Early stage
RPE atrophy and pigmentation: Granular RPE atrophy starting at the equator and mid-periphery, with pigmentation in the periphery.
Loss of the choriocapillaris: Begins in the periphery and progresses toward the mid-periphery.
Choroideremia
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Choroideremia?
Section titled “1. What is Choroideremia?”Choroideremia is a progressive choroidal dystrophy with X-linked inheritance caused by mutations in the CHM gene. First, the choroid (including iris vessels) atrophies, followed by the medium and large choroidal vessels, and subsequently the retinal photoreceptors and RPE (retinal pigment epithelium) are also affected. It is a disease that progressively impairs vision and is classified as a related disorder of retinitis pigmentosa. Onset occurs in early childhood, and chorioretinal atrophy progresses slowly 7).
It was first reported by Ludwig Mauthner in 1872. The name is derived from the ancient Greek words “chorion” (skin) and “eremia” (barren land).
The prevalence is estimated at 1 in 50,000 to 100,000 people 3). It mainly affects males; females are usually asymptomatic carriers. In the end stage, the choroid almost completely disappears, and the white sclera is exposed throughout the fundus.
The CHM gene is located at Xq21.2 and spans 186,382 bp. It consists of at least 15 exons and an ORF of 1,962 bp, encoding a 653-amino acid, 95 kDa Rab escort protein 1 (REP-1). REP-1 guides proteins from the cell membrane into the cytoplasm and functions as a coenzyme for Rab geranylgeranyltransferase, an enzyme involved in intracellular vesicle transport. Over 280 pathogenic mutations have been reported 5), showing high diversity. Even the five most frequent mutations account for only 11% of all mutations 1).
Q
Can choroideremia occur in women?
A
Because it is X-linked recessive, the disease primarily affects males. Female carriers are usually asymptomatic, but depending on the pattern of random X-chromosome inactivation, visual function abnormalities may appear in older age. In carriers, the fundus may show patchy retinal pigment epithelial depigmentation (spotty depigmented spots or granular pigmentation) in the mid-periphery 6).
2. Main symptoms and clinical findings
Section titled “2. Main symptoms and clinical findings”Subjective symptoms
Section titled “Subjective symptoms”Most affected males notice night blindness in their youth. Some may remain asymptomatic until middle age.
- Night blindness: The first symptom. Appears in childhood (ages 5–25) 2). It is perceived as reduced vision in the dark.
- Peripheral visual field loss: Progressively expands. Initially appears as a ring scotoma and becomes concentrically narrowed. Visual field testing reveals a ring scotoma in the early stages 7).
- Visual acuity loss: Relatively preserved until later stages. Often declines significantly after age 40 7), and many patients have visual acuity of 0.1 or less by ages 50–60. However, disease progression varies greatly among individuals.
- Color vision deficiency: Mainly tritan-type (blue-yellow color vision abnormality) 2).
Clinical findings
Section titled “Clinical findings”Characteristic fundus findings appear depending on the disease stage. Loss of the choriocapillaris occurs first.
Intermediate stage
Island-shaped choroidal atrophy: Patchy and island-shaped atrophic areas coalesce. Large choroidal vessels are visible.
Centripetal atrophy of residual choroid: The atrophic border progresses toward the center.
Advanced stage
Diffuse choroidal atrophy (white fundus): The choroid almost completely disappears, exposing the white sclera.
Foveal sparing: The foveal tissue remains as an island until the end1).
Differences from RP: Retinal vascular attenuation is less pronounced, and optic atrophy is also rarely seen.
The following findings are characteristic on imaging tests:
| Test | Characteristic findings |
|---|---|
| FAF | Loss of autofluorescence in the periphery progresses centripetally. Loss rate is 7.7% per year2) |
| OCT | Choroidal thinning, RPE loss, ellipsoid zone loss, retinal tubulation in the outer nuclear layer2) |
| ERG | Amplitude reduction is observed from the early stage7). In advanced cases, both rod and cone functions are not recordable. |
| FA | Areas of choriocapillaris loss show hypofluorescence, while residual perfused areas show hyperfluorescence. RPE atrophy allows easy visualization of choroidal vessels 7) |
| OCTA | Decreased choroidal vascular density precedes photoreceptor loss 2) |
Fundus of female carriers: Mosaic distribution of patchy depigmented spots in the mid-periphery 6). Vitelliform lesions in carriers have also been reported 6). ERG in carriers is nearly normal.
