Chapter 110 – Choroidal Dystrophies
GERALD A. FISHMAN
• Choroideremia is a progressive, diffuse, bilateral chorioretinal dystrophy with an X-linked recessive mode of inheritance.
• Gyrate atrophy of the choroid and retina is a progressive, diffuse, bilateral chorioretinal dystrophy with an autosomal recessive mode of inheritance.
• Choroideremia: involvement of the choroid, retinal pigment epithelium, and retinal photoreceptors; nyctalopia; midperipheral and, subsequently, far peripheral visual field loss.
• Gyrate atrophy: chorioretinal lesions of atrophic appearance with scalloped margins; nyctalopia; midperipheral and peripheral visual field loss.
• Choroideremia: often initial macular sparing; characteristic findings in female carriers.
• Gyrate atrophy: systemic hyperornithinemia.
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 on the basis of the initial or predominant site of the degenerative changes (macular, peripapillary, paramacular, 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.
Choroideremia is a progressive, bilateral dystrophy of the retina and choroid. It is an X-linked recessive disease, transmitted on the long arm of the X chromosome, that is characterized by a marked loss of vision at night and progressive loss of peripheral visual fields. Although encountered relatively infrequently, this disease is probably the second most common cause, after retinitis pigmentosa, of progressive, hereditary night blindness.
EPIDEMIOLOGY AND PATHOGENESIS
The exact pathogenesis for the degenerative changes observed in patients with and the cells primarily affected in choroideremia is yet to be defined with certainty. In the past this disease was thought to be caused primarily by degeneration of RPE cells or choroid, or both, with photoreceptors degenerating secondarily. However, recently it has been suggested that the primary defect may be in the rod photoreceptor cells of the retina.
The gene that causes choroideremia was isolated by positional cloning techniques and localized to the long arm of the X chromosome (Xq21).  The choroideremia gene (CHM) 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. Rab proteins probably exist in two forms: one, the inactive, guanosine diphosphate–bound state, and the other, the active, guanosine triphosphate–bound state. 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. This, then, probably acts as a chaperon to deliver the prenylated Rab protein to the cellular membrane. 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, which 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 a progressive chorioretinal degeneration in patients with CHM.
Impairment of night vision, which progresses over time, is the initial symptom in most patients who have choroideremia. It usually starts 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. The crystalline lens remains clear until the later stages of the disease. However, posterior subcapsular changes in the lens develop more frequently than in the general population. The vitreous shows fine, fibrillar degeneration at an early age.
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
Figure 110-1 Fundus changes found in choroideremia. Nummular areas of retinal pigment epithelial and choroidal atrophy in the midperipheral retina are shown.
Figure 110-2 Fundus changes of the right eye in a patient with an intermediate stage of choroideremia. Note the diffuse changes of the retinal pigment epithelium and prominent choroidal vessels.
( Fig. 110-1 ). In the intermediate stages of the disease, the atrophy of the RPE and choriocapillaris become more diffuse, while the intermediate and the larger choroidal vessels remain relatively more preserved ( Fig. 110-2 ). As the disease progresses, both the intermediate-size and large choroidal vessels become more atrophic, which exposes the underlying sclera. The macula initially is spared relatively often and is visible as a remaining island of choriocapillaris in the midst of surrounding white sclera ( Fig. 110-3 ). 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 or 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 until the fifth decade of life or even later. Visual acuity may be decreased because of degenerative maculopathy or the development of posterior subcapsular cataracts. A careful refraction is prudent, because such patients may have various degrees of myopia.
Figure 110-3 Fundus changes in the right eye in a patient with late-stage choroideremia.
Figure 110-4 Posterior fundus changes in the right eye in a carrier of choroideremia.
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. Pigmentary atrophy, mottling, and clumping also may be discernible more posteriorly ( Fig. 110-4 ). Areas of hyperpigmentation may be present as radial bands that extend from the midperiphery toward the ora serrata ( Fig. 110-5 ). 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. Vitreous fluorophotometry shows a normal blood–retinal barrier in carriers of choroideremia. 
DIAGNOSIS AND ANCILLARY TESTING
The clinical fundus features usually are diagnostic in the intermediate and late stages of the disease. Good central visual acuity and slowly progressive visual field changes aid in the diagnosis.
Figure 110-5 Peripheral fundus changes in a carrier of choroideremia. Note the radial bands of hyperpigmentation and some pigment clumping.
