What is the inheritance pattern of choroideremia?

X-linked recessive Choroideremia is an X-linked recessive inherited retinal dystrophy affecting predominantly males; female carriers show variable expression from X-chromosome inactivation.

Which gene product is deficient in choroideremia?

Rab escort protein-1 (REP1) Mutations in the CHM gene at Xq21.2 abolish Rab escort protein-1, which regulates Rab GTPases in vesicle trafficking, leading to degeneration.

Which three tissue layers degenerate together in choroideremia?

Retinal pigment epithelium, photoreceptors and choriocapillaris The distinctive tri-layer loss of RPE, photoreceptors and choriocapillaris begins in the mid-peripheral retina and moves centrally over time.

Nerve fibre layer, ganglion cells and optic nerve

Iris, ciliary body and trabecular meshwork

What is the estimated prevalence of choroideremia among males?

1 in 50,000 to 1 in 100,000 Choroideremia is rare, with an estimated prevalence of 1 in 50,000 to 1 in 100,000 males, and symptoms usually beginning in childhood or adolescence.

1 in 1 million to 1 in 5 million

What is typically the first symptom of choroideremia?

Night blindness in childhood Nyctalopia appears first in childhood, followed by progressive peripheral field loss and tunnel vision, with central vision usually preserved until the fifth or sixth decade.

Sudden painless central vision loss

What is the characteristic fundus appearance in choroideremia?

Scalloped mid-peripheral chorioretinal atrophy sparing the macula Scalloped patches of chorioretinal atrophy start in the mid-periphery with macular sparing in early and mid stages; bare sclera becomes visible in advanced disease.

Bone-spicule pigment clumping along the arcades

Yellow crystalline deposits at the posterior pole

Multiple flame-shaped haemorrhages in all quadrants

Which laboratory finding distinguishes gyrate atrophy from choroideremia?

Elevated plasma ornithine Gyrate atrophy is an autosomal recessive disorder of ornithine metabolism with elevated plasma ornithine, whereas choroideremia is X-linked and confirmed by CHM testing.

Raised serum angiotensin-converting enzyme

Positive antinuclear antibody titre

How is the diagnosis of choroideremia confirmed?

Genetic testing detecting a CHM gene mutation Diagnosis is clinical and supported by multimodal imaging, but confirmation comes from genetic testing showing a pathogenic CHM variant.

Fluorescein angiography showing late leakage

Ultrasound biomicroscopy of the ciliary body

Which emerging therapy for choroideremia has slowed degeneration in clinical trials?

Gene therapy with an AAV2-REP1 viral vector Clinical trials using AAV2-REP1 viral vectors have shown slowed degeneration and visual improvement in some patients; there is still no cure.

Monthly intravitreal anti-VEGF injections

Systemic immunosuppression with methotrexate

By which decades of life do many patients with choroideremia become legally blind?

Their forties to sixties The disease is slowly progressive, with most retaining useful central vision into middle age; many become legally blind in their forties to sixties.

Choroideremia Unveiling: What You Need to Know

Case Study

A 14-year-old boy presented to the clinic with complaints of progressive night blindness since early childhood and increasing difficulty navigating in dim environments.

His family reported that several male relatives on his mother’s side had become legally blind in their 40s. On fundus examination, there was widespread chorioretinal atrophy with preservation of the macula.

Optical coherence tomography (OCT) showed central retinal thinning, and fundus autofluorescence imaging demonstrated a characteristic scalloped edge of residual retinal pigment epithelium (RPE).

Genetic testing confirmed a pathogenic variant in the CHM gene. The diagnosis of choroideremia was established, and the patient and family received genetic counseling and were referred for low-vision rehabilitation and ongoing clinical trial eligibility assessment.

Disease Entity

Choroideremia is a rare X-linked recessive inherited retinal dystrophy primarily affecting males and characterized by progressive degeneration of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris.

Female carriers may show variable expression due to X-chromosome inactivation but usually have milder symptoms. The condition leads to gradual vision loss, beginning with nyctalopia (night blindness) in childhood, followed by peripheral vision loss, and eventually central vision deterioration in later decades.

Test your knowledge 10 questions from this article

Pathophysiology

Choroideremia results from mutations in the CHM gene located on Xq21.2, which encodes Rab escort protein-1 (REP1). This protein is essential for intracellular trafficking by regulating Rab GTPases involved in vesicle movement.

In the absence of functional REP1, cells of the RPE, photoreceptors, and choroid undergo progressive degeneration. This tri-layer loss is distinctive, with degeneration beginning in the mid-peripheral retina and moving centrally over time, often leaving an island of preserved macula until late stages.

Epidemiology

Prevalence: Estimated at 1 in 50,000 to 1 in 100,000 males.
Inheritance: X-linked recessive.
Gender distribution: Affects predominantly males; female carriers usually asymptomatic or mildly symptomatic.
Onset: Symptoms typically start in childhood or adolescence.

Clinical Features

Symptoms

Night blindness (nyctalopia): Often the first symptom, appearing in childhood.
Peripheral vision loss: Progressive over years, leading to tunnel vision.
Central vision: Usually preserved until the 5th or 6th decade.
Color vision defects: Can occur in late-stage disease.
Photophobia: May be present in some cases.

Signs

Fundus appearance:
- Scalloped patches of chorioretinal atrophy starting in the mid-periphery
- Sparing of the macula in early to mid-stages
- Visibility of bare sclera in advanced disease
Optical coherence tomography (OCT): Shows progressive thinning of the outer retina and RPE
Fundus autofluorescence: Demonstrates areas of RPE loss with a granular peripheral autofluorescence pattern
Electroretinography (ERG): Shows reduced or extinguished rod and cone responses.

