Subtle clumsy movements foreshadow Huntington's disease long before patients notice the onset of symptoms, according to a recent report from Johns Hopkins University. In patients at risk, tests for subtle motor deficits may have a role in predicting the onset of disease within the subsequent five to 10 years, researchers suggested in the February 3 issue of Nature. Another implication of the same line of research, according to lead author Maurice A. Smith, is that "the basal ganglia may be involved in [motor] error correction."

Patients from the Huntington Disease Center at Johns Hopkins were recruited for two experiments. The first involved 11 subjects positive for the IT-15 mutation who were symptomatic for Huntington's disease, 16 mutation-positive presymptomatic subjects, three mutation-negative subjects who had one parent with Huntington's disease, and 12 other age-matched controls. The second experiment included five symptomatic and nine presymptomatic subjects with Huntington's disease, eight age-matched controls, and six subjects with cerebellar lesions. Gene analysis determined trinucleotide repeats; subjects with more than 37 repeats were considered mutation-positive, and those with fewer than 34 repeats were considered mutation-negative. Four of the cerebellar-lesion cohort had generalized cerebellar atrophy and two had a history of stroke of the right posterior inferior cerebellar artery.

During both experiments the participants directed a double-jointed robotic arm toward 1-cm targets at a 10-cm distance; both the instrument and the targets were displayed on a computer monitor. The participants' arms were supported with slings for stability. Although the robot remained passive during the first experiment, it exerted a 70-ms bell-shaped force pulse in randomly preselected trials during the second experiment.

Range of movement (changes in direction, smooth or abrupt) in hand paths was analyzed to determine the ratio of smoothness to jerk. Smoothness was defined as the lack of abrupt change; jerk was defined as the rate of change of acceleration measured against time. The robot arm recorded the trajectory and velocity of the hand path. To estimate jerk, a fourth-order Savitsky-Golay filter was applied to a 250-ms window of velocity data.

A SENSITIVE INDICATOR

Ultimately, movement jerkiness was found to be a sensitive indicator of presymptomatic Huntington's disease. All participants with Huntington's disease and a number of the asymptomatic gene carriers exhibited above-normal jerk levels during the motor testing. Estimates of projected disease onset were based on parental age of onset and glutamate repeat length, the researchers explained. Many asymptomatic carriers who were estimated to be far from onset (more than seven years) displayed elevated jerkiness; and in subjects with a shorter estimated interval to onset (less than seven years), motor jerkiness measures were even higher.

"This study is very important because it gives us a marker of motor abnormalities in those with the Huntington's disease mutation before they become clinically affected," commented Christopher Ross, MD, PhD, Professor of Psychiatry and Neuroscience and Director of the Huntington Disease Center at Johns Hopkins. "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."

Identifying preclinical Huntington's disease and tracking improvements in subtle motor signs "could be useful in helping speed the development and testing of treatments," said Dr. Ross. Preventive therapy targeted to presymptomatic phases could be a major implication of the future.

The authors also expect their findings to facilitate further research into how Huntington's disease ravages the nervous system. Although basal ganglia degradation had already been implicated in imaging studies, links with specific symptom patterns have been unclear. The new findings suggest that "relatively unaffected feedforward control but dysfunctional feedback control … may help to explain the pattern of motor learning deficits reported" in the affected subjects.

A SMALL POPULATION OF NEURONS

In asymptomatic gene carriers of Huntington's disease, early pathologic changes may be limited to "a relatively small population of neurons" in the basal ganglia, said John C. Rothwell, PhD, of the Institute of Neurology, Queen Square, London, in an editorial commentary. However, he hypothesized, other regions of the brain may overcompensate as basal ganglia function declines. "So any deficit might actually reflect a secondary side effect of compensation, rather than being a result of the initial pathology," he proposed. As researchers decipher the human genome, "subtle subclinical deficits" and "pathological processes … confined to a relatively small part of the central nervous system" will increasingly be recognized, Dr. Rothwell predicted.

Nevertheless, predictive motor testing for Huntington's disease, like the genetic test that has been available since 1993, presents an ethical dilemma, Dr. Rothwell added. Citing the lack of meaningful treatment that can alter the "relentless downward clinical course," he quoted the blind prophet Tiresias, who said: "It is but sorrow to be wise when wisdom profits not."

—Kathryn Blair
Associate Editor

Suggested Reading
Smith M, Brandt J, Shadmehr R. Motor disorder in Huntington's disease begins as a dysfunction in error feedback control. Nature. 2000;403:544-549.
Rothwell J. A predictor of pathology. Nature. 2000;495-496.

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