Choroideremia

Alternative Names

Homozygous; Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers

Inheritance

Choroideremia (CHM) is a disorder that travels through family lines via an X-linked inheritance pattern. In such a pattern, the CHM gene resides on the X chromosome. Women, who have two X chromosomes, will often have the defective gene on just one of them. Because they have another X chromosome with a functioning gene that produces REP-1 (Rab escort protein-1), they generally don’t exhibit the intense symptoms associated with CHM.

However, it’s noted that female carriers can display a spectrum of eye abnormalities, from minor retinal changes to profound retinal degradation and diminishing visual fields, which can lead to reduced vision sharpness. A number of these patients, particularly in later years, will witness significant symptoms. There appears to be a correlation between the severity of the phenotype and the diminished expression levels of the normal CHM RNA, though these levels are typically gauged within the bloodstream. Men, possessing only one X chromosome alongside a Y chromosome, are more vulnerable to X-linked conditions.

Men are not simply carriers of X-linked disorders; if they are affected, they will transmit the gene found on their X chromosome to all their daughters, making them carriers as well. However, affected men cannot transmit an X-linked gene to their sons, since sons inherit only the Y chromosome from their fathers. Female carriers have a 50 percent chance, or a 1-in-2 probability, of passing the gene for an X-linked condition to their daughters, who will then also become carriers.

The CHM gene and how it works

The CHM gene is responsible for producing a protein known as Rab Escort Protein-1 (REP1), which serves a vital function across all human cells. REP1’s role is to escort other minute proteins, known as Rabs, to their proper locations within the cell, enabling these Rabs to perform their essential duties, which include facilitating the movement of nutrients into cells and the elimination of cellular waste.

In the absence of proper transport to their intended sites, these Rabs fail to execute their functions, leading to cellular starvation and the accumulation of waste, resulting in harm and eventual cell demise. Fortunately, humans possess an alternate version of this protein, Rab Escort Protein-2 (REP2), which is capable of effectively transporting Rabs within most cells of the body except in the retina.

Within the retinal cells, there is a particular group of Rab proteins that exhibit a preference for REP1’s assistance over that of REP2. Consequently, if the CHM gene is flawed and REP1 is absent, there is an accumulation of dysfunctional Rabs, culminating in a disease that specifically targets the retina. This disease leads to blindness in individuals who are otherwise healthy.

Symptoms

Choroideremia typically first manifests symptoms in childhood, with night blindness (nyctalopia) being an early sign within the first ten years. As individuals reach their teenage years, peripheral vision loss begins, yet central vision and visual acuity are often preserved until about the fifth to seventh decade of life. In the fifth decade, there is usually a noticeable and rapid decline in central vision.

The loss of color vision can precede the deterioration of visual acuity as the macula degenerates. Notably, there can be considerable differences in symptoms among males within the same family, with some experiencing less severe effects than others. While carriers of the condition, generally females due to the X-linked inheritance pattern, are usually without symptoms, they may experience mild to moderate night blindness. In some cases, clinical examinations can reveal signs of chorioretinopathy, retinal pigment epithelium (RPE) atrophy, and granular pigmentary changes in the peripheral areas of the retina.

Diagnosis

Fundus Examination

During a fundus examination, the initial indication of choroideremia is often the presence of widespread pigment clumps at the level of the retinal pigment epithelium (RPE).

This image is a fundus photograph of a patient with advanced choroideremia. Note an island of fovea remaining, surrounded by generalized atrophy of the neurosensory retina, retinal pigmented epithelium and choroid.

Fluorescein angiography

This image is a fluorescein angiographic image in the early venous laminar phase demonstrating an irregular island of hyperfluorescence in the fovea surrounded by a generalized absence of choriocapillaris, retinal pigmented epithelium and retina.

Fundus Autofluorescence

Fundus autofluorescence (FAF) imaging, a technique that maps the distribution of lipofuscin in the retinal pigment epithelium, reveals an early disappearance of autofluorescence from the peripheral areas of the retina that gradually moves centripetally.

