Introduction 

A dystrophy (singular form, Dystrophies – being plural) is a term used to refer to the process of something becoming worse and degrading rather than performing optimally.¹

Retinal dystrophies, therefore, account for the degradation of the retina (tissue layer at the back of the eye)⁵ due to various factors - in this case, the factor being an inherited cause.  

Inherited Retinal Dystrophies (IRDs) can be defined as a collection of retinal diseases that decrease vision gradually over time due to faulty genes.²

Overview Of IRDs  

The majority of vision loss is mainly caused by IRD, with around 2 million individuals being affected by this condition around the world.³ IRDs are caused by a mutation in a gene located in the DNA of cells that is passed down from parents, making them inherited. There are a few types of mutations that can present at different locations of the DNA, with a surplus of 270 genes that are associated with these mutations,⁴ therefore leading to multiple variations and types of IDR.³

IRDs can present themselves in different ways and levels of severity, such as having difficulties with brightness of sight, impaired colour perception, impaired night vision, and impaired peripheral vision. Where IRD can progress with certain individuals, over time, the gradual worsening of vision can result in total loss of vision.⁴

Choroideremia is one of the different types of IRD’s which comes about by a mutation in the CHM gene⁵(CHM Rab escort protein)⁶, which codes for a protein called REP1. In fully functional cells, REP1 engages in the transportation process of supplying the nutrients cells require to be healthy. However, in Choroidermia, the mutation of CHM means parts/all of the cell components are unable to receive these vital nutrients.⁵

In Choroidermia, the cells that are affected are called rods and cones (which are photoreceptors located in the retina) and retinal pigment epithelial cells. These degrade as a result of the CHM 

gene mutation causing a decline in its function - responding to light sensitivities and picking up on details within a person's field of vision.⁵

Genetic Basis  

Choroideremia is based on a genetically inherited mutation of the gene CMH. Genes are proteins that encode for other complementary proteins, and in this case, the CMH gene encodes for the RAB geranylgeranyl transferase holoenzyme ( REP1).⁶

This is an X-linked inherited condition.⁶ This is because the CMH gene is found on the X chromosome. People assigned female at birth have 2 X chromosomes, which identify their gender, whereas people assigned male at birth will have 1 X chromosome and 1 Y chromosome. This means that it’s more likely for people who are assigned male at birth to inherit the Choroideremia mutation, as they only have 1 copy of the X chromosome. In contrast, people assigned female at birth have 2, and therefore, in most cases, having the mutation in 1 X chromosome and not the other makes them carriers.⁵

CHM Gene And Rab Escort Protein 1 (REP1) 

The affected areas of the eye are cells in the retina called rods and cones, and retinal pigment epithelial cells.⁵ In the eye, the retina receives its blood supply through vessels called the choroid, located towards the back.⁵

A mutation in the CHM gene directly affects the REP1 protein as it’s complementary and encodes for it.⁵ Where REP1 would usually be involved in the transport of nutrients and oxygen within these cells, subsequently, a genetic mutation means REP1 cannot perform its function properly, and the components in the cells of rods and cones and retinal pigment epithelial cells are unable to receive vital nutrients, causing oxidative damage.⁵

Signs And Symptoms  

• Night blindness³ 
• Peripheral sight decline³  
• Central sight decline³ 
• Brightness insensitivity³  
• Abnormal blood vessel growth³  
• Retinal fibrosis³ 
• Tunnel vision⁵ 
• Colour vision impairment⁷ 

Gender Distribution  

Individuals assigned male at birth usually present the symptom of night blindness in childhood. This progresses over time as the condition worsens. Individuals assigned female at birth usually don’t show any symptoms, as they are usually carriers and the mutation doesn’t present any issues. In some cases, they may also experience night blindness also, and vision abnormalities.⁷ 

Prevalence  

In cases of this condition, visual impairment progresses over time. The rate of its development varies from person to person; however, it’s most common to lead to total blindness.⁵

Choroideremia starts off in childhood, where the first symptom of night blindness sets in.³ Gradually, the individual will experience a constriction of their field of vision as photoreceptors become less able to pick up on changes in the environment and light sensitivities, resulting in tunnel vision in the mature stages of life.⁵

Diagnosis   

Diagnosis is completed through observation of distinctive routine symptoms through techniques such as DNA examination, diagnostic imaging, and measurement of the retina’s electrical activity.⁴ Many IRDs display similar symptoms; therefore, like other IRDs, Choroideremia has a high likelihood of being under-identified.⁵

Treatment Methods  

Treating Choroidermia has been seen to prove challenging. At present, no complete methods of treatment or therapy exist for this condition. However, there has been promising progress with genetic therapy and mutation identification, though still in its research and trial phase.⁷

Helping affected individuals manage symptoms, receiving support to understand the genetic aspects of the disease, and receiving emotional support are important parts of treatment for IRD’s.⁷

Imaging Techniques And Identification  

Methods include: 

• Confocal adaptive optics scanning light ophthalmoscopy (AOSLO). This is useful to identify dystrophy processes within the retina, along with small micro cellular components⁷ 
• Microperimetry. This is useful to identify sensitivity change characteristics⁷ 
• Full-field electroretinograms (ERGs). This is useful for individuals assigned male at birth to identify any dysfunction around the light-sensing rod and cone cells in the retina⁷ 

Future Directions For Diagnosis And Treatment 

An encouraging direction for future treatment for this condition is gene therapy done through a series of clinical studies targeting the CMH gene, which is mutated in Choroiderma.⁸

Comparisons To Other IRD’s 

Many IRDs display similar and dissimilar features since they all affect the same area of the eye (the retina), and there are many different types of genetic retinal mutations that can occur.³ Similar symptoms displayed across all IRDs include night blindness, hereditary gene traits, peripheral sight decline, and fundus abnormalities.⁴

The mutational gene presented in Choroideremia, called CHM, shows similar signs with other eye conditions such as gyrate atrophy, retinitis pigmentosa, Kearns–Sayre syndrome (KSS), Bietti’s crystalline dystrophy, and thioridazine hydrochloride retinal toxicity.⁷

Summary  

Choroideremia is an X-linked inherited retinal dystrophy caused by a mutation in the CHM gene, which disrupts the Rab escort protein 1 (REP1) and leads to progressive vision loss. Symptoms include night blindness, tunnel vision, and peripheral vision decline, primarily affecting males, while females are usually carriers. Diagnosis involves genetic testing and retinal imaging, but no definitive treatment currently exists, though gene therapy is under research. Choroideremia shares features with other inherited retinal dystrophies but is distinguished by its specific genetic cause.