Advances in Tourette Syndrome Research: Histamine and Genomics

A recent NBC News article highlighted the importance of genetic research and the potential therapeutic application of histamine for individuals with Tourette Syndrome (TS). TS is a chronic neuropsychiatric disorder characterized by multiple motor and vocal tics. Onset of tics occurs before age 18 and is often associated with marked impairment and disability.

Decades of evidence from twin and family studies demonstrate that TS is inheritable, indicating a significant genetic contribution. However, the nature of the allelic architecture of the syndrome remains a highly researched topic, due to its complex, multifactorial, and heterogeneous nature. The NBC article focuses on a seminal study conducted by Castellan et al. (2014), which was published in the journal Neuron. The research stemmed from the identification of a mutation in histidine decarboxylase (Hdc)—an enzyme essential to the synthesis of histamine—in a family where a father and his eight children were affected by TS. In the study, the researchers created a sample of Hdc “knockout” mice which did not have the Hdc gene at all and another sample with just one copy of the gene, as opposed to two. The researchers utilized a parallel analysis to compare the nine-person family with the mutation and the Hdc KO mice, and found similarities in the increase in tics and tic-like stereotypies, respectively, and a reduction in histamine biosynthesis. In the mouse sample, these stereotypic movements were ameliorated by administration of histamine directly into the brain. The animals’ tic-like behaviors also improved when treated with haloperidol, a medication frequently used to help TS patients, thus reinforcing the relationship between the Hdc gene and the disorder. From these findings, the researchers postulate that H3 receptor antagonists could increase the release of histamine by “blocking inhibitory autoreceptors on histaminergic terminals”.

In line with the Castellan study, Mount Sinai’s Tics and Tourette’s Clinical Research Program, under the leadership of Barbara Coffey MD, MS, is similarly exploring the implications of genetics and histamine in TS.

One neurobiological study in which our Program is participating, A Collaborative Genomic Study of Tourette’s Syndrome, is currently underway to identify genetic factors that play a role in causing TS and comorbid disorders. This study, which includes scientists and clinicians specialized in TS from more than 20 sites across the United States, Europe, and South Korea that are part of an international TS genetics consortium, serves to identify susceptibility genes for TS and related conditions. Over a three-year period, more than 1,500 subjects will participate in this study. Essentially, probands (i.e., participants with TS) and at least two family members are asked to give DNA samples. Next-generation sequencing, as well as whole-exome sequencing, is then conducted on these family samples to search for rare, likely deleterious coding mutations that are shared by affected individuals within families.

Dr. Coffey’s team is also working on a histamine clinical trial. Currently, the TS treatment landscape is very limited, and consists of only two FDA-approved drugs, the conventional neuroleptics (antipsychotics) haloperidol and pimozide, and numerous other off-label antipsychotics (e.g., risperidone and aripiprazole) and alpha-agonist medications (e.g., clonidine and guanfacine). Therapeutic benefit from these medications is limited, and all may have clinically significant side effects.

The goal of Dr. Coffey’s research is to expand the variety of scientifically sound, evidence-based treatment options for TS patients, and thus to improve quality of life. In this new clinical trial, Dr. Coffey and her colleagues are looking at a novel histamine H3 receptor inverse agonist that shows promise for treatment of impairing tics in adolescents with TS. Study goals are to evaluate efficacy, tolerability, and safety of the drug.

“Given that we currently only have two FDA approved, very old medications for TS which are frequently associated with intolerable side effects, it is essential that we identify new effective and safe treatments,” says Dr. Coffey of the new clinical trial initiative. “But it is critical that we develop treatments based on scientific understanding of brain mechanisms of action, to better target the TS neural pathways and functions informed by current neuroimaging, genomics, and other neurobiological measures. This will be one important step in the direction of personalized medical treatment for each unique individual.”

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Barbara J. Coffey, MD, MS is an internationally known specialist in Tics and Tourette Syndrome. She joined Mount Sinai’s Behavioral Sciences Unit in 2012 to launch the Tics and Tourette’s Clinical and Research Program within the Department of Psychiatry. Throughout her career, she has focused on developing and implementing cutting edge treatments. Dr. Coffey has repeatedly been recognized by America’s Best Doctors, New York’s Best Doctors, and Boston’s Best Doctors.

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