Introduction

The human eye is an incredibly specialised sensory organ that enables us to see by capturing light and converting it into electrical signals for the brain. It’s made up of various parts that work together much like a camera. The cornea and lens focus incoming light onto the retina, which is the light-sensitive layer located at the back of the eye. The iris and pupil control how much light gets in. Within the retina, there are photoreceptor cells—rods for night vision and cones for colour and detail. These signals travel through the optic nerve to the brain, where they create images.

Supporting the eye are layers like the sclera (the white part of the eye), the choroid (a layer filled with blood vessels), and the retinal pigment epithelium (RPE), which nourish and protect the retina. Due to this intricate structure, even a single genetic defect in one layer can lead to progressive vision loss.

Choroideremia is a rare inherited condition that impacts your eyesight. It causes vision to deteriorate over time, ultimately leading to blindness. This condition is an incurable, X-linked, recessive retinal dystrophy caused by mutations in the CHM gene. It’s estimated to affect about 1 in 50,000 males. The disease is marked by the gradual degeneration of the retinal pigment epithelium, choroid, and photoreceptors, resulting in visual impairment and blindness. Unfortunately, there’s a significant unmet need for choroideremia, as there are currently no approved treatments available for those affected by this condition.

What causes choroidermia?

It is a genetic disorder, hence it is caused by mutations in the CHM gene, which encodes the Rab escort protein that is necessary for the functioning of the retinal pigment epithelium, which nourishes and protects the retina.

Although this gene is found in all body cells, the effects are most severe in the retina and surrounding tissues, leading to progressive vision loss. Since the condition follows an X-linked inheritance pattern, it affects mainly males, while females are usually carriers who may show mild signs.

Clinical significance

Progressive blindness leads to a slow decline in vision, starting with difficulty seeing at night and a gradual narrowing of the visual field. Over time, this can result in significant sight impairment.

This condition can really impact quality of life in various ways. Patients might find it challenging to pursue education, maintain employment, move around freely, and enjoy their independence.

It's not uncommon for symptoms to appear early, often beginning in childhood or adolescence, which can have a lasting effect.

The inheritance pattern is X-linked, making genetic counselling essential for families dealing with this condition.

Interestingly, female carriers might also show some retinal changes and can occasionally experience visual symptoms themselves.

This condition is often seen as a model for gene therapy and precision medicine, with ongoing clinical trials investigating potential treatment options.

Why do genotype-phenotype correlations matter?

Since it is a genetic disorder, this helps identify the severity or progression of the disease based on the percentage or type of mutations.

It allows doctors to give clearer expectations for vision preservation. 

It is also important to give the patients a promising treatment like gene therapy based on the responses given by different mutations.

Genetics of choroideremia

As told earlier, Choroideremia is an X-linked disorder, it is caused due to various mutations in the CHM gene, which is located on chromosome Xp21.2, and is inherited in a recessive manner. 

The CHM gene encodes for Rab escort protein-1 (REP-1). REP-1 is one of two Rab escort proteins, both of which are found throughout the body. 

REP-1 is involved in a complex system of intracellular trafficking of various lipid membrane-bound structures. These vesicular structures are guided by GTP-binding proteins (Rab proteins). 

For Rab proteins to be connected to the lipid membrane and allow intracellular trafficking, they need to be prenylated, which is the addition of geranylgeranyl groups to a molecule.

REP-1 proteins aid in this process by bringing Rab proteins to the Rab geranylgeranyltransferase (GGTase) complex, where the prenylation occurs.

REP-1 also facilitates the transfer of the prenylated Rab protein to its target location. Without this escort, the prenylated Rab would undergo inactivation.

Mutations in the CHM gene create defects in REP-1. This leads to improper intracellular vesicular trafficking and is thought to impair the transport of proteins from the Golgi apparatus to the outer segments in photoreceptors, as well as the impairment of phagocytosis and degradation of shed outer segments by RPE cells.

Inheritance pattern

Choroideremia follows an X-linked recessive inheritance pattern. This means the gene for the disorder is located on the X chromosome. 

Males are affected more often and more severely because they have only one X chromosome. A single mutated copy is enough to cause the condition. 

Females with one mutated copy are usually carriers. They often do not show symptoms due to random X-inactivation but may experience some vision impairment later in life.

Females are usually the carriers since the males inherit the X chromosome from their mother and chromosome from their father. 

Although fathers can transfer the X chromosome to their daughters, hence making them carriers for the disease.

