February 3, 2000
For more than a century, tremors and jerky movements have been recognized as the hallmarks of Huntington's disease (HD). Scientists have long known these motor control disturbances result from damaged brain cells. Now, researchers at Johns Hopkins think they may have identified the nervous system mechanism linked to these symptoms and the part of the brain causing them. They also found that subtle jerkiness in movements may appear in HD patients long before clinical symptoms of the disease are first seen, perhaps providing physicians with a new diagnostic tool for early HD.
According to a study published in the February 3 issue of Nature, a dysfunction exists in HD in the way the brain monitors movement, specifically in the way it corrects small errors in movement.
"If you're reaching for a glass of water, for example, the brain uses visual and other cues to constantly provide feedback to correct for errors. If everything functions properly, you end up with a glass in your hand and no spills," explains Maurice A. Smith, a doctoral student at Johns Hopkins University's Department of Biomedical Engineering and lead author of the study. "But with HD, something goes awry."
HD is known to attack the basal ganglia, a deep-brain cluster of nerve cells at the base of the cerebrum. "It's been a mystery exactly what this part of the brain does, but our study suggests that the basal ganglia may be involved in error correction because when it's damaged, error correction suffers," Smith says.
Huntington's disease, also known as Huntington's chorea, is an inherited condition caused by a genetic mutation in the Huntington gene that causes certain nerve cells in the cerebrum to deteriorate and die. It is a progressive degenerative disease marked by involuntary, jerky movements in the arms, neck, trunk and face. Other symptoms include a wide, prancing gait, hesitant speech and intellectual deterioration. Symptoms appear in the fourth or fifth decade of life, and then progress steadily during the succeeding 10 to 20 years. Death follows, and there are no effective treatments available.
The study was conducted using patients from the Huntington Disease Center at Johns Hopkins, directed by Christopher Ross, M.D., Ph.D., professor of psychiatry and neuroscience at Hopkins, and is funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke and the Huntington's Disease Society of America.
Researchers examined 11 asymptomatic patients who were known carriers of the HD gene, 16 others with symptomatic HD, 3 subjects who did not have the HD gene but who had parents with HD, and 12 other age-matched, disease-free persons. A second, similar study included six control subjects with cerebellar injuries. Researchers asked the subjects to reach quickly for targets while grasping a robotic arm. The arm continuously measured the movements for jerkiness and smoothness and the ability to stay on target -- called "aiming." Results were then analyzed by a computer.
While initial aiming was not dramatically disturbed in HD patients, all HD patients and several of the asymptomatic HD gene-carrier patients made movements with unusual jerkiness as the movement progressed. These results suggest, Smith says, that HD movements often begin normally, but become jerky and irregular at some point during their course because of impaired error feedback.
"This study is very important because it gives us a marker of motor abnormalities in those with the HD mutation before they become clinically affected," Ross said. "We saw a large percentage of these patients displaying elevated jerk even when more than seven years remained until symptoms of the disease were predicted to begin."
Smith cautions that the results of his study are not likely to lead to improved diagnosis or treatments for HD, but may lead to a better basic understanding of the disease and its manifestations. "This is really very basic research," he says. "But hopefully this information can give us better insights into the mechanisms of HD symptoms and the part of the brain that processes error corrections."
Ross says the results may help assess treatments for HD as they become available. "Using this test, we may be able to track improvements with experimental treatments in HD patients before they exhibit symptoms of the disease. This could be useful in helping speed the development and testing of treatments for HD."
Jason Brandt, Ph.D., professor of psychiatry at Hopkins, and Reza Shadmehr, Ph.D., assistant professor of biomedical engineering, are co-authors of the study.