Rare genetic mutation discovered in Tourette syndrome family

Courtesy Jeffrey Kramer

Jeffrey Kramer and his three sons. Kramer and two of his grown-up sons have been living with Tourette for decades. He’s excited by the new findings, but realistic about their impact on patients with the syndrome.

A rare genetic mutation that disrupts the production of histamine may help researchers unravel the mystery that surrounds Tourette syndrome.

The mutation discovered by Yale researchers can cause the kinds of tics and other abnormalities that are the hallmark of the syndrome, according to a study published Wednesday in the journal Neuron.

Thus far the genetic anomaly has been discovered only in nine members of a single family: a father and all eight of his children who have both the mutation and Tourette syndrome.

“We know that Tourette is about 90 percent genetic,” said study coauthor Dr. Christopher Pittenger, an associate professor of psychiatry and psychology at the Yale University School of Medicine and director of the Yale OCD research clinic. “But it’s been incredibly hard to find any genetic abnormalities that cause the syndrome. We have proven that this gene really is the cause of Tourette in this family and also looked at some of its downstream effects.”

If found in other patients, it would raise the possibility that Tourette syndrome might someday be treated with drugs that bump up the brain’s levels of histamine, a compound that’s involved in inflammatory and immune responses and causes many of the symptoms of allergies.What isn’t known yet is how, or if, this finding can be extended to other people with Tourette, Pittenger and other experts said.

Jeffrey Kramer and two of his grown-up sons have been living with Tourette for decades. He’s excited by the new findings, but realistic about their impact on patients with the syndrome.

“I think this is a step forward,” the Los Angeles TV producer said, “but I think it’s going to be a long road. It may take another generation until they can finally utilize the knowledge they have found.”

One hopeful sign, Pittenger said, is that researchers have found other histamine-related mutations in people with Tourette. “Now there are two genetic studies that looked at many people with Tourette and found other abnormalities in the histamine system,” Pittenger said. “This mutation is extremely rare, but histamine abnormalities in general are less rare.”

Once Pittenger’s team had isolated the histamine mutation, they created a group of so-called knock-out mice who didn’t have the gene at all and others who had just one copy instead of two. Those mice displayed many of the symptoms that are signatures of the syndrome, Pittenger said.

The scientists also learned that low or no histamine in the brain led to higher levels of an important brain chemical, dopamine, which is involved in movement.

The next step was to determine how important histamine is in producing Tourette-like symptoms in the mice. “We had to squirt a little directly into the rodent brains,” Pittenger said.

While that seemed to ameliorate symptoms in the mice, it’s not an option for people with the syndrome since there’s no way to squirt histamine on the brain in a non-invasive way.

But, Pittenger said, there are several drugs that had been developed to treat other conditions that might turn out to help with Tourette because they bump up histamine levels in the brain. The catch is that those drugs never made it all the way through the testing required to get approval from the Food and Drug Administration because they didn’t work for the conditions they were designed to treat.

But it would be possible for drug companies to start trials of those drugs in Tourette patients now, Pittenger said.

In the meantime, the researchers did note that there are dietary supplements that contain histimine, a precursor to histamine. It’s possible that those supplements could boost histamine levels in the brain, but no one knows if those products would have that effect.

“I think it’s a very nice study that was well done,” said Dr. Carol Mathews, a professor of psychiatry at the University of California, San Francisco, and a member of the medical advisory board for the Tourette syndrome Association. “It might be worth it for drug companies to look at [some of the medications that affect histamine production]. But my personal opinion is that this needs to be explored a little more before any clinical trials.”

As for the dietary supplement suggestion, Mathews said, “I wouldn’t do that. It’s really a stretch.”

“It’s not like everyone should get more histamine in their diets,” agreed Dr. Anthony Rostain, a professor of psychiatry and pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “But this research does give us a little window onto how the circuitry of the brain works in people with Tourette.

“The bottom line is this is a genetic mutation that is very, very rare. It can be used to study mice to learn more about the mechanism of brain circuits that are affected in Tourette. But I’d be very, very hesitant to say it gives any answers that would immediately help people with Tourette syndrome.”

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