Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by multiple motor tics and at least one vocal or phonic tic, and often one or more comorbid psychiatric disorders. Premonitory sensory urges before tic execution and desire for “just-right” perception are central features. The pathophysiology involves cortico-striato-thalamo-cortical circuits and possibly dopaminergic system. TS is considered a genetic disorder but the genetics is complex and likely involves rare mutations, common variants, and environmental and epigenetic factors. Treatment is multimodal and includes education and reassurance, behavioral interventions, pharmacologic, and rarely, surgical interventions.
Key points
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Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder characterized by multiple motor tics and at least one vocal or phonic tic, and often one or more comorbid psychiatric disorders.
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Premonitory sensory urges before tic execution and desire for “just-right” perception are central features.
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The pathophysiology involves cortico-striato-thalamo-cortical circuits and possibly dopaminergic system.
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TS is considered a genetic disorder but the genetics is complex and likely involves rare mutations, common variants, and environmental and epigenetic factors.
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Treatment is multimodal and includes education and reassurance, behavioral interventions, pharmacologic, and rarely, surgical interventions.
Introduction
The prevalence of Tourette syndrome (TS) is approximately 0.3% to 1% with a male to female ratio of 4:1.
TS is considered a disorder of cortico-striato-thalamo-cortical circuits that is involved in motor, cognitive, and motivational aspects of behavior. Direct striatonigral (dopamine D1 receptor) and indirect striatopallidal (dopamine D2 receptor) pathways are parallel loops in this circuit that provide excitatory and inhibitory feedback. Tics and unwanted behaviors can result from reduced activity of indirect striatopallidal (D2 receptor) pathway leading deficient inhibition of unwanted or off-target movements and behavior.
Consistently reported neuroanatomical abnormalities in TS include reduced caudate volumes across the lifespan, thinning of sensorimotor cortices correlating with tic severity in children, hypertrophy of the limbic and prefrontal cortices, and a smaller corpus callosum correlating with fewer symptoms in children. Focal ischemic damage to the striatum can produce tics. Similarly, tics and TS-like behavior abnormalities are elicited by local striatal disinhibition in monkeys.
Disruption of dopaminergic modulation in basal ganglia is implicated in TS, although other neurotransmitters are likely involved. The dopamine D2 receptor antagonists haloperidol and pimozide are among the most effective used to treat severe tics.
Although the evidence for a genetic contribution in TS is strong, its exact nature is not known. Monozygotic twins are concordant for TS approximately 50% of the time compared with 10% for dizygotic twins. When all tic disorders are considered, the concordance rate for monozygotic twins is 77% compared with 23% for dizygotic twins; studies estimate a sibling relative risk of 6 to 8.
Segregation analyses suggest that the transmission of TS and related phenotypes within families is complex, and likely involves many genetic loci. Up to 40% of pedigrees with multiple affected children have bilineal inheritance of tics and obsessive-compulsive disorder (OCD).
Linkage analyses results have been inconsistent; however, a locus on chromosome 2p was detected that achieved genome-wide significance ( p = 9.8 × 10 −8 ).
The genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene.
Cytogenetic abnormalities involving inner mitochondrial membrane protein 2L (IMMP2L), contactin-associated protein-like 2 (CNTNAP2), neuroligin 4, X-linked (NGLN4X), and Slit and Trk-like, Family Member 1 (SLITRK1) genes have been identified in rare patients with TS.
Chromosome microarray studies have suggested common copy number variants (CNVs) in TS and other neurodevelopmental disorders (eg, CNVs involving neurexins, neuroligins, and genes from the histaminergic and glutamatergic pathways). Several studies implicated CNVs that are seen in autism such as neurexin 1 (NRXN1), catenin, alpha 3 (CTNNA3); and 16p13.11deletions. Enrichment of genes involved in histamine signaling within CNVs, an excess of large (>500 Kb) CNVs compared with controls, and a higher burden of large deletions within regions previously known to harbor recurrent pathogenic CNVs in subjects with other neurodevelopmental disorders, have been reported.
A rare coding mutation in the gene l -histidine decarboxylase, which is the rate-limiting enzyme in histamine biosynthesis, has been described.
A genome-wide association study (GWAS) with 1285 TS European ancestry cases and 4964 ancestry-matched controls with a parallel GWAS of OCD demonstrated that the most TS heritability could be explained by common polymorphisms rather than rare mutations. In addition, TS and OCD had an estimated genetic correlation of 0.41, confirming the presence of shared genetic variation between the disorders.
Nongenetic factors, including perinatal complications, maternal smoking, and maternal stress during pregnancy, may play a role.
Whether the generation of tics in some individuals involves a postinfectious autoimmune component remains controversial.
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