The knowledge base for genetic eye diseases is rapidly changing. As investigators continue to unearth and study the genes responsible for these inherited diseases, it’s important to keep up with the latest information.

"There are a number of new developments about which ophthalmologists should stay informed," said John R. Heckenlively, M.D., Underwood Family Professor of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles. "I frequently have patients who do Internet searches prior to their visits with me, and it’s necessary to stay informed to answer their questions fully and scientifically. Many patients will mention articles that inaccurately report new treatments or cures for retinal diseases, and I need to tell them what the facts are," he added.

"I occasionally see retinitis pigmentosa (RP) patients who’ve been told they’ll go blind in a year or two, yet the normal time course for RP is 30 to 50 years," Dr. Heckenlively said. "I tell them RP is slowly progressive. They will lose vision over time, but it’s not normally a fast-moving disease."

Dr. Heckenlively recommends that you not find yourself at a loss for knowledge in these situations. Read on to learn some of the latest findings in genetic eye disease and to get a glimpse of your potential role in this area of medical science.

Since researchers identified the ABCR gene linked to Stargardt’s disease, controversy continues to brew regarding its connection to age-related macular degeneration (ARMD). Study findings conflict, said Kent W. Small, M.D., professor of Ophthalmology, Jules Stein Eye Institute, and director of the Macular Disease Center and the Retina Division Research Laboratory, University of California, Los Angeles.

"The bigger issue is, what data support that ARMD is a genetic disease?" he said. "I think most general ophthalmologists don’t have a good feeling on what the data are and how strong they are. Data that strongly support the hypothesis that age-related macular degeneration is a genetic disease in part."

To better understand the mechanism behind ARMD, investigators are also turning to other retinal degenerative diseases. "When you study a genetic disease, you need a few generations, but ARMD patients are 65 years old and their children aren’t affected yet because they’re too young to have the disease," said Radha Ayyagari, Ph.D., research investigator, department of ophthalmology, Center for Inherited Retinal and Macular Dystrophies, University of Michigan. "So another way of studying these diseases is to focus on those for which onset is earlier and symptoms are similar to those of ARMD."

The genetic disease issue is becoming increasingly complex. "The newest findings indicate that the concept that one gene equals one disease is no longer valid," said Dr. Heckenlively. "You can have different mutations in the same gene and they can cause different diseases."

For example, he said, the peripherin/RDS mutation is thought to cause RP, but some families with RDS mutations were found to have different changes. There were families with macular dystrophy and no sign of RP who had mutations in a different portion of the RDS gene. Another family with an RDS mutation showed a condition similar to retinitis punctata albescens.

"It doesn’t mean that every gene with multiple mutations will cause a different phenotype, but it’s happened often enough that it’s changed our thinking regarding the pathophysiology of these diseases," he said. In addition, he explained, researchers are investigating the role of secondary expression genes that affect the expression of the first gene.

To treat retinal degenerative diseases, researchers are studying a number of gene replacement therapies, Dr. Heckenlively explained.

In a University of Florida study, researchers use transgenic rodents that have dominant RP and then perform rescues. At the University of California, San Francisco, investigators are trying to use growth factors in rodents to slow retinal degeneration.

"They have identified a small number that appear to substantially slow the retinal degeneration and now they are trying to find the best way to deliver these growth factors within the eye, so that therapy will be safe and effective," explained Dr. Heckenlively.

Researchers are also studying apoptosis, or cell death, through which it’s believed retinal degeneration occurs. "They’re working out the genetics. It looks like you can actually interfere with the signal to die by genetic techniques or medication, even though there are problems in the cells from mutations that set off those signals," Dr. Heckenlively said.

The locations of specific genes and disease-causing mutations have been identified for less-common types of glaucoma such as Axenfeld-Rieger syndrome, aniridia, congenital glaucoma and pigment dispersion syndrome, as well as forms of primary open-angle glaucoma, according to R. Rand Allingham, M.D., associate professor of ophthalmology and director, Glaucoma Service, Duke University Eye Center.

