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See Inside July/August 2009

Shaking Hands--Neuroscience of Tremors

Researchers uncover the roots of essential tremor

If your hands and arms quiver when you write and do other tasks, you may have a common neurological condition called essential tremor (ET). As many as 7 percent of adults older than 65 suffer from ET, which may also affect the head and voice. In severe cases, it can be disabling. The cause of such shaking has long been mysterious. But researchers are beginning to uncover a biological explanation for the problem: they have found a gene that may contribute to its development as well as a pathological signature of the disorder in the brain.

Researchers knew that genetic factors underlie ET, as half or more of the cases run in families. But no one until now had succeeded in nabbing any of the responsible genes. To find such a gene, scientists at deCODE genetics in Iceland compared DNA blueprints from hundreds of tremor patients and thousands of unafflicted residents. In each person’s DNA, researchers looked at 305,624 single-nucleotide polymorphisms (SNPs), sites where the identity of the chemical unit (the pair of molecules that makes up each building block of a strand of DNA) commonly varies among people. Out of that analysis emerged one SNP that consistently differed between the patients and the others. The same chemical unit also turned out to be tied to ET in populations of patients whom the researchers recruited from Germany, Austria and the U.S.

The newly fingered SNP lies in a gene for a protein called LINGO1 that is present only in the brain and spinal cord—a distribution consistent with a role in neurological disorders, says neurologist Dietrich Haubenberger of the Medical University of Vienna in Austria, one of the study’s authors. The protein, which straddles the cell membrane, is thought to govern interactions among cells and to thereby influence neuronal integrity as well as function. LINGO1 also has been implicated in multiple sclerosis and Parkinson’s disease, but its precise role in these disorders and in ET is unclear.

Nevertheless, in the case of ET, some researchers theorize that variation in LINGO1 may preferentially affect cells in the brain’s cerebellum, a brain structure that edits rough motor programs to produce coordinated movements. Neurologist Elan Louis of Columbia University and his colleagues recently reported seeing degeneration within the brain’s cerebellum among individuals who had ET when they were alive. Such deterioration may reduce the quality of the motion editing in that brain structure, leading to tremors, Louis says.

Whatever LINGO1’s role in ET, the newly identified version of the gene does not by itself cause the disorder. Having one copy of the risky variant boosts a person’s chances of developing ET by 55 percent; having two copies confers a 140 percent greater risk—and the SNP contributes to the condition in only a fifth of cases. But although many more genes, along with external culprits, are likely to be involved, implicating the gene for LINGO1 in ET is an important step toward unraveling the roots of the condition.

Scientists hope that the emerging genetic and cellular story of ET ends with better treatments; today’s medications for the disorder are partially effective at best. “Studies like these that start to clarify the biology will form the basis of more biologically based therapies than we have today,” Louis predicts.

Note: This article was originally printed with the title, "Shaking Hands."

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