Tourette syndrome is a neurobehavioral disorder manifest particularly by motor and vocal tics and associated with behavioral abnormalities. Tics are sudden, brief, intermittent, involuntary or semi-voluntary movements (motor tics) or sounds (phonic or vocal tics). They typically consist ... Tourette syndrome is a neurobehavioral disorder manifest particularly by motor and vocal tics and associated with behavioral abnormalities. Tics are sudden, brief, intermittent, involuntary or semi-voluntary movements (motor tics) or sounds (phonic or vocal tics). They typically consist of simple, coordinated, repetitive movements, gestures, or utterances that mimic fragments of normal behavior. Motor tics may range from simple blinking, nose twitching, and head jerking to more complex throwing, hitting, or making rude gestures. Phonic tics include sniffling, throat clearing, blowing, coughing, echolalia, or coprolalia. Males are affected about 3 times more often than females, and onset usually occurs between 3 and 8 years of age. By age 18 years, more than half of affected individuals are free of tics, but they may persist into adulthood (review by Jankovic, 2001).
Gilles de la Tourette (1885) first described this disorder as a nervous affliction characterized by motor incoordination accompanied by echolalia and coprolalia (see HISTORY).
Kurlan et al. (1986) reported on a large Mennonite kindred from Alberta ... Gilles de la Tourette (1885) first described this disorder as a nervous affliction characterized by motor incoordination accompanied by echolalia and coprolalia (see HISTORY). Kurlan et al. (1986) reported on a large Mennonite kindred from Alberta with chronic motor tics and vocal tics inherited in a probable autosomal dominant pattern. Studies led them to conclude that 10 persons had definite and 15 probable Tourette syndrome, and that 3 had definite and 1 probable chronic motor tics. In this kindred, Kurlan et al. (1987) later found that 30% of 54 persons thought to be affected were unaware of tics noted by the examiners and only 18.5% of the affected members had sought medical care. From these findings, the authors concluded that most cases are mild and do not come to medical attention; therefore, the disorder may be more prevalent than is generally appreciated. Although one of the most notorious symptoms of the Tourette syndrome, coprolalia is rather infrequent. Goldenberg et al. (1994) found only 8% of their 112 patients exhibited coprolalia. Fabbrini et al. (2007) reported a large Italian family with Tourette syndrome. Fifteen individuals had tics or other behavioral abnormalities: 5 had definite GTS, 5 had chronic motor tics, 2 had nonspecific tic disorder, and 3 had obsessive-compulsive disorder without motor or phonic tics. The disorder spanned 5 generations and appeared to show autosomal dominant inheritance. The mean age at onset was 9.9 years. Motor tics involved mainly the head and neck, and included head turning, eye blinking, facial grimacing, and shoulder shrugging. One individual each had pathologic gambling (606349), panic disorder (167870), generalized anxiety disorder (607834), and major depression (MDD; 608516). No patients had coprolalia. The findings confirmed Tourette syndrome as a neuropsychiatric disorder with a strong genetic background. Ercan-Sencicek et al. (2010) reported a 2-generation family in which a father and all 8 of his children had Tourette syndrome. The father and 3 of the children also had OCD; 1 of the children with OCD also had Asperger (see 209850) and trichotillomania (TTM; 613229). The features of Tourette syndrome included eye rolling and blinking, throat clearing, limb moving, snorting, humming, swearing, jaw tightening or jutting, and shoulder shrugging, to name a few. Most family members also had evidence of a possible connective tissue disorder, with hypermobile joints and pectus excavatum, but only 1 individual was diagnosed with a variant of Ehlers-Danlos syndrome (130000). The mother, who did not have Tourette syndrome, had a history of Chiari malformation type I (118420) with tethered spinal cord, which was present in 5 of the affected children. In addition to 8 living children, the mother had had 7 miscarriages.
