Choroideremia

Choroideremia is a rare, inherited eye disease that causes progressive vision loss, eventually leading to blindness. Because it is linked to the X chromosome, it mostly affects men, while women are usually carriers who do not experience severe symptoms. The condition is caused by a change (mutation) in a specific gene called the CHM gene, which is responsible for producing a protein needed for the healthy function of cells in the retina (the light-sensitive tissue at the back of the eye). The first symptom of choroideremia is usually night blindness, which often begins in childhood. As the person gets older, they gradually lose their side (peripheral) vision, leading to "tunnel vision." For many years, people with choroideremia can still see clearly straight ahead, allowing them to read and recognize faces. However, usually between the ages of 40 and 60, the central vision also begins to decline rapidly, leading to legal blindness. Currently, there is no cure for choroideremia, but regular eye exams are important to monitor the condition and manage any complications, such as cataracts. Researchers are actively studying new treatments, including gene therapy, which aims to replace the faulty gene with a healthy one to stop or slow down the vision loss. Patients and families are encouraged to speak with a genetic counselor and a retinal specialist to understand the disease and explore potential clinical trials.

Condition category: Retinal Dystrophy

Prevalence: 1 in 50,000 to 1 in 100,000

Inheritance patterns: X-Linked

Age of onset: First decade of life (typically early childhood)

Clinical overview: Choroideremia (OMIM 303100) is a rare, X-linked recessive chorioretinal dystrophy characterized by the progressive degeneration of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris. The condition predominantly affects males and is caused by mutations in the CHM gene (OMIM 300390), which encodes the Rab escort protein 1 (REP1). The disease leads to a gradual loss of vision, ultimately resulting in legal blindness by late adulthood. The Orphanet number for choroideremia is ORPHA180. Clinically, choroideremia presents with nyctalopia (night blindness) in early childhood, followed by progressive peripheral visual field constriction. A hallmark of the disease is the characteristic fundus appearance, which shows widespread pigment clumping and well-defined regions of chorioretinal atrophy with visible underlying sclera and large choroidal vessels. The macula is typically spared until the later stages of the disease, allowing patients to maintain good central visual acuity for several decades. The condition is of significant clinical interest due to its progressive nature and the severe impact on patients' quality of life in later stages. While there is currently no approved cure, choroideremia has become a prime candidate for gene therapy. The relatively slow progression of the disease and the well-defined genetic etiology provide a window of opportunity for therapeutic intervention aimed at halting or slowing the degenerative process.

Patient and family guide: Choroideremia is a rare, inherited eye disease that causes progressive vision loss, eventually leading to blindness. Because it is linked to the X chromosome, it mostly affects men, while women are usually carriers who do not experience severe symptoms. The condition is caused by a change (mutation) in a specific gene called the CHM gene, which is responsible for producing a protein needed for the healthy function of cells in the retina (the light-sensitive tissue at the back of the eye). The first symptom of choroideremia is usually night blindness, which often begins in childhood. As the person gets older, they gradually lose their side (peripheral) vision, leading to "tunnel vision." For many years, people with choroideremia can still see clearly straight ahead, allowing them to read and recognize faces. However, usually between the ages of 40 and 60, the central vision also begins to decline rapidly, leading to legal blindness. Currently, there is no cure for choroideremia, but regular eye exams are important to monitor the condition and manage any complications, such as cataracts. Researchers are actively studying new treatments, including gene therapy, which aims to replace the faulty gene with a healthy one to stop or slow down the vision loss. Patients and families are encouraged to speak with a genetic counselor and a retinal specialist to understand the disease and explore potential clinical trials.

Symptoms and clinical features: The clinical presentation of choroideremia follows a progressive pattern, typically beginning in the first decade of life. The earliest and most common initial symptom is nyctalopia (night blindness), which occurs due to the early degeneration of rod photoreceptors. During this early stage, patients generally have normal visual acuity and visual fields under well-lit conditions, though fundus examination may reveal widespread pigment clumping at the level of the retinal pigment epithelium (RPE). In the intermediate stage, usually during the teenage years and early adulthood, patients experience progressive peripheral visual field loss. This manifests as patchy loss of midperipheral vision that gradually coalesces into a ring scotoma, eventually leading to severe visual field constriction or "tunnel vision." Despite the significant loss of peripheral vision, central visual acuity is typically well-preserved. Color vision may begin to decline as the degeneration encroaches on the macula. In the advanced stage, which typically occurs between the fifth and seventh decades of life, the remaining central island of vision begins to deteriorate rapidly. Patients experience a significant decline in central visual acuity, loss of color vision, and eventually legal blindness. In very advanced cases, only small islands of vision may remain in the far periphery or fovea. Female carriers are generally asymptomatic but may occasionally report mild nyctalopia or exhibit signs of chorioretinopathy on clinical examination.