Rare complications include retinoschisis 5) and choroidal neovascularization (CNV) 4).
Greig et al. (2022) reported that retinoschisis in choroideremia patients can resemble retinal detachment and can be differentiated by multimodal imaging 5). OCT and OCTA contribute to accurate diagnosis and avoidance of unnecessary surgery.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”Choroideremia is caused by loss-of-function mutations in the CHM gene. Approximately 30% of mutations are nonsense mutations 2). Almost all CHM mutations are loss-of-function 1)5), resulting in nearly zero residual REP-1 function.
Due to X-linked recessive inheritance, the main risk factors are male sex and family history (maternal carrier). If the father has choroideremia, 50% of daughters are carriers. When REP-1 is deficient, REP-2 partially compensates, but compensation is incomplete, and some Rab proteins such as Rab27a preferentially use REP-1, leading to dysfunction.
Large Xq21 deletions (approximately 13.5 Mbp involving 18 or more genes) result in syndromic choroideremia with developmental delay (78%) and hearing loss (56%) in addition to choroideremia 3).
Prenatal diagnosis is possible, but since there is currently no established treatment, consultation with a specialist is necessary.
Q
Is there a common pattern of CHM gene mutations?
A
More than 280 pathogenic variants have been reported, and many are unique to individual families. Even the five most frequent variants account for only 11% of all pathogenic variants 1), indicating high mutational diversity. About 30% are nonsense mutations 2). Identifying the type of mutation is important for determining which patients may be candidates for nonsense mutation-specific therapies such as ataluren.
4. Diagnosis and Testing Methods
Section titled “4. Diagnosis and Testing Methods”Characteristic fundus findings and family history provide diagnostic clues. Definitive diagnosis is made using one of the following:
- Fundus examination: early stage shows patchy or island-like choroidal atrophy; late stage shows characteristic white fundus
- Confirmation of inheritance pattern: X-linked recessive inheritance
- Direct testing of the CHM gene: identification of a pathogenic variant confirms the diagnosis
- Anti-REP-1 antibody immunoblot: detects reduced REP-1 protein levels in leukocytes (reported by MacDonald et al.). In male patients, REP-1 is almost completely absent, which is useful for definitive diagnosis
Fluorescein angiography (FA) allows easy visualization of choroidal vessels due to RPE atrophy and is useful for assessing the extent of choriocapillaris loss 7). OCT is important for differentiating retinoschisis from retinal detachment in some cases 5). Multimodal imaging (FA, FAF, OCT, OCTA) is useful for evaluating pathology and staging the disease.
In the RP clinical practice guidelines, choroideremia is classified as a related disease (Category IV) of retinitis pigmentosa 7), and differentiation from RP is important.
Differential Diagnosis
Section titled “Differential Diagnosis”The main differential diagnoses are listed below.
| Disease | Inheritance Pattern | Key Differentiating Features |
|---|---|---|
| Gyrate atrophy of the choroid | AR | Hyperornithinemia, OAT deficiency |
| Retinitis pigmentosa | Various | Bone spicule pigmentation and marked retinal vascular attenuation |
| X-linked RP | X-linked | Differentiate by genetic testing; distinction at end stage is important |
| Diffuse choroidal dystrophy | AD | Onset in 40s-50s |
Q
How to differentiate from retinitis pigmentosa?
A
Choroideremia is characterized by well-defined areas of choroidal atrophy and a white fundus in the end stage. In retinitis pigmentosa, bone spicule pigmentation and pigment deposition in the equatorial region differ, and there is marked attenuation of retinal vessels. In choroideremia, retinal vascular attenuation is less pronounced and optic atrophy is rarely seen, which are important differentiating points. After confirming X-linked recessive inheritance and family history, a definitive diagnosis is made by CHM gene testing.
