Clonidine is an alpha-adrenergic agonist which may alleviate emerging symptoms in Tourette syndrome, an observation that has fueled speculation regarding involvement of stress-sensitive central noradrenergic systems in this disorder. We conducted a retrospective study of 53 juvenile patients with Tourette syndrome to assess predictors of short-term behavioral and tic response to oral clonidine and to examine the relationship, if any, among pretreatment blood pressure, tic severity, and clonidine response. When adverse effects were considered, older subjects experienced a better therapeutic response to clonidine, independent of dose. Improvement in symptoms of attention-deficit hyperactivity disorder was associated with a longer duration of vocal tics before treatment. Baseline sitting diastolic blood pressure was directly correlated with measures of tic severity but not with tic response to clonidine. The findings (1) provide indirect support for involvement of central noradrenergic systems in tic expression; (2) suggest that emergence of a tic-related neurophysiologic dysfunction may be necessary for optimal behavioral response to clonidine in Tourette syndrome; and (3) provide broad guidelines for the clinician considering clonidine therapy for pediatric patients with Tourette syndrome, particularly those with comorbid attention-deficit hyperactivity disorder.
"Indirectement, ils seraient aussi liés à l'impulsivité chez le rat lorsqu'administré à des doses élevées (Bari, Eagle, Mar, Robinson, & Robbins, 2009) et lorsque injectés directement dans le cortex préfrontal dorsomédian (Bari et al., 2011). L'efficacité de ces agents noradrénergiques pour traiter le SGT pourrait donc indiquer une implication possible des systèmes noradrénergiques dans l'étiologie de ce trouble et plus particulièrement chez les patients ayant une comorbidité d'hyperactivité et d'impulsivité (Lichter & Jackson, 1996). Dans l'étude de Thibault et al. (2008), les auteurs avancent qu'une plus grande amplitude de la composante P300 de potentiels évoqués, chez les personnes atteintes du SGT, reflèterait une hyperactivité des systèmes noradrénergiques. "
[Show abstract][Hide abstract] ABSTRACT: Tics are defined as involuntary and repetitive contractions of related groups of squelettal muscles. Their frequency can be exacerbated in certain situations or diminished in others. Chronic tics or the Gilles de la Tourette Syndrome (GTS) may be accompanied by concomitant disorders related to impulsivity. If one knows that the impulsivity variable can be found in a large majority of GTS cases, very few studies have attempted to document its frequency or intensity. Over the past decade, knowledge of the neuropsychology of GTS and the mechanisms underlying impulsivity has progressed rapidly. The current review of the literature, will describe the biological bases of this syndrome and problems of impulsivity in patients with GTS.
[Show abstract][Hide abstract] ABSTRACT: Autism is a neurodevelpmental disorder characterized by impaired verbal communication, limited reciprocal social interaction, restricted interests and repetitive behaviours. Twin and family studies indicate a large genetic contribution to ASDs (Autism Spectrum Disorders). During my Ph.D. I have been involved in several projects in which I used different genetic approaches in order to identify susceptibility genes in autism on chromosomes 2, 7 and X:
1)High-density SNP association and CNV analysis of two Autism Susceptibility Loci.
The International Molecular Genetic Study of Autism Consortium (IMGSAC) previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we evaluated the patterns of linkage disequilibrium (LD) and the distribution of haplotype blocks, utilising data from the HapMap project, across the two strongest peaks of linkage on chromosome 2 and 7. More than 3000 SNPs have been selected in each locus in all known genes, as well as SNPs in non-genic highly conserved sequences. All markers have been genotyped to perform a high-density association analysis and to explore copy number variation within these regions. The study sample consisted of 127 and 126 multiplex families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Association and CNV analysis implicated several new genes, including IMMP2L and DOCK4 on chromosome 7 and ZNF533 and NOSTRIN on the chromosome 2. Particularly, my contribution to this project focused on the characterization of the best candidate gene in each locus:
On the AUTS5 locus I carried out a transcript study of ZNF533 in different human tissues to verify which isoforms and start exons were expressed. High transcript variability and a new exon, never described before, has been identified in this analysis. Furthermore, I selected 31 probands for the risk haplotype and performed a mutation screen of all known exons in order to identify novel coding variants associated to autism.
On the AUTS1 locus a duplication was detected in one multiplex family that was transmitted from father to an affected son. This duplication interrupts two genes: IMMP2L and DOCK4 and warranted further analysis. Thus, I performed a screening of the cohort of IMGSAC collection (285 multiplex families), using a QMPSF assay (Quantitative Multiplex PCR of Short fluorescent Fragments) to analyse if CNVs in this genic region segregate with autism phenotype and compare their frequency with a sample of 475 UK controls.
Evidence for a role of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family.
2)Analysis of X chromosome inactivation.
Skewed X chromosome inactivation (XCI) is observed in females carrying gene mutations involved in several X-linked syndromes. We aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 164 affected girls. The study sample included families from different european consortia. I analysed the XCI inactivation pattern in a sample of italian mothers from singletons families with ASD and also a control groups (144 adult females and 40 young females). We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (≥80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z score of 1.75 close to rs719489. In this region FMR1 and MECP2 have been associated in some cases with austim and therefore represent candidates for the disorder. I performed a mutation screen of MECP2 in 33 unrelated probands from IMGSAC and italian families, showing XCI skewness. Recently, Xq28 duplications including MECP2, have been identified in families with MR, with asymptomatic carrier females showing extreme (>85%) skewing of XCI. For these reason I used the sample of probands from X-skewed families to perform CNV analysis by Real-time quantitative PCR. No duplications have been found in our sample. I have also confirmed all data using as alternative method the MLPA assay (Multiplex Ligation dependent Probe Amplification).
3)ASMT as functional candidate gene for autism.
Recently, a possible involvement of the acetylserotonin O-methyltransferase (ASMT) gene in susceptibility to ASDs has been reported: mutation screening of the ASMT gene in 250 individuals from the PARIS collection revealed several rare variants with a likely functional role; Moreover, significant association was reported for two SNPs (rs4446909 and rs5989681) located in one of the two alternative promoters of the gene. To further investigate these findings, I carried out a replication study using a sample of 263 affected individuals from the IMGSAC collection and 390 control individuals. Several rare mutations were identified, including the splice site mutation IVS5+2T>C and the L326F substitution previously reported by Melke et al (2007), but the same rare variants have been found also in control individuals in our study. Interestingly, a new R319X stop mutation was found in a single autism proband of Italian origin and is absent from the entire control sample. Furthermore, no replication has been found in our case-control study typing the SNPs on the ASMT promoter B.
[Show abstract][Hide abstract] ABSTRACT: Increasing attention to comorbidity in Tourette syndrome has led to a search for factors that would help in the development of treatment strategies for attention deficit hyperactivity disorder. Despite arguments and some research supporting various viewpoints, it is still unclear to what extent the frequency of co-occurrence is high in Tourette syndrome. It also is unclear whether attention deficit hyperactivity disorder and obsessive-compulsive disorder are part of a spectrum with related genetic or environmental factors. One of the main difficulties is obtaining a truly representative community sample and agreeing upon the categorical boundaries. The consequences of this argument are discussed. Effective treatment of attention deficit hyperactivity disorder in the presence of tics and Tourette syndrome has undergone considerable change from an absolute contraindication of stimulants to cautious use. For those whom stimulants fail or produce unacceptable side effects, nonstimulant medications are available in increasing variety. Much more methodologically adequate research needs to be undertaken with them.
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