How can you help your family avoid glaucoma damage?

Several years ago, we did a study that asked 100 glaucoma patients to give us permission to call all their relatives and ask about glaucoma. We called 300 adult relatives of our patients and asked them what they knew about glaucoma, whether they knew they had a relative with it, if they knew it runs in families, and how often they had eye exams. Our results were disappointing. A lot of the family members did not know that they were at greater risk. The patients often hadn’t told family members they have glaucoma. Some people aren’t that close to family, and other patients said that they didn’t think telling family members would lead them to do anything. “You know how grown kids are, they don’t listen to me when I tell them to get eye exams,” said one older patient. Even worse, among the family members, more than half had never had a visual field test. Almost all of them said that they get their eyes “checked” every year, but they weren’t getting the best test for finding glaucoma. We can’t tell if that was because their eye doctor was choosing not to do the test or if he/she didn’t know that the patient had a family history of glaucoma.

When Dr. Kaleem was a kid, she saw her grandmother lose vision from glaucoma because she got diagnosed late. Now everyone in the family gets screened once per year. And thank goodness they do! Several family members were able to start treatment for glaucoma just in the nick of time and have been able to live normal, healthy, and highly functional lives. We tell every glaucoma patient to have all adult relatives (mother, father, sisters, brothers, adult children) go once a year to an eye doctor and say the following exact words: “My mom has open angle (or angle closure) glaucoma and I want a test of my angle, a dilated eye exam, images of my optic nerve, and a visual field test.” This makes sure that the correct tests are done and repeated every year. If you don’t have glaucoma at age 40 or 50, it can still develop later, increasingly after age 60. It may be that glaucoma severity is also inherited, meaning that if you have a family member with severe vision loss from glaucoma, you are more likely to have that, too. People can’t really be sure that their grandmother really had glaucoma without seeing the actual records from past doctors’ exams. Having old records is very valuable.

It’s one thing to say that a disease “runs in families” and quite another to know how the specific gene defects underlie the inherited tendency. Each gene functions like a recipe, telling the cell the ingredients needed to make a protein that your body needs. People have about 30,000 distinct genes, and scientists have only recently started to understand how some of them work. However, the process of looking for the “bad” genes has taught us some valuable lessons in medicine in the last 30 years. First, there is not one single gene that explains why people get a common disease. Glaucoma, like other complex disorders, has genetic factors, environmental factors, and other contributing features, so simple genetic errors (mutations) in one gene will not explain why most people get the disease. Second, when a defect in one gene is found in persons with a disease, there are often several areas of the same gene that can have mutations or changes that alter what the gene makes. If there is a mistake in the recipe, the protein can come out wrong, and there are many places where a mistake could be made. So, even within the same gene that is defective, it can malfunction in different ways in different people. Third, the disease-causing aspect can be how much product a gene makes rather than a defect in the gene code sequence for the molecule being made. Fourth, there are genetic disorders in which it takes two “hits” or gene defects in separate genes for the abnormality to happen (this is probably true for exfoliation syndrome and childhood forms of glaucoma - see section How did you get glaucoma?).

Hunting for genetic risk factors can be done by one of two approaches. Scientists look at the DNA of families with many members who have the disease, in a test called linkage analysis. They look for pieces of DNA that are linked to the presence of disease. In this method, the family relationships are very helpful for finding the gene, so the larger the family and more complete the information about who had the disease, the better. This method works best with rare mutations that greatly increase someone's chances of getting the disease. The other method, called an association study, doesn't use family information. In these studies, scientists compare the DNA of people who do or don't have the disease and again look for pieces of DNA more frequently associated with disease than you would expect by chance.

For open angle glaucoma, several zones in the human genome have been found, with 3 that have now been pretty well established to contribute to a small number of cases. Genes for the protein molecules called myocilin and optineurin are defective in certain subgroups of persons with open angle glaucoma. Myocilin mutations lead to high eye pressure at the age of 20 to 30 in families with this defect. Myocilin’s action, when abnormal, seems to block up outflow of aqueous humor. Optineurin mutations are said to be more common in those with glaucoma at lower eye pressure. One hypothesis for how it causes damage is to make ganglion cells more sensitive to dying. For the subgroup with exfoliation syndrome, there are differences in a chemical coded by the LOXL1 gene, whose function relates to the supporting tissues in the eye.

One might think that genetic testing of blood samples might be a good thing to do, to determine if you have one of these defects. Practically speaking, however, the chance that the average glaucoma patient has one of the known mutations is really very low. The tests are very expensive (thousands of dollars) and are not done in routine labs. Having the specific mutation or the variation in a particular zone (called a single nucleotide polymorphism or SNP) doesn’t mean that you have a 100% chance of glaucoma. So, at this time, it is only in research studies that gene testing has value.