Key Features
Choroideremia
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Involvement of the choroid, retinal pigment epithelium, and retinal photoreceptors.
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Nyctalopia.
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Midperipheral and, subsequently, far peripheral visual field loss.
Gyrate Atrophy
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Chorioretinal lesions of atrophic appearance with scalloped margins.
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Nyctalopia.
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Midperipheral and peripheral visual field loss.
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Frequently, they develop cataracts.
Introduction
Choroidal dystrophies are a group of progressive, hereditary disorders that are characterized by clinically apparent retinal pigment epithelial (RPE) and choroidal atrophy. Krill and Archer classified such dystrophies into two groups, one with a more regional involvement and the other with a diffuse involvement of the fundus. The regional dystrophies are subclassified further based on the initial or predominant site of the degenerative changes (macular, central areolar, peripapillary, or a combination) and the severity of involvement (involving only the choriocapillaris or, in addition, the larger choroidal vessels). Choroideremia and gyrate atrophy of the choroid and retina represent diffuse forms of choroidal dystrophies. Progressive bifocal chorioretinal atrophy phenotypically shows a regional involvement, but there is a diffuse reduction of retinal function.
Choroideremia
Introduction
Choroideremia is an X-linked recessive, bilateral, progressive chorioretinal dystrophy that is characterized by a marked loss of vision at night and progressive loss of peripheral visual fields.
Epidemiology and Pathogenesis
The exact pathogenesis of the degenerative changes observed in patients and the cells primarily affected in choroideremia are yet to be defined with certainty. In the past, it was thought that this disease was caused primarily by degeneration of RPE cells, the choroid, or both, with photoreceptors degenerating secondarily. It has been suggested that the primary defect may be in the rod photoreceptor cells of the retina. It has also been proposed that there may be independent degeneration of RPE cells and photoreceptor cells, based on a conditional knockout mouse model. A recent multimodal imaging of photoreceptor structure in choroideremia showed remnants of cone inner segments within “outer retinal tubulations” (ORTs) and the continuity of the ORTs with the preserved retina, thereby suggesting degeneration of RPE earlier than the photoreceptors.
The choroideremia gene (CHM) was isolated by positional cloning techniques and localized to the long arm of the X chromosome (Xq21). The CHM gene encodes the Rab escort protein-1 (REP-1) of Rab geranylgeranyl transferase, a two-component enzyme (components REP-1 and REP-2) that modifies Rab proteins. Rab proteins are low-molecular-weight guanosine triphosphatases that regulate intracellular vesicular transport. For Rab proteins to bind to membranes, they undergo lipid modification with the addition of 20 carbon units to the carboxy terminal of the protein, a process known as geranylgeranylation. Of interest, the CHM gene is expressed not only in ocular tissues but also in various cells of nonocular origin. However, CHM gene dysfunction affects only the retina. The proteins REP-1 and REP-2 are 75% identical, and their functions are mutually redundant. The functioning of the majority of the cells in the body that have a REP-1 deficiency can be taken over by REP-2 and, hence, can function adequately. However, the retina has a major Rab protein, Rab 27, which is prenylated more efficiently by REP-1 than REP-2. Since all mutations known so far in the CHM gene create stop codons and, hence, an absence of the gene product REP-1, there is progressive chorioretinal degeneration in patients with choroideremia.
Ocular Manifestations
A majority of patients with choroideremia present with progressive impairment of night vision. It usually begins in the first decade of life, although the onset may be delayed. Some patients can, however, have midperipheral visual field loss. The clinical features, including the rate of progression, can show both interfamilial and intrafamilial variability.
The ocular findings in the anterior segment are unremarkable. Posterior subcapsular changes in the lens develop more frequently than in the general population. Even those patients who do not show clinical cataract changes may have subclinical lens changes as demonstrated indirectly by increased light scatter.