5. Standard Treatment
Section titled “5. Standard Treatment”Currently, there is no approved effective treatment for choroideremia. There is no established treatment, and symptomatic therapy and low vision care are the mainstays. Treatment focuses on managing complications and regular follow-up.
Symptomatic therapy and low vision care
Section titled “Symptomatic therapy and low vision care”Symptomatic therapy tailored to the decline in visual function is the mainstay of treatment.
- Light-filtering glasses: Useful for reducing night blindness and photophobia. When going out at night, it is effective to use them together with assistive devices such as a white cane.
- Magnifying reading devices and loupes: Assistive tools to maximize the use of remaining visual function.
- Mobility assistance in dark places: White cane and orientation and mobility training (when visual field loss has progressed).
- Obtaining a physical disability certificate: Can be applied for depending on the degree of visual field loss and visual acuity decline. This leads to access to various welfare services.
- Employment support and social welfare systems: Utilization of disability welfare services and application for reasonable accommodations in the workplace.
Management of Complications
Section titled “Management of Complications”- When CNV (choroidal neovascularization) is present: Anti-VEGF therapy (e.g., ranibizumab) is used. There is a case report of maintaining visual acuity of 20/20 after 5 injections of ranibizumab4).
- When macular hole is present: Anatomical closure can be achieved with vitrectomy1).
Investigational Treatments (Currently Not Approved)
Section titled “Investigational Treatments (Currently Not Approved)”Research on gene therapy, cell therapy, etc., is progressing. For details, see the section “Latest Research and Future Prospects”.
Q
Is gene therapy already available?
A
As of 2026, no gene therapy drug has been approved. In the Phase III trial (STAR trial), the primary endpoint (3-line improvement) was not met 1), but a significant difference was observed for 2-line improvement 1). Currently, endpoint redefinition and new trials are ongoing, and future approval is anticipated.
6. Pathophysiology and Detailed Mechanism of Onset
Section titled “6. Pathophysiology and Detailed Mechanism of Onset”The pathology of choroideremia is a vesicular transport disorder caused by deficiency of REP-1 (Rab escort protein 1).
Function of REP-1
Section titled “Function of REP-1”REP-1 is a chaperone protein that promotes prenylation (addition of a geranylgeranyl group) of Rab GTPases 1). Prenylation confers hydrophobicity to Rab proteins, enabling their binding to intracellular membranes 1). Rab proteins are essential for endosomal-lysosomal vesicular transport and perform many cellular functions, including phagocytosis of photoreceptor outer segments in RPE cells 1).
Mechanism of Degeneration
Section titled “Mechanism of Degeneration”When REP-1 is deficient due to CHM mutation, prenylation of Rab proteins is impaired 1). REP-2 partially compensates, but some Rab proteins, such as Rab27a, preferentially use REP-1, so compensation is incomplete 2).
As a result of vesicular transport impairment, lipofuscin accumulates in RPE cells 1) and melanosomes decrease 1). Following a pattern of “cellular dysfunction first, cell death later,” RPE cells are lost, and secondarily, degeneration of photoreceptors and the choriocapillaris progresses 1). A pathological feature of this disease is that loss of the choriocapillaris precedes RPE degeneration and photoreceptor damage.
Reason for Onset in the Mid-Periphery
Section titled “Reason for Onset in the Mid-Periphery”As a mechanism for degeneration starting in the equator and mid-periphery, it has been pointed out that the density of photoreceptors per RPE cell is highest in that region 1). It is thought that damage occurs first in areas with the highest metabolic load. In the fovea, photoreceptor density is relatively low, and this area is preserved until the end (foveal sparing) 1).
Choroideremia is also called “a prototype of age-related eye diseases such as age-related macular degeneration” 1). A feature of this disease is that mechanisms similar to the decline in RPE function that occurs in normal aging progress from a young age.
