68 Choroideremia

. .

C (CHM, OMIM 303100) is a distinct diagnosis that can be clinically distinguished from other retinal degenerations, such as other forms of retinitis pigmentosa (RP). CHM represents 6% of cases in one practice that focused on RP-related conditions.10 Mauthner first used the term to indicate that the choroid was missing while the retinal vessels were preserved and no optic atrophy was noted.14 These characteristics set CHM apart from RP, which has significant pigment dispersion in the retina, retinal vessel narrowing, and optic nerve gliosis. In some cases, patients with CHM have posterior subcapsular cataracts that are also commonly seen in RP. CHM is an ocular disorder with no systemic manifestations. The extensive study of a large Canadian family with CHM by McCulloch and McCulloch in 1948 indisputably showed CHM to be X- linked.15

Clinical characteristics

Boys affected by choroideremia begin to recognize difficulty seeing at night during grade school years. The fundus will show signs of retinal pigment epithelial (RPE) mottling throughout the fundus, most marked in the equatorial region. These changes have been identified in boys as young as 3–10 months of age.12 The findings evolve with progressive loss of choriocapillaris, RPE, and retina in a scalloped fashion with coincident loss in visual field. The chorioretinal atrophy spans the entire peripheral retina, while the anatomy of the central macula remains relatively intact (figure 68.1). In some cases, remnants of normal retina remain near the optic nerve, which shows no gliosis or pallor. Deep choroidal vessels of normal diameter may be seen beyond the areas of chorioretinal atrophy, and the retinal vessels do not show narrowing that marks cases of RP. In a study of 115 patients with CHM from three centers, most patients retained central visual acuity and macular fields until their late sixties.18 Two cases of subretinal neovascularization have been reported in a CHM male and a carrier.5

Female carriers tend to be asymptomatic in their youth and middle years. Testing will demonstrate poor dark adaptation and in some cases defects in the visual field.12 Many older females will complain of trouble seeing at night. The fundus findings of patchy chorioretinal degeneration in the female begin predominantly in the midperiphery of the fundus (figure 68.2). An intravenous fluorescein angiogram

may occasionally be helpful in defining the extent of changes in the female carrier (figure 68.3), demonstrating pigment dispersion and atrophy of the choriocapillaris and RPE beyond what may be seen clinically.23 In our experience and that of others, these findings are slowly progressive and are not limited to the midperipheral fundus but may be seen with careful examination around the disk and in the macula.6 Occasionally, young female carriers may demonstrate a disorder as severe as the affected male, presumably as a result of lyonization.7,9

Electrophysiology

The electroretinogram (ERG) of an affected male may be nonrecordable but, early in the disorder, will mimic that of a patient with RP and is not specifically diagnostic. A certain amount of variability is seen in the ERG within families and between families affected by CHM. The ERG is frequently normal in a carrier of CHM despite a disproportionate degree of RPE mottling. By comparison, the ERG of a carrier of X-linked RP is frequently abnormal and minimal changes are seen with fundus examination.1 Sieving and colleagues showed that of the ERG responses to three stimuli— a dim blue flash, a dark-adapted white flash, or a flickering stimulus—not one response consistently predicted carrier status of CHM.22 Over a 10-year interval, they recorded a decrease in the ERG amplitudes in two CHM carriers, suggesting progressive loss of function. The electro-oculogram is not usually helpful to assess patients with CHM. Female carriers show a decrease in the Arden ratio with age, perhaps again consistent with the slow but progressive nature of the disorder.17 The visual field is a more practical clinical parameter than the ERG to monitor the function of a CHM patient over time.

Differential diagnosis

The end stage of CHM should not be confused with X- linked RP. In general, CHM does not show the degree of pigment migration into the retina that is seen in RP. Signs in a carrier female within the family that are consistent with CHM will help to differentiate the two diagnoses. Cystoid macular edema that is found occasionally in patients with X-linked RP has not been identified in patients with CHM.10

A

B

F 68.1 Fundus photographs of a 17-year-old CHM affected male showing preserved deep choroidal vessels and central macula, normal-appearing retinal vessels and optic nerve, and no pigment dispersion. A, OD. B, OS. Vision: 20/20 OU. (See also color plate 37.)

F 68.2 Fundus photograph (nasal midperiphery) of a 29- year-old female carrier with patchy RPE changes. Vision: 20/20 OS. (See also color plate 38.)

F 68.3 Intravenous fluorescein angiogram in a 34-year-old female carrier with areas of RPE and pigment disruption. Vision: 20/30 OS.

An association between CHM and deafness is rare and is due to a contiguous gene syndrome that results from the deletion of both the CHM gene and a gene for deafness, DFN3.16 Some cases of CHM and deafness could be confused with Usher syndrome. Usher syndrome is an autosomal-recessively inherited RP-related disorder with varying degrees of hearing impairment. The fundus of Usher syndrome does not show the distinct pattern of retinal degeneration that is typical of CHM.

Gyrate atrophy is often referenced as one of the disorders that might be confused with CHM. Gyrate atrophy is an autosomal-recessive metabolic disorder in which mutations in the gene for ornithine aminotransferase result in hyperornithinemia. The fundus of patients with gyrate atrophy and the progressive nature of the associated retinal degeneration could suggest CHM, but in general, the RPE in gyrate atrophy tends to be more hyperpigmental than that in CHM. The fundus of a patient with gyrate atrophy has bilateral midperipheral and peripheral areas of scalloped coalescent loss of retina, RPE, and choriocapillaris.11

Gene function

The CHM gene was identified by Cremers and colleagues, using a positional cloning strategy.3 The function of the gene was later revealed by Seabra and colleagues, who showed that the gene was homologous to component A of Rab geranylgeranyl transferase, now termed Rab escort protein-1 (REP-1).20 REP-1 functions in the prenylation of Rab GTPases by the covalent addition of 20-carbon geranylgeranyl units. Lymphocytes from patients with CHM show a marked inability to prenylate Rab proteins, in particular Rab27a.19,21 Rab proteins play a role in organelle formation and the trafficking of vesicles in exocytic and endocytic pathways. To date, all mutations and deletions of the CHM gene result in truncation of the gene product, resulting in its functional loss or absence. This fact allows the confirmation of the clinical diagnosis by noting the absence of REP-1 with immunoblot analysis of protein from peripheral white blood cells of affected males.13 As all mutations create the same effect, helpful genotype-phenotype correlations cannot be found in our experience and that of others.8

The absence of REP-1 in CHM and its relationship to the pathophysiology of the disorder remain to be determined. Another protein, REP-2, encoded by the CHM-like gene, may not function sufficiently in the eye to compensate for the lack of REP-1.2 No effective treatment has been found for choroideremia. Nutritional approaches may have some benefit as, for example, dietary supplementation with lutein to protect residual macular function.4

The authors thank Bernd Schwanke, Holly Ridyard, and Dr. Deborah Carper for their technical and editorial assistance.

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