. . . Summer 2002
Macular degeneration is a complex inherited disease whose many forms have puzzled researchers for decades. The macula is the central area in the retina, and as it progressively degenerates, patients see things fuzzily and then lose the ability to focus and to read. It is a slow, relentless deterioration of central vision that cannot be corrected with glasses or surgery and leads to blindness. But U-M researchers and clinicians are making steady progress in understanding the genetic processes involved in this debilitating condition, and their research is offering hope to millions.
"Macular degeneration is one of the leading causes of blindness in the world," says Radha Ayyagari, a researcher at U-M's Kellogg Eye Center. "With an aging population, we will see more of this disease in the years ahead. Thirteen million people in the United States now suffer from some form of the disease, and with a steadily aging population that number is expected to reach 45 million by 2030." Although most people begin to notice the effects of macular disease only after the age of 60, there can be wide variation in age of onset even within a family. "One person may suffer severe vision loss in his late teens, while other family members may have 20/20 vision well into their 50s." With no cure currently available, scientists are looking to genetic research for answers. Genes transmit early-onset macular degeneration primarily in three ways, through X-chromosome inheritance, dominant genes or recessive genes. "The process of transmission of age-related macular degeneration is complex," says Ayyagari, who received her doctorate in biochemistry from Osmania University in Hyderabad, India. "Perhaps it can be grasped best by focusing on X-linked transmission." Here's what happens: Fathers and sons Everyone gets one set of chromosomes from each parent. Females have two XX's; males have an X and a Y. "In an X-linked disease," Ayyagari explains, "every daughter of an affected male will inherit the affected X chromosome, or the X chromosome carrying the mutation, from her father, but since she can get a good X chromosome from Mom, she has a good chance not to be affected by the disease even though she will carry it." Sons, however, inherit only one X chromosome from their mothers and a Y chromosome from their fathers. "If the sons of a carrier female inherit the X chromosome that carries a gene associated with a disease, they will inherit that 'bad X,'" Ayyagari continues, "and therefore be more likely to inherit an X-linked disease. And fathers will pass the bad X to daughters who, in turn, don't get the disease, but pass it to the father's grandchildren. The X chromosome is not transmitted from father to son, and hence sons of an affected male do not inherit the bad X chromosome." Ayyagari adds that despite the role of the X chromosome, the disease affects men and women equally "because there are other forms of macular degeneration in addition to the X-linked form. Families touched by macular degeneration have been playing a vital role in helping Ayyagari's team and other Kellogg researchers study the role of genes in transmitting the hereditary forms of the disease. Four generations of seven or eight large families who suffer from the early-onset and late-onset forms have volunteered to take part in the study. The families came from the clinical practice of Kellogg ophthalmologist Dr. Paul Sieving, who was recently named director of the National Eye Institute at the National Institutes of Health. He notes the challenges of approaching an entire family about this sort of research: "When I give a patient a diagnosis of macular degeneration it can be devastating. The knowledge that other family members may develop this disease makes it more difficult. By participating in Dr. Ayyagari's research, family members-both those currently diagnosed and those who may be diagnosed in the future-know they are doing something positive to help." Ayyagari says that when physicians find patients who are beginning to lose central vision in their teens to early 40s, instead of age 60, the young patients "give us a chance to collect more information about their genetics and how the macula deteriorates over time."
Disease strikes at different ages Ayyagari is particularly interested in why members of a single family are affected at varying ages (or not at all). She uses a multigenerational chart or "pedigree" to give her an idea about the pattern of inheritance of the disease in each family. "A genetic defect obviously exists," she says, "but something is protecting certain family members from the disease. If you can identify what stimulates the good gene, you can protect other family members." Referring to the generational charts on her laboratory's wall, Ayyagari points out which family members do not show the effects of macular degeneration and which do. The chart tells how old they were when the condition emerged and the severity of the disease. Adjacent charts show images of the interior of the eye and trace the changes in eye tissues over the course of the study. "In the images of the eye, we see a 47-year-old with severe vision loss and his brother, 51, who has 20-20 vision," Ayyagari says as she points to the images. "But the older brother's eye is showing subtle changes. He has the same gene defect, though so far it causes very subtle symptoms. In contrast, here is a 15-year-old relative with severe macular degeneration due to the same gene defect. Our team is studying differences among the family members. It could be that a different gene is providing protection, or it could be the influence of different environments, dietary factors, exercise patterns (whether more or less), different exposure to light and so on."
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