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Two types of Fuchs corneal dystrophy have been identified--Early Onset Type and Late Onset Type

Researchers at the Wilmer Eye Institute recently identified a collagen VIII gene mutation for the Early Onset form of Fuchs Endothelial Corneal Dystrophy (FECD).  Read the research paper here.  In the Early Onset form, the disease starts very early in infancy and develops to an advanced stage by the time the patient is in his 30s or 40s.  Fortunately this type of FECD is rare. 

However, the other form, Late Onset FECD, is much more common (Clinical photos, Fig. 1 & 2).  It starts in middle age and develops to an advanced stage later in life.  It is more common in females. 

Patients who progress to advanced stage FECD (of either type) often require a corneal transplant due to corneal swelling and cloudiness. 

Both forms of FECD are characterized by a general attenuation (decrease) and degeneration of the corneal endothelium, plus thickening of Descemet’s membrane and formation of corneal guttae.  Because the corneal endothelium has as one of its main functions to pump water out of the cornea, when the endothelium is damaged, the cornea swells. 

Normal Histopathology of the Cornea

The normal corneal endothelium is a single layer of cells located on the posterior surface of the cornea facing the inside of the eye.  Endothelial cells normally operate as a “pump” to keep the corneal tissue in a relatively dehydrated state in order to maintain the clarity of the cornea.  The Descemet’s membrane (DM), the specialized basement membrane of the endothelium lies in front of the endothelial cells (Fig.3, top).

pathology of fuchs

Descemet’s membrane is comprised of two regions, the anterior banded zone and the posterior non-banded zone (Fig.4, left, Normal).  The anterior banded zone or layer (ABL), located between the corneal stroma and the posterior non-banded zone (PNBL), is identified by the presence of an extracellular matrix known as wide-spaced collagen. The region consists of regularly arranged collagen fiber bundles. The posterior non-banded zone is an amorphous conglomeration of extracellular matrix located between the banded zone and the corneal endothelium.

Histopathology of an FCD Cornea
Both the endothelium and Descemet’s membrane undergo marked changes in Fuchs dystrophy:  Corneal guttae (Fig.3, middle) refer to bumps (Fig. 3, middle, Late onset Fuchs) that form on the central part of Descemet’s membrane.  These guttae form first in the central cornea, and then closer to the periphery as the disease progresses.  The guttae are made of fibrils similar to those found in normal Descemet’s membrane, including wide-spaced collagen bundles with a banding pattern.  In the early onset form FCD, the Descemet’s membrane is markedly thickened with relatively small guttae or no guttae at all (Fig.3, bottom, Early Onset Fuchs).
FCD also causes the cells of the endothelium to fail.  As the endothelium starts to die, Descemet’s membrane starts to make abnormal (wide-spaced) collagen.  This makes Descemet’s membrane extra thick.  When Descemet’s membrane is too thick, the endothelium becomes unable to pump the proper amount of water out of the stroma and Descemet’s membrane, mainly because there are too few endothelial cells to deal with such a lot of membrane.

The endothelium swells and vacuoles (little sacs made of membrane in which all sorts of materials can be stored) form inside the endothelial cells.  This damage leads apoptosis in the endothelial cells, which leads to the dying off of endothelial cells.

Wide-spaced Collagen: Creates Guttae on Descemet's Membrane
Endothelial cell degeneration and thickening of Descemet’s membrane are the major histological features in FECD. 
In a normal Descemet’s membrane, wide-spaced collagen is present only in the anterior banded layer.  This type of collagen is produced by the endothelium during fetal life and reaches its full thickness by birth.  In normal corneas, wide-spaced collagen does not appear to be produced after birth.

In Fuchs Dystrophy, the cornea starts secreting wide-spaced collagen again (Fig. 4, inset for detailed structure of wide-spaced collagen; also in Figs. 5 & 6 in early onset form FCD).  This results in large amounts of deposited material that form an additional layer, called the posterior banded layer (PBL, Fig. 4, middle, Late onset form).  It is from this posterior banded layer that corneal guttae are formed.  This means that guttae contain wide-spaced collagen.  Wide-spaced collagen is made of collagen type VIII.

Guttae cause the endothelial cells to change shape to become thin.  Thinning is especially significant on the apices (tops) of the guttae.

Research at the Wilmer Eye Institute suggests that a special type of cell death, known as apoptosis, may be an important part of how things go wrong in a cornea affected with FECD. 

Apoptosis is often referred to as, “programmed cell death.”  In every cell in the body, there are special genes that the cell can use to commit suicide (to kill just that one cell) if there is something wrong with that one cell or if it is simply “time” for that cell to die.  Apoptosis is very complicated.  You can read more about it at this website.  Sometimes, a cell’s apoptosis genes get turned on (expressed) when they shouldn’t be.  This means the cell dies for no reason.  It is often very hard for scientists to figure out if a cell is mistakenly expressing apoptotic genes or if there is something else going wrong that we just can’t see, yet. 

There is Evidence of Apoptosis in FECD Corneas
Researchers at the Wilmer Eye Institute looked first at whether there was evidence of apoptosis in the FECD corneas. 

Scientists then turned to a special technique, called Serial Analysis of Gene Expression (SAGE).  SAGE allows researchers to find out what genes are being expressed (turned on) in a particular type of tissue, such as the cornea.  It turned out that corneas from people with FCD were expressing more apoptosis (programmed cell death) genes than were corneas from people without FCD. 
You can read this scientific paper here.

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