Rare genetic mutation confirmed as a cause of Tourette Syndrome

Brain researchers say they have confirmed for the first time that a rare genetic mutation can cause some cases of Tourette syndrome, with the fault disrupting production of histamine in the brain.

The New Haven, CT, researchers at the Yale School of Medicine say the histamine effect "is a cause of the tics and other abnormalities of Tourette syndrome." Tics are repetitive movements and vocal sounds, and they are unwanted and involuntary - they cannot be controlled.

Publishing their research on mice in the journal Neuron, the authors raise the question of investigating treatment of Tourette syndrome by drugs that target histamine receptors in the brain.

Drugs with such a mode of action are already being explored by pharmaceutical companies for the treatment of separate brain disorders, schizophrenia and ADHD.

Information from the national gene database about histamine describes the chemical's role - it is a messenger molecule released by nerves, among other functions.

Current neurological drugs under investigation target a certain gene-encoded histamine receptor known as the histamine H3 receptor.

Christopher Pittenger, of the Yale Child Study Center and associate professor of psychiatry and psychology, says of his particular study on histamine genetics:

"These findings give us a new window into what's going on in the brain in people with Tourette. That's likely to lead us to new treatments."

Histamine also has an important role in inflammation, which is why antihistamines work to reduce allergy symptoms. Interactions with the histamine system in the brain, say the Yale researchers, "explain why some allergy medications cause people to feel sleepy."

The specific gene in this study is called HDC (the histidine decarboxylase gene), which the researchers previously found to be mutated in a family that had nine members with Tourette syndrome.

Researchers found that mice with a faulty HDC gene showed symptoms similar to those found in Tourette syndrome.

That earlier finding of a faulty gene led the authors to confirm its effects on histamine in their present study with mice.

Mice with the same mutation carried by the Tourette family developed symptoms similar to those found in the syndrome, the Yale team showed, saying that this helps to prove that the histamine disruption can cause the tics.

Brain structures and chemicals

The study also found effects to do with dopamine, another brain chemical involved in communication between nerve cells.

There were abnormalities in dopamine neurotransmitter signaling in mice and in the patients carrying the faulty HDC gene.

The disruption was to dopamine effects in the basal ganglia, which is a network of structures responsible for movement - and the part of the brain that Dr. Pittenger focuses on toward the scientific understanding of neuropsychiatric diseases.

His research biography says:

"The basal ganglia are involved both in motor control and in the formation of habits.

Abnormalities in this circuit are implicated in a variety of conditions characterized by maladaptive, inflexible behaviors - habits gone bad.

These include obsessive-compulsive disorder, Tourette syndrome, and drug addiction."

The Tourette Syndrome Association of America - a non-profit whose mission "is to identify the cause of, find the cure for, and control the effects of Tourette Syndrome" - helped to fund the Yale study, which also received financial support from the Allison Family Foundation and the National Institutes of Health.

The US Centers for Disease Control and Prevention (CDC) does not have a firm estimate of the number of people affected by Tourette syndrome in America, but has run studies that indicate a prevalence of between 3 and 6 children out of every 1,000 in the population.

Other researchers, from the Massachusetts General Hospital and the University of Chicago, have also found family genetics behind Tourette's - and obsessive compulsive disorder (OCD), too. Their PLOS Genetics study published in October 2013 found insights into genetic architecture.

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New approach for those with Tourette Syndrome being tested in clinical trials

Medical researchers are hopeful that a new investigational drug being tested in clinical trials will prove to be an effective treatment for Tourette Syndrome – an inherited, misdiagnosed, misunderstood neurological disorder that presents in childhood and causes involuntary motor and vocal tics.

The new drug, AZD5213, targets the human histamine H3 receptor.  In the brain, this receptor regulates neurotransmitters associated with Tourette Syndrome – including dopamine and histamine.A mutation that affects histamine synthesis was recently confirmed to be the cause of TS in a father and all eight of his children, a finding supported by research in mice.

If approved for treatment of Tourette, AZD5213 might represent an alternative to antipsychotics, which don’t work well in all patients and can cause serious negative side effects.  Discovered by AstraZeneca, AZD5213 has been shown to have a favorable safety profile, with no serious drug-related side effects reported in Phase 1 and Phase 2 clinical trials completed at the time of this report.

“AZD5213 represents an exciting new approach to the treatment of Tourette Syndrome, and we are currently recruiting teenagers suffering from the disorder to participate in the clinical trial,” says Dr. Roger Kurlan, Director of the Movement Disorders Program at Overlook Medical Center’s Atlantic Neuroscience Institute in Summit, N.J.

Dr. Kurlan, who frequently collaborates with the NJ Center for Tourette Syndrome & Associated Disorders (NJCTS) in Somerville, N.J., is a leading expert in the treatment of Tourette and is one of approximately six medical researchers involved in the clinical trial.