Both the electroretinogram and electro-oculogram can show marked impairment. The electroretinogram may rarely be normal in amplitude initially ( Fig. 110-6 ) or occasionally show only mild impairment in the very early stages. The fundus findings initially may be only normal or minimally abnormal ( Fig. 110-7 ). 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. There is a wide intrafamilial and interfamilial variability in electroretinographic amplitudes with age. The electro-oculogram is markedly abnormal in men with choroideremia ; the degree of electro-oculogram abnormality in carriers, although usually normal, varies. In one study the ratio of light–peak to dark–trough was abnormal in about one fourth of carriers; this ratio significantly decreased with increasing age.
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.
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 CHM in the majority of male patients can be confirmed by an immunoblot analysis with anti–REP-1 antibody. The basis, again, is 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 of CHM cannot be identified with this technique, because their REP-1 expression is not totally absent.
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 help 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
Figure 110-6 Electroretinographic recordings from a male patient with choroideremia at ages 9 and 11 years showing normal light-adapted flicker and single flash (A) and dark-adapted rod-isolated and maximal (B) responses.
Figure 110-7 Fundus photograph of the right eye of the same patient as in Figure 110-6 at age 11 years, showing normal optic discs and retinal vessels. Also shown is a mild-to-moderate degree of pigment mottling anterior to the vascular arcades.
phenotypic similarity to patients who have choroideremia. However, patients who have X-linked retinitis pigmentosa have a reduction in central 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, decreased vision, 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 can be differentiated easily.
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. Examination of other family members, especially carriers, helps facilitate the diagnosis.
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, and microblepharia.
In male patients with choroideremia, light microscopy shows a widespread chorioretinal atrophy, especially the choriocapillaris, along with degenerative changes in the RPE, outer retinal layers (especially the photoreceptors), and larger choroidal vessels ( Fig. 110-8 ). 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 ( Fig. 110-8 ). End-stage disease can show widespread neural retinal gliosis and atrophy.
A recent histopathological study in an 88-year-old choroideremia carrier showed patchy areas of degeneration of photoreceptors and RPE cells which were not necessarily concordant. The choriocapillaris was normal except 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 this 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
At present there is no treatment for choroideremia. The disease is invariably progressive, but the rate of progression can be highly variable.
Figure 110-8 Choroideremia. A, Histological section showing absence of retinal pigment epithelium and atrophy of both the overlying neural retina and the underlying choroid (V, vitreous; R, atrophic retina; S, sclera; C, atrophic choroid). B, Electron micrograph shows choroidal vessel deep to choriocapillaris. Both endothelial (E) and pericyte (P) basement membranes are absent centrally. A small amount of fragmented basement membrane (arrow) persists on the left. (A, Presented by Dr. WS Hunter at AOA-AFIP meeting, 1969; B, from Cameron JD, et al. Ophthalmology. 1987;94:187.)
Gyrate atrophy of the choroid and retina is a slowly progressive chorioretinal dystrophy. Like many metabolic disorders, it is inherited in an autosomal recessive manner. Gyrate atrophy is characterized by discrete areas of chorioretinal atrophy in the midperipheral retina. These are sharply demarcated from the more posterior retina, which is initially of normal appearance. This dystrophy is associated with hyperornithinemia to levels 10–15-fold above normal, shown to be caused by a deficiency of ornithine ketoacid aminotransferase, also known as ornithine aminotransferase (OAT). This enzyme depends on a cofactor, pyridoxal phosphate (vitamin B6 ).
EPIDEMIOLOGY AND PATHOGENESIS
Simell and Takki in 1973 were the first to report the finding of hyperornithinemia with gyrate atrophy. Sengers et al. first reported a deficiency of the mitochondrial matrix enzyme OAT in patients who have gyrate atrophy. Ornithine, a nonessential amino acid, is an intermediate compound in the formation of urea ( Fig. 110-9 ). The major pathway for utilization of ornithine is by enzymatic conversion into glutamic-?-semialdehyde by OAT, a vitamin B6 –dependent enzyme, and subsequently to proline. OAT has been found with high activity in the retina, liver, and kidney. An experimental model that resembles gyrate atrophy has been found in animals injected with intravitreous ornithine.
Since OAT is dependent on cofactor B6 , treatment with oral vitamin B6 has been tried. Patients who have gyrate atrophy are categorized into two groups, depending on a lowering of plasma ornithine levels in response to vitamin B6 . The vitamin
Figure 110-9 Pathway of ornithine metabolism.
B6 –responsive patients, although considerably fewer in number than nonresponders, appear to have a milder disease and better visual function than the nonresponsive group.