Initial fundus changes most often begin in the midperipheral retina in the form of patches of pigment mottling and hypopigmentation. Nummular areas of patchy RPE and choroidal atrophy can develop subsequently in the midperipheral retina ( Fig. 6.16.1 ). In the intermediate stages of the disease, the atrophy of the RPE and choriocapillaris becomes more diffuse, while the intermediate and the larger choroidal vessels remain relatively more preserved ( Fig. 6.16.2 ). As the disease progresses, both the intermediate- and large-sized choroidal vessels become more atrophic, which exposes the underlying sclera. The macula is often initially relatively spared and is visible as a remaining island of choriocapillaris in the midst of surrounding white sclera ( Fig. 6.16.3 ). The macula can be relatively well preserved even in the late stages of the disease. Only in the more advanced stages do the retinal arterioles become attenuated, while the optic disc does not tend to become as pale or waxy pale as occurs in patients with retinitis pigmentosa.
The loss of visual field often corresponds to the clinically discernible areas of chorioretinal atrophy. Visual field examination initially shows a slightly restricted peripheral field, midperipheral scotomas, or both. With time, these scotomas coalesce to form a ring scotoma. The fields progressively constrict and finally leave a small central island. The visual acuity often is not notably affected and remains favorable until the seventh decade of life or even later. According to another study, there is a significant decline in visual acuity after age 50 years. Visual acuity may be decreased because of a degenerative maculopathy or the development of posterior subcapsular cataracts. A careful refraction is prudent, because such patients may have various degrees of myopia.
The female carriers are typically asymptomatic. There is a wide spectrum of clinical fundus appearance, which ranges from a fundus of normal appearance to a full-blown picture of choroideremia, as in an affected male. Characteristically, however, pigmentary changes in the fundus, described as moth-eaten in appearance, occur predominantly in the midperipheral retina. Areas of hyperpigmentation may be present as radial bands that extend from the midperiphery toward the ora serrata ( Fig. 6.16.4 ). The visual acuity may be decreased and visual fields reduced, depending on the extent of involvement of the photoreceptors. Usually these defects appear late, if at all, and are often mild. Most carriers do not show any electroretinographic amplitude reductions, although those who have more advanced fundus degenerative changes can show appreciable amplitude reductions.
Diagnosis and Ancillary Testing
The clinical fundus features are usually diagnostic in the intermediate and late stages of the disease. Good central visual acuity and slowly progressive visual field changes aid in the diagnosis. Both the electroretinogram and electro-oculogram can show marked impairment. The electroretinogram may rarely be normal in amplitude initially ( Fig. 6.16.5 ) or occasionally show only mild impairment in the very early stages. However, with the progression of the disease, there is progressive loss of retinal function ( Fig. 6.16.6 ). The fundus findings initially may be normal or only minimally abnormal ( Fig. 6.16.7 ). Once fundus changes become discernible, however, the electroretinogram is affected, usually notably. It often shows markedly reduced isolated rod responses with prolongation of rod b-wave implicit times in affected men. However, the isolated cone responses are initially either normal or moderately reduced in amplitude, with a delayed b-wave implicit time. The electro-oculogram is markedly abnormal in men with choroideremia ; the degree of electro-oculogram abnormality in carriers, although usually normal, varies.
Dark adaptation testing often shows elevated thresholds. In the early stages, only the rod portion of the curve is affected, while cone thresholds subsequently also become elevated.
Spectral-domain optical coherence tomography (SD-OCT) can show cystic macular lesions ( Fig. 6.16.8A ) and peripapillary nerve fiber layer defects ( Fig. 6.16.9 ), including thickening and thinning in various areas in some patients with choroideremia.
Fluorescein angiography is not useful in the diagnosis of choroideremia. It can, however, define the extent of choriocapillaris atrophy more accurately than ophthalmoscopy. Fluorescein angiography also may be superior to ophthalmoscopy in defining the extent of degenerative changes of the RPE, evident from hyperfluorescence seen on the angiogram.
The clinical diagnosis of choroideremia in the majority of male patients can be confirmed by an immunoblot analysis with anti-REP-1 antibody. The value of this test is based on the knowledge that all genetic mutations identified so far create stop codons that result in the absence of REP-1. The predictive value of this test, however, has not yet been established. Also, female carriers cannot be identified with this technique, because their REP-1 expression is not totally absent.
