Choroideremia (CHM) is a rare genetic eye disease that affects the retina, which is the area at the back of the eye that processes all we see into signals that are sent to the brain via the optic nerve.

Choroideremia is a rare genetic retinal disease, which causes blindness in males during middle age. We still have much to understand about how the biochemical defect causes the retinal-specific disease and if it has any hidden effects on the rest of the body. Recently, there have been suggestions that CHM patients may be at risk of higher blood cholesterol or fat levels, and this is under currently investigation as part of detailed natural history studies. CHM has been used as a prototype retinal degeneration for developing novel gene therapies and hence, has provided much hope for those affected with the disease but also patients with similar inherited retinal disorders. Choroideremia affects about 1 in 50,000 individuals and is caused by a genetic defect in one single gene called the CHM gene, which is located on the X-chromosome. Male patients manifest the severe blinding form of the disease and suffer from a progressive retinal degeneration with obliteration of the light sensing cells (photoreceptors), their support cells (the retinal pigment epithelium) and part of the blood supply to these retinal layers (the choroid). The healthy orange retina is lost and the pale white sclera (tough white coat of the eye) can be seen when you look into the eye. Females are carriers and largely unaffected, however they can develop mild symptoms of visual impairment, such as night blindness, in more in later stages of life.

Choroideremia is Genetic
Choroideremia is caused by mutations in the CHM gene. The condition is passed down in families by the X-linked pattern of inheritance. In this type of inheritance, the mutated gene for the disease is located on the X chromosome. Females have two X chromosomes and can carry the disease gene on one of their X chromosomes. Because they have a healthy version of the gene on their other X chromosome, carrier females are usually not affected by X-linked diseases. Males have only one X chromosome (paired with one Y chromosome) and are therefore genetically susceptible to X-linked diseases. Males with X-linked diseases pass their Y chromosome to their sons, and therefore will never pass an X-linked disease to their sons. Female carriers have a 50 percent chance (or 1 chance in 2) of passing the X-linked disease gene to their daughters, who become carriers, and a 50 percent chance of passing the gene to their sons, who are then affected by the disease.

How the CHM Gene Works
The CHM gene encodes a protein called Rab Escort Protein-1 (REP1). This protein works in all our cells by helping to shuttle other small proteins (called Rabs) to their correct destination so they can undertake their role, such as allowing nutrients to pass across cells and removal of waste products. If these small proteins cannot be transported to their correct location to fulfill their job, the cells can starve and waste products build up causing damage and cell death. Humans are fortunate to have a second copy of REP1 called Rab Escort Protein-2 (REP2), which works well to transport Rabs in all the cells of our body except for the retina. The photoreceptors and retinal pigment epithelium have a subset of Rab proteins that prefer to be escorted by REP1 over REP2. Therefore, in the presence of a defective CHM gene with lack of REP1, there is a buildup of Rabs that are not able to function appropriately, and this leads to a retinal-specific disease that causes blindness in an otherwise fit and healthy individual.

Choroideremia Symptoms and Disease Progression
As an X-linked disease, choroideremia occurs primarily in males. In childhood, night blindness is the most common first symptom. As the disease progresses, there is loss of peripheral vision or “tunnel vision” and later a loss of central vision. Progression of the disease continues throughout the individual’s life, although both the rate and the degree of visual loss can vary, even within the same family. In affected male patients, the first symptom of CHM is night blindness, which is most commonly noticed in early childhood from as early as five or six years of age. The disease continues to progress with loss of the peripheral field of vision, this occurs at a relative fast rate in late adolescence and into the early twenties, leaving the patient with only a small area of central “tunnel” vision. The rate of decline lessens but the retinal degeneration continues to progress slowly over the next few decades, patients lose depth perception, color perception and finally loss of central vision with complete blindness into their fifties and sixties. Both the rate of disease progression and the degree of visual loss are variable among those affected, even within the same family. Female carriers are usually unaffected, but some do experience symptoms of night blindness later in life with some patchy loss in vision. This occurs because despite women having two X-chromosomes, one is switched off in every cell to ensure the correct amount of gene product (protein) is being produced. This process is random, called X-inactivation or lyonization, and means if the healthy X-chromosome is inactivated, then the X-chromosome carrying the defective CHM gene will prevent normal function in that particular retinal cell leading to disease in a patchy distribution.

Disorders with Similar Symptoms
Symptoms of the following disorders can be similar to those of choroideremia. Comparisons may be useful for differential diagnosis: X linked retinitis pigmentosa (RP) is the most common inherited vision disorder that has similar symptoms to choroideremia. X linked RP is passed from a mother (who carries or has RP) to a son. In RP, the retina degenerates, vision decreases and can be lost. Symptoms include night blindness leading to progressive loss of peripheral vision, followed by tunnel vision. Night blindness is usually the first noticeable symptom, generally occurring during childhood. This is followed by tunnel vision (loss of peripheral vision). The extent and progression of symptoms is variable. An eye doctor can differentiate between RP and choroideremia with an eye exam. Gyrate atrophy of the choroid and retina is characterized by a circular degeneration in the choroid and retina of the eye. Because this eye disorder results from the accumulation of ornithine in the blood, a blood test can be used to help diagnose it. In general, patients with this eye condition as have other medical problems such as muscle weakness. Very rarely, a single genetic variant in the RPE65 gene can cause a dominantly inherited condition that affects the retinal pigment epithelium and looks like choroideremia. The key feature is the pattern of inheritance is not X-linked.

How to Diagnose Choroideremia
A diagnosis can be made by an ophthalmologist with a specialist interest in genetic eye disease. They will have the expertise to interpret the patient history, signs from the clinical examination and investigations such as electrophysiology, fundus autofluorescence and optical coherence tomography. But ultimately, a genetic test to screen the CHM gene for mutations is required to make a definitive diagnosis. There have been rare cases of patients with a retinal appearance similar to CHM, but upon genetic testing have shown mutations in different genes known to cause other retinal dystrophies, such as RPE65. Another genetic condition called gyrate atrophy, which is an inborn error of metabolism, displays similar clinical features to CHM. It is caused by mutations in the ornithine ketoacid aminotransferase (OAT) gene found on chromosome 10.Patients show an increase in plasma levels of ornithine, however, reduction of the amino acid arginine in the diet prevents disease progression. This highlights the need to see a specialist so that CHM can be diagnosed correctly.

 What are the Treatments Ooptions
There is currently no cure or effective treatment for CHM. Much research is underway to seek a viable and sustainable therapy and there are a number of promising gene-based approaches under development. Firstly, the use of a drug administered orally to patients, which has the ability to override a specific genetic mutation, called a nonsense mutation, has been used which introduces an abnormal stop signal into the CHM gene. Nonsense mutations account for over 30% of CHM.

May 2024