People with Tourette syndrome are plagued by unwanted movements and verbal tics that run the gamut from extra eye blinks and grimaces to involuntary grunts or even cursing. Although the disorder tends to run in families, little is known about its genetic basis. Now researchers have found a mutated gene that appears to cause the disorder in one extremely unusual family with nine afflicted individuals. Although this mutation is not the cause of the vast majority of Tourette syndrome cases, it may push researchers to investigate a mechanism—and potential treatments—they otherwise would not have considered.
Since the French neurologist Georges Gilles de la Tourette first described his namesake condition 125 years ago, scientists have puzzled over the cause. Much recent attention has focused on a brain region called the basal ganglia that is involved in repetitive behaviors and on the neurotransmitter dopamine. In 2005, a team led by child psychiatrist and geneticist Matthew State of Yale University School of Medicine, reported one of the first genetic clues to the disorder, a mutation in a gene called SLITRK1 that seems to be responsible for a rare handful of cases. But the function of SLITRK1 and its contribution to Tourette syndrome are still largely a mystery.
In the new study, State and colleagues examined a family in which the father and all eight offspring (six sons and two daughters) have the syndrome. Extensive genetic detective work led them to a mutation in a gene called HDC, which encodes L-histidine decarboxylase, an enzyme involved in the production of histamine, a signaling molecule with a wide variety of roles throughout the body. The same mutation was present in all members of the family who had Tourette but was absent in thousands of DNA samples from control subjects, who included unrelated people with similar ethnic backgrounds as well as a group of 720 Tourette patients, the researchers report today in The New England Journal of Medicine. The mutated version of the HDC gene likely results in a truncated version of the enzyme, which would result in reduced histamine levels, State says.
Histamine may be best known for its role in provoking sneezing and itchy eyes during allergy season, but it also functions as a neurotransmitter in the brain. Exactly how histamine abnormalities would contribute to the symptoms of Tourette syndrome isn't clear, but State notes that knocking out the equivalent of the HDC gene makes mice more prone to head bobbing, spinning, and other repetitive behaviors. Moreover, he says, there's evidence that certain histamine receptors cluster in the basal ganglia and that histamine signaling can act as a brake on dopamine signaling.
"They make a very compelling argument that this mutation in this family is responsible for Tourette's," says Jon McClellan, a psychiatrist at the University of Washington, Seattle. "If histamine is actually an active player in Tourette's syndrome, it really would open up a whole new avenue of treatment" involving drugs that boost histamine, says Jeremiah Scharf, a behavioral neurologist and neurogeneticist at Harvard Medical School in Boston. But he cautions that a lot more work is needed to determine if the findings from this one family can be put to use to help the thousands of other people with the disorder.