The human OAT gene has been cloned and mapped to 10q26, and more than 60 mutations have been identified. An OAT-deficient mouse model (Oat-/-) has been developed by gene targeting that has hyperornithinemia levels 10–15 times the normal, as in patients with gyrate atrophy. This has improved the potential for a better understanding of the pathogenesis and possible therapeutic outcome of this disease.
Patients with gyrate atrophy of the choroid and retina develop nyctalopia during the second to third decade of life. Initially it is mild to moderate in severity and slowly progressive. The earliest appearance may occur in the form of a restriction in peripheral field. Usually visual acuity is preserved until a later stage. Visual acuity may be decreased from involvement of the macula by the disease itself or secondarily from cystoid macular edema or cataracts.
The fundus shows atrophy of the RPE and choriocapillaris during the earlier and intermediate stages, with sharply demarcated scalloped areas of atrophy ( Fig. 110-10 ) and a tendency for pigment clumping to occur at the margins. The atrophy usually starts in the midperipheral and peripheral areas, often referred to as a garland-shaped fashion, and then progresses centrally as well as peripherally. Ultimately it involves the entire fundus, including the peripapillary area, with relative sparing of the macula. Fine granular and velvety pigmentation may be observed in the macula area and retinal periphery, respectively, in a number of patients.  With progressive atrophy, the larger choroidal vessels are also involved. The optic disc and retinal arterioles usually are normal until the later stages. Vitreous changes, such as posterior vitreous detachment, and development of epiretinal membranes with cystoid macular edema, have been observed with gyrate atrophy of the choroid and retina. 
Visual field defects correspond to the atrophic areas in the choroid. The field loss begins in the midperipheral area as regionally dense scotomas, which eventually coalesce to form a
Figure 110-10 Fundus changes in the left eye of a patient with an intermediate stage of gyrate atrophy of the choroid and retina. Note the well-demarcated, scalloped areas of atrophy.
ring scotoma. Progressive field loss ultimately leaves the patient with only small residual central fields. Usually by 40 years of age, the visual fields are substantially restricted.
Moderate-to-marked myopia is found in most patients, and lens changes are seen in almost all patients who have this disease. Posterior sutural and subcapsular cataracts and, in isolated cases, anterior subcapsular plaque-like cataracts have been described.
DIAGNOSIS AND ANCILLARY TESTING
A history of night blindness and the typical fundus feature of scalloped areas of atrophy of the RPE and choroid are suggestive of the diagnosis. The electroretinogram is subnormal in the early stages, with marked reduction or nondetectable a-wave and b-wave responses in the later stages. The rod responses are affected more severely in the early stages, but later both rods and cones become affected. Some patients also have a delayed cone implicit time response when tested using a 30?Hz flicker stimulus.  The electro-oculogram is affected mildly or not at all in very early stages of the disease. However, with progression of the disease, electro-oculogram light-peak to dark-trough ratios become markedly reduced. Overall, the electroretinographic responses, including oscillatory potentials, and electro-oculogram light-peak to dark-trough ratios are better maintained in vitamin B6 –responsive patients. Dark-adaptation curves may show a slightly prolonged cone–rod break time. Again, in a vitamin B6 responder or in early childhood, when the disease is not as severe, notably less extensive changes occur in dark-adaptation function. However, in later stages of the disease, more marked elevation of cone or rod, or both, thresholds develop.
Fluorescein angiography, not unexpectedly, shows RPE transmission defects in the areas of chorioretinal atrophy. These areas of transmission defects often are larger than the clinically visible atrophic areas.
High ornithine levels are found in the urine, plasma, aqueous humor, and cerebrospinal fluid of these patients, often elevated to 10–20 times the normal levels. No evidence exists of any correlation of age or severity of involvement with the concentration of ornithine in plasma. The 24-hour urine creatine excretion is normal.
Gyrate atrophy of the choroid and retina is diagnosed by means of the typical fundus feature of scalloped areas of retinal and choroidal atrophy, an autosomal recessive inheritance, and hyperornithinemia. However, a gyrate atrophy–like fundus phenotype
Figure 110-11 Fundus changes in the left eye of a patient with choroideremia. The scalloped areas of atrophy resemble the lesions found in gyrate atrophy of choroid and retina.
with a possible autosomal dominant inheritance pattern and normal plasma ornithine levels has also been described. Gyrate atrophy also can show certain phenotypic similarities to choroideremia, myopic degeneration, and hereditary choroidal atrophy. It is mainly in its later stages that gyrate atrophy of the choroid and retina clinically may most resemble the retinal findings seen in choroideremia. However, in earlier stages of the disease, patients who have choroideremia may show scalloped or nummular areas of RPE and choroidal atrophy ( Fig. 110-11 ). Typical retinitis pigmentosa usually can be differentiated from gyrate atrophy, but atypical retinitis pigmentosa sometimes may show certain phenotypic similarities. Bone-spicule pigment in the retina and attenuated retinal arterioles at an earlier stage aid in the diagnosis of retinitis pigmentosa. In gyrate atrophy, the pigment clumps usually are more dense and associated with the atrophic lesions.