Of particular importance, researchers have identified a gene producing a form of primary open-angle glaucoma. An abnormality in the gene which makes the protein called myocilin or TIGR causes the disease. Although its function is not fully known, the gene is expressed in cells of the trabecular meshwork and other ocular and nonocular tissues. "Interestingly, different mutations in the gene coding for myocilin cause primary open-angle glaucoma with varying ages of onset from early teens to late adult life," Dr. Allingham said. "This inherited form of glaucoma is responsible for only 3% of open-angle glaucoma cases," he continued. "Therefore, it appears myocilin is a part player in glaucoma. However, this discovery is important in understanding a major glaucoma pathway, where many proteins – and their respective genes – play a role in normal and abnormal function of the trabecular meshwork. Other proteins – and their genes – in this pathway may be responsible for the major genetic source of primary open-angle glaucoma."

"The real advantage of genetic research is that it will enable us to specifically identify and treat patients with different forms of glaucoma, rather than relying on today’s only proven method – reducing intraocular pressure once trabecular meshwork function is abnormal and after optic nerve damage may have already occurred," Dr. Allingham said. "Future therapies for glaucoma may target prevention of optic nerve damage, rather than normalization of intraocular pressure."

Strabismus is tied to family history. According to Elias Traboulsi, M.D., head of the department of pediatric ophthalmology, and director of the Center for Genetic Eye Diseases, Cleveland Clinic Foundation Eye Institute, researchers will analyze how strabismus and ocular formations are inherited and how to map the genes responsible.

"Three different genes have been mapped for one form of strabismus called congenital fibrosis of the extraocular muscles," Dr. Traboulsi said. "When more is known, we will be able to detect strabismus earlier in patients with a family history. By examining children early and detecting strabismus early, we can prevent amblyopia, which is a leading cause of unilateral blindness in children and young adults."

Researchers are also examining how developmental genes contribute to malformations of the eye.

Physicians have known that some patients with aniridia are more likely to develop Wilms’ tumor, Dr. Traboulsi said, because the gene for the tumor is next to the aniridia gene. "Since the aniridia gene has been identified," he said, "we can analyze it and if we find a mutation in the aniridia gene alone, we can feel fairly secure that the patient won’t develop Wilms’ tumor, eliminating repeated clinical testing," he said.

About one-third of metabolic and genetic diseases involving multiple organ systems affect the eyes, Dr. Traboulsi said. "The ophthalmologist plays a key role in helping pediatricians and geneticists make a diagnosis by identifying the characteristic or diagnostic ocular finding for a certain disease," he said.

These diseases include neurofibromatosis, Marfan syndrome and polyposis of the colon. "About 80% of patients with familial polyposis also have congenital hypertrophy of the retinal pigment epithelium or pigmented ocular fundus lesions, which are present from birth," he said. "Children who carry the trait can be identified very early and can be screened for polyps. Then they can have appropriate surgical treatment before they develop colon cancer."

As investigators grapple with these genetic puzzles, you can help accelerate their progress by referring patients to studies. "Many institutions in the country are investigating inherited disorders," said Dr. Allingham, of the Duke University Eye Center. "Where there’s a striking family history or a very unusual appearance of a disorder, a phone call to those researching the problem helps because those researchers can contact the family and invite them to participate in studies to identify the genes responsible for their diseases."

As advances are made in genetic research, patient history will become increasingly important. "We’ll be looking at patients and their risk profiles more, and using this profile in how we manage them, how frequently we see them and how aggressive we are when we treat them," said Dr. Allingham.

Meanwhile, you can help your genetic-disease patients by emphasizing what they can do to help themselves. While investigators weigh the effects of diet, environment and other factors, emphasize good overall health to your patients.

"It does make sense to recommend a multivitamin, maybe supplemental C and E, and eating more spinach and other foods that are good for your eyes and body," Dr. Allingham said. "It’s amazing how readily people will follow these recommendations once they know about them."

"Today, our knowledge is in transition, and so are the ways in which we approach genetic diseases," said Dr. Heckenlively. "We’re facing a crisis in education because even residents at this moment aren’t receiving the education they’re going to need to treat these patients in 10 years from now. That’s mainly because the field is moving so quickly that a gap is emerging between what’s known scientifically and how it’s translated into clinical practice. One of the challenges I see for the future is to bridge this gap with educational courses and other methods, and perhaps using Internet resources, so that doctors can keep up."