Did Abraham Lincoln have ataxia? Groundbreaking research provides new insight into this neurological disease—and a glimpse into history.
For the past dozen years, people who are related to Abraham Lincoln have been gathering in Indiana, Iowa, and Kentucky—and University of Minnesota researchers have been there.
The researchers, led by Laura Ranum, Ph.D., come not to hear stories of the Great Emancipator or to share potato salad and coffee, but to collect DNA samples and to learn more about the Lincoln family’s medical history. The 299 vials of blood they have carried back to Minnesota over the years contain vital clues to the mystery of spinocerebellar ataxia, a devastating neurological disease that affects about 150,000 Americans.
These scientists are especially qualified to sort through the clues contained in those blood vials. And their work has not only uncovered a genetic secret encoded in the Lincoln family DNA for at least 11 generations; it has also led them to discoveries that may shed light on the mysteries of Alzheimer’s disease, Lou Gehrig’s disease, and other neurological disorders.
What is ataxia?
Ataxia is not kind. Those with the disease suffer from a deterioration of the cerebellum, brain stem, and spinal cord regions of the nervous system that govern muscle control. “Ataxic patients are loosely defined as anyone with clumsiness and a lack of coordination from cerebellar degeneration,” says John Day, M.D., Ph.D., a professor of neurology at the University’s Institute of Human Genetics who is collaborating with Ranum on the Lincoln project.
In many patients, ataxia results from genetic defects and typically appears in middle age. In these people, a genetic flaw causes the elaborately structured cells of the cerebellum to die off. The disease proceeds gradually, eventually robbing its victims of the ability to walk, hold objects, move their eyes, speak, and perform common activities of daily life. If patients lose control of the muscles for swallowing, they can develop pneumonia or even choke to death.
The Minnesota connection
Ataxia research in Minnesota began in the 1950s when John Schut, M.D., a local neurologist, started investigating its genetic causes. He had personal reasons for his work: His Dutch ancestors had a history of ataxia, and to date at least 65 members of the Schut family have succumbed to the disease. John Schut founded the National Ataxia Foundation with his brother Henry in 1957. When John himself died from complications of ataxia, his nephew Larry Schut, M.D., a neuro-logist at the CentraCare Clinic in St. Cloud, carried on the family work.
Larry Schut eventually joined forces with Harry Orr, Ph.D., a professor of laboratory medicine and pathology at the Institute of Human Genetics. It was there, in 1993, that researchers identified SCA1, the first genetic defect known to cause ataxia.
In 1983 the beloved Minnesota Twins left-fielder Bob Allison was diagnosed with nonhereditary ataxia. Determined to make a difference for others with ataxia, Allison and his family established the Bob Allison Ataxia Research Center in 1990 to raise vital funds for University researchers. Five years later, the disease ended Allison’s life. But over the years, his legacy has helped the region—and particularly the University—grow into a world center of ataxia research.
Ranum, now a professor of genetics, cell biology, and development in the Institute of Human Genetics, has long focused on defining the genetic causes of neurological disease. Previously, as a postdoctoral fellow in Orr’s lab, she took part in the 1993 discovery of the SCA1 mutation. More recently, Ranum’s own group has discovered the genes for several other ataxias and neuro-degenerative disorders.
“Finding the genes that cause ataxia provides an immediate benefit for those who want to know if they will develop the disease or pass on the gene to their children,” she says, “but our long-term goal is to find a cure.”
Unraveling the mystery
Ranum began her Lincoln family gene hunt in 1992 when she received a phone call from an Ohio physician who described a patient with familial ataxia. When she called the patient, the patient’s mother, and several cousins afflicted with the disease, she learned that all were related to President Lincoln. Some even referred to the ataxia in the family as “Lincoln’s disease.”
Shortly after that, Schut and Ranum began to collect blood samples from the family. “It was obvious that the family had something different than SCA1,” Ranum recalls. “They had a milder disease.” They retained their mobility longer, lived longer, and suffered less severe cerebellar degeneration.