By genomewide linkage analysis followed by candidate gene sequencing in a large 2-generation family with Gilles de la Tourette syndrome, Ercan-Sencicek et al. (2010) identified a heterozygous nonsense mutation in ... - Mutation in the HDC Gene By genomewide linkage analysis followed by candidate gene sequencing in a large 2-generation family with Gilles de la Tourette syndrome, Ercan-Sencicek et al. (2010) identified a heterozygous nonsense mutation in the HDC gene (W317X; 142704.0001) in all 9 affected individuals. In vitro studies indicated that the mutation exerted a dominant-negative effect on the protein, resulting in lack of enzyme activity. Ercan-Sencicek et al. (2010) noted that animal studies had shown that lack of Hdc in mice results in increased locomotor and stereotypic behaviors, as well as increased anxiety. Overall, the findings suggested a role for histaminergic neurotransmission in neurobehavioral actions, such as tics. - Variation in the SLITRK1 Gene Abelson et al. (2005) studied SLITRK1 as a candidate gene for GTS on chromosome 13q31.1 because of its proximity to a de novo chromosomal inversion in a child with the syndrome and no family history. Although they found no mutation in the child, they identified 2 different mutations in the SLITRK1 gene among 174 unrelated probands with GTS. The proband in 1 family, who had GTS and ADHD, had a single-base deletion in the coding region, leading to a frameshift mutation (609678.0001). The mutation was also found in the patient's mother, who had trichotillomania (613229). In 2 other probands, who had GTS and symptoms of OCD, they identified a single-base change (designated var321) in the 3-prime UTR of the gene (609678.0002). The base change corresponds to a highly conserved nucleotide within the predicted binding site for a microRNA, hsa-miR-189. The var321 mutations occurred on different haplotypes in the patients, indicating that they arose independently. Abelson et al. (2005) demonstrated that SLITRK1 mRNA and hsa-miR-189 have an overlapping expression pattern in brain regions previously implicated in Tourette syndrome. Wildtype SLITRK1, but not the frameshift mutant, enhanced dendritic growth in primary neuronal cultures. Abelson et al. (2005) concluded that their findings support the association of rare SLITRK1 sequence variants with Tourette syndrome. There is controversial evidence about whether or not variation in the SLITRK1 gene plays a role in Tourette syndrome. Deng et al. (2006) and Chou et al. (2007) did not find the var321 change or any other potentially pathogenic changes in the SLITRK1 gene in 82 Caucasian and 160 Taiwanese patients with GTS, respectively. Fabbrini et al. (2007) also excluded the SLITRK1 as a basis for Tourette syndrome in a large Italian family. Although Fabbrini et al. (2007) did identify the var321 change in a few family members and 1 spouse, it did not segregate with the disorder. In addition, a genomewide linkage study by the Tourette Syndrome Association International Consortium for Genetics (2007) showed no support for a locus on chromosome 13 in Tourette syndrome. - Exome Sequencing Studies By whole-exome sequencing of a 3-generation family in which 7 individuals had Tourette syndrome/chronic tic disorder, Sundaram et al. (2011) identified 4 novel nonsynonymous variants that segregated perfectly with the phenotype in all 7 affected family members. These variants included a pro45-to-ser (P45S) substitution in the PVRL3 gene (607147); a ser75-to-asn (S75N) substitution in the MRPL3 gene (607118); an ala2057-to-ser (A2057S) substitution in the DNAJC13 gene (614334); and an arg129-to-gly (R129G) substitution in the OFCC1 gene (614287). Three of the variants (in the MRPL3, DNAJC13, and OFCC1 genes) could be validated by Sanger sequencing; the PVRL3 variant could not be reliably verified. None of the variants were present in 100 controls or in the 1000 Genomes project. Comorbid disorders in affected individuals included obsessive-compulsive disorder (OCD; 164230) and attention deficit-hyperactivity disorder (ADHD; 143465). Subsequent analysis of 94 patients with GTS/chronic tics found that 2 carried a variant in the 5-prime untranslated region of the OFCC1 gene. Functional studies were not performed, and Sundaram et al. (2011) could not provide any insight into a potential disease mechanism based on the known functions of these genes. However, the authors postulated that the disorder may be caused by multiple rare variants in different genes.
Kurlan et al. (1987) cited a prevalence of 28.7 per 100,000 in school children of Monroe County in New York. Kurlan (1994) estimated that 'developmental Tourette syndrome' occurred in at least 3% of all children and that up ... Kurlan et al. (1987) cited a prevalence of 28.7 per 100,000 in school children of Monroe County in New York. Kurlan (1994) estimated that 'developmental Tourette syndrome' occurred in at least 3% of all children and that up to 25% of children requiring special education may have mild to moderate Tourette syndrome. He proposed that these were the milder forms of the clinical spectrum that, at the extreme end, included the smallest group, patients with 'full-blown' Tourette syndrome. Comings (1987) suggested that GTS is one of the most common genetic disorders affecting man, with a frequency of about 1 in 100, and that the complete range of behavioral problems is much broader than merely motor and vocal tics.