protein involved in fatty acid elongation and is highly expressed in rod and cone photoreceptors. Mutations in ELOVL4 identified in STGD3 families generate a truncated protein product with altered elongase activity and abnormal aggregation properties. The likely mechanism of macular degeneration in STGD3 patients appears to be dominant negative inhibition (when the mutant gene product inhibits the normal, wild-type gene product within the same cell) of ELOVL4 elongase activity with consequent deficiency in normal fatty acid elongation.

North Carolina macular dystrophy (NCMD) was first described in 1971 by Lefler, Wadsworth, and Sidbury, referring to their work with a large North Carolina family descended from three Irish brothers who settled in Spartanburg, South Carolina, in 1790. Subsequently, unrelated pedigrees of affected families have been described throughout the world. NCMD is an autosomal dominant disorder with complete penetrance. The presentation is variable, and the course can be nonprogressive. The onset is infantile or congenital, and visual acuity typically ranges from 20/20 to 20/200.

The macular phenotype in NCMD ranges from central macular yellow-white drusen (grade 1), to confluent drusen with or without RPE atrophy, pigmentary changes, or disciform lesions (grade 2, Figures 3a, b), to lesions previously labeled colobomatous or staphylomatous (grade 3, Figure 3c). More recently, the term macular caldera has been proposed to describe grade 3 lesions with deep chorioretinal excavations that do not involve the sclera. These macular atrophic lesions are surrounded by heaped-up subretinal gliosis or fibrosis. Such lesions may be due to hemorrhage in utero with subsequent exuberant organization; however, further studies are needed to explain the pathogenesis of grade 3 lesions. Occasionally choroidal neovascularization develops in NCMD (Figure 3d), and geographic atrophy has also been described, further highlighting the similarities with AMD.

Color vision, ERG, and EOG results are typically normal. Genetic studies have mapped NCMD to the MCDR1 locus on chromosome 6q, but the particular disease gene remains elusive despite extensive study. The identification of this mutant gene should shed light on the molecular genetics of disease pathogenesis in NCMD and AMD.

Initially described in 1949 by Sorsby and Mason, Sorsby fundus dystrophy (SFD), is a rare, progressive, autosomal dominant retinal dystrophy that can cause bilateral central vision loss in the fourth or fifth decade of life. It is also known as Sorsby pseudoinflammatory macular dystrophy.

Vision loss is secondary to macular RPE atrophy and choroidal neovascularization, resulting in disciform scarring similar to that seen in neovascular AMD (Figure 4). Nyctalopia and peripheral retinal degeneration have also been described. Patients often present in the third and fourth decades of life. Ophthalmoscopic findings include exudative and atrophic macular lesions, lipid-containing deposits at the level of Bruch's membrane, and subretinal yellow plaquelike deposits. ERG is usually normal.

The condition is caused by mutations in the TIMP3 gene, the tissue inhibitor of metalloproteinase 3, on chromosome 22q. This gene encodes a protein secreted from the RPE and incorporated into and involved in the remodeling of the extracellular matrix of Bruch's membrane. Many mutations have been reported in TIMP3 to cause SFD, most of which involve cysteine residues and disulfide bond formation. As mutant TIMP3 proteins likely retain their matrix metalloproteinase inhibitory properties, and large intermolecular protein aggregates are believed to form secondary to disulfide bonding of these unpaired residues, it has been proposed that increased TIMP3 deposition in Bruch's membrane is the inciting event in SFD pathogenesis. Mutant TIMP3 has been shown to induce apoptosis of RPE cells. Additionally, TIMP3 has been shown to inhibit angiogenesis by blocking VEGF binding to VEGF-2 receptors; therefore, the mutant form of TIMP3 can potentiate choroidal neovascularization formation.

Doyne honeycomb retinal dystrophy (DHRD) was first reported in 1899 by Doyne in England, and Malattia leventinese was separately described in 1925 in the Leventine valley in Switzerland. In 1999 these diseases were found to share the same single missense mutation in the EFEMP1 gene. These rare, fully penetrant autosomal dominant diseases are characterized by drusen (focal, yellow-white deposits of extracellular material between the RPE and Bruch's membrane) in the macula and around the optic disc. Over time, the drusen become confluent, forming a solid plaque at the level of Bruch's membrane, which is followed by atrophy (Figures 5a, b). Patients are usually asymptomatic until the fourth or fifth decade of life, when they present with decreased visual acuity, relative scotomas, photophobia, dyschromatopsia, or metamorphopsia. In advanced stages, central vision diminishes with funduscopic changes that include pigmentary alterations, geographic atrophy, and choroidal neovascularization. Visual acuity less than 20/200 is common between the ages of 70 to 80 years. Late in the disease process, ERG may be abnormal, and FA can demonstrate hyperfluorescent lesions, predominantly in the submacular and peripapillary areas.

