Causes and origins of Tourette syndrome

Causes and origins of Tourette syndrome have not been fully elucidated. Tourette syndrome (abbreviated as Tourette's or TS) is an inherited neurodevelopmental disorder that begins in childhood or adolescence, characterized by the presence of multiple motor tics and at least one phonic tic, which characteristically wax and wane. Tourette's syndrome occurs along a spectrum of tic disorders, which includes transient tics and chronic tics.[1][2]

The exact cause of Tourette's is unknown, but it is well established that both genetic and environmental factors are involved.[3] The overwhelming majority of cases of Tourette's are inherited, although the exact mode of inheritance is not yet known,[4] and no gene has been identified.[5] Tics are believed to result from dysfunction in the thalamus, basal ganglia, and frontal cortex of the brain,[3] involving abnormal activity of the brain chemical, or neurotransmitter, dopamine. In addition to dopamine, multiple neurotransmitters, like serotonin, GABA, glutamate, and histamine (H3-receptor), are involved.[6]

Non-genetic factors—while not causing Tourette's—can influence the severity of the disorder. Some forms of Tourette's may be genetically linked to obsessive-compulsive disorder (OCD), while the relationship between Tourette's and attention-deficit hyperactivity disorder (ADHD) is not yet fully understood.

Genetic factors

The exact cause of Tourette's is unknown, but it is well established that both genetic and environmental factors are involved.[7][8][9] Genetic epidemiology studies have shown that Tourette's is highly heritable,[10] and 10 to 100 times more likely to be found among close family members than in the general population.[11] The exact mode of inheritance is not known; no single gene has been identified, and hundreds of genes are likely involved.[10][11][12] Genome-wide association studies were published in 2013[13] and 2015[8] in which no finding reached a threshold for significance.[13] Twin studies show that 50 to 77% of identical twins share a TS diagnosis, while only 10 to 23% of fraternal twins do.[7] But not everyone who inherits the genetic vulnerability will show symptoms.[14][15] A few rare highly penetrant genetic mutations have been found that explain only a small number of cases in single families (the SLITRK1, HDC, and CNTNAP2 genes).[16]

In some cases, tics may not be inherited; these cases are identified as "sporadic" Tourette syndrome (also known as tourettism) because a genetic link is missing.[17]

A person with Tourette syndrome has about a 50% chance of passing the gene(s) to one of their children. Gender appears to have a role in the expression of the genetic vulnerability, with males more likely to express tics than females.[5] Tourette syndrome is a condition of incomplete penetrance, meaning not everyone who inherits the genetic vulnerability will show symptoms. Tourette's also shows variable expression—even family members with the same genetic makeup may show different levels of symptom severity. The gene(s) may express as Tourette syndrome, as a milder tic disorder (transient or chronic tics), or as obsessive compulsive symptoms with no tics at all.[18] Only a minority of the children who inherit the gene(s) will have symptoms severe enough to require medical attention.[19] There is currently no way to predict the symptoms a child may display, even if the gene(s) are inherited.

Recent research suggests that a small number of Tourette syndrome cases may be caused by a defect on chromosome 13 of gene SLITRK1. Some cases of tourettism (tics due to reasons other than inherited Tourette's syndrome) can be caused by mutation.[17] The finding of a chromosomal abnormality appears to apply to a very small minority of cases (1–2%).

Pathophysiology
The basal ganglia and thalamus are implicated in Tourette syndrome.

The exact mechanism affecting the inherited vulnerability has not been established, and the precise cause of Tourette syndrome is not known. Tics are believed to result from dysfunction in the central nervous system,[20] in the cortical and subcortical regions, the thalamus, basal ganglia, and frontal cortex of the brain.[3] Neuroanatomic models implicate failures in circuits connecting the brain's cortex and subcortex,[5] and imaging techniques implicate the basal ganglia and frontal cortex.[21][22][23] Research presents considerable evidence that abnormal activity of the brain chemical, or neurotransmitter, dopamine is involved.[24] Dopamine excess or supersensitivity of the postsynaptic dopamine receptors may be an underlying mechanism of Tourette syndrome.[25][26][27][28]

Multiple neurotransmitters, like histamine (H3R), dopamine, serotonin, GABA and glutamate are involved in the etiology.[6] After 2010, the central role of histamine (H3-receptor in the basal ganglia) came into focus in the pathophysiology of Tourette syndrome.[29] The striatum is the main input nucleus of the basal ganglia circuit in the disorder, which is linked to the involvement of the histaminergic H3-receptor.[30]

Non-genetic influences

Psychosocial or other non-genetic factors—while not causing Tourette's—can affect the severity of TS in vulnerable individuals and influence the expression of the inherited genes.[31][5][9][11] Pre-natal and peri-natal events increase the risk that a tic disorder or comorbid OCD will be expressed in those with the genetic vulnerability. These include paternal age; forceps delivery; stress or severe nausea during pregnancy; and use of tobacco, caffeine, alcohol,[31] and cannabis during pregnancy.[13] Babies who are born premature with low birthweight, or who have low Apgar scores, are also at increased risk; in premature twins, the lower birthweight twin is more likely to develop TS.[31]

