1. Choroideremia? The name's complicated, but the core idea is simple

1.1 Humans are XY or XX, and CHM is on the X chromosome

Humans have two sex chromosomes. Males have XY, and females have XX. So, if we inherit a Y sex chromosome from our dad and an X from our mom, we're born a son; otherwise, it's a daughter. The CHM gene is found on the X chromosome. Since males only have one X chromosome, if there's a problem with this gene, the disease manifests immediately. Therefore, CHM mutations mainly appear in males. In females, even if one X sex chromosome has a problem, the other X often compensates, so they often remain carriers with little to no disease manifestation.

1.2 When the CHM gene breaks, REP1 protein isn't made

The CHM gene acts as a blueprint for creating a protein called Rab Escort Protein 1 (REP1). This protein helps Rab proteins, which are responsible for transporting substances within cells, to do their job. Our bodies are mostly made of proteins, and each protein needed to build different parts of the body has a unique shape and role. Genes are what meticulously design these individual proteins. In fact, many seemingly vast differences are often due to a tiny difference in just one part of a gene. The difference between someone with perfect vision and someone who can't see at all might just be a single molecular structure in one part of a gene.

From now on, remember these two: REP1 protein and Rab protein.

1.3 Without REP1, Rab proteins can't do their job

Rab proteins are in charge of transporting vesicles to the correct locations inside cells. Vesicles are like **little transporters that carry proteins, enzymes, signaling molecules, and even cellular waste**. But without REP1, Rab proteins can't function properly, and the entire intracellular logistics system grinds to a halt. This leads to a gradual loss of function in cells related to the retina.

So, if there's a problem with the CHM gene, REP1 protein can't be made. Without REP1 protein, Rab proteins can't function. And if Rab proteins can't function, vesicles can't do their job – that's the approximate flow of how **CHM gene mutations** cause the disease.

2. What's Happening Inside Your Eye?

2.1 RPE → Choroid → Photoreceptors: The Decline Progression

The first area affected is the retinal pigment epithelium (RPE). These cells are like the maintenance crew for photoreceptors. They even clean up the daily waste produced by photoreceptors. (Photoreceptors are the cells that convert light into electrical signals our brain can understand, and the choroid is a layer of blood vessels that supplies oxygen and nutrients to the eye.) But if the RPE is damaged, the photoreceptors above it lose their support and gradually deteriorate. It's like producing waste every day, but the person who always cleaned it up suddenly stops, and the toxins build up, causing your body to break down, if that makes sense?

At the same time, the underlying blood vessel layer, the choroid, which usually actively interacts with the RPE, starts to degenerate. Since the RPE cells are dying, the choroid no longer needs to supply nutrients to them or receive waste. So, blood flow itself decreases, leading to its gradual atrophy and degeneration.

That's why the disease choroideremia is named as such – because the shrinkage of the choroid is prominently observed. However, the atrophy of the choroid itself isn't the root cause of the disease.

2.2 Eventually, Vision Loss Progresses to Central Vision

Initially, atrophy begins in the peripheral vision, with few noticeable symptoms. However, as it progresses, it eventually invades central vision, leading to blindness in the late stages.

3. RP and CHM Are Clearly Different Diseases

3.1 RP Involves a Problem with the Photoreceptors Themselves

RP (Retinitis Pigmentosa) is a disease where there's a problem with genes that encode photoreceptor proteins themselves, such as RHO and RPGR. It's characterized by rapid onset of night blindness and peripheral vision loss.

On the other hand, CHM (Choroideremia) is a bit different. When there's a problem with the CHM gene → REP1 protein, which helps Rab proteins, isn't made → then intracellular vesicle transport gets tangled, and the RPE (retinal pigment epithelium) breaks down first → as a result, photoreceptors lose support and gradually deteriorate, and eventually the underlying choroid also degenerates.

In short, CHM is a disease that indirectly damages photoreceptors,
while RP is a disease that directly damages photoreceptors. That's the difference.

3.2 CHM Starts with a Problem in the Intracellular Transport System

Repeating what was just said, CHM starts in the cells that support and maintain photoreceptors (RPE, choroid) rather than the photoreceptors themselves. There's a structural difference: RP is direct photoreceptor damage → CHM is the collapse of the cell maintenance system.

4. How Do Gene Mutations Affect Things?

4.1 Nonsense and Frameshift Mutations Are Common

Most CHM gene mutations are **mutations that stop protein production itself**. Examples: nonsense mutation (premature termination), frameshift mutation (frame shift), etc.

4.2 Protein Production Stops After a Specific Point

Human DNA is made of four types of bases called adenine (A), thymine (T), guanine (G), and cytosine (C), arranged in a specific order. This sequence is the genetic information. But for example, if at the 526th base of the CHM gene, a C is replaced by a T, that codon changes into a premature stop signal, and protein production halts mid-way. In this case, the REP1 protein is cut off before it can gain its function.

A codon is a unit made of three bases. RNA is like a copy of DNA, and an intermediate messenger that goes out before making proteins. For example, if DNA has the sequence ATG, when it's transcribed into RNA, it becomes an AUG codon. This codon acts as a command to produce a specific amino acid. But if one base is missing or wrong in ATG, that part also gets twisted in the RNA, preventing it from being divided into normal codon units, eventually causing a chain reaction that messes up the entire protein blueprint.

5. How Far Has Treatment Come?

5.1 AAV-based Gene Therapy is in Phase 3 Clinical Trials

CHM is a representative example of a monogenic disease with a clear causative gene, making gene replacement therapy a viable option. Currently, AAV2 vector-based treatments (e.g., SPK-7001) are in Phase 3 clinical trials.

5.2 Preserving Structure is Key, Early Treatment is Beneficial

Since it's difficult for damaged tissue to recover, receiving treatment as early as possible while retinal structure is maintained is crucial for a good prognosis.

6. Summary: CHM is Rare but Has a Clear Target

CHM is a rare disease caused by a single gene defect, but its pathogenesis is relatively well understood, and gene-based therapy possibilities are actively being researched. Accurate understanding, early diagnosis, and access to treatment are important.

I'll keep updating this article regularly!