CHOROIDEREMIA

Choroideremia is an X-linked recessive choroidal dystrophy. It is characterized by a progressive degeneration of the retinal pigment epithelium (RPE), choroid, and choriocapillaris. Typically, most male patients experience the onset of symptoms in the first or second

decade of life.

Symptoms

Affected males experience night blindness and peripheral visual field loss. Central vision becomes affected later in the course of the disease. Color vision is usually unaffected. Female carriers are commonly asymptomatic.

Clinical Features

Early in the disease course, the fundus shows pigment mottling near the equator. As the disease progresses, areas of choroidal and retinal pigment epithelial atrophy develop in the midperiphery and spread toward the macula and toward the periphery. In female carriers, the fundus appearance shows generalized or localized pigment mottling.

Ancillary Testing

Fluorescein angiography reveals loss of the retinal pigment epithelium and choriocapillaris. Fluorescein angiography also shows a delayed filling of the choroidal vasculature. However, there may be a relative sparing of the RPE and choriocapillaris in the central macular region.

The electroretinogram (ERG) is abnormal in the early stages of the disease and becomes extinguished later. If recordable, the scotopic response is markedly reduced, whereas the photopic response may be reduced but with delayed implicit times. Female carriers have normal ERG responses.

Pathology/Pathogenesis

The genetic defect in choroideremia is a deletion in Rab escort protein (REP-1) gene. The locus of this gene has been mapped to Xq21.1-21.3. This gene product is a component of Rab geranylgeranyl transferase, which regulates intracellular protein transport. Histopathologic studies reveal atrophy of the RPE, choroid, choriocapillaris, and outer retina. However, the pathogenesis of this atrophy is not understood.

Treatment/Prognosis

There is no known treatment for choroideremia. Usually, central vision becomes poor in the later stages of the disease.

Systemic Evaluation

No systemic associations have been reported in choroideremia.

Choroideremia is an X-linked recessive disorder characterized by atrophy of the retinal pigment epithelium and choroid. This atrophy unmasks the larger choroidal vessels.

This patient with choroideremia demonstrates atrophy of the retinal pigment epithelium and choroid.

Focal areas of atrophy are first visualized in the midperipheral and posterior fundus. The center of the macula is spared until the late stages of the disease.

A fluorescein angiogram of the patient in the previous figure demonstrates marked hypofluorescence as the result of choroidal atrophy. Only the larger choroidal vessels remain.

Advanced choroideremia, with marked atrophy of the retinal pigment epithelium and choroid, reveals the underlying sclera.

In female carriers, the fundus appearance shows generalized or localized pigment mottling. This woman’s son had advanced choroideremia.

Cone dystrophies consist of a group of disorders characterized by cone dysfunction. Cone dystrophies can be congenital and nonprogressive in nature, such as in rod monochromatism (autosomal recessive) and blue-cone monochromatism (X-linked recessive). Noncongenital progressive cone dystrophies may be autosomal recessive, autosomal dominant, or X-linked recessive.

Symptoms

Patients with rod monochromatism or achromatopsia and blue-cone monochromatism usually experience nyctalopia, poor vision, abnormal color vision, and photoaversion. Affected males with X-linked blue-cone monochromatism are typically myopic. Individuals with progressive cone dystrophies present with progressive central visual loss, poor color vision, and aversion to light. The age at onset of symptoms of these hereditary progresssive cone dystrophies ranges from the first to the sixth decade of life.

Clinical Features

Patients with congenital nonprogressive cone dystrophies may have a normal-appearing fundus, while others show minimal pigmentary disturbances or bull’s eye macular changes. Affected patients with progressive cone dystrophies present initially with a normal-appearing fundus; as the disease progresses, a bull’s eye maculopathy develops. Some patients can develop macular staphylomas. If rod photoreceptors become involved, optic

disc atrophy, attenuated vessels, and bone spicule-like pigmentation may evolve with time.

Ancillary Testing

In rod monochromatism, the electroretinogram (ERG) is characteristic, showing an absent or markedly reduced cone response and normal rod response. Rod monochromatism also has typical findings on dark adaptation. There is no cone segment or cone-rod break in the darkadapted curve. Blue-cone monochromatism reveals a blue-cone response on ERG. Progressive cone or conerod dystrophies have a marked reduction of the ERG cone response. Rod response may be affected later in the course of the disease.

Pathology/Pathogenesis

Rod monochromatism has been mapped to 2q11, 8q21-22, and 14. Histopathologic studies have shown a diminution of extrafoveal cones and ultrastructural abnormalities of foveal cones. Blue-cone monochromatism has been mapped to Xq28. This condition occurs secondarily to a functional defect on the red and green cone pigments. Progressive cone dystrophies have been mapped to different loci (chromosomes 1, 6, 8, 12, 17, 19, X). Functional abnormalities of cone pigments and

impairment in processing by bipolar cells have been proposed as possible etiologies. Mutations in the guanylate cyclase activator 1A gene, which encodes guanylate cyclase activating protein-1, have been determined to be responsible for some cases of dominant cone-rod dystrophy. Histopathologic studies have shown loss of the outer nuclear layer and pigmentary changes as well.

Treatment/Prognosis

This heterogeneous group of conditions has no known treatment. Rod monochromatism and blue-cone monochromatism tend to be stationary, while cone or cone-rod dystrophies are progressive, with variability in onset, severity, and rate of progression.

Systemic Evaluation

No known systemic associations have been reported.

In some patients with cone dystrophy, the fundus may appear normal or have mild mottling of the retinal pigment epithelium.

The classic fundus finding in a patient with cone dystrophy is a bull’s eye maculopathy.

The fellow eye of the patient in the previous figure demonstrates a slightly more noticeable pattern of retinal pigment epithelial atrophy. Note the subtle temporal disc pallor.

Bull’s eye maculopathy refers to a pattern of retinal pigment epithelial alterations in the macula characterized by a central region of hyperpigmentation surrounded by a zone of hypopigmentation reminiscent of an aiming target.

Occasionally, patients with cone dystrophy may develop central geographic atrophy.

A fluorescein angiogram of the patient in the previous figure reveals a “window” defect corresponding to the region of atrophy.