This is the first neurodegenerative disease shown to be caused by mutations in the protein â-III spectrin which plays an important role in the maintaining the health of nerve cells. The scientific discovery has historical implications as well--the gene was identified in an 11-generation family descended from the grandparents of President Abraham Lincoln, with the President having a 25 percent risk of inheriting the mutation.
"We are excited about this discovery because it provides a genetic test that will lead to improved patient diagnoses and gives us new insight into the causes of ataxia and other neurodegenerative diseases, an important step towards developing an effective treatment," said Laura Ranum, Ph.D., senior investigator of the study and professor of Genetics, Cell Biology and Development at the University of Minnesota.
Understanding the effects of this abnormal protein, which provides internal structure to cells, will clarify how nerve cells die and may provide insight into other diseases, including amyotrophic lateral sclerosis (Lou Gehrig's disease) and Duchenne muscular dystrophy. The research will be published in the February print issue of Nature Genetics, and posted online Jan. 22, 2006.
Ataxia is a hereditary disease that causes loss of coordination resulting in difficulty with everyday tasks such as walking, speech, and writing. About 1 in 17,000 people have a genetic form of ataxia.
Spinocerebellar ataxia type 5 (SCA5) is a dominant gene disorder; if a parent has the disease, each of their children has a 50 percent chance of inheriting the mutation and developing ataxia sometime during their lifetime. The onset of SCA5 usually occurs between the ages of 30 and 50, but can appear earlier or later in life, with reported ages of onset ranging from 4 to more than 70 years of age.
Now that researchers have identified the specific mutation that causes SCA5, testing of patients at risk of developing this disease is possible before any symptoms appear. The availability of predictive testing allows people with a family history of the disease to determine whether they will develop the disease and whether their children are at risk of inheriting the mutation. In addition, the prognoses of the different types of ataxias vary greatly, so identifying the specific type of ataxia provides patients with a more accurate picture of what the future holds.
Ranum added: "Finding the SCA5 mutation in Lincoln's family makes it possible to test Lincoln's DNA - if it becomes available - to unequivocally determine if he carried the mutation and had or would have developed the disease." Biographical texts of Lincoln include descriptions of his uncoordinated and uneven gait, suggesting the possibility that he showed early features of the disease.
Ranum started this historical and scientific journey more than a decade ago. She and her colleagues John Day, M.D., Ph.D., University of Minnesota, and Larry Schut, M.D., CentraCare Clinic in St. Cloud, Minn., examined and collected DNA samples from more than 300 Lincoln family members who live across the country, tracking descendants from two major branches of the family.
Support for this study was provided by the Bob Allison Ataxia Research Center, the National Ataxia Foundation, the Paul and Sheila Wellstone Muscular Dystrophy Center, and the National Institutes of Health.