Types of mutation

• Large Deletion
• Small Deletion and Insertion
• Nonsense Mutation
• Splice-site Mutation
• Missense Mutation
• Frame-shift Mutation
• X-linked translocation

Phenotypic spectrum 

The choroideremia phenotype spectrum encompasses a range of disease severities and clinical signs in both male and female carriers. This results from different mutations in the CHM gene. 

Males usually face progressive night blindness and loss of peripheral vision. 

Female carriers may show anything from mild symptoms to severe retinal atrophy, often with a distinct "fishnet" pattern of pigmentary mottling.

The broad range in how the disease shows up, sometimes within the same family, underscores the importance of proper genetic testing and diagnosis to accurately identify cases and evaluate them for possible treatments like gene therapy.

Clinical progression in affected males

1. Night Blindness (Nyctalopia):  

Symptoms usually start in the first decade of life, causing difficulty seeing in low light.

• Peripheral Vision Loss:  

In the teenage years, peripheral vision begins to worsen, eventually resulting in tunnel vision.  

• Central Vision Loss:  

By the fourth or fifth decade, central vision also starts to decline, leading to significant visual loss.  

• Fundus Appearance:  

There is a distinct atrophy of the choroid. This can create a pale, "barren" or "desert-like" fundus as the underlying sclera shows through.  

Characteristics in female carriers

• Milder Symptoms:  

Female carriers are generally asymptomatic or experience mild symptoms like nyctalopia. 

• Fundus Changes:  

They may exhibit subretinal pigmentary changes, RPE atrophy, or patchy areas of chorioretinal degeneration. These changes are often visible with special imaging techniques such as fundus autofluorescence.

Genotype-phenotype correlations

While establishing a clear link between genotype and phenotype in choroideremia (CHM) is difficult due to the wide variety of mutations and the protective role of REP2, some patterns are emerging. Specifically, mutations that cause a non-functional REP1 protein, like complete gene deletions or nonsense mutations, usually lead to a severe disease phenotype. In contrast, a "hypomorphic" or missense variant that allows for some residual function of REP1, such as the c.940+3delA splicing mutation, can result in milder phenotypes and a slower disease progression. Other factors, including REP2 compensation, genetic modifiers, and environmental influences, may also affect phenotypic variation.

Challenges in establishing correlations  

• Diverse Mutations:  

CHM is caused by mutations in the CHM gene. These mutations can include large deletions, translocations, missense mutations, nonsense mutations, and splicing site mutations. This wide range of mutation types makes it hard to establish simple correlations.  

• REP1/REP2 Interaction:  

The CHM gene produces REP1 (Rab escort protein 1), which is essential for cellular prenylation. However, REP2, a closely related protein, can partially compensate for the loss of REP1. This interaction likely contributes to the variability in phenotypes and complicates the direct link between a specific mutation and its severity.  

Emerging correlations  

• Severe Phenotypes:  

Mutations that result in a near-complete absence of functional REP1 protein, such as large deletions or disruptive nonsense mutations, generally lead to severe choroideremia.  

• Milder Phenotypes:  

Hypomorphic mutations lead to a partially functional but reduced amount of REP1 protein. This can cause milder disease phenotypes.  

c.940+3delA: This noncanonical splicing variant results in very low levels of correctly spliced mRNA, which improves the disease phenotype and suggests a slower disease progression.  

• Missense Mutations:  

Some missense mutations, although they do not completely eliminate the protein, can decrease REP1 expression or disrupt protein structure. This can also result in a mild or variable phenotype.  

Treatment

Gene Therapy: This is the primary therapeutic strategy, with potential to provide a functional copy of the CHM gene, which the use of an adeno-associated virus (AAV) vector to deliver a safe and effective means of gene therapy. The concepts have been validated in a variety of animal models, in vitro studies, and entered clinical development.

Nonsense Suppression Therapy: For those patients whose choroideremia is attributable to a nonsense mutation that stops production of the protein prematurely, the development of a medication that involves translational readthrough is being investigated for therapeutic potential. 

Retinal Prosthesis Systems (RPS): In advanced stages of the disease with significant retinal degeneration, retinal prostheses may provide a means of restoring some rudimentary vision by directly stimulating the retina. 

Cell-Based Techniques: Where there is loss of retinal tissue, we may need to think about cell replacement or regeneration, and these methods are currently being explored as a potential treatment for advanced cases.

Summary

Choroideremia is an X-linked recessive disease that causes retinal degeneration due to mutations in the CHM gene.

The disease begins with night blindness and peripheral vision loss, progressing to severe vision loss or blindness, mainly in males, while female carriers show variable signs due to X- X-inactivation. 

Genotype-phenotype correlations are lacking, as patients with the same mutation may show different disease severity. Understanding this is very important for prognosis, genetic counselling, and gene therapy.