What Is Choroideremia?

Introduction to choroideremia

Choroideremia is a rare inherited eye disorder that primarily affects males, causing progressive degeneration of the choroid, retina, and retinal pigment epithelium, leading to gradual vision loss. Choroideremia is caused by mutations in the CHM gene and results in night blindness, tunnel vision, and eventual blindness. Choroideremia is estimated to occur in 1 in 50,000 to 100,000 people.¹ The name comes from the ancient Greek word “khórion” meaning skin (choroid) and “eremia” meaning desert. Choroideremia, therefore, means skin that has a barren appearance like a desert.² This article will discuss the genetics, symptoms, diagnosis, and advancements in gene therapy for choroideremia.

Genetics of choroideremia

Role of the CHM gene

Mutations in the CHM gene are the cause of choroideremia. CHM encodes Rab Escort Protein 1 (REP1), which helps a protein called Rab move small sacs called vesicles around the retina and the retinal pigment epithelium.³

Inheritance pattern

Choroideremia is an X-linked recessive disorder, meaning that the gene is found on the X chromosome. People assigned male at birth (AMAB) have only 1 X chromosome compared to people assigned female at birth (AFAB), who have two X chromosomes. For people with AMAB, a single CHM mutation is enough to get choroideremia, while for people with AFAB, both X chromosomes must have a CHM gene mutation to inherit choroideremia. Most individuals with AFAB will only inherit a mutation on one X chromosome while the other X chromosome is normal, resulting in no symptoms. Carriers of choroideremia may still pass the mutation on to their child.⁴

Components of the eye involved in Choroideremia

• Choroid: is located at the back of the eye and contains blood vessels
• Retina: is a layer at the back of the eye where light triggers electrical signals to the optic nerve that tells the brain what you see
• Retinal pigment epithelium: is a layer between the retina and the choroid, which is important for the health of the retina and vision

Symptoms and disease progression

People with AMAB with choroideremia usually show symptoms of:^5,6 

• Poor night vision (night blindness) in childhood
• Progressive loss of peripheral vision (tunnel vision) in adulthood
• Eventual blindness, usually around ages 50 to 70

Choroideremia in people with AFAB presents differently from individuals with AMAB. It usually presents with no symptoms but, in rare cases, can be severe.⁵ Severe cases of choroideremia in people with AFAB are thought to occur through a process called X chromosome inactivation, where one X chromosome is randomly “switched off” in cells. This means that the other X chromosome determines all the genetic information and whether the CHM gene mutation is inherited.¹ Some patients AFAB also experience night blindness and vision loss over time; however, this occurs at a slower rate than people with AMAB.⁷

Molecular basis of vision loss

Mutations in the CHM gene lead to degeneration of the retinal pigment epithelium, photoreceptors in the retina, and the choroid region of the eye from defects in the REP1 protein. Although the exact mechanisms that lead to the disease are not fully understood, loss of REP1 function means normal cellular processes in the eye cannot occur.^5,6

Diagnosis

Clinical diagnosis

Individuals with a family history of choroideremia or individuals that are experiencing night blindness in childhood may be tested by:^4,5

• Looking at the eye using an ophthalmoscope that shines light into the pupil to find any changes to the retina (fundus examination)
• A visual field test to determine how far you can see on either side when looking straight ahead (peripheral vision)
• An electroretinogram to test how well the cells in the retina are working, which includes the light processing cells rods and cones
• Optical Coherence Tomography (OCT) is used to take images of the retina in layers using light waves. This identifies thickness at the centre of the retina, usually observed during childhood in choroideremia patients.
• Fundus autofluorescence (FAF) is used to take images of the retina, facilitated by a fluorescent molecule called lipofuscin in the retinal pigment epithelium, which can show areas of diseased retina.