Autoimmune processes may affect the onset of tics or exacerbate them. Both OCD and tic disorders may arise in a subset of children as a result of a post-streptococcal autoimmune process.[32] Its potential effect is described by the controversial hypothesis called PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), which proposes five criteria for diagnosis in children.[33][34] PANDAS and the newer PANS (pediatric acute-onset neuropsychiatric syndrome) hypotheses are the focus of clinical and laboratory research, but remain unproven. There is also a broader hypothesis that links immune-system abnormalities and immune dysregulation with TS.[8][32]

Relation with OCD and ADHD

Some forms of OCD may be genetically linked to Tourette's,[35] although the genetic factors in OCD with and without tics may differ.[7] The genetic relationship of ADHD to Tourette syndrome, however, has not been fully established.[36][37][38] A genetic link between autism and Tourette's has not been established as of 2017.[39]

Notes
  1. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (Fifth ed.). Arlington, VA: American Psychiatric Publishing. pp. 81–85. ISBN 978-0-89042-555-8.
  2. Black, KJ. Tourette Syndrome and Other Tic Disorders. eMedicine (March 22, 2006). Retrieved on June 27, 2006.
  3. Walkup JT, Mink JW, Hollenback PJ, (eds). Advances in Neurology, Vol. 99, Tourette Syndrome. Lippincott Williams & Wilkins, Philadelphia, PA, 2006, p. xv. ISBN 0-7817-9970-8
  4. Robertson MM (March 2000). "Tourette syndrome, associated conditions and the complexities of treatment" (PDF). Brain. 123 (3): 425–62. doi:10.1093/brain/123.3.425. PMID 10686169.
  5. Zinner SH (November 2000). "Tourette disorder". Pediatr Rev (Review). 21 (11): 372–83. doi:10.1542/pir.21-11-372. PMID 11077021.
  6. Paschou P, Fernandez TV, Sharp F, Heiman GA, Hoekstra PJ (2013). "Genetic susceptibility and neurotransmitters in Tourette syndrome". Int. Rev. Neurobiol. International Review of Neurobiology. 112: 155–77. doi:10.1016/B978-0-12-411546-0.00006-8. ISBN 9780124115460. PMC 4471172. PMID 24295621.
  7. Fernandez TV, State MW, Pittenger C (2018). "Tourette disorder and other tic disorders". Handb Clin Neurol (Review). Handbook of Clinical Neurology. 147: 343–54. doi:10.1016/B978-0-444-63233-3.00023-3. ISBN 9780444632333. PMID 29325623.
  8. Dale RC (December 2017). "Tics and Tourette: a clinical, pathophysiological and etiological review". Curr. Opin. Pediatr. (Review). 29 (6): 665–73. doi:10.1097/MOP.0000000000000546. PMID 28915150.
  9. Baldermann JC, Schüller T, Huys D, et al. (2016). "Deep brain stimulation for Tourette syndrome: a systematic review and meta-analysis". Brain Stimul (Review). 9 (2): 296–304. doi:10.1016/j.brs.2015.11.005. PMID 26827109.
  10. Cavanna AE (November 2018). "The neuropsychiatry of Gilles de la Tourette syndrome: The état de l'art". Rev. Neurol. (Paris) (Review). 174 (9): 621–27. doi:10.1016/j.neurol.2018.06.006. PMID 30098800.
  11. Efron D, Dale RC (October 2018). "Tics and Tourette syndrome". J Paediatr Child Health (Review). 54 (10): 1148–53. doi:10.1111/jpc.14165. PMID 30294996.
  12. Bloch M, State M, Pittenger C (April 2011). "Recent advances in Tourette syndrome". Curr. Opin. Neurol. (Review). 24 (2): 119–25. doi:10.1097/WCO.0b013e328344648c. PMC 4065550. PMID 21386676.
  13. Stern JS (August 2018). "Tourette's syndrome and its borderland" (PDF). Pract Neurol (Historical review). 18 (4): 262–70. doi:10.1136/practneurol-2017-001755. PMID 29636375.
  14. van de Wetering BJ, Heutink P (May 1993). "The genetics of the Gilles de la Tourette syndrome: a review". J. Lab. Clin. Med. (Review). 121 (5): 638–45. PMID 8478592.
  15. Paschou P (July 2013). "The genetic basis of Gilles de la Tourette Syndrome". Neurosci Biobehav Rev (Review). 37 (6): 1026–39. doi:10.1016/j.neubiorev.2013.01.016. PMID 23333760.
  16. Barnhill J, Bedford J, Crowley J, Soda T (2017). "A search for the common ground between Tic; Obsessive-compulsive and Autism Spectrum Disorders: part I, Tic disorders". AIMS Genet (Review). 4 (1): 32–46. doi:10.3934/genet.2017.1.32. PMC 6690237. PMID 31435502.
  17. Mejia NI, Jankovic J (March 2005). "Secondary tics and tourettism" (PDF). Braz J Psychiatry. 27 (1): 11–7. doi:10.1590/s1516-44462005000100006. PMID 15867978. Archived from the original (PDF) on 2007-06-28.