The EFEMP1 gene is located on chromosome 2p16. Most patients with adult dominant drusen share a single missense mutation (R345W). The normal EFEMP1 protein is widely expressed in the extracellular matrix, but its function is unknown. EFEMP1 is in the fibulin family of proteins (fibulin-3). Misfolding and aberrant accumulation of the mutant protein within RPE has been proposed as the mechanism of drusen formation. Also, mutant protein expression and accumulation has been shown to cause RPE dysfunction and increased VEGF levels, which could explain choroidal neovascularization formation and macular degeneration in the disease.

Best vitelliform macular dystrophy (BVMD), also known as Best disease, was originally described by Best in 1905. BVMD is a dominantly inherited, progressive, juvenile-onset macular dystrophy with highly variable expressivity. Characteristic fundus findings include bilateral, symmetric round or oval subretinal deposits, classically referred to as an "egg-yolk" appearance. Such lesions are usually detected in the first or second decade of life and are caused by an accumulation of lipofuscin at the level of the RPE (Figures 6a–c).

The hallmark finding of BVMD is a normal ERG and an abnormally diminished EOG, even in the setting of a normal ophthalmoscopic examination. The EOG finding is present in all individuals with the mutant gene, and indicates diffuse RPE dysfunction. FA usually demonstrates completely blocked background fluorescence corresponding to the macular lesion observed clinically.

The prognosis in Best disease is relatively good. Visual acuity remains for the most part preserved over time. However, in the late stages of disease, following gradual absorption of the macular lesion, RPE atrophy and scarring due to subretinal neovascular membranes with hemorrhage can result in central vision loss.

Five clinical stages of disease have been described:

There is as yet no explanation for the highly variable expressivity of the disease phenotype in BVMD—including the fact that some individuals with mutations in BEST1 and an abnormal EOG have a normal-appearing macula. While environmental factors and an individual's genetic background likely influence the disease phenotype, more studies into the pathophysiology of BVMD are necessary.

The BEST1 gene (previously VMD2) responsible for BVMD is located on chromosome 11q13. The gene encodes the protein bestrophin, known to be a chloride channel mainly expressed in RPE cells. More than 100 mutations in BEST1 have been found to cause the disease. Mutations may result in alterations of fluid and ion transportation in the RPE, diminished interactions between RPE and photoreceptors, and secondary photoreceptor degeneration.

Adult vitelliform macular dystrophy (AVMD), also known as adult-onset foveomacular vitelliform dystrophy, is a heterogeneous group of diseases that are similar to Best disease and the pattern dystrophies. However, the age of onset of AVMD is later than in Best disease (after the third or fourth decade). EOG results are normal, foveal lesions are smaller (one-third to one-half disc diameters), and AVMD does not show the same progressive macular lesion changes. The prognosis is favorable, although some individuals develop secondary degenerative changes (Figures 7a, b).

Many individuals with AVMD have mutations in the peripherin/RDS gene on chromosome 6p, while others may have mutations in BEST1. Some favor the inclusion of AVMD within the pattern dystrophies of the RPE, while other investigators suggest that those with BEST1 mutations be subcategorized within BVMD.

The pattern dystrophies are heterogeneous, autosomal dominant diseases of the RPE clinically characterized by bilateral yellow, orange, or gray deposits in the macula. The visual prognosis is typically good, with only mild reduction in central vision presenting later in life around the fifth decade. However, the disease may slowly progress with age, resulting in more severe visual loss in the long term. The most well-known pattern dystrophies based on clinical phenotype include butterfly-shaped pattern dystrophy (BPD), reticular dystrophy (RD), AVMD, multifocal pattern dystrophy simulating fundus flavimaculatus, and fundus pulverulentus. These disorders can be thought of clinically as one disease with variable expressivity, as one type of pattern dystrophy may develop into another within the same patient, and different forms may exist in related individuals with the identical mutation. Full-field ERGs are generally normal for the pattern dystrophies, although they may be reduced in the advanced stage of multifocal pattern dystrophy simulating fundus flavimaculatus. EOG is often abnormal in the pattern dystrophies (except in AVMD). FA can be a useful diagnostic tool, especially in BPD.

The pattern dystrophies are genetically heterogeneous, but mutations in peripherin/RDS on chromosome 6p21.2 are often reported. Several mutations have been identified. They are suspected to cause disease by disrupting the photoreceptor cell membrane, as the normal gene product is a glycoprotein believed to be involved in maintenance of photoreceptor outer segment discs.

Congenital retinoschisis, or juvenile X-linked retinoschisis (XLRS), is a rare, progressive, bilateral, clinically variable disease that often presents with decreased central vision in childhood. XLRS was first described in 1898, and the X-linked recessive inheritance pattern was identified in 1938. It has a prevalence of 1 in 5,000 to 1 in 25,000 worldwide and is the most common juvenile-onset macular degeneration in males. Fundus examination reveals a cystic spoke-like or stellate foveal schisis (Figures 8a, b) and, in roughly half of male patients, peripheral retinoschisis. The reduction in vision is usually mild and relatively stable as long as complications such as vitreous hemorrhage and retinal detachment do not occur. Nonspecific macular degeneration develops late in the disease.