When a newspaper reporter in Louisville wrote a story about “Lincoln’s disease,” another offshoot of the family contacted Ranum. This time the relative was descended from President Lincoln’s Aunt Mary. The identification of this second branch of the family means that one of President Lincoln’s paternal grandparents must also have had the disease. And that, according to Ranum, means that Lincoln himself had a 25 percent chance of carrying the mutation.
In 1994 the University of Minnesota team mapped the gene to the 11th chromosome and named this newly discovered genetic form of ataxia SCA5.
Although the trips to Lincoln family reunions spanned more than a decade, the hardest part of the gene hunt was yet to come. Ranum and members of her lab studied the DNA contained in the blood vials collected from Lincoln’s extended family. The search for this gene was particularly difficult because it fell near a tightly-packed region of chromosome 11 called a centromere.
“Sorting through the DNA in this sticky region of chromosome 11 made our search much more difficult,” says graduate researcher Katie Dick. She and fellow researcher Yoshio Ikeda, M.D., Ph.D., patiently searched for this elusive gene for years.
In 2005 the group finally found what it had long been seeking: the specific mutation responsible for the Lincoln family’s ataxia.
“Any family member with the gene will develop ataxia if they live long enough,” Ranum says. “And their children have a 50 percent chance of getting it, too.”
Eventually the researchers demonstrated that the mutation, an accident of chemistry, affects the function of another protein, called a glutamate transporter, that normally regulates how much stimulation the brain’s neurons receive. Failure to control this stimulation leads to damaged neurons; in fact, it is what likely causes the death of the cerebellum cells. With the loss of enough of these cells, patients lose control of the movements of their legs, arms, and eyes.
Ranum’s work opens the door to an entirely new cause of ataxia and suggests a new approach to studying the effect of genetic mutations on the brain.
“The discovery of this mutation supports the idea that over-excitation of the nerve cells is part of what’s going on in ataxia, and that similarly damaged cells are possibly connected to ALS [Lou Gehrig’s disease], Huntington’s disease, and Alzheimer’s,” Ranum notes.
Ranum and colleagues from the University of Minnesota, Johns Hopkins University, the Hôpital de la Salpêtrière in Paris, and the Universities of Lübeck and Tübingen in Germany—along with Larry Schut, M.D.—published their findings on SCA5 ataxia in the January 2006 issue of the journal Nature Genetics.
“The phone rang off the hook for a while,” says Ranum. The story first appeared in the Star Tribune and Pioneer Press only to be followed by the New York Times, CBS, CNN, and media outlets worldwide. What captured attention was not the discovery of the mutation itself but the fact that the Lincoln family carried it. Everyone wondered whether the president himself either had ataxia or would have developed it later in life.
Medical historians have long speculated that President Lincoln’s tall stature may have resulted from Marfan syndrome, a disorder of the body’s connective tissue. Ranum says that family history and historical accounts of Lincoln’s gait make it much more likely that he suffered from ataxia. Finding the mutation in his family allows researchers to conclusively test whether Lincoln had the SCA5 gene.
Lincoln’s last direct descendant, Robert Todd Lincoln Beckwith, died in 1985 along with genetic evidence that might have shed light on the question. But it’s possible that Abraham Lincoln’s own DNA remains available in tissue samples and on items splattered with blood after his 1865 assassination.
Although some believe that the question of the president’s possible ataxia is irrelevant to the scientific study of the disease, University of Minnesota researchers disagree. If Lincoln is found to carry the mutation, “It would help increase awareness of this devastating disorder,” says Day.
“Ataxia is easily ignored by those not directly affected. The overall funding for ataxia research is not yet what it should be. A direct Lincoln connection would help strengthen efforts to understand and ultimately control this disease,” he says.
Regardless of the Lincoln question, the University’s ataxia research has already made a difference in people’s lives. Scientists’ understanding of the cellular mechanisms involved has improved by leaps and bounds, and genetic testing is now available.
“It’s all extremely gratifying to me,” says Schut, whose relatives
carrying the SCA1 ataxia mutation have dropped in number from dozens to
only three. “It makes me wish that my uncle and my dad, who got my
interest going, could be here to see the genes discovered and our place
in history at the threshold of finding new treatments.”
By Jack El-Hai