Tourette's Syndrome - What's going on?

Pathogenesis of Tourette syndrome

Genetics

Tourette syndrome is believed to be inherited as a monogenic autosomal dominant disorder with high (but not complete) penetrance and variable expressivity of the pathological gene, which is expressed in the development of not only Tourette syndrome, but possibly OCD, chronic tics - XT and transient tics - TT. Genetic analysis shows that XT (and possibly TT) may be a manifestation of the same genetic defect as Tourette syndrome. A study of twins has shown that the concordance rate is higher in monozygotic pairs (77-100% for all tic variants) than in dizygotic pairs - 23%. At the same time, significant discordance in the severity of tics is observed in identical twins. Genetic linkage analysis is currently underway to identify the chromosomal localization of the possible Tourette syndrome gene.

Basal ganglia dysfunction

It is believed that the basal ganglia are primarily involved in the pathological process of Tourette syndrome. Movement disorders such as Parkinson's disease and Huntington's chorea are associated with dysfunction of the basal ganglia. Data from neuroimaging studies are accumulating that indicate the presence of structural or functional changes in the basal ganglia in patients with Tourette syndrome. For example, the volume of the basal ganglia (especially the lentiform nucleus, which regulates movement) on the left side in patients with Tourette syndrome was slightly smaller than in the control group. In addition, in many patients with Tourette syndrome, the asymmetry of the basal ganglia that is normally detected is absent or is reversed. Another study found a significant decrease in activity in the basal ganglia on the right side in 5 of 6 patients with Tourette syndrome, but in none of the healthy controls. A study of 50 patients with Tourette 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 for tic severity, twins with more severe disease had a relative decrease in the volume of the right caudate nucleus and left lateral ventricle. The absence of normal asymmetry of the lateral ventricles was also established. The volume of other brain structures and the degree of their asymmetry did not differ between pairs of twins, but all twins concordant for handedness lacked normal asymmetry of the caudate nuclei. In a study of monozygotic pairs discordant for the severity of Tourette syndrome, the level of binding of the radiopharmaceutical iodobenamide, which blocks dopamine D2 receptors, in the caudate nucleus of twins with more severe symptoms was significantly higher than in twins with mild symptoms. This allowed us to suggest 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 environmental factors influencing the phenotypic expression of Tourette syndrome.

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Neurochemical hypotheses

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

Possible dysfunction of noradrenergic systems is suggested by the therapeutic effect of a2-adrenergic receptor agonists and other neurochemical studies. Children and adults with Tourette syndrome have a flattened growth hormone secretion curve in response to clonidine. Patients with Tourette syndrome also have increased cerebrospinal fluid levels of NA and its major metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) compared with those in the control groups and in patients with OCD. In addition, plasma adrenocorticotropic hormone (ACTH) levels before and after lumbar puncture and urinary NA excretion in patients with Tourette syndrome were higher than normal. Urinary NA levels correlated with tic severity scores.

Scientists have found significantly higher concentrations of corticotropin-releasing factor (CRF) in the cerebrospinal fluid of patients with Tourette syndrome - compared to the norm and similar indicators in patients with OCD. The interaction between CRF and NA in the development of a stress response may explain the increase in tics with increased anxiety and stress.

The involvement of the opioid system in the pathogenesis of Tourette syndrome is possible through damage to endogenous opioid projections from the striatum to the pallidum and substantia nigra. This opinion is supported by data indicating the expression of dynorphin (an endogenous opioid) by GAM-ergic projection neurons of the striatum, as well as the possibility of induction of the prodynorphin gene through D1-like dopamine receptors. On the other hand, the gene encoding preproenkephalin is under the tonic inhibitory influence of dopamine D1 receptors. Changes in dynorphin content have been noted in patients with Tourette syndrome. Other neurotransmitter systems are also involved in the pathogenesis of Tourette syndrome: serotonergic, cholinergic, as well as excitatory and inhibitory pathways with amino acid mediators.

Exogenous factors

A study of monozygotic twins discordant for the severity of symptoms of Tourette syndrome showed that the twin with more severe symptoms had a lower birth weight than the twin with milder symptoms. Other exogenous factors, particularly those acting in the perinatal period (including toxic substances, maternal medications, maternal stress), as well as overheating, cocaine, psychostimulants, or anabolic steroids, may also influence the phenotypic expression of Tourette syndrome. Infections, especially group A beta-hemolytic streptococcus, may also play a role.

Some scientists believe that autoimmune neuropsychiatric disorder may be a partial expression of Sydenham's chorea, which manifests externally as Tourette's syndrome. The features of this disorder include: sudden onset of the disease with the development of OCD symptoms, excessive movements and/or hyperactivity, an undulating course with alternating exacerbations and remissions, the presence of anamnestic or clinical signs of a recent streptococcal infection of the upper respiratory tract. During the acute phase, neurological examination may reveal muscle hypotonia, dysarthria, choreiform movements. Observations have revealed an increased level of antineuronal antibodies to the caudate nucleus in patients with Tourette's syndrome, which is consistent with Husby's discovery of an increased level of antineuronal antibodies in Sydenham's chorea. Recent studies have shown that some patients with OCD and tics that began in childhood have a B-cell marker previously found in rheumatism.

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