Choroideremia
Choroideremia is an X-linked recessive eye disorder characterized by the progressive degeneration of the choriocapillaries, retinal pigment epithelium, and photoreceptors in the retina. This condition primarily affects males, leading to a gradual loss of night vision, peripheral vision, and ultimately central vision, typically manifesting in the first or second decade of life. The prevalence of choroideremia is estimated to be between 1 in 50,000 to 100,000 individuals, but it is often misdiagnosed as other retinal diseases, complicating accurate prevalence estimates. Genetic factors play a significant role in choroideremia, with the responsible gene located on the X chromosome, where mutations lead to a nonfunctional protein involved in retinal health.
Symptoms commonly begin with nonspecific issues such as glare and night vision disturbances, escalating to significant vision loss over time. Diagnosis involves comprehensive ophthalmic examination and visual field testing, with a differentiation from other retinal disorders being crucial. Currently, there is no cure for choroideremia, but ongoing research, including gene therapy trials, brings hope for future treatments. Genetic counseling is recommended for families with a history of the disorder to identify carriers and affected individuals. Overall, awareness and regular ophthalmic evaluations are essential for those at risk.
Choroideremia
ALSO KNOWN AS: Diffuse total choroidal vascular atrophy of X-linked inheritance; progressive tapetochoroidal dystrophy; tapetochoroidal dystrophy (TCD)
DEFINITION Choroideremia is an X-linked recessive eye disorder causing progressive degeneration of the choriocapillaries, retinal pigment epithelium, and photoreceptors of the retina. Choroideremia causes progressive loss of night vision, peripheral vision, and finally central vision in affected males in the first or second decade of life.
The prevalence of choroideremia is estimated to be 1 in 50,000 to 100,000 people, although choroideremia may be misdiagnosed as other retinal degenerative conditions such as retinitis pigmentosa or gyrate dystrophy, which makes the estimation of prevalence inexact. Thioridizine (Mellaril) toxicity and Bietti crystalline dystrophy must also be considered in the differential diagnosis.
Risk Factors
Family history of choroideremia with a usual pattern of X-linked recessive inheritance with female carriers will pose a risk for the children of the carrier. Consistent with X-linked recessive inheritance, choroideremia will predominantly affect males; however, female carriers may exhibit mild findings of retinal dysfunction.
Etiology and Genetics
Choroideremia was reported by Clement McCulloch in 1969 in a family with 1,600 descendants of an Irish man who immigrated to Canada in 1850. His determination that choroideremia was an X-linked recessive disorder was controversial due to the fact that female carriers in some cases showed mild clinical forms of the disease. Subsequently, other lineages including a large Finnish family have been identified with the X-linked recessive pattern of inheritance of choroideremia.
The Xq21.2 locus of the long arm of the X chromosome has been identified in choroideremia. The Finnish lineage, which comprise a large proportion of all choroideremia patients worldwide, all carry the same mutation, while J. A. Van Den Hurk and colleagues described different point mutations in other lineages. All these mutations result in a termination of a codon, which results in a truncated protein. The gene product REP1 of the CHM gene is nonfunctional in choroideremia patients. REP1 is a Rab escort protein geranylgeranyl transferase involved in trafficking of Rab proteins in the cell. This protein attaches isoprenoids to TAB 27. A result of a nonfunctional REP1 product is degenerations of the layers of the retina.
There has been some debate about whether the primary degenerative effect occurs in the vascular basement membranes of the choriocapillaries, leading in turn to degeneration of the other layers of the retina. More recent research points to the retinal pigment epithelium as the site of the primary defect. In the end stages of severe choroideremia, the retinal layers thin to reveal the underlying sclera.
Additional syndromes can involve degeneration of the choroid in association with intellectual disability, deafness, and cleft lip and palate. These syndromes are considered distinct from isolated choroideremia.
Symptoms
The age of onset is variable; however, most patients present between age ten and thirty. Initial symptoms may be nonspecific and can include glare as well as night vision disturbance. As the disorder progresses, there is an increasing loss of peripheral vision and in the later stages a loss of central vision.
Anyone with a known family history of choroideremia should have regular ophthalmic examinations including visual field testing. In a case of symptoms with no known history of choroideremia, a baseline eye examination from an ophthalmologist is recommended. In the case of persistent symptoms, repeat examinations over a period of time may detect a progressive condition.
Screening and Diagnosis
Affected males and female carriers should undergo a complete dilated eye examination by a qualified ophthalmologist. Visual field testing and multifocal electroretinogram (ERG) testing is helpful to establish a diagnosis. A retinal specialist may be consulted to differentiate between choroideremia and other retinal disorders such as gyrate dystrophy and retinitis pigmentosis.
Treatment and Therapy
There is no treatment for choroideremia. However, in 2024, researchers were optimistic that a treatment may be found in the future. Timrepigene emparvovec (Biogen) was among the first gene therapies to have made it to phase 3 trials and possible approval by the Food and Drug Administration (FDA). Their trials have shown that some individuals treated with either a high or low dose of the therapy showed improvement on a standard vision chart, while those in the study who were not treated with the therapy showed no improvement.
Prevention and Outcomes
Carriers of choroideremia and affected individuals may be detected through genetic counseling. Families with a history of choroideremia should have a high index of suspicion and consult with genetic counseling and ophthalmology specialists to access tests that may identify affected individuals and carriers.
Bibliography
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Genetics Home Reference. "Choroideremia." Genetics Home Reference. NIH/NLM, 14 July 2014. Web. 18 July 2014.
Foundation Fighting Blindness. "Choroideremia." Foundation Fighting Blindness. Foundation Fighting Blindness, 2014. Web. 18 July 2014.
Hilton, Lisette. "Phase 3 Study on Gene Therapy for Inherited Retinal Disease Choroioderemia Offers Important Insight." Miller School of Medicine, news.med.miami.edu/phase-3-study-on-gene-therapy-for-inherited-retinal-disease-choroideremia-offers-important-insight/. Accessed 5 Sept. 2024.
Kalatzis, Vasiliki, Christian P. Hamel, and Ian M. MacDonald. "Choroideremia: Towards a Therapy." American Journal of Opthamology 156.3 (2013): 433–7.e3. MEDLINE with Full Text. Web. 18 July 2014.
McCulloch, C. “Choroideremia.” Transactions of the American Ophthalmological Society 67 (1969): 142–195. Print.
Merin, Saul. Inherited Eye Diseases: Diagnosis and Management. 2d ed. Hoboken: Taylor, 2013. Digital.
American Academy of Opthamology. Basic and Clinical Science Course (BCSC) Section 12: Retina and Vitreous. San Francisco: American Academy of Ophthalmology, 2012. Print.