Family-pattern blindness is coming into focus (Part 2 of 2)

Two genes are identified

Ayyagari hopes her research will lead to treatments that will delay the onset, slow the progression or prevent the disease altogether. She and her co-workers have already mapped and identified two genes associated with macular diseases by tracking them in families that carry the trait. Grants from the Michigan Life Sciences Corridor Fund, the Foundation Fighting Blindness, Research to Prevent Blindness and National Institutes of Health will help the Kellogg team attempt to clone those genes and develop an effective general therapy. Their goal is to better understand all of the biological processes involved in macular degeneration.

"We assume a defective gene is causing the disease," Ayyagari says. "In 10 families, the likelihood is we may find 10 different genes. But sometimes the same gene may be causing the disease in more than one family. We'll see."

Ayyagari's laboratory is also investigating, with the help of a large collection of families, the involvement of genes associated with the perception of red and green colors in their research on a form of macular degeneration called blue cone monochromacy. Cones are the light-receptors in the retina responsible for daylight and color vision. They are most densely concentrated in the center, where visual acuity is greatest. When they work healthily, our brains can distinguish 10,000,000 different hues and focus on things near and far to the standard of 20/20 vision. Blue cone monochromacy (BCM) causes severe loss of focusing and a deficiency in color perception.

"Persons with BCM often have normal peripheral vision but cannot focus their central vision through the macula," Ayyagari says. The macula is rich in red, green and blue cones. In BCM, the red and green cones are defective, causing those colors to be seen as grayish.

The condition is identified through tests like those taken for a driver's license, but BCM is a much worse disability than the more common problem of "color blindness, which impairs the ability to distinguish red from green. Like macular degeneration, BCM is an X-chromosome, "pedigree disease," Ayyagari says, which means males are much more likely to inherit it.

Ayyagari is hopeful that research will lead to a "better understanding of the molecular basis of clinical variation in affected individuals and the role of other genes in macular atrophy."

Diverting the damage downstream

Early-onset macular degeneration Another kind of photograph of the back of the eyes of affected males (M) and females (F) in a family with early-onset macular degeneration. These pictures show how macular degeneration looks in individuals of different ages within this family. Ages of these individuals are shown in the photograph. Arrows point to the region of the macula that is affected. In this family, out of 50 members studied, 28 were affected with the disease.

Greatly complicating the research task is the fact that each gene is different. "We can figure out the design of some genes, while others are still a big puzzle," Ayyagari says. "Gene replacement is the one main hope for cure, but it's not the only effective treatment. If we see what a specific gene does and the effects it has, we can ease or eliminate the effects of a mutant gene in other ways. We might figure out how to clear up or divert the process that the mutant gene carries out. Let's say we have water flowing somewhere we don't want it to. We can control or divert its flow and prevent damage downstream. In the same way, if we protect the target site downstream from the mutant gene, we can provide effective therapy even if we don't yet know how to replace the gene."

This diversionary tactic already works in glaucoma therapy, Ayyagari points out, "when we lower intraocular pressure to prevent the disease."

Claims abound for dietary protection against macular degeneration. Ayyagari says that no concrete evidence shows that any single substance is significantly protective. "But there is evidence," she says, "that vitamin A, zinc, antioxidants and other dietary factors provide some protection, and also evidence that smoking increases the risk of age-related macular degeneration."

After identifying the gene or genes that cause macular degeneration, Ayyagari will eventually be able to develop a test to help diagnose individuals at risk. She emphasizes that "Kellogg is grateful to the families who participate in this research and share their struggles with this disease. They, more than anyone, are aware of the importance of the work we are doing. We hope by the time the children of 'our families' turn 40 we will have a cure."

In addition to the many books on the subject of color and vision, readers may also consult Tom Henderson's discussion in "The Physics Classroom" at http://www.physicsclassroom.com/Class/light/U12L2a.html/

The research on macular degeneration that Radha Ayyagari and Paul Sieving are conducting at Kellogg Eye Center will be featured this fall on a national broadcast "When Genes Go Wrong." American Public Television is distributing the program on public channels. For scheduling in your area, see www.aptvs.org/ or contact your local stations.

Ayyagari in her laboratory. The laboratory provides genetic testing 'for macular degenerations for which genes have been cloned, ' she says. 'This helps in identifying individuals at risk before the onset of disease, and also helps individuals who are not affected discover that they are not at risk to develop disease at a later stage.' Readers who seek further information about genetic testing may call (734) 647-6347.

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