3.2. Tourette syndrome

TS is a childhood-onset neuropsychiatric disorder that is characterized by multiple motor tics, i.e., involuntary, rapid, non-rhythmic skeletal movements and vocalizations. The prevalence of TS varies in different age-groups and is presently estimated as 1% of school-age children, whereas the prevalence of tic disorders (chronic motor or vocal tics) vary between 6 to 12% among children (Singer, 2005). Similar to ADHD, TS is more frequent in males (3:1 ratio). Family studies have shown that TS is highly heritable, and small-scale twin studies indicate that TS has 80–90% heritability (O’Rourke et al., 2009). TS is rarely present without comorbid conditions, and most often, it is accompanied by OCD and/or ADHD (Singer, 2005). This pattern of comorbidity indicates that genetic risk factors closely connected with TS may be responsible for a spectrum of disorders, including OCD on one side of the spectrum and ADHD on the other. At the two endpoints of the spectrum, OCD and ADHD can exist separately with unique etiologies (O’Rourke et al., 2009). The most widely studied candidate genes in TS belong to the dopamine system; however, serotonergic genes have also been analyzed because of the frequent comorbidity with OCD.

The dopamine hypothesis of TS is based on pharmacological and neuroimaging evidence. Classic antipsychotic (neuroleptic) drugs, such as haloperidol, can effectively suppress tics through DRD2 antagonism (Singer, 2005). Most SPECT studies have shown increased DAT densities in the striatum of TS patients compared to controls (Albin and Mink, 2006), and post-mortem analyses have revealed elevated DAT and DRD2 levels in the frontal brain regions (Yoon et al., 2007a). In the early 1990s, all of the investigated dopaminergic genes were excluded from TS pathology because of the assumed autosomal dominant inheritance in the linkage studies. Comings et al. (1996) suggested that polygenic inheritance was involved in TS, and subsequent genetic analyses were based on complex inheritance (e.g., by studying allele transmission in families).

The DRD2 TaqI A1-allele has been implicated in TS by a series of case-control association studies (summarized by Comings et al., 1996). To date, only one case-control study from Taiwan supported this finding (Lee et al., 2005), and family-based studies did not observe over-transmission of the A1-allele (Nothen et al., 1994; Diaz-Anzaldua et al., 2004). For the DRD4 VNTR, case-control studies (Cruz et al., 1997; Comings et al., 1999; Yoon et al., 2007b) and family-based studies (Grice et al., 1996; Hebebrand et al., 1997; Diaz-Anzaldua et al., 2004; Tarnok et al., 2007) resulted in contradictory findings. There are only a few published studies that investigated the involvement of the dopamine synthesizing and catabolizing enzyme genes with mostly negative findings for TH and COMT, and positive findings for MAOA (reviewed by O’Rourke et al., 2009). For the DAT1 3′ UTR VNTR, the categorical analyses showed a significant association (Comings et al., 1996) and a tendency towards an association with the 10-repeat allele (Diaz-Anzaldua et al., 2004). Later studies did not observe significant associations with TS diagnosis (Tarnok et al., 2007; Yoon et al., 2007b). However, after applying a dimensional approach, the 9-repeat allele was associated with a greater tic severity (Tarnok et al., 2007). Based on the results of the largest SPECT studies where the 9-repeat allele was linked to a higher DAT density, we may speculate that this gene variant is a risk factor for TS and/or for tic severity. Further studies should apply quantitative trait and endophenotype analyses for TS to yield more consistent results, in a manner similar to that done in ADHD studies during the last decade.