Nanette Mol Debes

Validation of the Presence of Comorbidities in a Danish Clinical Cohort of Children With Tourette Syndrome

Tourette syndrome (TS) is characterized by the presence of motor and vocal tics and is often accompanied by comorbid symptoms. We assessed the frequency of the comorbid symptoms obsessive-compulsive disorder obsessive-compulsive disorder, attention-deficit hyperactivity disorder (ADHD), rage attacks, sleeping disturbances, and depressive symptoms in a Danish clinical cohort of 314 children with TS using validated diagnostic instruments. For the assessment of symptoms of seasonal affective disorder and stuttering, we used a nonvalidated systematic interview. In total, only 10.2% of the children did not have any comorbid symptoms at all. If ADHD and/or obsessive-compulsive disorder were present, the rates of the comorbidities rage, symptoms of seasonal affective disorder, sleep disturbances, and depressive symptoms were significantly higher than if ADHD and/or obsessive-compulsive disorder were absent. The most severe tics were found in the group for which both ADHD and obsessive-compulsive disorder were present. Furthermore, there was a tendency toward more severe tics if other comorbid symptoms were present.

The Presence of Attention-Deficit Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder Worsen Psychosocial and Educational Problems in Tourette Syndrome

We assessed the psychosocial and educational consequences of Tourette syndrome using a structured interview and child behavior checklist in 314 children with Tourette syndrome and 81 healthy controls. Of the children with Tourette syndrome, 59.0% needed some kind of educational support, 44.7% had been teased, and 61.8% withheld themselves from taking part in social activities because of Tourette syndrome-related problems. There were significantly more psychosocial and educational problems in children with Tourette syndrome compared with healthy controls. A higher rate of these problems was also seen if the comorbidities attention-deficit hyperactivity disorder (ADHD) and/or obsessive compulsive disorder were present. It is very important for the physicians, teachers, and other professionals to be aware of the high prevalence of these social and educational problems to be able to deal with them and to teach the families to cope with them.

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome

Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor and vocal tics, and the disorder is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology, but the underlying environmental and genetic factors are largely unknown. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, we identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher (P=0.0447) compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5′-exons (one including the ATG start codon). We showed that both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus. The current findings give further evidence for the role of IMMP2L as a susceptibility factor in Tourette syndrome and suggest that intronic changes in disease susceptibility genes should be investigated further for presence of alternatively spliced exons.

Microduplication of 15q13.3 and Xq21.31 in a family with tourette syndrome and comorbidities

Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit‐hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology.

A Functional Magnetic Resonance Imaging Study of a Large Clinical Cohort of Children With Tourette Syndrome

There is evidence that cortico-striato-thalamo-cortical pathways are involved in the pathophysiology of Tourette syndrome. During the performance of neuropsychological tests in subjects with Tourette syndrome there are suggestions for increased activity in the sensimotor cortex, supplementary motor areas, and frontal cortex. To replicate findings, the authors examined 22 medication-naive children with Tourette syndrome only, 17 medication-naive children with Tourette syndrome and comorbidity, and 39 healthy controls with functional magnetic resonance imaging (MRI). There were no differences in activation in brain regions between the children with Tourette syndrome (divided according to the presence of comorbidity) and healthy controls after correction for the confounders age, sex, and intelligence. Activation in the cingulated gyrus, temporal gyrus, and medial frontal gyrus was correlated significantly with obsessive-compulsive disorder score. The authors did not find significant correlations between activation patterns and age, sex, duration of disease, intelligence, severity of tics, and attention-deficit hyperactivity disorder (ADHD) score.

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort

BACKGROUND Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.

