Genetics’ role in glaucoma diagnosis and treatment

As researchers unravel the mysteries of glaucoma, genetic testing is not yet indicated for widespread use.

By Lisa B. Samalonis, Contributing Editor

Genetic testing for glaucoma is best used at this time for particular types of cases, especially early onset glaucoma, but holds the potential for new gene-based therapies in the future, according to experts in the field. (For more on the genetic testing process, see the online version of this article at www.ophthalmologymanagement.com.)

Many of the genes that cause rare forms of glaucoma — such as congenital glaucoma, and juvenile onset open-angle glaucoma, among others — are now being identified, and it is possible to have those tested for if a family history exists, says Rand Allingham, MD, director, glaucoma service, at Duke University Eye Center. “We are not at the point that we would treat it differently, but we would know the risk was very high and we would be following these people much earlier in life and we would catch it when it started, if it started,” he says.

Also, Dr. Allingham notes that prevention is key because the loss of visual field from advanced glaucoma can never be repaired. “By catching it early we can prevent all that damage, and people can live a very normal life with glaucoma,” he says. “It is very controllable, but we can’t fix the damage that it causes.”

In many cases, by having routine comprehensive eye exams every year or two after age 40 (with pressure checks and examinations of the structures of the eye and optic nerve), it is very likely to pick up glaucoma when it happens and before it is far advanced, he says. “In general, it may be reasonable to test for glaucoma in cases where it is a very early onset, but for those who have older onset, it is probably not that useful,” says Dr. Allingham.

THE CASE FOR GENETIC TESTING

Early onset glaucoma patients

Janey L. Wiggs, MD, PhD, associate chief, ophthalmology clinical research, and associate director, Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, in Boston, says the research indicates potential for genetic testing.

“There is good evidence that patients who have early onset of glaucoma should have genetic testing,” Dr. Wiggs says. “Our experience — I am in the process of writing a paper with these results — is that for patients who are referred with onset before age 40 who may or may not have a family history of glaucoma, we find mutations about 20% of time with the current collection of genes.”

She notes that the definition of early onset glaucoma is not clearly defined but typically includes patients who have onset before age 40 or patients who have onset before age 50 and have a strong family history. “In about 20% of those individuals we find a mutation,” she says.

Research shows potential

Eight genes have been identified that tend to cause glaucoma with an early onset, and advances in research and technology could reveal more. “There is a lot of active work going on right now, and, for the patients who don’t have mutations and known genes, we have several research protocols where we then enroll them in genomic studies to find new genes,” Dr. Wiggs says. “We have made significant progress; we have four interesting genes already that we are currently working on that look like they could be early onset glaucoma genes.”

Gene mutations can signal the severity of disease, which provides critical information for treatment. “For example, one of the genes that cause early onset glaucoma is myocilin and it is now understood how myocilin causes disease,” Dr. Wiggs says. “There are treatments that are targeted toward that mechanism, so it could change a patient’s choice of therapy based on that.”

Some myocilin mutations are associated with very severe disease and those patients should probably just go straight to surgery. Others with different myocilin mutations may have a much later onset of disease and could be managed with medical treatment, Dr. Wiggs adds.

Different inheritance patterns also exist for these different genes depending on which gene has the mutation. Therefore, the risk to family members is different depending on the gene mutation.

“We can provide much better risk estimates to other people in the family if we know which gene is underlying the disease,” Dr. Wiggs says.

A genetic test can also reveal related health issues, as some of the glaucoma genes have systemic disease association. “For example, some patients who have the PAX6 mutation, the gene that causes aniridia glaucoma, also have a mutation in a nearby gene that causes a kidney tumor — they need to be screened for that,” Dr. Wiggs says. “This is another piece of information you can get from the test.”

AAO research

Genetic testing could have a positive impact on individuals and families affected with inherited eye disease, such as glaucoma, notes the AAO genetic testing task force report.¹ “When properly performed, interpreted and acted on, genetic tests can improve the accuracy of diagnoses and prognoses, can improve the accuracy of genetic counseling, can reduce the risk of disease occurrence or recurrence in families at risk and can facilitate the development and delivery of mechanism-specific care,” the task force reported.