Full-field ERG is critical for diagnosis and demonstrates the distinctive finding of reduced b-wave amplitude. OCT can also be a useful tool for diagnosis and monitoring and may demonstrate macular cystoid changes and foveomacular schisis in the inner nuclear layer or multiple retinal layers. No leakage in the macula is seen on FA, and the EOG is normal. Clinical management involves treating amblyopia and surgical correction of vision-threatening complications. Limited studies in XLRS patients suggest that short-term treatment with carbonic anhydrase inhibitors may improve foveal cystic-appearing lesions and retinal function.

XLRS1 has been identified as the disease-causing gene, located on chromosome Xp22. The gene encodes the secreted retinoschisin (RS1) protein in photoreceptors and bipolar cells, which is involved in cell adhesion or cell-cell interactions. Numerous disease-causing mutations (more than 150) have been reported in XLRS1.

Initially described in 1976, dominant cystoid macular dystrophy (DCMD), or dominant cystoid macular edema, is an extremely rare, progressive, bilateral autosomal dominant disease. It usually presents in the fourth decade of life and carries a poor visual prognosis. The FA in all patients demonstrates cystoid macular edema due to perifoveal capillary leakage. Additional disease characteristics include normal ERG, subnormal EOG, and moderate to high hyperopic refractive errors. Histopathologic changes predominantly affect the inner nuclear layer, and OCT may be useful in defining the pathology and etiology of DCMD. While no approved therapies exist, a limited study using a somatostatin-analogue reported reduced cystoid edema and stabilized vision in DCMD. Genetic linkage to 7p15-p21 has been defined, but the gene and underlying mutation(s) causing the disease remain unknown.

Central areolar choroidal dystrophy (CACD) is a rare, inherited macular disease that presents between the third and fifth decade of life, with progressive central visual deterioration and a poor final visual prognosis, often worse than 20/200. Nettleship likely described the first case of CACD in 1884, but it was not defined as a clinical entity until Sorsby did so in 1939. Bilateral, symmetric changes can be observed ophthalmoscopically. Early findings include subtle, mottled depigmentation in the macula, followed by gradual atrophy of the RPE and choriocapillaris, revealing the underlying atrophic choroid and sclera. Photoreceptor death occurs within this well-circumscribed round to oval atrophic zone. Flecks and drusen are usually absent, and the peripheral retina usually appears normal.

FA and fundus autofluorescence are quite helpful in identifying early macular changes. Early in the disease, fundus autofluorescence reveals a speckled increase in autofluorescence, while there is markedly diminished or absent autofluorescence in the late stages. Early FA findings include small parafoveal hyperfluorescent areas that increase in size as the window defect enlarges with disease progression. Full-field ERG and EOG are often normal, while multifocal ERG, pattern ERG, and color vision studies may be abnormal based on the particular genetic mutation underlying CACD.

CACD most frequently demonstrates autosomal dominant inheritance, although it can be inherited as an autosomal recessive trait and sporadic cases have also been reported. While the autosomal dominant form is genetically heterogeneous, mutations in the peripherin/RDS gene (RDS/Peripherin) on chromosome 6 are most commonly associated with the disease. Another locus at chromosome 17p13 was discovered in a large Northern Irish family with autosomal dominant CACD, but the precise gene has not been identified. Additionally, linkage analyses and mutational screening studies in Tunisian and Chinese families with autosomal dominant CACD did not demonstrate mutations in the peripherin/RDS gene or at the CACD locus, further highlighting the heterogeneous genetics of CACD. While the involvement of the peripherin/RDS gene is also important because mutations in this gene underlie a wide range of central and peripheral retinal dystrophies, including the AVMD, pattern dystrophies, and retinitis pigmentosa, with an even broader spectrum of clinical phenotypes. The proposed pathophysiology in CACD due to peripherin/RDS mutations is that the mutant peripherin/RDS protein no longer fulfills its essential function in creating, maintaining, and renewing photoreceptor outer segments. This ultimately results in photoreceptor and RPE death and choriocapillaris atrophy.

The cone dystrophies are a genetically and phenotypically heterogeneous group of inherited retinal diseases characterized by progressive photopic dysfunction with preserved scotopic function. Patients present with the classic triad of photophobia, loss of color vision, and reduced central visual acuity. The fundus may appear normal or have mild changes early in the disease process that can progress to bull's-eye maculopathy and central RPE atrophy later. Diagnosis may depend on characteristic ERG changes, including a depressed full-field photopic ERG. FA is often normal until the advanced stage of the disease. Cone dystrophy may present as an autosomal dominant, autosomal recessive or X-linked recessive trait. Autosomal dominant loci have been localized to 6p21.1 (COD3, GCAP1), 6q25-q26 (RCD1), and 17p12-13 (Ret-GC1).