Genetic studies lend pieces to glaucoma puzzle

New Orleans-Glaucoma genetics should help physicians understand the pathophysiology of glaucoma and lead to the development of better tests and better treatments, according to Wallace L.M. Alward, MD.

"Each genetic discovery is like a piece of the puzzle," Dr. Alward said at the American Glaucoma Society subspecialty day lecture during the American Academy of Ophthalmology annual meeting. "The big question to me is: 'How big is this puzzle?' Right now it looks pretty big, but I think we have a lot of optimistic things to look forward to from glaucoma genetic studies.

"A hopeful view of the future is that when [patients] turn 40, they'll have a simple cheek swab performed that will determine their risk of developing glaucoma, and a specific medication will be begun that would delay or prevent the onset of ganglion cell damage," continued Dr. Alward, professor of ophthalmology, University of Iowa, Iowa City.

"As we all know, glaucoma is understood poorly as a disease, despite the efforts . . . to make more sense of it," Dr. Alward added. "We feel that the discovery of genes holds the hope of making sense of the molecular pathways involved in the development of glaucoma."

Genetic research has helped explain how diseases such as Axenfeld-Rieger syndrome have such diverse, systemwide involvement from a mutation in a single gene. It has been learned that transcription factor genes, such as PITX2 and FOXC1, do not code for structural proteins but instead function as "traffic cop" genes.

"They regulate the expression of other genes in time and in space, and that helps explain this diverse systemic involvement," Dr. Alward said.

Significance of myocilin Another advancement in understanding the pathophysiology of glaucoma was the discovery of myocilin, which was found in 1997 to be a cause of juvenile open-angle glaucoma and up to 5% of adult-onset POAG.

"This gave us the first glimpse into the molecular mechanisms of primary open-angle glaucoma," Dr. Alward said. "In many ways, it was the first piece of the puzzle of primary open-angle glaucoma genetics. There's intense interest in unraveling the workings of this gene in healthy individuals and in glaucoma patients."

Following the discovery of myocilin, researchers hoped that more commonly mutated genes would soon be found. Optineurin was subsequently identified, but it apparently causes less than 0.1% of adult-onset POAG.

"The sad truth is that myocilin at 3% to 5% of primary open-angle glaucoma may be the most commonly mutated gene, and other genes may be smaller contributors," Dr. Alward said. "It may turn out that there are dozens or hundreds of genes that contribute to the diseases that we call POAG."

However, finding even some of these genes could lead to the development of better tests for diagnosis, prognosis, screening, and therapy. Genetic testing is already available, but a key question is when such testing should be done, Dr. Alward said, adding that since he can do genetic testing at no cost to the patient, he is probably more liberal in ordering these tests than physicians in other settings.

"Despite that, outside of a study situation, I think there is rarely a reason to do genetic testing in 2004," he added.

Dr. Alward occasionally tests for myocilin mutations, primarily when seeing a very young patient with a strong family history of early-onset glaucoma. He has tested for optineurin mutations only once and suggested that testing for this gene was unlikely to become common in a routine practice setting.

Testing for mutations in the genes that cause Axenfeld-Rieger syndrome or other forms of developmental glaucoma may be advisable for patients with unusual presentations that suggest these diseases, Dr. Alward said.