The report also states that genetic testing information carries some risks that vary from patient to patient regarding plans to have children, relationships with family members and anxiety.

For eye diseases, the benefits of genetic testing outweigh the risks, says Dr. Wiggs. “Anytime you look at heritability in a family or in an individual, there are always ethical issues,” she says. “If nothing else, sometimes you can reveal paternity issues. It is rare, but we see it from time to time.”

In most cases, she says the information gathered from the test could potentially help direct the patient to the right kind of disease surveillance or treatment for their disease, or help them considerably with genetic counseling so that they understand what the risk is to their offspring or siblings.

Adult-onset glaucoma

Genetic testing for other types of glaucoma is being robustly researched. A handful of adult-onset glaucoma genes were discovered through the genome-wide association studies.^2-7 Adult onset genes are very different, Dr. Wiggs says.

“For early onset genes, the mutations in those genes, it is like hitting an egg with sledgehammer,” she says. “They are big impact gene mutations. They cause disease — you have the mutation, you have the disease. For the adult onset genes, each mutation in a disease gene has a small incremental effect. It is an aggregate of multiple genes or multiple genes and environment exposures that finally reaches a disease threshold.”

As a result, researchers only know a few of the adult-onset genes, and much more work is left to do in terms of identifying genes that cause and contribute to the disease processes. “We know some of them,” Dr. Wiggs says. “We don’t have enough of them that we can offer a comprehensive test panel that has clinical significance.”

GLAUCOMA THERAPY

On the horizon

Although gene specific therapy is not used for any of the early onset glaucoma mutations at this time, gene-specific therapy is on the horizon.

“With some genes, like CYP1B1 and myocilin where these are not developmental problems, there are opportunities to target the actual disease mechanism with gene replacement therapies or gene activation therapies, or by even using small molecules that ameliorate the problematic circumstance created by the mutation,” Dr. Wiggs says. “Of course, as we find more genes that cause glaucoma, then there will be additional genes that could be targeted using gene-based therapies.”

“In the future, genetic testing may help us identify those at great risk, and those people can be followed more closely,” says Dr. Allingham. Then, if the patient tests negatively for glaucoma after repeated visits, they can be advised to not be seen as frequently, which he says could help reduce the cost of healthcare. “Ultimately, all the testing and all the work we have done in genetics becomes broader, less expensive and more powerful over time.”

FUTURE RESEARCH

Determining glaucoma’s etiology

Dr. Allingham notes that genetic research being conducted worldwide could reveal more information about glaucoma’s etiology. “Currently, we have an idea for most of these genes that their variants are associated with increased risk, but we don’t know specifically what is in the gene that is doing it,” he says. “These genes are associative but not causative. So that means we have a lot of work to do.”

Also, Dr. Allingham expressed a need for researchers to figure out a DNA code in the associated group that increases a person’s risk for glaucoma. “Once we know what that is, then we can test for that,” he says. “That’s the part of the picture we don’t have yet. But there is a lot of research going on in every population in the world. Progress is really moving very quickly, but it is very complicated also.”

Environmental factors are another piece of the puzzle. “We focus on the genetics like it is just a DNA problem, but the reality is there is probably a significant influence on environmental factors,” Dr. Allingham says.

For example, patients seem to be higher risk for exfoliation glaucoma if they live at higher latitude and altitude or if they have increased ultraviolet exposure in general, he says. Therefore, in some cases, a genetic predisposition might never trigger the disease. Discovering the environmental triggers could lead to prevention and information toward treatment recommendations.

Summary

While great strides in genetic glaucoma research have been made, especially in the area of early onset glaucoma, more definitive research is needed before genetic testing and gene-based therapies will be used for the majority of glaucoma patients.

Still, experts agree that the research findings are exciting and additional answers should soon be revealed. OM

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