Performance on Wechsler intelligence scales in children with Tourette syndrome

BACKGROUND There is some evidence that Tourette syndrome is associated with cognitive disabilities. AIMS To examine the cognitive performance of a clinical cohort of children with Tourette syndrome. METHODS 266 children with Tourette syndrome have been examined with Wechsler Intelligence Scales. The presence of the co-morbidities attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) was assessed using validated diagnostic instruments. Eighty healthy controls matched a part of the TS cohort. RESULTS The children with Tourette syndrome had a mean verbal IQ (VIQ) of 92.9, performance IQ (PIQ) of 87.1, and full-scale IQ (FSIQ) of 88.8. We found statistically significant higher PIQ and FSIQ in the control group compared with a matched TS cohort and a trend towards a higher VIQ among the healthy controls. There was a statistically significant influence of age at onset of tics on PIQ. The children with co-morbid OCD scored higher on FSIQ compared with the other groups. The children with co-morbid ADHD and OCD showed problems in motor tasks and speed tasks and the children with co-morbid ADHD showed attention deficits. CONCLUSIONS Children with Tourette syndrome have lower IQ scores than the general population (but less than one standard deviation below) and our control group. Early onset of tics and the presence of co-morbidities might cause specific deficits on cognitive performance.

The Presence of Comorbidity in Tourette Syndrome Increases the Need for Pharmacological Treatment

Tourette syndrome is often accompanied by other syndromes, like attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder, and its treatment is symptomatic. Because there are no European guidelines for pharmacological treatment in Tourette syndrome, we wanted to contribute to a better insight into the common practice in Scandinavia. Furthermore, we wanted to elaborate the influence of the presence of comorbidities and of the severity of tics on pharmacological treatment. We have examined the frequency, art, and reason for pharmacological treatment in a Danish clinical cohort of 314 children with Tourette syndrome. In total, 60.5% of the children once had received pharmacological treatment. Mostly, the treatment was started because of tics or ADHD. If ADHD or obsessive-compulsive disorder were present, more children received pharmacological treatment and more different agents were tried. The children who received pharmacological treatment had more severe tics than those without medication.

A t(3;9)(q25.1;q34.3) translocation leading to OLFM1 fusion transcripts in Gilles de la Tourette syndrome, OCD and ADHD

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder with a strong genetic etiology; however, finding of candidate genes is hampered by its genetic heterogeneity and the influence of non-genetic factors on disease pathogenesis. We report a case of a male patient with GTS, obsessive compulsive disorder, attention-deficit/hyperactivity-disorder, as well as other comorbidities, and a translocation t(3;9)(q25.1;q34.3) inherited from a mother with tics. Mate-pair sequencing revealed that the translocation breakpoints truncated the olfactomedin 1 (OLFM1) gene and two uncharacterized transcripts. Reverse-transcription PCR identified several fusion transcripts in the carriers, and OLFM1 expression was found to be high in GTS-related human brain regions. As OLFM1 plays a role in neuronal development it is a likely candidate gene for neuropsychiatric disorders and haploinsufficiency of OLFM1 could be a contributing risk factor to the phenotype of the carriers. In addition, one of the fusion transcripts may exert a dominant-negative or gain-of-function effect. OLFM1 is unlikely to be a major GTS susceptibility gene as no point mutations or copy number variants affecting OLFM1 were identified in 175 additional patients. The translocation described is thus a unique event, but further studies in larger cohorts are required to elucidate involvement of OLFM1 in GTS pathogenesis.

Sequence analysis of SLITRK1 for var321 in Danish patients with Tourette syndrome and review of the literature.

Tourette syndrome (TS) is a complex neuropsychiatric disorder characterized by multiple motor and vocal tics and is often accompanied by comorbidities such as attention deficit hyperactivity disorder and obsessive–compulsive disorder. The complex etiology of TS and its co-occurrence with other disorders impedes linking genetic changes with disease segregation. One of the few genes that has been linked to TS is the SLITRK1 (Slit and Trk-like 1) gene, where four variations have been suggested as possible disease-associated changes. One of these variations, which has been reported in six unrelated TS patients, was a noncoding variant (var321) at the 3′-untranslated region of SLITRK1 within a conserved binding site for microRNA has-mir-189. To elucidate the potential role of var321 in disease pathogenesis, a cohort of 112 deeply phenotyped Danish TS patients was investigated for this variation. We could not detect var321 in the present cohort, suggesting that this is not a common variant among Danish TS patients.