Lecture 24 Part II: Tourette Syndrome

What is Tourette Syndrome?

• Childhood-onset neurodevelopmental disorder.

• Characterized by sudden involuntary motor movements and vocal outbursts called tics.

• Full name: Gilles de la Tourette Syndrome.

What are the prevalence and risk factors of Tourette Syndrome?

• 1 in 160 school-aged children (~0.625%); ~50% go undiagnosed.

• 3-4x more common in boys than girls; affects all races/ethnicities.

• High heritability (~60%), but few contributing genes are known.

What distinguishes the three tic disorder categories?

• Transient/Provisional: tics lasting less than 1 year.

• Chronic Motor or Phonic: tics lasting more than 1 year, but only motor or vocal (not both).

• Tourette Syndrome: both multiple motor AND vocal tics, lasting more than 1 year.

What are the types of vocal tics?

• Simple: throat clearing, humming, grunting, sniffing, whistling.

• Complex: stuttering, echolalia (repeating others' words), palilalia (repeating own words), coprolalia (involuntary obscene words/phrases).

What are the types of motor tics?

• Simple: eye blinking, shoulder shrugging, head jerking, facial grimacing.

• Complex: jumping, spinning, hitting objects/self, biting lips

• Special types: echopraxia (imitating others' movements), copropraxia (obscene gestures).

What is the onset and progression of tics in Tourette Syndrome?

• Tics appear between the ages 5-10.

• Become most frequent during early adolescence (~ages 8-13).

• In some cases, tics decrease or disappear in adulthood; in others, they worsen.

What environmental/prenatal factors influence tic severity?

• Stress during pregnancy.

• Smoking during pregnancy.

• Low maternal weight.

• β-hemolytic streptococcus infection.

What are the common comorbidities of Tourette Syndrome?

• ADHD.

• OCD.

• Anxiety.

• Mood disorders.

• Academic challenges.

What is the genetic basis of Tourette Syndrome?

• Polygenic: several genes and loci involved, no single causative gene.

• Most associated gene: SLITRK1 on chromosome 13 (13q31.1).

• Only 1–2% of cases caused by SLITRK1 mutations; del1264C = single base pair deletion → short, non-functional protein.

• Other candidate genes: AADAC, BTBD9, HDC, MAOA, DRD2, DRD4, NRXN1.

• Epigenetic factors: low birth weight, pregnancy complications, encephalitis, head injury.

What does the SLITRK1 protein do normally?

• Found in: basal ganglia, cerebral cortex, frontal lobe, hippocampus, thalamus, amygdala.

• Regulates cell migration, axonal guidance, axonal branching, and excitatory/inhibitory synapse function.

• Helps organize TrkB receptors at the synapse to support BDNF/TrkB neurotrophic signaling.

What happens molecularly when SLITRK5 is absent?

• BDNF signaling is reduced; TrkB receptors are not maintained and are degraded.

• Synapses lose adhesion molecules needed to stay connected.

• Result: abnormal synapse formation → impaired inhibitory control in motor circuits → disinhibition of movement → involuntary tics.

How does basal ganglia dysfunction cause tics in Tourette Syndrome?

• Normally: basal ganglia inhibit thalamic neurons, preventing over-signaling to the motor cortex.

• In TS: faulty basal ganglia fail to suppress unwanted signals to the motor cortex.

• Also: increased activity in motor pathways generates additional movement.

• Net effect: high motor activity + low inhibition = involuntary tics.

What is the dopaminergic mechanism in Tourette Syndrome?

• Direct pathway (D1 receptor) → excitatory.

• In TS: direct pathway is overactive relative to indirect pathway → net excitation → tics.

What are the treatment options for Tourette Syndrome?

• No methods of prevention.

• Dopamine antagonists for severe cases: haloperidol, pimozide, aripiprazole (suppress tics).

• Speech and behavioral therapy.

• Deep brain stimulation (reduces tic severity).

• Managing emotional stress during childhood is crucial to prevent worsening in adulthood.

What is Identity-By-Descent (IBD) Analysis?

• Identifies genomic regions inherited from a common ancestor; shared IBD segments in affected relatives may indicate disease-causing variants.

• Useful for detecting rare inherited variants in large pedigrees or isolated populations.

• Method: genotype family members → find shared haplotypes → focus on regions shared in affected individuals → sequence to find rare/deleterious variants.