Electromyograms are abnormal in most tested patients,  although only a few complain of slight muscle weakness. Electromyographic observations include a myopathic pattern of short-duration, low-amplitude motor unit action potentials, and increased polyphasic potentials. Muscle biopsy shows atrophic type 2 muscle fibers with tubular aggregates visible on electron microscopy. Abnormal electrocardiographic features may include a broad P-wave, prolonged QT interval, and flattening of the T-wave. Electroencephalograms also may be abnormal in some patients.   The changes include an increase in slow activity, focal slow-wave abnormalities, and focal sharp waves.
Various rare associations of a clinical picture that resembles gyrate atrophy have been seen with microcephaly, spinocerebellar ataxia, subluxation of the lens, pituitary dysfunction, and congenital muscular dystrophy. All of these associations were found with normal levels of plasma ornithine.
Reports exist of fine, sparse hair with patches of alopecia, skeletal muscle abnormalities, hepatic mitochondrial changes, and subnormal intelligence. Massive cystinuria and lysinuria with hypermetropia and diabetes also have been observed with gyrate atrophy. Chorioretinal lesions that resemble gyrate atrophy with vitreochorioretinal degeneration, associated trichomegaly, and normal plasma ornithine levels also have been reported.
Limited information on pathological findings is available on patients with gyrate atrophy. The atrophic areas in the midperipheral retina show a marked atrophy of the choroidal vessels, including the choriocapillaris, RPE, and photoreceptors. The regions of clinically normal appearance in the posterior pole show focal areas of photoreceptor cell loss. The RPE at the posterior pole, however, has been reported to be hyperplastic. The photoreceptors show a shortening of their outer segments in the transitional area and are absent in the atrophic areas. Histological examination of cataractous lenses shows markedly widened spaces at the posterior sutures, filled with denatured proteins.
Electron microscopy shows abnormal mitochondria in the corneal endothelium, smooth muscle of the iris and ciliary body, and epithelium of the ciliary body. Mitochondrial abnormalities include enlarged and dilated mitochondria with an electron-lucent matrix and disruption of cristae. Slight mitochondrial changes are observed in those photoreceptors that look normal structurally but are close to the area of chorioretinal atrophy. Dilated mitochondria are present mainly in rod ellipsoids but also in cone ellipsoids. The mitochondria in the RPE initially are normal.
Histopathological studies in the OAT-deficient mouse model showed earliest changes in the RPE cells in the form of occasional necrotic cells with pale cytoplasm and swollen organelles at 2 months of age. By 7 months, these RPE cells were engorged with phagocytosed outer segment membranes. Photoreceptor cells, which were normal at 2 months of age, lost 33% of their total number and underwent 60% reduction of their outer segment length by 10 months.
TREATMENT, COURSE, AND OUTCOME
Since ornithine is produced from other amino acids, mainly arginine, some investigators advocate that patients be restricted to a rigid schedule of a low-protein diet, including near-total elimination of arginine, with supplementation of essential amino acids. Administration of high doses of vitamin B6 has reduced the plasma ornithine level in a limited number of such patients. These forms of treatment, although useful to reduce the elevated levels of plasma ornithine, have not convincingly improved or arrested the chorioretinal degeneration.  A long-term study of an arginine-restricted diet in six pairs of affected siblings was encouraging, because it showed that a substantial reduction of ornithine levels occurred when such patients were fed an arginine-restricted diet over a period of 5–7 years. Also, the younger of the sibling pairs, who were started on this diet at an earlier age, showed markedly fewer signs of the disease compared with the older siblings. The study suggests that an arginine-restricted diet may cause a decrease in the progress of the chorioretinal degeneration. Consistent with this observation, correction of ornithine accumulation by an arginine-restricted diet in the Oat-/- mouse model entirely prevented retinal degeneration. This suggests that it may not be necessary to restore the activity of OAT enzyme to metabolize the accumulating ornithine for treating this condition but, instead, restrict the substrate, arginine, from which ornithine is formed.
As with other inherited retinal degenerative disorders, a better understanding of the pathogenetic mechanisms by which the retinal cells degenerate in patients who have various choroidal dystrophies will ultimately lead to more effective treatment strategies in the future.
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