Choroideremia

The CHM gene codes Rab escort protein-1 (REP-1), which attaches to several Rab GTPases. REP-1 is a key component of Rab geranylgeranyl transferase, an enzyme complex that mediates intracellular vesicular transport. Most of the mutations in CHM result in a truncated product that is degraded. This results in chorioretinal degeneration. The presence of crystals in peripheral blood lymphocytes, significant plasma fatty acid abnormalities, and red blood cell membrane abnormalities suggests that choroideremia (CHM) may be a systemic condition.


CHM is an X-linked recessive condition that should be suspected in male patients with a history of nyctalopia and progressive chorioretinal degeneration. Patients also experience peripheral visual field loss that initially manifests as a ring scotoma that follows the initial changes in the fundus appearance but progresses to severe constriction. Fundus changes are seen generally by the second decade of life. The estimated prevalence is 1:50,000. Individuals present with a characteristic fundus, which consists of patchy areas of chorioretinal degeneration that generally begin in the midperiphery and proceed posteriorly (▶ Fig. 21.1). Areas of degeneration typically demonstrate marked retinal pigment epithelium (RPE) and choriocapillaris loss, but with preservation of the deep choroidal vessels. RPE loss is the primary cause of photoreceptor degeneration in CHM, with a thinner choroid from early stages, which is consistent with a developmental defect. Photoreceptors lose outer segments following loss of underlying RPE. The central macula is usually preserved until late in the disease course and appears as a preserved island of retina often with somewhat scalloped edges. Affected males may not note any symptoms until their teenage years. Visual acuity usually deteriorates after the third decade. Severe visual field constriction is present by their 40s, although central visual acuity can be spared until even later. As the disease progresses, CHM may have midperipheral “bone spicule” pigmentary clumps. About 40 to 60% of CHM patients will have macular cystic spaces in at least one eye on optical coherence tomography (OCT). Posterior subcapsular cataracts can be found in one-third of affected males. Female carriers have patchy chorioretinal changes (▶ Fig. 21.2) that may correspond to visual field scotomas, but generally they do not have symptoms. Adverse lyonization can result in even more demonstrable changes. While no accepted treatment exists for CHM, promising approaches using viral vector gene therapy are entering clinical trials. Results from the first gene therapy trial revealed sustained visual improvement over 6 months post-treatment, though long-term follow-up is needed.



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Fig. 21.1 Severe chorioretinal atrophy in a patient with choroideremia.



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Fig. 21.2 Fundus photography of a female carrier of a mutation in the CHM gene showing areas of retinal pigment epithelium change and atrophy due to lyonization.


21.2 Molecular Genetics


CHM (Xq21.2) is the only known gene associated with CHM. The mutation detection rate is nearly 95%. Nonsense mutations are the most commonly observed, although other pathogenic variants such as missense changes, complete gene deletions, intragenic deletions, and frameshifts have been reported. There is no consistent genotype–phenotype correlation.


21.3 Differential Diagnosis


21.3.1 Retinitis Pigmentosa


The retinal appearance of CHM and end-stage RP may be almost indistinguishable due to the similar advanced chorioretinal atrophy and CHM may have midperipheral “bone spicule” pigmentary clumps. Both disorders have nyctalopia and constricted visual fields with preserved central acuity. RP may be X-linked recessive. RP is distinguished from CHM by the usual degree of pigment clumping. Peripheral scalloped degeneration is not seen in RP. Molecular genetic testing may be required to make the correct diagnosis.


21.3.2 Usher Syndrome Type 1 (OMIM 276900)


This condition can be confused with CHM in the context of an Xq21 contiguous deletion syndrome, because of retinal abnormalities and deafness (deletion of the POU3F4 gene). Nevertheless, Usher syndrome does not present with the scalloped areas of chorioretinal degeneration and like RP, early choroidal atrophy is not seen. The inheritance pattern of Usher syndrome is autosomal recessive (AR).


21.3.3 Gyrate Atrophy (OMIM 258870)

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Apr 7, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Choroideremia

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