Tourette's Syndrome: What's Happening?

Pathogenesis of Tourette's Syndrome

Genetics

It is believed that Turetg's syndrome is inherited as a monogenic autosomal dominant disease with high (but not complete) penetrance and variable expressiveness of the pathological gene, manifested in the development of not only Tourette's syndrome, but also OCD, chronic ticks-XT and transient tics-TT. Genetic analysis shows that XT (and possibly TT) can be a manifestation of the same genetic defect as Tourette's syndrome. In a study of twins, it was found that in monozygotic pairs the level of concordance is higher (77-100% for all ticks) than in dizygotic vapors - 23%. At the same time, identical twins have pronounced discordance in terms of the severity of tics. A genetic linkage analysis is currently underway to identify the chromosomal location of a possible Tourette syndrome gene.

Dysfunction of basal ganglia

It is suggested that, primarily in the Tourette syndrome, the basal ganglia are involved in the pathological process. With dysfunction of the basal ganglia, such movement disorders as Parkinson's disease or Huntington's chorea are associated. The data of neuroimaging studies that indicate the presence of structural or functional changes in the basal ganglia in patients with Tourette's syndrome accumulate. For example, the volume of basal ganglia (especially the lenticular nucleus providing regulation of movements) on the left side of patients with Tourette's syndrome was slightly less than in the control group. In addition, in many patients with Tourette's syndrome, the asymmetry of the basal ganglia that is normal is absent or reversed. Another study found a significant decrease in basal ganglia activity on the right side in 5 of 6 patients with Tourette's syndrome, but none of the healthy controls. A study of 50 patients with Tourette's syndrome revealed hypoperfusion in the left caudate nucleus, anterior cingulate and dorsolateral prefrontal cortex on the left.

In a quantitative MRI study of monozygotic pairs, discordant in severity of tics, in twins with a more severe disease, a relative decrease in the volume of the right caudate nucleus and the left lateral ventricle was noted. There is also a lack of normal asymmetry of the lateral ventricles. The volume of other brain structures and the degree of their asymmetry did not differ in pairs of twins, however, all twins concordant for the dominant hand lacked the normal asymmetry of tailed nuclei. In the study of monozygotic pairs, discordant in severity of Tourette's syndrome, the binding level of the radiopharmaceutical of iodobenoamide blocking dopamine D2 receptors in the tail nucleus in twins with more severe symptoms was significantly higher than in twins with mild symptoms. This allowed us to assume that the severity of tics depends on the hypersensitivity of dopamine D2-receptors. On the other hand, similar studies among twins indicate the importance of external factors affecting the phenotypic expression of Tourette's syndrome.

[1], [2], [3], [4], [5], [6], [7], [8]

Neurochemical hypotheses

The role of dopaminergic dysfunction in the pathogenesis of Tourette's syndrome is demonstrated by the weakening of symptoms under the influence of dopamine receptor blockers and their enhancement under the action of substances that enhance the activity of central monoaminergic systems (L-Dopa, psychostimulants). Postmortem studies indicate an increase in the number of either the dopaminergic neurons themselves, or zones of presynaptic reuptake of dopamine in the caudate nucleus and the shell. These findings are confirmed by a study that revealed an increase of 37% in the accumulation in the striatum of a ligand specifically binding to a presynaptic dopamine transporter. Another result, also confirming the involvement of dopaminergic systems, is a decrease in the level of homovanic acid in the cerebrospinal fluid, which may reflect a decrease in the circulation of dopamine in the central nervous system.

The possible dysfunction of noradrenergic systems is indicated by the therapeutic effect of a2-adrenoreceptor agonists and other neurochemical studies. Children and adults with Tourette's syndrome have a flattened growth hormone secretion curve in response to the administration of clonidine. Patients with Tourette's syndrome also had an increase in the level of HA and its main metabolite of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebro-spinal fluid, compared with those in control groups and in patients with OCD. In addition, the plasma level of adrenocorticotropic hormone (ACTH) before and after lumbar puncture and urinary excretion of NA in patients with Tourette's syndrome was higher than normal. The content of NA in urine correlated with the assessment of the severity of tics.

Scientists have identified a significantly higher concentration of corticotropin-releasing factor (CRF) in the cerebrospinal fluid of patients with Tourette's syndrome - compared with the norm and similar indicators in patients with OCD. The interaction between CRF and NA in the development of a stress reaction can explain the increase in tics with increased anxiety and stress .

The involvement of the opioid system in the pathogenesis of Tourette's syndrome is possible through the defeat of endogenous opioid projections from the striatum into the pallidum and black substance. This view is confirmed by data showing the expression of dinorphin (endogenous opioid) by GAM-ergic projection neurons of the striatum, as well as the possibility of induction of the prodrinorhin gene via Dl-like dopamine receptors. On the other hand, the gene encoding preproeneckephalin is under the tonic inhibitory effect of dopamine D1 receptors. The change in the content of dinorfin was noted in patients with Tourette's syndrome. In the pathogenesis of Tourette's syndrome, other neurotransmitter systems are involved: serotonergic, cholinergic, and excitatory and inhibitory pathways with amino acid mediators.

Exogenous factors

The study of monozygotic twins, discordant in severity of symptoms of Tourette's syndrome, showed that a twin with more severe symptoms had a lower birth weight than a twin with lighter manifestations. The phenotypic expression of Tourette's syndrome may also be affected by other exogenous factors, in particular those acting in the perinatal period (including toxic substances, mother's medications, maternal stress), as well as overheating, taking cocaine, psychostimulants or anabolic steroids. A certain role can also be played by infections, especially beta-hemolytic streptococcus of group A.

Some scientists believe that autoimmune neuropsychiatric disorder can be a partial expression of Sydenham's chorea, manifested externally as Tourette's syndrome. The peculiarities of this disorder include: a sudden onset of the disease with the development of symptoms of OCD, excess movements and / or hyperactivity, a wavy course with alternating exacerbations and remissions, the presence of anamnestic or clinical signs of a recent streptococcal upper respiratory tract infection. During the acute phase with a neurologic examination, muscle hypotension, dysarthria, and choreiform movements can be detected. The observations made revealed in patients with Tourette's syndrome an increased level of antineuronal antibodies to the caudate nucleus, which is consonant with the detection of Husby's elevated level of antineuronal antibodies in Sydenham's chorea. Recent studies have shown that in some patients with OCD and tics that began in childhood, a marker of B cells detected earlier in rheumatism is identified.

[9], [10], [11], [12], [13], [14], [15]