Molecular pathology: Choroideremia is caused by mutations in the CHM gene, which encodes Rab escort protein 1 (REP1). REP1 is a ubiquitously expressed 95 kDa protein that plays an essential role in the intracellular trafficking of proteins, substrates, and organelles. This trafficking is regulated by small GTP-binding proteins known as Rab proteins. For Rab proteins to attach to lipid membranes and mediate transport, they must undergo prenylation, which involves the addition of geranylgeranyl groups by the enzyme geranylgeranyl transferase 2 (GGTase2). REP1 is crucial in this process as it binds to newly synthesized Rab proteins, presents them to GGTase2 for prenylation, and then escorts the prenylated Rab proteins to their target intracellular membranes. In the absence of functional REP1, a subset of Rab proteins (particularly Rab27a, Rab27b, Rab38, and Rab42) remain unprenylated and inactive. This leads to defective intracellular vesicular trafficking. In the eye, this impairment disrupts the transport of proteins from the Golgi apparatus to the outer segments of photoreceptors and impairs the phagocytosis and degradation of shed outer segments by the retinal pigment epithelium (RPE). This cellular dysfunction ultimately results in the progressive degeneration of the RPE, photoreceptors, and choriocapillaris.

Genetics: Choroideremia is inherited in an X-linked recessive manner and is caused by mutations in the CHM gene, located on chromosome Xq21.2. The CHM gene spans 186,382 base pairs and consists of 15 exons. To date, over 280 pathogenic variants have been identified, including deletions, insertions, duplications, translocations, nonsense, splice-site, frameshift, and missense mutations. The majority of mutations in the CHM gene are null mutations, either through deletions (25-50%) or nonsense mutations (30%), which result in a truncated, dysfunctional, or completely absent Rab escort protein 1 (REP1). Despite the variety of mutations, there is no established genotype-phenotype correlation, as most mutations lead to a near-universal lack of REP1 protein expression. Because of the X-linked inheritance, males are predominantly affected. Female carriers have one normal and one mutated copy of the CHM gene and are typically asymptomatic due to random X-chromosome inactivation (lyonization). However, skewed lyonization can occasionally result in female carriers exhibiting more severe clinical features similar to affected males.

Diagnostic evaluation: Clinical diagnosis of choroideremia is based on characteristic fundus findings, electrophysiology, and imaging. On fundus examination, the earliest manifestation is widespread pigment clumping at the level of the RPE, distinct from the bone-spicule pigmentation of retinitis pigmentosa. This progresses to well-defined regions of chorioretinal atrophy with visible underlying sclera and large choroidal vessels, typically starting in the postequatorial region and advancing centripetally. The macula is often spared until late stages. Optical coherence tomography (OCT) demonstrates preservation of inner retinal layers but progressive subfoveal retinal thinning and reduction in subfoveal choroidal thickness. Outer retinal tubulations and inner retinal microcysts may be present. Fundus autofluorescence (FAF) shows early loss of peripheral autofluorescence with sharp scalloped edges of demarcation, which helps track disease progression. Electroretinography (ERG) is abnormal early in the disease course, showing a reduced scotopic component before the photopic component, and becomes extinguished by midlife. The diagnosis is confirmed by genetic testing identifying a pathogenic variant in the CHM gene. Differential diagnosis includes X-linked retinitis pigmentosa, gyrate atrophy, and other forms of retinitis pigmentosa.

Differential diagnosis: Differential diagnosis of choroideremia includes: (1) Retinitis pigmentosa (X-linked) — bone spicule pigmentation rather than scalloped chorioretinal atrophy; RPGR/RP2 mutations. (2) Gyrate atrophy — similar chorioretinal atrophy but autosomal recessive, elevated plasma ornithine, OAT mutations. (3) Thioridazine toxicity — acquired, medication history, nummular pigment clumping. (4) Bietti crystalline dystrophy — crystalline deposits in cornea and retina, CYP4V2 mutations. (5) Myopic degeneration — high myopia, posterior staphyloma, lacquer cracks. (6) Geographic atrophy (AMD) — older onset, drusen, no family history of X-linked pattern.

Natural history: The natural history of choroideremia is characterized by a slow, progressive decline in visual function. The disease typically becomes symptomatic in the first decade of life with the onset of nyctalopia (night blindness). During the teenage years and early adulthood, patients experience progressive peripheral visual field loss, leading to a constricted visual field or "tunnel vision." Despite the peripheral vision loss, central vision and visual acuity are often maintained until the fifth to seventh decade of life. Around the fifth decade, most patients experience a rapid deterioration in central vision, eventually leading to legal blindness. The rate of progression can vary significantly between individuals, even within the same family. Recent natural history studies, such as the NIGHT study, have shown that while the mean change in visual acuity is slow, it is heterogeneous, and visual acuity can become asymmetrical in late-stage disease. Anatomical progression, measured by the shrinkage of the intact RPE area on fundus autofluorescence, provides a reliable marker for tracking disease progression over time.

