Genetic animal models of Tourette syndrome : the long and winding road from lab to clinic

Tourette syndrome (TS) is a disabling neuropsychiatric disorder characterised by persistent motor and vocal tics. TS is a highly comorbid state, hence, patients might experience anxiety, obsessions, compulsions, sleep abnormalities, depression, emotional liability, learning problems, and attention deficits in addition to tics. In spite of its complex heterogeneous genetic aetiology, recent studies highlighted a strong link between TS and genetic lesions in the HDC (L-histidine decarboxylase) gene, which encodes the enzyme that synthetises histamine, and the SLITRK1 (SLIT and TRK-like family member 1) gene, which encodes a transmembrane protein that was found to regulate neurite outgrowth. In addition to validating the contribution of a specific genetic aberration to the development of a particular pathology, animal models are crucial to dissect the function of disease-linked proteins, expose disease pathways through examination of genetic modifiers and discover as well as assess therapeutic strategies. Mice with a knockout of either Hdc or Slitrk1 exhibit anxiety and those lacking Hdc, display dopamine agonist-triggered stereotypic movements. However, the mouse knockouts do not spontaneously display tics, which are recognised as the hallmark of TS. In this review, we explore the features of the present genetic animal models of TS and identify reasons for their poor resemblance to the human condition. Importantly, we highlight ways forward aimed at developing a valuable genetic model of TS or a model that has good predictive validity in developing therapeutic drugs for the treatment of tics, hence potentially accelerating the arduous journey from lab to clinic.peer-reviewe

A D4-es dopamin receptor gén 5' régiójának haplotípus szerkezete: molekuláris és pszichiátriai vonatkozások = Haplotype structure of the 5' region of the D4 dopamine receptor gene: molecular and psychiatric aspects

Napjaink egyik fő kutatási területe a poligénes rendellenességek (pl. pszichiátriai betegségek) genetikai hátterének elemzése. Munkánk során a Tourette-szindróma kialakulásában szerepet játszó genetikai tényezőket vizsgáltuk. Elsőként a D4-es dopamin receptor gén 5? nem kódoló régiójának polimorfizmusait elemeztük, mivel az itt található variációknak feltehetően hatása van a génexpresszióra, a D4-es dopamin receptor pedig a terápiás tapasztalatok alapján szerepet játszik a kórkép kifejlődésében. Munkánk első fő mérföldköve ezen polimorfizmusok (120 bp duplikáció, -616CG, -615AG és -521CT SNP polimorfizmusok) vizsgálatára alkalmas hatékony genotipizáló és haplotipizáló eljárások kidolgozása volt. Az SNP-ket a nagyobb megbízhatóság kedvéért két módszerrel elemeztük, a haplotípust direkt molekuláris technikákkal határoztuk meg. Mivel a Tourette-szindróma genetikai háttere meglehetősen komplex, a szerotonerg neurotranszmisszió fontosabb genetikai polimorfizmusait is bevontuk munkánkba. Egy új típusú variáció, a génszám polimorfizmus (CNV) vizsgálatára alkalmas technikákat is beállítottunk. Megállapítottuk, hogy a MAOA gén 5? régiójában lévő ismétlődési polimorfizmus asszociációt mutat a betegséggel. Emellett a kórkép jellegzetes tünete, a ticek súlyossága és a dopamin transzporter 3? polimorfizmusa között sikerült statisztikailag szignifikáns összefüggést kimutatni. Ezen polimorfizmusok a betegség genetikai rizikófaktorai lehetnek. | One of the most thoroughly investigated topics of today?s genetic research is the analysis of the background of complex, multifactorial (e.g. psychiatric) diseases. The goal of project was the study of those genetic components that might play a role in the development of Tourette-syndrome. The major target of our experiments was the variants in the 5? region of the dopamine D4 receptor gene, as these polymorphisms are supposed to contribute to gene expression regulation. The first milestone of our work was the elaboration of efficient techniques for the investigation of the genotype and haplotype of the 120 bp duplication, -616CG, -615AG and -521CT polymorphisms localized in this region. For higher reliability two independent methods were used for SNP analysis, the haplotype was determined by direct molecular techniques. As the background of Tourette-syndrome is rather complex, candidate genes of the serotonerg system were also involved in the study. Moreover novel methods were elaborated for the analysis of copy number variation (CNV) polymorphisms. It was demonstrated that 5? repeat polymorphism of the MAOA gene showed association with the illness, and connection was showed between a characteristic symptom, tic severity and the 3? polymorphism of dopamine transporter gene as well. Consequently these polymorphisms and genes might be genetic risk factors of Tourette-syndrome