  18. van de Wetering BJ, Heutink P (May 1993). "The genetics of the Gilles de la Tourette syndrome: a review". J. Lab. Clin. Med. 121 (5): 638–45. PMID 8478592.
  19. Tourette Syndrome Association. Tourette Syndrome: Frequently Asked Questions. Retrieved on February 8, 2005.
  20. Bagheri MM, Kerbeshian J, Burd L (April 1999). "Recognition and management of Tourette's syndrome and tic disorders". Am Fam Physician (Review). 59 (8): 2263–72, 2274. PMID 10221310. Archived from the original on March 31, 2005.
  21. Haber SN, Wolfer D (1992). "Basal ganglia peptidergic staining in Tourette syndrome. A follow-up study". Adv Neurol. 58: 145–50. PMID 1414617.
  22. Peterson B, Riddle MA, Cohen DJ, et al. (May 1993). "Reduced basal ganglia volumes in Tourette's syndrome using three-dimensional reconstruction techniques from magnetic resonance images". Neurology. 43 (5): 941–9. doi:10.1212/wnl.43.5.941. PMID 8492950.
  23. Moriarty J, Varma AR, Stevens J, et al. (August 1997). "A volumetric MRI study of Gilles de la Tourette's syndrome". Neurology. 49 (2): 410–5. doi:10.1212/wnl.49.2.410. PMID 9270569.
  24. Singer HS, Walkup JT (January 1991). "Tourette syndrome and other tic disorders. Diagnosis, pathophysiology, and treatment". Medicine (Baltimore). 70 (1): 15–32. doi:10.1097/00005792-199101000-00002. PMID 1988764.
  25. Singer HS, Butler IJ, Tune LE, Seifert WE, Coyle JT (October 1982). "Dopaminergic dsyfunction in Tourette syndrome". Ann. Neurol. 12 (4): 361–6. doi:10.1002/ana.410120408. PMID 6184010.
  26. Klawans HL, Falk DK, Nausieda PA, Weiner WJ (October 1978). "Gilles de la Tourette syndrome after long-term chlorpromazine therapy". Neurology. 28 (10): 1064–6. doi:10.1212/wnl.28.10.1064. PMID 284201.
  27. Butler IJ, Koslow SH, Seifert WE, Caprioli RM, Singer HS (July 1979). "Biogenic amine metabolism in Tourette syndrome". Ann. Neurol. 6 (1): 37–9. doi:10.1002/ana.410060109. PMID 292354.
  28. Singer HS (May 1997). "Neurobiology of Tourette syndrome". Neurol Clin. 15 (2): 357–79. doi:10.1016/s0733-8619(05)70318-2. PMID 9115467.
  29. Rapanelli M, Pittenger C (July 2016). "Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions". Neuropharmacology. 106: 85–90. doi:10.1016/j.neuropharm.2015.08.019. PMID 26282120.
  30. Bolam JP, Ellender TJ (July 2016). "Histamine and the striatum". Neuropharmacology. 106: 74–84. doi:10.1016/j.neuropharm.2015.08.013. PMC 4917894. PMID 26275849.
  31. Hollis C, Pennant M, Cuenca J; et al. (2016). "Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis" (PDF). Health Technology Assessment. 20 (4): 1–450. doi:10.3310/hta20040. PMC 4781241. PMID 26786936.CS1 maint: multiple names: authors list (link)
  32. Robertson MM (February 2011). "Gilles de la Tourette syndrome: the complexities of phenotype and treatment". Br J Hosp Med (Lond). 72 (2): 100–07. doi:10.12968/hmed.2011.72.2.100. PMID 21378617.
  33. "PANDAS". National Institutes of Health. Archived from the original on February 12, 2012. Retrieved November 25, 2006.
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  35. Swain JE, Scahill L, Lombroso PJ, King RA, Leckman JF (August 2007). "Tourette syndrome and tic disorders: a decade of progress". J Am Acad Child Adolesc Psychiatry (Review). 46 (8): 947–68. doi:10.1097/chi.0b013e318068fbcc. PMID 17667475. S2CID 343916.
  36. Denckla MB (2006). "Attention deficit hyperactivity disorder: the childhood co-morbidity that most influences the disability burden in Tourette syndrome". Adv Neurol (Review). 99: 17–21. PMID 16536349.
  37. Hirschtritt ME, Darrow SM, et al. (January 2018). "Genetic and phenotypic overlap of specific obsessive-compulsive and attention-deficit/hyperactive subtypes with Tourette syndrome". Psychol Med. 48 (2): 279–93. doi:10.1017/S0033291717001672. PMID 28651666.
  38. Hirschtritt ME, Lee PC, Pauls DL, et al. (April 2015). "Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in Tourette syndrome". JAMA Psychiatry. 72 (4): 325–33. doi:10.1001/jamapsychiatry.2014.2650. PMC 4446055. PMID 25671412.
  39. Robertson MM, Eapen V, Singer HS, et al. (February 2017). "Gilles de la Tourette syndrome". Nat Rev Dis Primers (Review). 3: 16097. doi:10.1038/nrdp.2016.97. PMID 28150698.
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