Abnormalities in brain histamine may be key factor in Tourette syndrome

HistamineSince the first case description in the 19th century, the causes of Tourette syndrome have been a mystery.  Now researchers have identified a rare gene mutation responsible for the disorder in one family.  The gene is needed for producing histamine, a small molecule with many roles in the body, including signaling in the brain.

“This finding gives us an important glimpse at the molecular pathways that could be involved in Tourette syndrome generally,” said Laura Mamounas, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which contributed major funding for the work.  Other funding for the study came from the National Institute of Mental Health (NIMH) and several private foundations.

The study was published in the New England Journal of Medicine1 and led by Matthew State, M.D., Ph.D., an associate professor in the Child Study Center and in the departments of psychiatry and genetics at Yale University in New Haven, Conn. and co-director of the Yale Program on Neurogenetics.

Tourette syndrome is characterized by tics, which are involuntary movements (such as shoulder shrugs or head jerks) and vocalizations (such as throat-clearing, grunting, or outbursts of profanity) that happen in rapid succession.  More than 50 percent of people with Tourette syndrome also have attention deficit hyperactivity disorder (ADHD) or obsessive compulsive disorder (OCD).  Meanwhile, Tourette syndrome and other tic disorders are sometimes observed in children with autism.

Tourette syndrome clearly has a strong genetic component, but in most families, the inheritance patterns tend to be complicated, which has made it difficult to link specific genes to the disorder, said Dr. State.

The new study focuses on a family referred to Dr. State by the Tourette Syndrome Association.  The father has Tourette and OCD, all eight children have Tourette, and two also have OCD.  Dr. State and his team found that all of the affected family members share a mutation in the HDC gene, which encodes an enzyme needed to produce histamine.  The mutation reduces the activity of the enzyme.

In the general population, mutations in this gene are very rare and probably contribute to very few cases of Tourette syndrome.  The researchers did not find the family’s mutation in DNA from more than 700 other individuals with Tourette syndrome, or in DNA from nearly 2000 individuals free of any known neurological disorders.  The team also failed to find any copy number variants (CNVs) – meaning deletions or duplications – of the HDC gene in 840 individuals with Tourette syndrome or 10,000 other individuals.

The true value of the gene discovery lies in its potential to reveal how brain function is altered in Tourette syndrome, said Dr. Mamounas.  She likened it to the discovery that mutations in the alpha-synuclein gene can cause Parkinson’s disease.  Such mutations are very rare, but they have helped researchers understand how nerve cells die in Parkinson’s.

Although histamine helps promote immune responses, Dr. State theorizes that Tourette syndrome is tied to histamine’s function in the brain.  Mice that lack the HDC gene are prone to repetitive behaviors that resemble tics, but the mice improve when they are given drugs that act on histamine receptors found only in the brain.  There are also interactions between histamine and dopamine, a common target of drugs that are used to reduce tics in Tourette patients.

“The deeper you go into the literature, the more it seems that we should have been thinking of histamine as a potential player in Tourette syndrome all along,” Dr. State said.

The family continues to be involved in research to explore histamine’s role in Tourette.  The father, mother and adult children are undergoing brain imaging tests to determine if they have detectable changes in histamine or dopamine neurotransmission.  Dr. State is also recreating the family’s HDC mutation in mice to see if that leads to an improved mouse model of Tourette syndrome.

Meanwhile, genetic research on Tourette is moving ahead on other fronts.  Dr. State reported several years ago that mutations in the SLITRK1 gene are associated with Tourette syndrome in a small fraction of cases.  He is continuing to investigate how strong that association is, and how the gene fits into the disorder.  A recent NIH-funded study in Nature Medicine2 shows that in mice, deletion of a related gene called SLITRK5 leads to OCD-like behaviors.

Finally, in a study published in Neurology3, researchers at Wayne State University in Detroit conducted a genome-wide search for CNVs in 111 Tourette patients and 73 unaffected individuals.  This analysis revealed five genomic regions of interest, including a gene previously associated with autism.  The results were not statistically significant, but they raise “thought-provoking questions about the relationship between Tourette syndrome and other neurodevelopmental conditions,” according to an editorial in Neurology4.  The study was funded by an NIH Clinical and Translational Science Award (CTSA), and utilized DNA samples from the NINDS Human Genetics DNA and Cell Line Repository.

-By Daniel Stimson, Ph.D.