Electroretinography

Optical Coherence Tomography

Optical coherence tomography (OCT) often reveals that the inner layers of the retina remain intact throughout the progression of the disease. In the early phases, there is typically a slight increase in the thickness of the central retina while visual acuity remains unaffected. However, over time, there tends to be a gradual thinning beneath the fovea, coinciding with a deterioration in visual acuity. Additionally, OCT may detect a decrease in the thickness of the choroid layer underneath the fovea.

Visual Field

The pattern of visual field deterioration corresponds with the areas affected by chorioretinal degeneration. Initially, patients often experience a spotty decline in mid-peripheral vision. As the condition advances, the atrophy becomes more widespread, resulting in scattered blind spots, which may progress to an almost total loss of both central and peripheral vision. In the later stages of the disease, patients might retain small pockets of vision in the foveal region and may still be able to detect light in the extreme peripheral field.

OCT Angiography

OCT angiography, a noninvasive method that builds upon traditional OCT, allows for detailed imaging of the retinal and choroidal blood vessels. In advanced choroideremia, changes in the structure of the neurosensory retina, retinal pigment epithelium (RPE), and choriocapillaris can occur, which may complicate the assessment of findings from fluorescein angiography (FA) and OCT imaging.

Differential diagnosis with defining features

• Gyrate atrophy: Choroideremia in early stages may mimic gyrate atrophy of retina and choroid. Examination of fundus of family members, early presentation, and X-linked inheritance pattern are important features to clinically differentiate choroideremia from gyrate atrophy.
• Retinitis Pigmentosa: Waxy disc pallor, peripheral RPE bone spicule like degeneration, retinal arteriolar attenuation
• Myopic Degeneration: Absence of nyctalopia, tessellated fundus, lacquer cracks, diffuse atrophy, patchy atrophy, posterior staphyloma, high axial length, macular atrophy, straightened and stretched vessels, high rates of choroidal neovascularization, temporal peripapillary atrophic crescent, hemorrhages and tilting of the optic disc
• Ocular albinism: Infantile nystagmus, iris translucency, substantial hypopigmentation of ocular fundus, foveal hypoplasia, aberrant optic pathway projection associated with asymmetry of cortical responses on visual evoked potential testing
• Usher syndrome type 1: Autosomal recessive, pigmentary retinopathy, congenital deafness, imbalance from vestibular dysfunction
• Thioridazine hydrochloride retinal toxicity: History of medication use, loss of night vision, decreased ERG amplitudes, accumulation of fine or coarse pigment clumps, geographic RPE and choriocapillary atrophy
• Bietti crystalline dystrophy: Autosomal recessive, corneal deposits, yellow-white crystalline retinal deposits, progressive atrophy of the RPE, loss of choriocapillaris, progressive nyctalopia, visual field constriction, legal blindness in the fifth or sixth decades of life

Outlook / Prognosis

How do I take care of myself?

You can take care of yourself by following guidelines for a healthy life, including:

Maintaining a balanced diet rich in green leafy vegetables, a variety of other vegetables, fruits, and lean proteins, while limiting the intake of salt, sugar, and unhealthy fats, is beneficial for health.

Engaging in regular physical exercise is essential.

If you currently smoke, ceasing this habit is crucial for overall well-being.

Ensuring routine eye examinations to monitor and maintain ocular health.

Prioritizing adequate sleep to support your body’s overall health.

Living with choroideremia

Choroideremia is a degenerative disease that progressively worsens over many years. Initially, the symptoms are often subtle, with affected children typically having difficulty seeing in low light or darkness. They may also struggle with discerning objects against a backdrop of a similar color due to a decline in visual sharpness, depth perception, and color discernment.

As the disease progresses, vision loss becomes more pronounced, often presenting as tunnel vision where peripheral vision diminishes, significantly affecting daily life. Over the course of several decades, choroideremia can lead to complete blindness.

There are tools designed to assist those with choroideremia in making the most of their remaining vision, such as telescopic and magnifying lenses, and technology aids like speech-to-text programs can also enhance their quality of life.

Deciding on the type of support to utilize is a personal choice. Genetic testing and counseling are commonly advised, offering valuable insights not only for the individual diagnosed with choroideremia but also for their family members.