Shahmeer Hamid

Introduction

Choroideremia (CHM) is a rare, X-linked recessive chorioretinal dystrophy characterized by the progressive degeneration of the choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors. The condition was first described by the Austrian ophthalmologist Ludwig Mauthner in 1872. The genetic basis was elucidated in 1990 when potential cloning identified the CHM gene located on chromosome Xq21.2 (1).

The CHM gene encodes the Rab Escort Protein-1 (REP-1), a protein ubiquitously expressed in human tissues. REP-1 is essential for the prenylation (lipid modification) of Rab GTPases, which regulate intracellular membrane trafficking. The absence of functional REP-1 leads to the accumulation of unprenylated Rab proteins, causing defective vesicular transport and subsequent cell death, particularly in the RPE and photoreceptors (2).

Clinical Stages

Choroideremia presents differently in males (hemizygous) and females (heterozygous carriers).

Carrier Females

●​Asymptomatic: Most carriers have normal vision and electrophysiological function.

●Fundus Appearance: A characteristic “moth-eaten” appearance with patchy, irregular pigmentation in the mid-periphery is common. This retinal mosaicism arises from random X-inactivation (lyonization) (3).

Affected Males

●​Childhood (Early Onset): The earliest symptom is nyctalopia (night blindness), often presenting in the first decade of life. Fundoscopy reveals diffuse pigmentary mottling and areas of RPE atrophy in the mid-periphery.

●​Adolescence/Early Adulthood (Progression): Progressive constriction of visual fields occurs. Areas of atrophy enlarge and coalesce, exposing the underlying bare white sclera and large choroidal vessels.

●Late Stage: The atrophy advances centripetally (inward toward the fovea). Patients typically retain a small, central island of functional retina, preserving visual acuity until the fifth or sixth decade.

●​End Stage: Eventually, the central island degenerates, leading to severe visual impairment or total blindness (4).

Investigations

Diagnosis is supported by multimodal imaging and confirmed by genetics.

Fundus Autofluorescence (FAF)

The most useful modality for monitoring progression. It typically shows a central island of preserved hyperautofluorescence surrounded by a distinct border of hypoautofluorescence (atrophy) (5).

Optical Coherence Tomography (OCT)

Demonstrates abrupt transition from preserved retina to atrophy. “Outer Retinal Tubulations” (ORTs)—circular rearrangements of surviving photoreceptors—are a hallmark structural feature seen in the degenerating retina.

Electroretinogram (ERG)

Scotopic (rod) responses are affected early; photopic (cone) responses are preserved longer but eventually become extinguished.

Genetic Testing

Identification of a pathogenic variant in the CHM gene is the gold standard for diagnosis.

Differential Diagnosis

Conditions to differentiate from Choroideremia include:

●​Retinitis Pigmentosa (RP): Distinguished by “bone-spicule” pigment deposits (versus the scallop-edged atrophy of CHM) and retinal vessel attenuation.

●​Gyrate Atrophy: Characterized by hyperornithinemia (elevated plasma ornithine) and distinct, circular “punched-out” lesions.

●​Usher Syndrome: Associated with sensorineural hearing loss (hearing is typically normal in CHM).

●​Ocular Albinism: X-linked; presents with foveal hypoplasia and iris transillumination defects, which are absent in CHM (6).

Management

Current management involves supportive care, though targeted therapies are in advanced development:

Supportive Care

Low vision aids, regular refraction, and UV-blocking sunglasses to reduce light sensitivity/glare.

Gene Therapy

Choroideremia has been a primary target for gene therapy trials (e.g., AAV2-REP1). Early-phase clinical trials have demonstrated safety and potential for maintaining visual acuity, with ongoing studies aiming to slow disease progression (7).

Genetic Counseling

Essential for affected families due to the X-linked inheritance pattern (daughters of affected males are obligate carriers; sons are unaffected).

Prognosis

The prognosis for Choroideremia is generally better than for other retinal dystrophies regarding central vision retention. Male patients often maintain good visual acuity (e.g., 20/40 or better) well into their 40s or 50s, despite significant peripheral field loss (“tunnel vision”). However, the rate of decline accelerates once the fovea is involved, typically leading to legal blindness by the sixth or seventh decade (8).

Conclusion

Choroideremia is a progressive X-linked degeneration caused by REP-1 deficiency, leading to the relentless loss of the RPE and choroid. It is clinically distinguished by its preservation of a central retinal island until late in the disease course. While currently incurable, it remains a leading candidate for gene replacement therapy, offering hope for future vision-preserving interventions.

References

1.​ Cremers FP, van de Pol DJ, van Kerkhoff LP, Wieringa B, Ropers HH. Cloning of a gene that is rearranged in patients with choroideraemia. Nature. 1990;347(6294):674-677. doi:10.1038/347674a0

2.​ Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. Science. 1993;259(5093):377-381. doi:10.1126/science.8380507

3.​ MacDonald IM, Hume S, Zhai Y, et al. Choroideremia. 2003 Feb 21 [Updated 2021 Mar 4]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1337/

4.​ Coussa RG, Traboulsi EI. Choroideremia: a review of general findings and pathogenesis. Ophthalmic Genet. 2012;33(2):57-65. doi:10.3109/13816810.2011.620056

5.​ Jolly JK, Xue K, Edwards TL, Groppe M, MacLaren RE. Characterizing the Natural History of Visual Function in Choroideremia Using Microperimetry and Multimodal Retinal Imaging. Invest Ophthalmol Vis Sci. 2017;58(12):5575-5583. doi:10.1167/iovs.17-22486

6.​ Huckfeldt RM, Bennett J. Promising first steps in gene therapy for choroideremia. Hum Gene Ther. 2014;25(2):96-97. doi:10.1089/hum.2014.2503