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It’s in their genes: father and daughter help generations of a family with hereditary glaucoma

Erin Boese, MD, with her father Lee Alward, MDA 27-year-old man from Galesburg, Illinois came to the University of Iowa Glaucoma Clinic in 1986 seeking surgery for his glaucoma. He recognized that the few people with glaucoma in his family who were not blind had undergone surgery, and he knew he needed help if he were to keep his sight. The man had juvenile open angle glaucoma (JOAG), which is characterized by very high eye pressures at a very young age (teens to twenties) and is not typically responsive to drop treatment. Another unique characteristic of JOAG is that it is a dominantly inherited disease. This inherited type of glaucoma was what had caused so many of this man’s family members to lose their sight. The man had surgery, which has preserved the vision in one of his eyes. 

A year later, when the man came in for a follow-up, Dr. Wallace Alward was the new head of the Glaucoma Service and Dr. Edwin Stone was a resident. Dr. Stone had a Ph.D. in molecular genetics, and Drs. Alward and Stone began delving into the man’s family. They started the arduous process of tracking down as many family members as they could. By 1993 they had studied 134 members of this man’s extended family. From this research they were able to link this genetic defect to an area on chromosome one. This was the first time a genetic link to glaucoma had ever been found.  

But this was just the first step, Alward explained: “The linkage just meant that there's a gene somewhere on the long arm of chromosome one. Identifying the gene itself took until 1997. I was just a small part of that—I was the guy tracking down the families. Dr. Stone, [Dr. Val] Sheffield, and [Dr. John] Fingert were the ones who did the bench work in the lab.” After four years, with the help of a cast of world-class researchers, they’d finally pinpointed the affected gene. The gene is called myocilin, which was the first, and still the most important, gene related to glaucoma. The findings were first reported in the journal Science and is the 13th most cited paper in history with the word “glaucoma” in the title.  

While the identification of the myocilin gene was a huge step and helped diagnose JOAG before any symptoms occurred, the family of the man from Galesburg was still only able to use the standard therapies that lowered the eye pressure but did not specifically address the underlying problem. Further complicating this, many of the surgical treatments for glaucoma aren’t designed for, and aren’t as effective in, patients under the age of 40—let alone in their teens or younger.  

As Alward continued to see and treat members of this family, his own daughter, Dr. Erin Boese, joined the glaucoma faculty at Iowa. As a part of the glaucoma team, Boese began working with the next generation of the family Alward got to know in the 1980s through his genetics studies. Boese sought to capitalize on the decades of research her father and others had done. Not only were they able to now diagnose JOAG at a very early age, they also had found out that myocilin mutations specifically affected just one area of the eye, the trabecular meshwork. The trabecular meshwork is the small mesh-like structure covering the natural drain of the eye that gets clogged from the myocilin mutation. Knowing this information, Boese and her team asked the question, “if the trabecular meshwork is where the problem is, what happens if we take it out all together?”  

It was around this time that a new surgery called gonioscopy-assisted transluminal trabeculotomy (GATT) was developed. This surgery removes the entire trabecular meshwork covering Schlemm canal (the vein-like structure that drains the clear aqueous fluid from the eye), similar to removing a clogged screen from house’s gutters. Compared to traditional surgical approaches, GATT has the advantage of being much less invasive with fewer risks. Although GATT had never been used to treat JOAG from myocilin mutations, Boese quickly saw the potential and began speaking with members of the affected family about this surgical option. Boese says the history her father has had with these families was essential when discussing GATT surgery for the youngest generation. “I wasn't starting from square one. The relationship [Alward] had built with these families really helped them trust us as we took these next important steps. It’d be one thing to sign yourself up for a surgery that hasn't been done specifically for this disease. I think it's another thing entirely when it's your kid.” 

To date Boese has now performed GATT surgery on 8 eyes of 4 young patients, all under the age of 18 years. To date, the surgery has been remarkably effective. Prior to surgery, all of these children had poorly controlled eye pressures despite being on every medication available. Now, all are well controlled, and 7 of the 8 eyes are off of medications entirely. To put this into perspective, their affected parents have an average of 2.8 glaucoma surgeries per eye, and despite this, more than half are legally blind.  

It all started 36 years ago with the man who first walked into the glaucoma clinic with the unusual request for glaucoma surgery. Now three of his young family members are directly benefiting from the story that has unfolded since. Thanks to the advancements in genetics, research, and surgery, these young patients are looking towards a brighter future. “GATT is the first genetically-driven surgery that we've had for glaucoma,” Boese said. “It is amazing that we now have the ability to individualize treatment based on a single genetic mutation.” 

Tuesday, April 4, 2023