Regarding the complication of retinoschisis, it is presumed that impaired secretory function of the RPE due to REP-1 deficiency is involved 5).
7. Latest Research and Future Prospects (Research-stage Reports)
Section titled “7. Latest Research and Future Prospects (Research-stage Reports)”Gene therapy (AAV2.REP1)
Section titled “Gene therapy (AAV2.REP1)”Gene therapy for choroideremia is the most advanced area. The size of the CHM cDNA (1.96 kb) fits within the packaging capacity of AAV1), and subretinal injection using an AAV2 vector has become the standard procedure. In 2014, MacLaren et al. reported the first Phase 1/2 clinical trial results, showing at least short-term efficacy8). The surgery involves injecting BSS into the subretinal space to induce a localized retinal detachment, followed by injection of the AAV solution1).
Multiple Phase I/II trials have been conducted, with a median ETDRS change of +1.5 across 40 patients2). The Oxford group reported a median ETDRS improvement of +5.5 in 14 patients2).
The Phase III trial (timrepigene emparvovec / STAR trial) enrolled 140 patients. The primary endpoint (3-line improvement) was not met, but the visual acuity change in the high-dose group was -0.3 ETDRS (vs. -2.3 ETDRS in the control group), and a significant effect was observed for 2-line improvement1).
In the REGENERATE trial, preservation of the smooth zone (uniform autofluorescence area on SW-AF) was observed in early-stage patients1). It has been proposed that future trials adopt a 2-line improvement as the primary endpoint1).
Other research approaches
Section titled “Other research approaches”Alternative gene therapy
4D-110 (intravitreal injection type): An intravitreal vector that does not require subretinal injection. Currently being tested in NCT044834402).
Ataluren (PTC124): A treatment targeting readthrough effects in approximately 30% of patients with nonsense mutations2).
Cell and genome editing
iPSC-derived RPE transplantation: Research on transplantation of RPE differentiated from stem cells is ongoing2).
CRISPR: Gene replacement of CHM cDNA is at the proof-of-concept stage. Combination with surgical robots is also being studied1).
- Immunosuppressive therapy: For inflammation management after gene therapy, a protocol of prednisolone 1 mg/kg/day for 10 days followed by tapering is used2).
- Electronic retinal implants: Investigation of visual assistive devices for end-stage patients2).
- Oxidative stress intervention: Basic research using zebrafish models is ongoing2).
For symptomatic choroideremia (Xq21 large deletion), detailed analysis of the relationship between deletion size and phenotype is progressing, deepening genetic understanding3).
8. References
Section titled “8. References”- Abdalla Elsayed MEA, Cehajic-Kapetanovic J, MacLaren RE. Gene therapy for choroideremia: progress, potential and pitfalls. Expert Opin Biol Ther. 2025;25(3):257-263.
- Abbouda A, Avogaro F, Moosajee M, Vingolo EM. Update on gene therapy clinical trials for choroideremia and potential experimental therapies. Medicina. 2021;57(1):64.
- Jung EH, Duemler A, Iannaccone A, Alekseev O. A novel large multi-gene deletion in syndromic choroideremia. Ophthalmic Genet. 2024;45(5):546-550.
- Ranjan R, Verghese S, Salian R, Manayath GJ, Saravanan VR, Narendran V. OCT angiography for the diagnosis and management of choroidal neovascularization secondary to choroideremia. Am J Ophthalmol Case Rep. 2021;22:101042.
- Greig LC, Gutierrez KG, Oh JK, Levi SR, Korot E, Tsang SH, Mahajan VB. Multimodal imaging reveals retinoschisis masquerading as retinal detachment in patients with choroideremia. Am J Ophthalmol Case Rep. 2022;26:101543.
- Torm MEW, Eckmann-Hansen C, Christensen SK, Larsen M. A unilateral foveal vitelliform lesion in a choroideremia carrier. Retinal Cases & Brief Reports. 2022;16(5):663-666.
- 日本網膜色素変性症研究会. 網膜色素変性診療ガイドライン（第2版）. 日眼会誌. 2026.
- MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383:1129-1137.