Overview

Choroideremia is an X-linked inherited disease that causes visual degeneration and eventual blindness. This condition primarily affects males and is caused by mutations in the CHM gene. Choroideremia is characterised by the degradation of the retina and the blood network supplying it. Early recognition is crucial in the treatment and diagnosis of the condition, and understanding the differences between choroideremia and other dystrophies is most important in ensuring the best outcomes for patients.

Genetic background

Choroideremia primarily affects males, as a result of the CHM gene being X-linked. The term “X-linked” refers to genes encoded by the X chromosome. In males, there is only one X chromosome, and in cases of genetic mutation, only the mutated gene exists. In females, however, there are two X chromosomes, and in the case of a mutation, there is an opportunity for a copy that works correctly to be used. Females with mutated genes are known as carriers. Carriers ‘carry’ the faulty gene and can pass it down to their offspring, while they themselves typically display very minimal symptoms, if any.¹

Pathophysiological background

The condition is caused by a mutation in the CHM gene. The CHM gene is crucial in the development of the Rab escort protein. This escort protein aids molecules and ensures they reach the correct departments of the cell. In choroideremia, this protein is not present, and this leads to impaired transportation of molecules. This causes a disruption in the movement of proteins and organelles, and specifically within the eyes, it leads to the premature death of photoreceptors and retinal pigment epithelium (RPE), causing progressive vision loss.^1,2,3 Degradation of vision typically occurs first in the RPE, followed by the photoreceptors, and finally the choroid. The RPE is a single layer of cells in the eye that supports the photoreceptor cells of the retina, providing protection, transporting nutrients, and removing waste products. In choroideremia, the RPE degenerates and all of these become impaired, leading to a loss of this support. This progresses to a degeneration of the photoreceptor cells. Photoreceptor cells are cells that are responsible for the detection of light and the conversion of this light into electrical signals. There are two types of photoreceptors, and these are rod and cone cells. Rod cells are responsible for low-light vision, and the loss of these cells leads to night blindness, an early symptom of the condition.

This progresses further to a degradation of cone cells and choroidal cells. Cone cells are responsible for bright light and visual acuity, and in choroideremia, these cells ultimately degenerate, leading to loss of colour vision and detail.⁴ Photoreceptors are especially vulnerable as these cells have a high metabolic demand, and must be constantly renewed to maintain function. Choroideremia further progresses into the deterioration of the choroid. The choroid is a layer of blood vessels between the retina and the sclera. The choroid is responsible for providing oxygen and nutrients to the retina. Damage to the choroid is what leads to the loss of peripheral vision, through impairment to the retina, as blood is not effectively transported.⁵ Late-stage choroideremia further progresses and affects the inner layers of the retina. These layers are preserved initially but undergo thinning because of a loss of support from the outer layers. The loss of these layers occurs in late adulthood and is responsible for the central vision loss in the late stages of the condition.⁶

Clinical clues and diagnosis

The first sign of choroideremia is night blindness, caused by the loss of rod cells. This typically occurs in early childhood. The next sign is typically the loss of peripheral vision, and this creates ‘tunnel vision’. This ‘tunnel vision’ expands and further reduces the range of vision. Other symptoms as the condition progresses include reduced acuity, reduced colour vision, and eventual complete vision loss.³ Females who are carriers may experience minimal symptoms such as glare sensitivity. Choroideremia is commonly misdiagnosed as retinitis pigmentosa (RP), as RP has similar symptoms and also causes progressive vision loss. There are, however, some subtle differences that clinicians must consider before deciding on a diagnosis. Fundus examination is a procedure in which the interior of the eye is examined. During the examination, there are differences that present when examining the two conditions. Choroideremia presents with prominent RPE streaking and atrophy of the choroid and RPE. RP, however, displays migration of pigment within the retina - the pigment cells in the RPE move into the neural retina, and display as irregular spots during examination.⁷

These slight differences are crucial in ensuring that the correct diagnosis is made. Further examinations can be used, such as an ERG or OCT, for continued investigation. An ERG measures the retina's response to light, directly examining the activity of rods and cones and monitoring degradation. This test can potentially be used to first assist in the diagnosis of the condition and then to further monitor the degeneration of the rod and cones.⁸ An OCT also uses light, but instead evaluates the layers of the retina: RPE, photoreceptors, and choroid, allowing for the assessment of progressive degradation in these retinal layers.⁹ Choroideremia can also be confused with other conditions like central areolar choroidal dystrophy and cone-rod dystrophies. These two conditions, however, cause much earlier central vision loss than choroideremia, and this is a crucial clue when differentiating the conditions.^10,11,12 Initial suspicions of choroideremia can be confirmed through family history and genetic testing. Testing aims to identify the specific CHM gene variation and is required for definitive diagnosis. The condition being present in the father of the patient also strengthens the suspicion of the diagnosis.^5,13

Importance of early diagnosis and treatment options

Although choroideremia is incurable, early diagnosis allows for the effective management of the symptoms and for genetic counselling. A correct diagnosis allows for a plan to be created that helps the patient cope with current symptoms, whilst also allowing for the preparation for future symptoms and further progression of the condition. Early diagnosis also allows for the informing of parents in cases where there is a possibility of future children. Management of symptoms can involve the use of low vision aids such as magnifiers and contrast-enhancing filters. Magnifiers aim to provide patients with assistance with close-up tasks and provide an increase in image size. Contrast-enhancing filters are used to reduce glare and improve acuity.¹⁴

Early diagnosis is also important, as although there are no assurances of successful treatment, there are opportunities for participation in ongoing clinical trials that aim to develop a cure for the condition. Prompt diagnosis allows patients to be available if any of these trials have available spaces. These trials typically employ gene therapy that aims to insert a working CMH gene into the patient’s retinal cells. This is done using a viral vector that the retinal cells incorporate, and this allows production of the functional protein. This treatment aims to prevent or slow further visual loss, and even potentially lead to the reversal of previous vision loss.¹⁵

Future directions

Future directions for choroideremia focus on further expanding possible gene therapy options for patients. However, because of the nature of the mutations within the CHM gene, widespread gene editing using techniques such as CRISPR/CAS9 is potentially problematic, as there could be unforeseen off-target effects; adverse reactions as a result of a gene editing treatment that impact other molecules rather than the intended target.¹⁶ Further investigation is also being done to analyse nonsense mutations specifically. Nonsense mutations are mutations in which the genetic code is altered and the resulting sequence no longer ‘makes sense’ and can not 

produce a protein. These mutations account for ~30% of all patients, and therapies like ataluren are being trialled to allow the reformation of the full protein.¹⁷

Summary

Choroideremia is a rare condition that significantly impacts patients. The early diagnosis and correct interpretation of subtle symptoms are crucial to the implementation of correct management plans for current and future symptoms. Diagnosis involves a multi-step analysis of 

symptoms, imaging techniques, such as fundal examinations, and the investigation of both familial history and genetic testing. Timely diagnosis allows patients to benefit from appropriate management and potentially gain access to ongoing and future therapies that could significantly increase their quality of life.