The finding of a rare mutation in the gene involved with the histamine system in a father and eight of his children with Tourette syndrome (TS) point to a role for histaminergic neurotransmission in the mechanism and modulation of TS and tics.
Doctors usually treat the symptoms of Tourette syndrome (TS) with dopamine blockers aimed at suppressing tics. But a new study points to a rare mutation in a gene involved in the histamine system, which researchers say could lead to new developments in treating and understanding the disease.
The study, published in the May 20 issue of the New England Journal of Medicine, looked at one family where the father and all eight children were diagnosed with TS.
Figure. AN ILLUSTRATION (left) of an HDC complex, which synthesizes histamine when two normal (wild type) copies of the protein are present and bound together. (A model of a non-functional HDC complex (right) consisting of the wild type protein (blue) bound to the mutant protein (green) that was identified in a family affected with Tourette syndrome.
Although all the children had the neurological disorder, the mother did not carry the mutation, said Matthew W. State, MD, PhD, co-director for the Program on Neurogenetics and deputy chairman for research in the Department of Psychiatry at Yale University School of Medicine.
Researchers mapped the 51 genes in the region, looking at each one to find a mutation that might be responsible for TS in the family, said Dr. State. They were looking for large-scale chromosomal abnormalities in the 51 known genes in the region, but they were originally expecting affected patterns to be located in the dopaminergic system.
“There were many other genes in the interval that we considered more likely suspects and tested first,” Dr. State said. “But when we finally found the rare mutation in the HDC [encoding 1-histodine decarboxylase] and started looking at the literature [on the role of the mutation in animal models of TS], it was clear we should have placed this gene at the top, not the bottom of our list.”
“Given that Tourette's syndrome has a population prevalence of 1 percent and a rate of recurrence of 10 to 15 percent among first-degree relatives of an affected person, it is extremely unlikely that all eight offspring of an affected parent would have Tourette's syndrome by chance, suggesting that this kindred indeed carries a mendelian form of the syndrome,” the authors wrote.
The findings, together with previously published data from animal models of TS, point to a role for histaminergic neurotransmission in the mechanism and modulation of TS and tics, Dr. State said. There is a large body of prior evidence showing its function in regions of the brain involved in movement disorders, including the striatum and cortex, areas of the brain usually implicated in TS.
In mouse studies, he added, decreased brain histamine has led to an increase in stereotypic behaviors — rearing, sniffing, and biting — that appear similar to human tics. In addition, highly selective antagonist and inverse agonists increase histaminergic neurotransmission and decrease these behaviors in mice.
Figure. DR. MATTHEW W. STATE:“There were many other genes in the interval that we considered more likely suspects and tested first. But when we finally found the rare mutation in the HDC [encoding 1-histodine decarboxylase] and started looking at the literature [on the role of the mutation in animal models of TS], it was clear we should have placed this gene at the top, not the bottom of our list.”
Commenting on the study, Mark Hallett, MD, noted that despite the fact that the father and all eight children were diagnosed with TS, neither the mother, nor her extended family had the disorder. That in itself is highly unusual, said Dr. Hallett, MD, chief of the NIH Human Motor Control Section, who was not involved with the study. For an autosomal dominant disease generally only about half the children inherit the illness, he said.
Although the study results came as a surprise to researchers, doctors said they were hesitant to jump to any conclusions about the widespread role of the gene in the disease. In the study, researchers evaluated the DNA sequences of 720 other TS patients, without finding a similar mutation.
Dr. Hallett said although the mutation is very rare, that does not mean that it is a useless finding. “Even if it is a rare genetic abnormality, it could give useful insights into how TS occurs in the more common forms of the disease,” he said. “The first gene identified in Parkinson disease was a relatively rare one in terms of the abnormality, but it has given great insight into the pathophysiology of the disorder. It's nice to have some clues even if the specific abnormality is rare.”
Jeremiah M. Scharf, MD, PhD, director of the Partners Neurology Tic Disorders clinic at Massachusetts General and Brigham and Women's Hospitals and a neurology instructor at Harvard Medical School, said the study suggests new pathways, not only for treatment, but also in the origins of the disease.
“The study suggests the patients in this family may not be making enough histamine, and that this reduction in histamine is the cause of TS in this family,” said Dr. Scharf.
Histamine has different receptors in the brain, and the study suggested that the relevant receptors may be H3R and H2R, found in the region of the brain believed to function abnormally in patients with TS, Dr. Scharf explained. So the next step may be to look at those H3 and H2 modulators for targeting tics, he said.
“As with other neurological conditions, there have been cases in which rare mutations in a gene identify an important pathway that may turn out to be responsible for the disease in other patients, for example. through mutations in other genes in that pathway,” he said.
Right now, doctors said, the study explains the disease in one particular family. It's too soon to generalize to other patients.
Figure. DR. JEREMIAH M. SCHARF said the study suggests new pathways, not only for treatment, but also in the origins of the disease.
The hope is that this finding will help researchers and pharmaceutical companies develop new treatments. Typically TS is treated with neuroleptics, such as haloperidol, which affects dopamine receptors in the brain. However, while the medications suppress the symptoms, they do not usually eliminate them entirely and often have side effects including drowsiness and “cognitive dulling.” There can also be issues with long-term use.
Figure. DR. MARK HALLETT:“Even if it is a rare genetic abnormality, it could give useful insights into how TS occurs in the more common forms of the disease.”
Because the mutation is rare, patients or family members of those with the disease, should not rush out to ask for a genetic test looking for the mutation, doctors said.
Nor should they stock up on allergy medicine, which often works as a histamine blocker. Dr. Scharf noted that patients have found tics are worse during allergy season and some found relief with allergy medications, whereas others have found they made the tics worse.
Dr. State said the investigators are already working with pharmaceutical companies to see if medications, already in development, might have an effect on TS patients. They are also looking deeper into the links of the histamine and the striatal systems.
“It's a really interesting study, but we need to do more science,” Dr. State said. “The chance to move from a rare genetic finding to testing a novel molecular target in the clinic is quite unusual and pretty exciting.”
• Ercan-Sencicek AG, Stillman AA, State MW, et al. 1-histidine decarboxylase and Tourette's syndrome. 2010; E-pub 2010;2010 May 5.