Management and treatment research: ### Current management and supportive care There is currently no treatment approved specifically for choroideremia that stops or reverses the underlying retinal degeneration. Care focuses on monitoring remaining vision, treating related eye problems when present, and supporting safety and independence. Management may include: - Regular follow-up with an inherited retinal disease specialist, with retinal imaging and vision testing to monitor changes over time. - Low-vision rehabilitation, including magnifiers, telescopic devices, screen-reading software, glare control, lighting adjustments, and other assistive technology. - Orientation and mobility training, which may be especially helpful as night vision and peripheral (side) vision decrease. - Genetic testing and counseling. Choroideremia is usually caused by disease-causing changes in the **CHM** gene and is most often inherited in an X-linked pattern. - Treatment of other eye conditions when needed. For example, cataracts may be treated surgically, and cystoid macular edema (fluid-related swelling in the central retina) may be evaluated and managed by an eye specialist. ### Approved therapies No gene therapy, medicine, cell therapy, or optogenetic treatment is currently approved specifically for choroideremia. ### Investigational gene therapy Gene-replacement therapy is designed to provide retinal cells with a working copy of the **CHM** gene. This gene provides instructions for making REP1, a protein needed for normal cell function. - **4D-110 (CHM)** is an investigational adeno-associated virus (AAV) gene therapy. It uses a modified viral delivery vehicle, called the 4D-R100 capsid, to carry a codon-optimized human **CHM** gene. It is delivered by an intravitreal injection, meaning an injection into the gel-like vitreous inside the eye, rather than surgery beneath the retina. The Phase 1 dose-escalation study is active but not recruiting (**NCT04483440**). Phase 1 studies primarily assess safety and help identify suitable dose levels. ### Investigational vision-restoration approaches These approaches are intended for advanced retinal degeneration, when many photoreceptors—the retina’s light-sensing cells—have been lost. They aim to make remaining retinal cells responsive to light and are not expected to restore normal photoreceptors. - **RTx-015** is an investigational optogenetic gene therapy delivered by intravitreal injection. Optogenetics uses a gene-based approach to make surviving cells light-sensitive. RTx-015 is designed to target retinal ganglion cells, which send visual signals from the eye to the brain. The Phase 1 ENVISION study includes people with retinitis pigmentosa or choroideremia and is active but not recruiting (**NCT06460844**). - **KIO-301** is an investigational small-molecule photoswitch for advanced retinitis pigmentosa and choroideremia. Photoswitches are light-responsive compounds intended to help remaining retinal ganglion cells respond to light after photoreceptor loss. It is listed as a Phase 2 program (**NCT06096493**); its current enrollment status should be confirmed through the study site or trial registry. ### Clinical trial participation Clinical research may include treatment trials, natural-history studies, registries, and imaging studies. These studies can improve understanding of disease progression and help develop reliable measures of retinal structure and visual function. Examples include: - Inherited Retinal Degenerative Disease Registry (**NCT02435940**), recruiting - High Resolution Retinal Imaging study (**NCT01866371**), recruiting - Observational retinal-degeneration endpoint study (**NCT06375239**), recruiting - Longitudinal Study of a Bionic Eye (**NCT05158049**), enrolling by invitation Eligibility can depend on age, genetic findings, retinal structure, visual function, and previous treatments. An inherited retinal disease specialist can help identify studies that may be appropriate.

Outlook: The prognosis for patients with choroideremia involves inevitable, progressive vision loss leading to legal blindness. While central visual acuity is often preserved until the fifth to seventh decade of life, the severe constriction of the visual field significantly impacts mobility and independence much earlier. The eventual loss of central vision profoundly affects the quality of life, requiring significant adaptations and low-vision support. Factors affecting prognosis include the individual rate of disease progression, which can vary widely even among family members with the same mutation. The development of secondary complications, such as posterior subcapsular cataracts or cystoid macular edema, can also negatively impact visual outcomes. Early diagnosis and monitoring are essential for providing appropriate low-vision aids and psychological support to help patients maintain their quality of life as the disease progresses.

Epidemiology: Choroideremia is a rare inherited chorioretinal dystrophy with an estimated prevalence of 1 in 50,000 to 1 in 100,000 individuals. Due to its X-linked recessive inheritance pattern, it predominantly affects males. The condition has been reported worldwide, but the highest reported prevalence is in Northern Finland, where a founder effect has been identified. It is estimated that there are more than 500 affected males in the United Kingdom and around 3,000 throughout Europe. Female carriers are generally asymptomatic but may show mild fundus changes.

Selected references: 1. MacDonald IM, Hume S, Zhai Y, et al. Choroideremia. 2003 Feb 21 [Updated 2021 Feb 18]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. PMID: 20301511 2. Mitsios A, Dubis AM, Moosajee M. Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments. Ther Adv Ophthalmol. 2018;10:2515841418817490. PMID: 30627697 3. Pennesi ME, Birch DG, Duncan JL, Bennett J, Girach A. CHOROIDEREMIA: Retinal Degeneration With an Unmet Need. Retina. 2019;39(11):2059-2069. PMID: 31021898 4. 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. PMID: 29084330 5. Li S, Zhang Q, Xue F, et al. Phenotypic and genotypic characterization of a Chinese cohort with choroideremia. Ophthalmic Genet. 2014;35(4):213-221. PMID: 24304044 6. Mura M, Smailhodzic D, Omar A, et al. Clinical and functional findings in choroideremia due to complete deletion of the CHM gene. Arch Ophthalmol. 2007;125(8):1107-1113. PMID: 17698758