Differential Diagnosis
The differential diagnosis for choroideremia includes other night-blinding disorders, particularly retinitis pigmentosa. Fundus features of a pale optic disc, attenuated retinal arterioles, typical bone-spicule-like pigmentation, and a higher prevalence of posterior subcapsular cataracts associated with retinitis pigmentosa usually helps differentiate the latter disease from choroideremia. Nevertheless, some patients who have the X-linked form of retinitis pigmentosa, who can show higher degrees of myopia and prominent choroidal vessels, may have a phenotypic similarity to patients who have choroideremia. However, patients who have X-linked retinitis pigmentosa have a reduction in central visual acuity early in the course of their disease, while patients with choroideremia do not characteristically manifest bone-spicule-like pigment clumping.
Patients who have ocular albinism may show some degree of phenotypic similarity to those with choroideremia; however, absence of nyctalopia, presence of nystagmus, iris transillumination defects, and normal electroretinographic amplitudes help to differentiate these two disorders.
Features distinguishing gyrate atrophy of the choroid and retina from choroideremia include autosomal recessive inheritance, well-demarcated, scalloped areas of chorioretinal atrophy, and association of hyperornithinemia with the former. It sometimes may be difficult to differentiate end-stage gyrate atrophy from an advanced case of choroideremia.
Generalized choroidal atrophy, which may show phenotypic similarities to an intermediate stage of choroideremia, is inherited in an autosomal dominant or occasionally autosomal recessive fashion. The various regional types of choroidal atrophies usually cause a milder visual dysfunction and, in general, can be differentiated easily without notable difficulty.
Another form of a diffuse choroidal dystrophy, progressive bifocal chorioretinal atrophy 2, is an autosomal dominant dystrophy. Its phenotype includes an involvement of the macula from birth, and hence nystagmus and reduced central visual acuity, a relatively higher incidence of retinal detachment and diffuse reduction of rod and cone responses on electroretinography. The phenotype of this disease has a distinctly different fundus appearance, time of onset, and genetics than are observed in choroideremia.
Myopic retinal degeneration sometimes may mimic choroideremia. However, the myopic degeneration usually is not as diffuse as the lesions of choroideremia, and patients with myopic degeneration do not characteristically complain of night blindness.
Systemic Associations
Isolated reports show the association of a choroideremia-like phenotype with mental deficiency, acrokeratosis, anhidrosis, and skeletal deformity; uveal coloboma; obesity and congenital deafness; congenital deafness and mental retardation; hypopituitarism; distal motor neuropathy; and nystagmus, myopia, dental deformities, optic nerve head drusen, and microblepharia.
Pathology
In male patients with choroideremia, light microscopy shows widespread chorioretinal atrophy, especially of the choriocapillaris, along with degenerative changes in the RPE, outer retinal layers (especially the photoreceptors), and larger choroidal vessels. A graded atrophy occurs: The equatorial area is most affected while the macular, peripapillary, and ora serrata areas are relatively spared. In the late stages, the far periphery and the central regions also may be severely involved. Retinal bipolar and ganglion cells appear normal. Electron microscopy shows extensive loss of photoreceptors and RPE, especially away from the macula. End-stage disease can show widespread neural retinal gliosis and atrophy.
A histopathological study in an 88-year-old choroideremia carrier showed patchy areas of degeneration of photoreceptors and RPE cells that were not necessarily concordant. The choriocapillaris was normal except where corresponding to areas of severe retinal degeneration, as reported previously. However, immunofluorescence analysis localized the CHM gene product (REP-1 with a mouse monoclonal antibody) to the rod cytoplasm and amacrine cells but not in the cones. This suggests that the primary site of the disease may be in the rods rather than RPE or choroid. This labeling, which was seen in small vesicles in the rod cytoplasm, is consistent with the association of REP-1 with intracellular vesicular transport.
