12.4.4  Generalized Choroidal

Dystrophies

Unlike retinitis pigmentosa and other primary neurosensory degenerations, choroidal dystrophies are a rare group of conditions that involve loss of subretinal tissue, including retinal pigment epithelium and choriocapillaris, prior to retinal involvement. Angiographic loss of choriocapillaris precedes observable retinal changes. Large areas of pigmentary changes predominate instead of bone spicule deposits, which helps distinguish these choroidal degenerative entities from their primarily retinal counterparts. Choroideremia [93] is the best known of the diffuse chorioretinal degenerations. It is further distinguished by its X-linked pattern of inheritance. Gyrate atrophy is an autosomal recessive dystrophy with peripheral choroidal degeneration attributable to an inborn error of metabolism [94]. The prognosis of these slowly progressive heterogeneous diseases is similar to retinitis pigmentosa with variable, gradual loss of visual function in the first few decades of life [95]. The central choroidal degenerative disorders including central areolar choroidal atrophy are discussed in a separate chapter.

12.4.4.1  Genetics

Although generalized choroidal dystrophies with autosomal dominant and recessive inheritance patterns have been encountered rarely, the most prominently described choroidal degeneration is the X-linked choroideremia. Caused by a CHP gene mutation on Xq13-q22, the locus has recently been identified to encode Rab 1 escort protein REP-1 [96]. The gene product is thought to be involved in facilitation of vesicular transport in the cells and proper functioning of Rab geranylgeranyl transferase [97], an enzyme required for posttranslational modification of cell membrane proteins. The gene carriers are usually asymptomatic, but can have a slightly abnormal fundus appearance without marked electrophysiologic deficits. Gyrate atrophy is another choroidal dystrophy with a known biochemical mechanism. It is a rare autosomal recessive disorder caused by defects in the ornithine aminotransferase (OAT) enzyme [98]. Over 50 mutations have been found in the associated gene, located on chromosome 10q26 [99]. As with retinal degenerative disorders, heterogeneity appears to be the rule than exception.

12.4.4.2  Pathophysiology

The initiating defect in the choroidal degenerations is thought to be subretinal, in the choriocapillaris and retinal pigment epithelial layer, followed by diffuse atrophy of the overlying retina. Given the rarity of these conditions, histologic specimens from early forms of these disorders have not been readily available and further study of disease pathogenesis has been limited. Recent study of animal models supports a role for the choroideremia gene product in vascular development [100]. However, the mouse phenotype that is defective in choroideremia gene copies is not confined to the eye and early lethality, occurs in utero [101]. Defective formation of placental vasculature is thought to be the source of early lethality in this mouse model. This necessitates study of heterozygous females for the choroideremia model, who have been found to display photoreceptor degeneration. In the gyrate atrophy model, animals null for the OAT gene copies died at birth. Arginine supplementation leads to the rescue of these mutants, but with the development of a slowly degenerative chorioretinal disorder.

12.4.4.3  Incidence

The Incidence does not exceed 1 in 50,000, even among Scandinavians where the disease incidence is highest [95].

12.4.4.4  Evaluation and Prognosis

Like other degenerative retinal conditions, choroidal dystrophies have variable onset and progression and can occur in the pediatric population in the first two decades of life. Nyctalopia, loss of vision, anisometropia, and amblyopia are common presenting symptoms. Central vision is generally preserved in early disease. Anterior segment findings are essentially normal, with the exception of posterior subcapsular cataracts that are sometimes seen with gyrate atrophy.

Peripheral choroidal and retinal pigment epithelial atrophy are the predominant findings on fundus exam. Choroideremia demonstrates a diffuse loss of pigment, whereas gyrate atrophy is notable for a scalloped loss of pigment epithelium and choriocapillaris (Fig. 12.2). Unlike retinitis pigmentosa, retinal

Fig. 12.2  Fundi of a patient with choroidal atrophy. Representative central fundus (a, c) and peripheral fundus photographs (b, d) are shown

a

c

b

d

pigment deposition is relatively rare, with a few large pigment clumps instead of multiple bone spicules. Optic nerve pallor is common and vascular attenuation may also be present, although not prominent in early phases of disease.

12.4.4.5  Diagnostic Testing

Several studies help distinguish these disorders from similar retinal degenerative conditions. ERG studies reveal marked reduction in both scotopic and photopic signals with near complete loss of both signals. Fluorescein angiogram shows diffuse loss of choriocapillaris and extensive window defects. In cases of gyrate atrophy, the pattern is scalloped and delineated with the margins of the area showing some fluorescent staining. Elevated serum ornithine levels in the order of several-fold are crucial to establishing the diagnosis of gyrate atrophy. Diagnosis of choroideremia may be facilitated by the recently developed CHM immunoblot assay, which detects the REP-1 gene product in lymphocytes of affected patients [102].

12.4.4.6  Treatment

Treatment options for most choroidal degenerative disorders are currently limited, and generally follow the outline described for retinitis pigmentosa. Low vision aids, refractive correction and supportive measures to help the patients cope with vision deterioration are indicated. A subset of patients with gyrate atrophy may have a pyridoxine responsive form, and may benefit from pyridoxine supplementation to reduce the rate of vision loss. Additional benefit in patients with gyrate atrophy may come from early implementation of an austere arginine restricted diet [103, 104].

12.4.4.7  Complications and Disease Associations

Gyrate atrophy has a known association with skeletal muscle involvement, specifically myopathy caused by atrophy of Type 2 muscle fibers [105]. Abnormal EEG findings and premature degeneration of CNS white matter on magnetic resonance imaging have also been associated with gyrate atrophy [106]. Cataracts

generally occur by the second decade in these patients. Choroideremia is generally an isolated condition. Rare reports exist of choroideremia associated with deafness and ovarian failure [107], hypopituitarism and neurologic abnormalities [108], and distal hereditary motor neuropathy [109].

12.4.4.8  Social Considerations

Physicians dealing with these patients should be sensitive to the overall impact of the disease and the unique needs of the patient and family. Referral to appropriate supportive services should be made in order to maximize the function of a visually disabled child. A blind child with a degenerative retinal disorder in addition to other potential neurologic deficits can be a major challenge requiring involvement of multiple social services agencies for their overall care. Initial counseling and appropriate social referral can place the family in better control of the environment both in school and at home, and maximize the functionality of the visually disabled patient. RP societies and support groups can further help the patient and families cope with the overall impact of the disease and optimize the quality of life for

Clinical features of hereditary retinal degenerations

these families. Additionally, speech therapy and hearing aid may be needed for patients with hearing loss.

Support groups and centers for assisting patients with visual aid and adaptation are an important part of the overall care for patients with retinitis pigmentosa. These groups allow the parents to work with children to adapt to their conditions. Gradual visual decline combined with the plasticity of early neural development in some ways may temper the overall negative impact of retinitis pigmentosa in the pediatric population.

Because the decline in vision is gradual, compensatory adaptation frequently prevents early symptoms and detection unless a family history is present. Many children do not come to the attention of an ophthalmologist until the visual fields are severely constricted and even then only subtle difficulties with navigation or retrieval of dropped items are noted. Due to this adaptation, it is important to avoid unnecessary discouragement of parents regarding disease prognosis. Frequently, the patients and parents can be told that the patient will continue to have visual function for many years to come. With steps taken to adequately illuminate the environment of these patients at home and in school, mildly affected patients may function well despite their relative visual compromise for many years.