Potential Role for Histamine Identified in Tourette's Syndrome

Emma Hitt, PhD

May 06, 2010

May 5, 2010 — A potential role for histaminergic neurotransmission has been identified in the condition underlying Tourette's syndrome and nervous tics, according to the findings of a genetic analysis published online May 5 in the New England Journal of Medicine.

"This is the first observation of a link between histaminergic neurotransmission and tics in humans and one of the few times that a clearly functional coding mutation has been found in a family with Tourette's syndrome," said the study's principal investigator Matthew W. State, MD, PhD, with the Yale Child Study Center in New Haven, Connecticut.

"Given the availability of pharmacological agents that specifically increase histaminergic neurotransmission, the finding suggests a novel approach to treating Tourette's syndrome," he told Medscape Neurology.

According to the researchers, Tourette's syndrome has a population prevalence of 1% and a rate of recurrence of 10% to 15% among first-degree relatives of an affected person. Although a genetic contribution to Tourette's syndrome is well established, thus far, findings have been nonreproducible.

Dr. State and colleagues analyzed linkage in a 2-generation pedigree and identified a rare functional mutation in the HDC gene, which codes for histidine decarboxylase, the rate-limiting enzyme involved in histamine synthesis.

Rare Mutation

The pedigree family included 1 father and 8 offspring all of whom had been diagnosed as having Tourette's syndrome. The father and 2 of the 8 offspring also had obsessive-compulsive disorder. The mother and her family of origin were free from Tourette's syndrome, chronic tics, and obsessive-compulsive disorder.

Given the presence of the syndrome in the offspring but the absence in the maternal side, the researchers concluded that Tourette's syndrome was an autosomal dominant trait in this family.

Further polymerase chain reaction analysis identified a heterozygous guanine to adenosine transition at position 951 in exon 9 of the HDC gene. This mutation resulted in a premature termination codon, W317X, that was present in the affected father and all offspring but was absent in the unaffected mother.

According to Dr. State, although the mutation is extremely rare, their approach is based on the hypothesis that rare examples of common disease may provide a window into biological mechanisms and, in turn, that these may be highly relevant to the broader group of affected individuals.

"This is a strategy that has proven effective in a variety of other human diseases, including Alzheimer, Parkinsonism, hypertension, and cancer," he said.

"The rare mutation found in the family would be expected to decrease histamine production in the central nervous system," Dr. State added.

In addition, animal studies have shown that decreased brain histamine leads to an increase in stereotypic behaviors that appear similar to human tics.

"It has already been shown that compounds that increase brain histamine (typically targeting the histamine 3 autoreceptor) reverse this effect in mice. Histamine 3 receptor inverse agonists and antagonists are already in late-stage development and early clinical trials for disorders other than Tourette's syndrome and, based on the current work, would be hypothesized to be a novel approach to moderating tics."

Hypothesis Generating, Not Generalizable

Dr. State pointed out that this is only a hypothesis-generating study. Some dietary supplements contain the histamine precursor, L-histidine, which increases brain histamine, he said.

"These, however, would also be expected to increase histamine peripherally and may lead to untoward side effects. As there have been no clinical trials of histamine-promoting agents in Tourette's syndrome, any treatment based on this finding would be premature," he said.

Joseph Jankovic, MD, professor of neurology, at the Baylor College of Medicine in Houston, Texas, and an independent researcher in the area of Tourette's syndrome,noted that this is potentially "an important finding as there are very few clues to the genetics of Tourette's syndrome, even though Tourette's syndrome is one of the most common childhood genetic disorders."

According to Dr Jankovic, the search for a Tourette's syndrome gene(s) has been frustrating because of the lack of a disease-specific/sensitive biologic marker and often a result of a bilineal transmission (both parents affected), which was apparently not the case in this family.

Dr. Jankovic pointed out, however, that the reported finding is based on only 1 family with Tourette's syndrome, so the results cannot be generalized to other Tourette's syndrome patients.

"Furthermore, although the patients met DSM-IV [Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)] criteria, their clinical features are not described in detail, so it is not clear whether any atypical features were present," he said. 

The study was not commercially funded. Dr. State and Dr. Jankovic have disclosed no relevant financial relationships.

N Engl J Med. Published online May 5, 2010.