Finding the genetic mechanisms behind Tourette syndrome

Pieter Hoekstra: “Tic research doesn't stand a chance without international cooperation”

'Gilles de la Tourette Syndrome' (GTS) or 'Tourette Syndrome' (TS) is just one example of many disorders of which the causes are covered in a thick haze of fragmented research results. Although TS cannot be considered a rare disorder – over one percent of children are affected with this syndrome – proper scientific research is only possible through international cooperation. TS researcher professor Pieter J. Hoekstra explains why he is obliged to perform his quest in the international arena. Professor Hoekstra is a state of the art speaker at the 2017 ESCAP Congress in Geneva.

prof Pieter J. Hoekstra (Groningen, Netherlands)“Like many disorders in child psychiatry, Tourette syndrome is seen as an interplay between genetic and environmental factors. Much of the research targets this interaction, aiming at a better understanding of the genetic mechanisms that cause tic disorders. That is our ambition. Today we know as much that there surely is a hereditary factor. The next question is which genes are involved, and only after that we hope to get to the mechanisms. This points out that we have a long way to go”, says Hoekstra, who lectures child and adolescent psychiatry at the University Medical Center Groningen (Netherlands) and who is involved in a number of international research consortia on TS and related disorders (such as TIC Genetics, EMTICS and TS-Eurotrain). 

Two approaches
EMTICS has chosen two separate approaches. “On the one hand we study a high risk cohort where we look at young children – commonly TS reveals itself not before the seventh year of age – of whom we may expect a considerable subgroup to develop the syndrome, as all children have at least one first degree relative with TS, a parent or a sibling. In this group we try to discover certain triggers that are present before the disorder comes to the surface. This is the kind of study that really doesn't stand a chance without international cooperation. To be able to look at a large cohort of these high risk children we absolutely need to work together with several research centres.”
“The other approach is studying children over seven years old who already have the disorder and in which we look for factors associated with tic fluctuations over time.”
In both approaches, researchers aim to study the hypothesis that the onset of a tic disorder, or its worsening, is associated with a specific Streptococcal (GAS) infection in association with the patient’s genetic background.

Rare variants
Sometimes single large pedigrees with multiply affected family members can be very informative in determining a major TS causing gene. The best known example of such a single family approach is a study led by Matthew W. State MD, PhD (Yale School of Medicine), published in the New England Journal of Medicine, May 2010, where the research team actually identified a single, histamine related gene, associated with TS based on an affected father and his eight children who all had TS as well. However, when looking for involvement of the histamine related gene in larger groups of patients with TS, in none of these the same gene appeared to be involved. Hoekstra: “This study has shown us the complexity of TS genetics and it suggests that there are – perhaps many – different ways that genes can lead to tic syndromes. Families like these are extremely valuable for better understanding of disease mechanisms, but we need to do a whole lot more work to fully elucidate TS genetics. I am convinced that joining forces by building major collaborations in the field of tic disorders is the only way to go.”

Genetic heterogeneity
TS experts now break their heads over the question why it is so difficult to find genes that are associated with TS? One theory claims that the genetic heterogeneity causes a lot of the complexity. The genes in one patient causing the syndrome may be completely different from the ones that cause the same disorder in another person. “But for all I know, the problem that we look at here could even be more inextricable”, Hoekstra says. “You may think of dozens of different genes that interact with each other and also with many different environmental factors in a large number of complex combinations. In the individual patient we thus see only one unique combination out of an enormous amount. This is in my opinion why we have so much difficulty in finding the genetic causes of TS. To discover patterns in this complexity we need large cohorts of patients and their families. Much larger even than the numbers we work with at this moment.”
To make things even more complicated, researchers are confronted with high rates of comorbidity with associated disorders, particularly OCD and ADHD, which increases the number of 'complex combinations' even further. Large scale studies show that only twelve percent of individuals with TS have no reported comorbidity.

