LOS ANGELES (Embargoed until April 15, 2002; 4:00 p.m., Central) -- Researchers at Cedars-Sinai Medical Center and at the Centro Investigación Rehabilitación de Ataxia, in Holguin, Cuba have identified a gene that affects the severity and onset of a rare brain disease. The condition, called spinocerebellar ataxia, is a disease caused by a gene mutation and characterized by a loss of balance and coordination. The finding, reported at the 54th Annual Meeting of the American Academy of Neurology, may lead to new ways to effectively treat the disease.
“Our research shows that a certain form of SCA6, a gene that regulates the entry of calcium into the cells, influences the severity of spinocerebellar ataxia,” said Stefan-M. Pulst, M.D., who holds the Carmen and Louis Warschaw Chair in Neurology at Cedars-Sinai Medical Center and is senior author of the study.
Spinocerebellar ataxia is caused by a loss of function in the cerebellum, the part of the brain that controls coordination. The disease causes clumsiness and a loss of coordination in the hands, arms, legs, speech and eye movements. Usually SCA2 occurs in adulthood, but it can also occur in childhood or very late in life despite identical gene mutations. In either situation, SCA2 is caused by a gene mutation made up of very long “repeats” of three chemical bases (C-A-G) in the DNA sequence that tend to get bigger over time. In successive generations, for example, the length of the C-A-G repeat becomes longer and causes the disease to occur at an earlier age. However, only about 60 percent of the variation in age of onset can be explained by the C-A-G repeat length, with the remaining 40 percent having no relationship to the size of the repeat.
To determine why people with identical gene mutations developed the disease at different ages and degrees of severity, the investigators analyzed 331 patients with SCA2 from Holguin, Cuba, where SCA2 is common due to a large Founder effect – or where a specific gene variant is concentrated in a particular population.
Two groups of patients were then chosen based on being above or below the average age for developing the disease. The first group was comprised of 33 patients who developed SCA2 at a much later age, while the second group was made up of 31 patients who contracted the disease considerably earlier, often as children or teens. The investigators simultaneously analyzed several genes associated with the development of SCA2 to determine whether any genetic differences stood out among the two groups. They found that there was significant variation in SCA6, a gene that regulates the entry of calcium into cells and SCA1.
“We found that a certain form of the SCA6 gene leads to an earlier onset of SCA2,” said Dr. Pulst. “This may mean that the severity of SCA2 is caused by altered calcium entry into the cells of the cerebellum. It could be that we can treat patients with SCA2 and other neurodegenerative diseases with drugs that control the flow of calcium into cells.”
Future studies will determine which other genetic and environmental factors may play a role in modifying severity and progression in this neurodegenerative disease.
Cedars-Sinai Medical Center is one of the largest non-profit academic medical centers in the Western United States. For the fifth straight two-year period, Cedars-Sinai has been named Southern California’s gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthrough in biomedical research and superlative medical education. Named one of the 100 “Most Wired” hospitals in health care in 2001, the Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.