Etiology

The cause of TS remains unclear, although evidence from genetic studies suggests that TS is inherited.[19]

Genetic factors seem to be the most important etiology given significant familial aggregation and supporting twin studies.[20][21] Monozygotic twin studies show 53% concordance for TS and 77% for persistent (chronic) motor tics, whereas dizygotic twins show 8% and 23% concordance, respectively.[22]

Chromosomal rearrangement, candidate gene, and genome-wide linkage and association studies have been conducted; however, a disease-causing mutation has remained elusive. Linkage studies in families have revealed 3p21.3, 7q35-36, 8q21.4, 9pter and 18q22.3 as areas of interest.[23] A candidate gene, SLITRK1, has been located near 13q31 and is thought to be involved with dendritic growth.[24] However, further studies have shown that SLITRK1, and more specifically, SLITRK1var321, are not necessarily associated with familial TS.[25][26]

Various other genes that impact the dopaminergic, noradrenergic, and serotonergic systems are also being explored. A rare mutation in L-histidine decarboxylase, an enzyme expressed in the central nervous system histamine pathway, was reported in two generations of a family with TS.[27] Results from a genome-wide association study indicate a possible role for COL27A1 and NTN4, while a copy number variant study has implicated synaptic genes NRXN1 and CNTN6.[28][29][30]

Environmental factors, including perinatal insults, sex-hormone exposure during brain development, and psychosocial stressors, are also thought to contribute; thus, the overall expression of TS is thought to be multifactorial.[23]

Pathophysiology

Although direct evidence is still lacking, imaging and postmortem studies suggest that TS is a disorder characterized by disinhibition of synaptic transmission in the corticostriatal-thalamic-cortical circuitry, particularly the caudate nucleus and inferior prefrontal cortex.[31][32][33]

One hypothesis suggests that the underlying problem lies in abnormally active striatal neurons leading to inhibition of the globus pallidus interna or substantia nigra pars compacta neurons, which results in disinhibition of the thalamocortical (or brainstem) circuits that causes a hyperkinetic state (i.e., tics).[34] Aberrations in the normal neural oscillations within this circuitry may also contribute to the behavioral components seen in TS.[35][36] Other functional and structural neuroimaging and neuropathological studies suggest additional contributions from the frontoparietal network involved in adaptive task control.[37][38]

One study of resting state functional connectivity between brain task-control networks has shown that a dysmaturation of connectivity may underlie the generation of tics.[39] Cortical excitability is increased in children with TS, but normalizes over time during adolescence in most patients.[40] Studies suggest that insula-supplementary motor area hyperconnectivity underlies tic urges.[41]

Classification

Diagnostic and statistical manual of mental disorders, 5th ed., text revision (DSM-5-TR): tic disorders[4]

Tourette syndrome (TS, also known as Tourette disorder) is one of the neurodevelopmental tic disorders.

It is the most complex of the spectrum of tic disorders, which comprises the following (onset is before age 18 years in all cases):

  • Tourette disorder (both multiple motor tics and one or more vocal tics persisting for more than 1 year since first tic onset)

  • Persistent (chronic) motor or vocal tic disorder (single or multiple motor or vocal tics [but not both] persisting for more than 1 year since first tic onset )

  • Provisional tic disorder (single or multiple motor and/or vocal tics that have been present for less than 1 year since first tic onset).

See Diagnostic criteria.

There is some genetic evidence to support this spectrum.[5] Although tics are a prominent defining characteristic of TS, a variety of behavioral and psychiatric symptoms and disorders frequently co-occur.[6] OCD and ADHD, the most common comorbid disorders, occur in up to 60% to 70% of patients and support the classification of TS as a neurodevelopmental or neurobehavioral disorder.[4][7]

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