Managing the symptoms
Treatment of tic disorders today is symptom management, and nowhere near addressing their causes. Hoekstra: “One way of treatment is to learn to live with it: acceptance and feeling at ease with the discomfort. Another way is teaching children by behavioral therapeutic techniques to suppress the symptoms, or replace them by different movements: a way of habit reversal. A third method is medication, which of course is also suppression, but from the outside.”
“Addressing symptoms rather than underlying neurobiological mechanisms is by the way commonplace for almost all psychiatric disorders. Some twenty years ago tic disorder researchers were a lot more optimistic than today when it comes to finding a major gene. Perhaps too optimistic I must say, because we the full understanding of TS genetics is still a long shot. For addressing the cause of TS we would have to know the precise underlying mechanisms. If there would only be one – that also is uncertain. Similar symptoms could be caused by very different combinations of genetic and environmental factors. If you want me to add some optimism, I could say that this might change overnight. Tomorrow some research lab may lay its finger on a hitherto unknown gene, which could lead to a major breakthrough.”

Respond to this subject.
At the 2017 ESCAP Congress in Geneva, Pieter Hoekstra's lecture was titled: Tourette syndrome: an update on newest findings on treatment and pathophysiology.

  • La maladie des tics: history and guidelines

    Georges Gilles de la Tourette (1857-1904)

    Gilles de la Tourette syndrome, is an inherited neuropsychiatric disorder with onset in childhood, characterised by multiple motor tics and at least one vocal tic. In two thirds of the patients tics have remitted at an adult age. Both the causes of the onset and of the disappearance of the disorder are unknown. Tourette syndrome is part of a spectrum of tic disorders, which includes provisional, transient and persistent chronic tics.

    The French physician Georges Gilles de la Tourette (1857-1904) first described the symptoms in nine patients in 1884, naming them 'maladie des tics'. His mentor and well known neurologist Jean-Martin Charcot renamed the syndrome 'Gilles de la Tourette's Illness'.

    Clinical guidelines for Tourette Syndrome have been described in English by the ESSTS Guideline Group and by NICE (the UK National Institute for Health and Care Excellence). Diagnostic and treatment protocols for tic disorders are available in English at the Dutch Knowledge Centre for Child and Adolescent Psychiatry.

  • European and US grants for Tourette research

    Dr Hoekstra's research group at the University Medical Center Groningen (UMCG) is taking part in the international premier league of scientific research on tic disorders. In 2011 the UMCG team managed to retrieve substantial funds. The EU Seventh Framework Programme granted six million euro for the EMTICS consortium that represents 21 research teams from ten European countries. This was followed by a Marie Curie initial training network grant coordinated by Dr Paschou (Greece). The United States National Institute of Mental Health (NIMH) provided a grant to a consortium of American, Korean and European researchers (the TIC Genetics consortium) in which Hoekstra's team participates as well.

    ESSTS: International
    commitment
    started at Bari

    The European Society of Tourette Syndrome (ESSTS) was originally established in the year 2000, but became active after the 2008 Italian Neurological Society meeting in Bari. Dr Hoekstra attended this meeting where he remembered that “researchers full heartedly committed themselves to international cooperation both in the scientific work as well as in looking for funding possibilities.”

     

  • Portuguese study on TS comorbidities

    A Portuguese research team at the Medical Faculty of Coimbra University is currently preparing a publication on Gilles de la Tourette syndrome. The article is a systematic and updated review of all comorbidities associated with Tourette syndrome. The authors have not found any other article in the scientific literature which has provided a comprehensive analysis of all disorders associated with this syndrome. The article analyses why Tourette syndrome is associated with so many neuropsychiatric disorders, knowing that Tourette syndrome is in the interface between Neurology and Psychiatry and that neurosciences have clarified several other psychiatric disorders. Therefore, the authors think their study can enhance the understanding of Tourette syndrome and other psychiatric disorders. Read the abstract.