Kandidatengenuntersuchungen zum Gilles de la Tourette Syndrom

Candidate gene research in Gilles de la Tourette syndrome Gilles de la Tourette syndrome (GTS) is a common neuropsychiatric disorder clinically characterized by a combination of vocal and motor tics. In addition to movement disorders, GTS patients develop psychopathological abnormalities such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). So fare, the cause of GTS is unknown. There is growing evidence that both genetic and autoimmune factors are involved in the pathogenesis of GTS. Allele-association studies were undertaken in different candidate genes. The investigations were carried out in 88 GTS trios (affected child and both parents) to avoid false positive results due to population stratification. To analyze the data, the extended transmission disequilibrium test (ETDT) was applied to analyze for transmission disequilibrium. Three different studies were undertaken: There is clinical overlap between GTS and ADHD and the existence of shared genetic susceptibility factors has been suggested. A significant association between polymorphisms in dopamine system genes and ADHD has been reported: the 480 bp allele of the dopamine transporter gene (SLC6A3), a TaqI-polymorphism of the dopamine-beta-hydroxylase (DßH), a 120-bp repeat promotor polymorphism of the dopamine 4 receptor gene (DRD4), the 148 bp allele of a dinucleotide repeat polymorphism of the dopamine 5 receptor gene (DRD5) and the 157 bp allele of a dinucleotide repeat polymorphism at the DXS7 locus of the X chromosome. This study investigated whether any of the genes/polymorphisms found to be associated with ADHD may also constitute genetic susceptibility factors for GTS. More over two other polymorphisms at the monoamine oxidase A gene (MAO-A) locus were investigated: a Fnu4H1-restriction length polymorphism (RFLP) and a 30-bp repeat polymorphism near the coding sequence of the MAO-A gene. The ETDT failed to detect transmission disequilibrium for any of the ADHD-associated alleles in the 88 GTS trios. Therefore the results of this study make the existence of shared genetic susceptibility factors for GTS and ADHD less likely. To investigate the influence of immunological factors in the pathogenesis of GTS modern, PCR-based HLA-DRB typing, was undertaken in 83 GTS trios to investigate whether GTS might be associated with a particular HLA-DRB allele. In classical autoimmune disorders such as diabetes mellitus or multiple sclerosis genetic susceptibility is at least in part conferred by human leucocyte antigen (HLA-) subtypes, in particular by distinct HLA-DRB alleles. 13 different HLA alleles were found. The ETDT failed to detect transmission disequilibrium for any allele at the DRB1 locus. These results imply that the HLA-DRB locus does not confer genetic susceptibility to GTS. In the isolated Afrikaner population, several genetic markers at three distinct chromosomal loci have been found to be associated with GTS, but it is currently unclear whether these findings are of relevance in other populations. 88 German GTS trios were therefore tested for association and linkage with the markers D2S139, D8S1988 and D11S1377 previously found to be most strongly associated with GTS in the isolated Afrikaner population. The ETDT failed to detect transmission disequilibrium for any of the three markers. The results do not provide supportive evidence for an important role of the chromosomal loci on 2p11, 8q22 and 11q23-24 in the pathogenesis of sporadic GTS in a non-isolated population.