Ultraviolet Light Exposure Identified as Factor Linked to Eye Disease Fuchs Endothelial Corneal Dystrophy

A discovery by Mass. Eye and Ear clinician-scientists provides new clues that may help better prevent and treat a genetic eye disease that causes vision loss called Fuchs Endothelial Corneal Dystrophy (FECD).

Researchers for the first time have experimentally shown a mechanism that represents a breakthrough in understanding for why the condition only affects certain portions of the eye, and why women tend to be far more likely to be diagnosed, according to a company news release.Specifically, they found that exposure to Ultraviolet A (UVA) light sets off an enzyme reaction that causes the DNA damage seen in patients with FECD, a reaction the team found was far more pronounced in females. They were able to replicate this damage in mouse models and human cornea cell tissue.

FECD is a complex disorder that has multiple genetic factors that cause the disease that manifest in a similar way despite the different backgrounds, explained lead study author Ula Jurkunas, MD, an NIH-funded Principal Investigator, who performs corneal and refractive surgery at Mass. Eye and Ear. That drove their team to look for unifying mechanisms that happened on cellular level, regardless of genetics, she said.

“This research finally offers an explanation for clinical observations that ophthalmologists have long seen in patients with this complex disorder,” Dr. Jurkunas told Focus. “It is so crucially important to identify modifiable risk factors for genetic diseases like FECD, as it enables clinicians to tell our patients that there might be ways to reduce risk for the disease regardless of genetics.”

Disease First Presents as Blurry Vision That Won’t Go Away

FECD is a vision disorder that typically starts for people between their 50s and 60s, when they experience symptoms such as blurry vision in the mornings, significant glare from headlights and other light sources, and visional disturbances that can last the whole day. Ophthalmologists conduct their diagnosis based on a clinical exam including a slit lamp exam, and measures of corneal thickness and swelling with a noninvasive imaging called specular microscopy.

Some studies have estimated 1 to 4 percent of the popular to have FECD, and research has shown the disease is far more common in women. FECD is a leading cause of corneal transplantation worldwide, with an estimated 75 percent of these transplant cases occurring in women.

Partial thickness corneal transplant, also known as descemet membrane endothelial keratoplasty (DMEK),  is the most common surgical treatment, in addition to experimental therapies such as descemet stripping without endothelial keratoplasty (DWEK) . Much research over the past decade has looked closely genetic factors that cause FECD, but until now, a study has not reported on underlying mechanism that may represent a modifiable risk factor.

Observations in Clinic Spur Study

As one of the highest-volume treatment programs of FECD, Dr. Jurkunas is referred patients from all over the country each year. It was during this time her clinical observations of hundreds of patients showed similarities, such as FECD caused scarring that always occurred in the center of the back layer of the central cornea, while the periphery is often clear and unaffected by disease. The center of the cornea is what gets light exposure, so the team postulated that UV light exposure may play a role in the disease.

They put this to the test by exposing the central cornea in adult mice to UVA light, where they were able to induce formation of Fuchs dystrophy. This was confirmed through years of additional testing.

Next, they came across a more unexpected finding, that female mice were more likely to have more severe and earlier onset of FECD compared to males. Knowing from clinical observation and previous research that women were more affected than males and more likely to get surgery, Dr. Jurkunas and her team wanted to see if the UVA light somehow played a role in the sex differences.

They tested this theory by providing UVA light exposure to a human corneal endothelial cell culture in a petri dish. They then discovered a novel pathway where the UVA light causes increased expression of an enzyme called CYP1B1, that jump starts an estrogen metabolite pathway that interacts with the DNA to damage it. This increased estrogen formation correlates with the sex-dependent differences in disease presentation, they reported.

“That is the mechanism that that explains what we have been seeing in our patients,” said Dr. Jurkunas. “We tell our patients with cataracts and macular degeneration to avoid exposure to UVA light, and our study suggests we should start telling our Fuchs patients as well,” said Dr. Jurkunas.

Future Research to Look at Interaction Between Genes and Light Exposure

FECD has been a long-standing basic science research focus for Dr. Jurkunas and her colleagues for more than a decade. In 2010, Dr. Jurkunas’ lab was the first the show extensively that there’s a link between oxidative stress and Fuchs dystrophy.  A 2016 paper from this team identified a link between mitochondrial dysfunction in corneal endothelial cells and the development of FECD.

Future studies from her group will look at the interplay between genetic and environmental factors to address why certain people, notably women, are more likely to develop FECD than others. Many people get significant exposure to UV light but not all get the disease. More epidemiological studies are needed to better determine this risk, but for now, people at risk for FECD due to genetics may want to wear protective eye wear and avoid light protection.