Examination Findings

Visual acuity: Normal in early stages; decreases with central involvement
Visual field testing: Mid-peripheral scotomas progressing to concentric narrowing
OCT: Retinal thinning and ellipsoid zone loss with foveal sparing
Autofluorescence imaging: Helps track the progression of RPE loss
ERG: Abnormal or absent responses, particularly rods

Differential Diagnosis

Retinitis pigmentosa (RP): More pigmentary changes (bone spicules), inheritance patterns vary
Gyrate atrophy: Autosomal recessive, ornithine metabolism disorder, elevated plasma ornithine
Bietti crystalline dystrophy: Crystals in the retina and cornea
Cone-rod dystrophies
Chronic uveitis with chorioretinal atrophy

Diagnosis

The diagnosis is primarily clinical, supported by multimodal imaging and confirmed by genetic testing.

Diagnostic tools:

Genetic testing: Detection of mutations in the CHM gene
OCT: Assessment of retinal layers
Fundus autofluorescence: Mapping of RPE integrity
ERG: Functional assessment of photoreceptors
Visual field testing: Evaluation of peripheral vision loss

Management

There is no cure yet, but ongoing research, including gene therapy trials, is showing promising results.

Current Management Strategies

Low vision aids: For improving the quality of life and daily functioning
Orientation and mobility training
Genetic counseling: Essential for affected individuals and family planning
Regular monitoring: To document disease progression and trial eligibility
Protection from phototoxicity: Use of sunglasses and light filters

Emerging Therapies

Gene therapy: Clinical trials using viral vectors (AAV2-REP1) have shown slowed degeneration and visual improvement in some patients
Stem cell therapy: Under investigation
Retinal prosthetics: In research for late-stage blindness

Prognosis

Slowly progressive: Most patients retain useful central vision into middle age
Legally blind: Many affected individuals become legally blind in their 40s to 60s
Variable severity: Even among family members with the same mutation
Carrier females: Often asymptomatic but may develop mild visual changes later in life.

Prevention

Currently, there is no prevention for disease onset
Genetic counseling and carrier detection: Important for families with known mutations
Prenatal and preimplantation genetic diagnosis: Options for families considering reproduction

Conclusion

Choroideremia is a rare but increasingly understood inherited retinal dystrophy. Characterized by night blindness and peripheral vision loss in males, it progresses to central vision loss in adulthood.

Advances in imaging and genetic testing allow for earlier and more accurate diagnosis, while emerging therapies—especially gene therapy—offer hope for modifying disease progression.

Early diagnosis, multidisciplinary care, and participation in clinical trials are key for optimal management and future outcomes.

References

MacDonald IM, Russell L, Chan CC. Choroideremia: New Findings from Ocular Pathology and Review of Recent Literature. Surv Ophthalmol. 2009.
Xue K, MacLaren RE. Gene therapy for choroideremia using an adeno-associated viral (AAV) vector. Cold Spring Harb Perspect Med. 2014.
van den Hurk JA, et al. The clinical spectrum of choroideremia and carrier state in the Netherlands. Br J Ophthalmol. 2007.
Edwards TL, et al. Assessment of Visual Function in Clinical Trials for Choroideremia. Eye. 2016.
Dimopoulos IS, et al. Macular Structure and Function in Choroideremia: Correlation with Disease Stage and Implications for Gene Therapy. Invest Ophthalmol Vis Sci. 2017.

Test yourself

A few questions straight from this article.

1 / 10 0 correct

What is the inheritance pattern of choroideremia?
Choroideremia is an X-linked recessive inherited retinal dystrophy affecting predominantly males; female carriers show variable expression from X-chromosome inactivation.
Which gene product is deficient in choroideremia?
Mutations in the CHM gene at Xq21.2 abolish Rab escort protein-1, which regulates Rab GTPases in vesicle trafficking, leading to degeneration.
Which three tissue layers degenerate together in choroideremia?
The distinctive tri-layer loss of RPE, photoreceptors and choriocapillaris begins in the mid-peripheral retina and moves centrally over time.
What is the estimated prevalence of choroideremia among males?
Choroideremia is rare, with an estimated prevalence of 1 in 50,000 to 1 in 100,000 males, and symptoms usually beginning in childhood or adolescence.
What is typically the first symptom of choroideremia?
Nyctalopia appears first in childhood, followed by progressive peripheral field loss and tunnel vision, with central vision usually preserved until the fifth or sixth decade.
What is the characteristic fundus appearance in choroideremia?
Scalloped patches of chorioretinal atrophy start in the mid-periphery with macular sparing in early and mid stages; bare sclera becomes visible in advanced disease.
Which laboratory finding distinguishes gyrate atrophy from choroideremia?
Gyrate atrophy is an autosomal recessive disorder of ornithine metabolism with elevated plasma ornithine, whereas choroideremia is X-linked and confirmed by CHM testing.
How is the diagnosis of choroideremia confirmed?
Diagnosis is clinical and supported by multimodal imaging, but confirmation comes from genetic testing showing a pathogenic CHM variant.
Which emerging therapy for choroideremia has slowed degeneration in clinical trials?
Clinical trials using AAV2-REP1 viral vectors have shown slowed degeneration and visual improvement in some patients; there is still no cure.
By which decades of life do many patients with choroideremia become legally blind?
The disease is slowly progressive, with most retaining useful central vision into middle age; many become legally blind in their forties to sixties.