Treatment, Course, and Outcome
A phase I/II clinical trial with subretinal injection of an adeno-associated viral gene vector encoding for REP1 (AAV-REP1), showed that this was safe and reported significant visual acuity improvement in 2 of 6 patients enrolled. This improvement in visual acuity was sustained at 3.5 years. Several other similar treatment trials are underway in the United States ( ClinicalTrials.gov Identifier: NCT02341807) and Canada ( ClinicalTrials.gov Identifier: NCT02077361).
The cystic macular changes associated with choroideremia, as seen by SD-OCT, can diminish or resolve when treated with topical 2% dorzolamide, leading to decreased macular thickness (see Fig. 6.16.8B–C ) in at least some patients.
Epidemiology and Pathogenesis
The exact pathogenesis of the degenerative changes observed in patients and the cells primarily affected in choroideremia are yet to be defined with certainty. In the past, it was thought that this disease was caused primarily by degeneration of RPE cells, the choroid, or both, with photoreceptors degenerating secondarily. It has been suggested that the primary defect may be in the rod photoreceptor cells of the retina. It has also been proposed that there may be independent degeneration of RPE cells and photoreceptor cells, based on a conditional knockout mouse model. A recent multimodal imaging of photoreceptor structure in choroideremia showed remnants of cone inner segments within “outer retinal tubulations” (ORTs) and the continuity of the ORTs with the preserved retina, thereby suggesting degeneration of RPE earlier than the photoreceptors.
The choroideremia gene (CHM) was isolated by positional cloning techniques and localized to the long arm of the X chromosome (Xq21). The CHM gene encodes the Rab escort protein-1 (REP-1) of Rab geranylgeranyl transferase, a two-component enzyme (components REP-1 and REP-2) that modifies Rab proteins. Rab proteins are low-molecular-weight guanosine triphosphatases that regulate intracellular vesicular transport. For Rab proteins to bind to membranes, they undergo lipid modification with the addition of 20 carbon units to the carboxy terminal of the protein, a process known as geranylgeranylation. Of interest, the CHM gene is expressed not only in ocular tissues but also in various cells of nonocular origin. However, CHM gene dysfunction affects only the retina. The proteins REP-1 and REP-2 are 75% identical, and their functions are mutually redundant. The functioning of the majority of the cells in the body that have a REP-1 deficiency can be taken over by REP-2 and, hence, can function adequately. However, the retina has a major Rab protein, Rab 27, which is prenylated more efficiently by REP-1 than REP-2. Since all mutations known so far in the CHM gene create stop codons and, hence, an absence of the gene product REP-1, there is progressive chorioretinal degeneration in patients with choroideremia.
Ocular Manifestations
A majority of patients with choroideremia present with progressive impairment of night vision. It usually begins in the first decade of life, although the onset may be delayed. Some patients can, however, have midperipheral visual field loss. The clinical features, including the rate of progression, can show both interfamilial and intrafamilial variability.
The ocular findings in the anterior segment are unremarkable. Posterior subcapsular changes in the lens develop more frequently than in the general population. Even those patients who do not show clinical cataract changes may have subclinical lens changes as demonstrated indirectly by increased light scatter.
Initial fundus changes most often begin in the midperipheral retina in the form of patches of pigment mottling and hypopigmentation. Nummular areas of patchy RPE and choroidal atrophy can develop subsequently in the midperipheral retina ( Fig. 6.16.1 ). In the intermediate stages of the disease, the atrophy of the RPE and choriocapillaris becomes more diffuse, while the intermediate and the larger choroidal vessels remain relatively more preserved ( Fig. 6.16.2 ). As the disease progresses, both the intermediate- and large-sized choroidal vessels become more atrophic, which exposes the underlying sclera. The macula is often initially relatively spared and is visible as a remaining island of choriocapillaris in the midst of surrounding white sclera ( Fig. 6.16.3 ). The macula can be relatively well preserved even in the late stages of the disease. Only in the more advanced stages do the retinal arterioles become attenuated, while the optic disc does not tend to become as pale or waxy pale as occurs in patients with retinitis pigmentosa.
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