Genetic testing

To confirm clinical tests for choroideremia, genetic testing for the CHM gene involved in choroideremia is performed. This involves taking a sample of DNA to identify genetic mutations that lead to a missing or smaller REP1 protein.¹ Genetic testing also helps to identify people AFAB that are carriers of choroideremia mutations. In individuals with a family history of choroideremia, genetic testing can confirm the disease before symptoms arise.²

Differentiating Choideremia from Other  Inherited Retinal Diseases

Choroideremia has similar symptoms to another inherited retinal disease called retinitis pigmentosa, a condition that involves impaired night vision and loss of peripheral vision. Retinitis pigmentosa is also an X-linked condition, yet unlike choroideremia, it is caused by mutations in various genes.¹

To differentiate between the two conditions, an eye exam can show the presence of pigment migration in retinitis pigmentosa but not choroideremia. Degeneration of the choroid and the retina only occurs in choroideremia, which can be seen in fundus autofluorescence. In retinitis pigmentosa, the optic nerve is damaged and blood vessels in the retina narrow, which does not occur in choroideremia.¹

Genetic testing is important to confirm whether an individual has choroideremia or retinitis pigmentosa, as only choroideremia is caused by mutations in the CHM gene. Testing the blood for REP1 protein expression can be used to differentiate choroideremia from retinitis pigmentosa.¹ 

Treatment

Although there is currently no cure for choroideremia, researchers have been working on gene therapies. Gene therapy would replace the mutated CHM gene with a functional copy, thereby improving vision. Clinical trials for gene therapies of choroideremia are currently at phase 3 out of a total of 4 phases of testing involved in clinical trials.^2,7

Adeno-associated virus (AAV) gene therapy

A method being developed is using a virus to deliver a working copy of the REP1 gene into the eye, which is called a viral vector. The adeno-associated virus 2 (AAV2) carrying REP1 (AAV2-REP1) is injected under the retina.⁸ A similar method using AAV2 has already been approved for treating Leber congenital amaurosis, another inherited retinal disease.⁹

Advancements in gene therapy for Choroideremia

The phase I/II clinical trials for the AAV2-REP1 gene therapy show promising results for potential approval of the treatment for choroideremia in the coming years.⁷ A completed phase III study (STAR study) of the AAV-2-REP1 gene therapy was done, which did not meet its targets for effectiveness and safety of the treatment shared in the topline results by the sponsor.

Further studies are necessary to determine the effectiveness and safety of this method for the treatment of choroideremia. There is another phase III clinical trial, titled the SOLSTICE study in progress, which may address these concerns in the search for an effective treatment for choroideremia.

Summary

Choroideremia is a rare genetic eye condition with an X-linked inheritance pattern, with people AMAB more likely to show symptoms. Females are often carriers of the disease with no symptoms. Choroideremia is caused by mutations in the CHM gene, resulting in a defective REP1 protein. Individuals with choroideremia experience night blindness starting in childhood, followed by progressive loss of peripheral vision and, eventually, blindness. The choroid, retina, and retinal pigment epithelium of the eye are affected by the disease. Genetic testing for the presence of mutations in CHM is important for diagnosis and is combined with other clinical tests, including fundus examination, visual field test, electroretinogram, OCT, and FAF. Choroideremia is often misdiagnosed as retinitis pigmentosa, another inherited retinal condition that has similar symptoms. Genetic testing is the key test that can differentiate between the two conditions. There is no cure for choroideremia; however, ongoing clinical trials involving adeno-associated virus (AAV) gene therapy using AAV2-REP1 have shown some promising initial results, with a further phase III trial underway.

Frequently asked questions

What causes choroideremia?

Choroideremia is caused by mutations in the CHM gene, which causes progressive vision loss. People with choroideremia experience gradual vision loss due to damage to the light-sensitive cells in the retina, retinal pigment epithelium, and choroid.

What do people with choroideremia see?

Those affected initially have night blindness during childhood, followed by a progression of vision loss by a shrinking field of vision (tunnel vision) and eventual blindness.

What is the prognosis for choroideremia?

The prognosis for choroideremia varies, but most individuals experience significant visual impairment by midlife.

How do you treat choroideremia?

There is currently no cure for choroideremia. However, potential treatments include gene therapy, which aims to replace the defective gene with a functional one. Clinical trials are ongoing to evaluate the safety and effectiveness of injecting the adeno-associated virus (AAV) and a working copy of REP1 protein under the retina to slow or halt the progression of choroideremia.