Fuchs endothelial dystrophy is a condition that causes vision problems. The first symptom of this condition is typically blurred vision in the morning that usually clears during the day. Over time, affected individuals lose the ability to see details (visual acuity). People with Fuchs endothelial dystrophy also become sensitive to bright lights.

Fuchs endothelial dystrophy specifically affects the front surface of the eye called the cornea. Deposits called guttae, which are detectable during an eye exam, form in the middle of the cornea and eventually spread throughout the cornea. These guttae contribute to the ongoing cell death within the cornea, leading to worsening vision problems. Tiny blisters may develop on the cornea, which can burst and cause eye pain.

The signs and symptoms of Fuchs endothelial dystrophy usually begin in a person's forties or fifties. A very rare early-onset variant of this condition starts to affect vision in a person's twenties.

The late-onset form of Fuchs endothelial dystrophy is a common condition, affecting approximately 4 percent of people over the age of 40 in the United States. The early-onset variant of Fuchs endothelial dystrophy is rare, although the exact prevalence is unknown.

For reasons that are unclear, Fuchs endothelial dystrophy affects women two to four times more frequently than men.

The genetics of Fuchs endothelial dystrophy are unclear. Researchers have identified several genes and regions within a few chromosomes that they think may play a role in the development of Fuchs endothelial dystrophy. However, many of these genetic associations have been found in only a few affected individuals or families and it is unclear what role they have in the development of the condition.

Fuchs endothelial dystrophy affects a thin layer of cells that line the back of the cornea, called corneal endothelial cells. These cells regulate the amount of fluid inside the cornea. An appropriate fluid balance in the cornea is necessary for clear vision. Fuchs endothelial dystrophy occurs when the endothelial cells die and the cornea becomes swollen with too much fluid. Corneal endothelial cells continue to die over time, resulting in worsening vision problems. It is thought that mutations in genes that are active (expressed) primarily in corneal endothelial cells or surrounding tissue contribute to the death of corneal endothelial cells, resulting in Fuchs endothelial dystrophy.

Some cases of the early-onset variant of Fuchs endothelial dystrophy are caused by mutations in a gene called COL8A2. This gene provides instructions for making a protein that is part of type VIII collagen. Type VIII collagen is largely found within the cornea, surrounding the endothelial cells. Specifically, type VIII collagen is a major component of a tissue at the back of the cornea, called Descemet's membrane. This membrane is a thin, sheet-like structure that separates and supports corneal endothelial cells. COL8A2 gene mutations that cause the early-onset variant of Fuchs endothelial dystrophy lead to an abnormal Descemet's membrane, which causes corneal endothelial cells to die and leads to the vision problems in people with this condition.

Mutations in additional, unidentified genes are also thought to be involved in the development of both the early-onset variant of Fuchs endothelial dystrophy and the later onset form of the disorder.

Normal Function

The COL8A2 gene provides instructions for making a component of type VIII collagen called alpha 2(VIII) collagen. Type VIII collagen is largely found within the front surface of the eye, called the cornea. Type VIII collagen is a major component of Descemet's membrane, which is a tissue at the back of the cornea. This membrane is a thin, sheet-like structure that separates and supports corneal endothelium cells. These cells regulate the amount of fluid inside the cornea. An appropriate fluid balance in the cornea is necessary for clear vision.

To construct type VIII collagen, one subunit of the alpha 2(VIII) collagen protein interacts with two subunits of another protein called alpha 1(VIII) collagen. These three proteins twist together to form a triple-stranded, rope-like molecule known as procollagen. Procollagen molecules are secreted by the cell and processed by enzymes to remove extra protein segments from the ends. Once these molecules are processed, they arrange themselves into long, thin bundles of mature type VIII collagen.

Health Conditions Related to Genetic Changes

Fuchs endothelial dystrophy

At least two mutations in the COL8A2 gene have been found to cause a variant of Fuchs endothelial dystrophy, an eye disorder characterized by progressively blurry vision and sensitivity to bright light. COL8A2 gene mutations are associated with the rare, early-onset variant of Fuchs endothelial dystrophy, in which vision problems typically begin in a person's twenties.

The COL8A2 gene mutations that cause the early-onset variant of Fuchs endothelial dystrophy replace single protein building blocks in alpha 2(VIII) collagen. One mutation replaces the amino acid leucine with the amino acid tryptophan at position 450 (written as Leu450Trp or L450W). Another mutation replaces the amino acid glutamine with the amino acid lysine at position 455 (Gln455Lys or Q455K). These mutations impair the structure of alpha 2(VIII) collagen, probably preventing the abnormal protein from being incorporated into type VIII collagen fibers. As a result, there is a reduced amount of type VIII collagen in the cornea, specifically in Descemet's membrane. This abnormal Descemet's membrane leads to the death of the corneal endothelial cells, causing the cornea to become swollen with fluid. Corneal endothelial cells continue to die over time, which causes the vision problems in people with the early-onset variant of Fuchs endothelial dystrophy.

Other Names for This Gene

• CO8A2_HUMAN
• collagen alpha-2(VIII) chain
• collagen alpha-2(VIII) chain precursor
• collagen type VIII alpha 2
• collagen VIII, alpha-2 polypeptide
• collagen, type VIII, alpha 2
• endothelial collagen

Genomic Location

In many cases, the inheritance pattern of Fuchs endothelial dystrophy is unknown.

In some families, Fuchs endothelial dystrophy appears to be inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. When this condition is caused by a mutation in the COL8A2 gene, it is inherited in an autosomal dominant pattern. In addition, an autosomal dominant inheritance pattern is apparent in some situations in which the condition is caused by alterations in an unknown gene.

Some cases result from new mutations in a gene and occur in people with no history of the disorder in their family.

Diagnosis of Fuchs corneal endothelial dystrophy requires a slit-lamp examination to view the cornea changes that are characteristic for this condition. The earliest observable change suggestive of Fuchs' dystrophy is the presence of guttae. Guttae are bumps on the back surface of the cornea.

Additional tests that may be done include pachymetry to measure the thickness of the cornea, a specular microscope examination to look at the endothelium cells, and a visual acuity test.

Pachymetry is a good way of gauging the increase in corneal edema. The thickness can be compared with the new readings on subsequent visits. Increasing thickness of the cornea means increasing corneal endothelial decompensation. Presence of Descemet folds, epithelial bedewing, and corneal thickness of greater than 0.62 mm indicates potential decompensation.