AZD5213 already has been studied in other clinical trials, including those for Alzheimer’s disease. With Tourette Syndrome, which is associated with changes in brain chemistry that appear to cause the characteristic symptoms of the disorder, AZD5213 might be able to counteract these changes – with the potential to provide symptomatic relief with less of the negative side effects associated with existing treatments.  More than 200 human subjects have already received single or multiple doses of AZD5213, with no serious drug-related adverse side effects.

The clinical trial is a 6-month, multicenter, randomized, safety, tolerability, pharmacokinetic, and preliminary efficacy study of AZD5213 in adolescents 12 to 17 years of age with Tourette Syndrome. The trial includes an up to 21-day screening period, 6 months of once-daily treatment with placebo or AZD5213, and a 3-week follow-up period.

Because of the crossover design of the trial, all enrolled patients will receive AZD5213 for at least part of the trial. Approximately 24 subjects will be treated in this study.  Safety will be carefully ensured by a battery of safety tests administered at visits throughout the study, and efficacy will be determined by means of questionnaires designed to assess the severity of symptoms associated with Tourette Syndrome.

According to the Centers for Disease Control and Prevention (CDC), 1 in 100 children show signs of Tourette Syndrome. The disorder is three times as likely in boys as in girls, and most patients experience their worst symptoms in their early teen years. There is no cure, and symptoms can persist throughout life – although most patients see improvement as they approach and enter adulthood.

Exaggerated portrayals of Tourette Syndrome have been used for comic relief in films and TV shows, usually featuring characters who shout obscenities involuntarily. In reality, this type of verbal tic – known as coprolalia – is present in only 10 to 15 percent of those with TS.

“In real life, Tourette’s is no laughing matter,” Dr. Kurlan says. “These patients often struggle with self-esteem and socialization issues, which generally arise at a crucial time in their social development. Sadly, many are victims of bullying and the ridicule of their peers.”

Tourette’s is most often present in combination with other neurological disorders, such as attention deficit-hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD), and Tourette’s patients are commonly troubled by depression, anxiety and developmental delays.

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Study replicates Tourette's syndrome in mice

Scientisits have managed to replicate Tourette syndrome in mice.

Hartford, Connecticut: A team of Yale researchers says it has found a genetic cause of Tourette syndrome, a discovery that could lead to better medications for the hard-to-treat disorder.

In a study published in the US on Wednesday in the journal Neuron, the researchers say a genetic mutation that blocks histamine also leads to Tourette syndrome, a neurological disorder that can cause various tics, such as repeated motions and involuntary verbal utterances. But Tourette's experts say that the way the researchers studied the gene mutation - a specially bred mouse - might be the real breakthrough.

In 2010, the Yale researchers studied a family of eight children, all with Tourette's. Their father also had the disorder. They all carried a mutation of a gene known as histidine decarboxylase (HDC), which blocks histamine production.

It wasn't until the most recent study, however, that they were able to prove that the gene mutation and the blocked histamine actually caused Tourette syndrome. Although histamine is a compound most commonly associated with allergies and the immune system, it also serves as a neurotransmitter, a chemical that sends signals throughout the brain. To measure levels of histamine in the brain - and determine what happened when those levels were disrupted - the scientists needed animal models.

The researchers took two groups of mice, one bred to have Tourette's, and a control group. They then examined the activity of histamine and dopamine - another neurotransmitter that plays a major role in the cause of Tourette's - in the part of the brain known as the basal ganglia.

"We found that the neurons are more active in the animal model (with Tourette's) and that they had a little more of the neurotransmitter dopamine," said Christopher Pittenger, senior author of the study. But when the researchers increased histamine levels in the mice's brains, they found that doing so reduced dopamine levels.

Exactly why increased activity in the basal ganglia can lead to Tourette's isn't understood, Professor Pittenger said.

"What I really hope is that this is going to lead us to new insights as to what's out of balance," he said.

The US Centre for Disease Control and Prevention identifies other possible causes of Tourette being researched, including smoking and drinking during pregnancy, complications during birth, and streptococcal infection.

Kevin Black, a professor of psychiatry at the University of Washington in St. Louis, said the Yale study was an impressive one overall.

"I would say it's one of the first chances there's been to follow up and test whether a specific gene can really cause tics and whether it can give clues as to how to treat those tics," he said.

Carol Mathews, a professor of psychiatry at the University of California, San Francisco, who serves on the medical advisory board for the Tourette Association, said that the study could help understand the biology of Tourette syndrome.

"It won't solve the problem of Tourette's, but it's one more piece of the puzzle," she said. Because you can't take direct samples of the brain, she said, it's difficult to study and diagnose certain neurological disorders.

"This gives us another way of looking at (Tourette syndrome) by using the animal model," Professor Mathews said.

Drugs now on the market can control dopamine activity, but they can also have serious side effects, such as significant sedation and weight gain, Professor Pittenger said. But he said medications that control histamine, which then controls the levels of dopamine, might mean better treatment.

The disorder affects between 0.7 per cent and 1 per cent of children. Most of those affected improve significantly by adulthood, Professor Pittenger said.

Although the disorder is commonly depicted as producing wild and often vulgar utterances, experts say that most cases involve fairly mild symptoms, such as repeated throat-clearing or blinking.

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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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