Targeted Re-Sequencing Approach of Candidate Genes Implicates Rare Potentially Functional Variants in Tourette Syndrome Etiology

Although the genetic basis of Tourette Syndrome (TS) remains unclear, several candidate genes have been implicated. Using a set of 382 TS individuals of European ancestry we investigated four candidate genes for TS (HDC, SLITRK1, BTBD9, and SLC6A4) in an effort to identify possibly causal variants using a targeted re-sequencing approach by next generation sequencing technology. Identification of possible disease causing variants under different modes of inheritance was performed using the algorithms implemented in VAAST. We prioritized variants using Variant ranker and validated five rare variants via Sanger sequencing in HDC and SLITRK1, all of which are predicted to be deleterious. Intriguingly, one of the identified variants is in linkage disequilibrium with a variant that is included among the top hits of a genome-wide association study for response to citalopram treatment, an antidepressant drug with off-label use also in obsessive compulsive disorder. Our findings provide additional evidence for the implication of these two genes in TS susceptibility and the possible role of these proteins in the pathobiology of TS should be revisited

A diszlexia jelensége és lehetséges magyarázatai

Az olvasás folyamatának megértése és ezzel kapcsolatban a diszlexia, az olvasási nehézségek feltérképezése az utóbbi időben gyors ütemben elindult, a kérdés azonban továbbra is nyitott, és számos probléma megválaszolatlanul maradt. Az alábbi összefoglaló tanulmányban néhány aspektust szeretnénk ezzel kapcsolatban áttekinteni, többek között az olvasás mechanizmusának egyfajta konnekcionista, holisztikus modelljét bemutatni, amely modell magyarázatul szolgálhat a diszlexia által különbözően érintett agyterületek és funkciók zavaraira. További eredményeket mutatunk be a diszlexia öröklődésével kapcsolatban, valamint a modern képalkotó eljárások segítségével áttekintjük azokat az agyi strukturális elváltozásokat, valamint funkcionális zavarokat, amelyek fellelhetőek diszlexia során. Fontos és izgalmas kér­dés a nemek különbségének a kérdése, amely bizonyos nemek szerinti fejlődési minta különbözőségére hív­hat­ja fel figyelmünket

Gyermekkori pszichiátriai kórképek frontostriatális érintettségének neuropszichológiai vizsgálata

A tanulmány bemutatja a gyermekpszichiátriai kórképekben megfigyelhető végrehajtó működési zavarok klinikai profilját, majd a funkciók vizsgálatára készített és adaptált kognitív eljáráskészletet. A több száz gyermek- és serdül_

Reduced fronto-cortical brain connectivity during NREM sleep in Asperger syndrome:an EEG spectral and phase coherence study

OBJECTIVE: To investigate whether sleep macrostructure and EEG power spectral density and coherence during NREM sleep are different in Asperger syndrome (AS) compared to typically developing children and adolescents. METHODS: Standard all night EEG sleep parameters were obtained from 18 un-medicated subjects with AS and 14 controls (age range: 7.5-21.5years) after one adaptation night. Spectral, and phase coherence measures were computed for multiple frequency bands during NREM sleep. RESULTS: Sleep latency and wake after sleep onset were increased in AS. Absolute power spectrum density (PSD) was significantly reduced in AS in the alpha, sigma, beta and gamma bands and in all 10 EEG derivations. Relative PSD showed a significant increase in delta and a decrease in the sigma band for frontal, and in beta for centro-temporal derivations. Intrahemispheric coherence measures were markedly lower in AS in the frontal areas, and the right hemisphere over all EEG channels. The most prominent reduction in intrahemispheric coherence was observed over the fronto-central areas in delta, theta, alpha and sigma EEG frequency bands. CONCLUSION: EEG power spectra and coherence during NREM sleep, in particular in fronto-cortical derivations are different in AS compared to typically developing children and adolescents. SIGNIFICANCE: Quantitative analysis of the EEG during NREM sleep supports the hypothesis of frontal dysfunction in AS

Geographically Separate Increases in the Frequency of the Derived ADH1B*47His Allele in Eastern and Western Asia

The ADH1B Arg47His polymorphism has been convincingly associated with alcoholism in numerous studies of several populations in Asia and Europe. In a review of literature from the past 30 years, we have identified studies that report allele frequencies of this polymorphism for 131 population samples from many different parts of the world. The derived ADH1B*47His allele reaches high frequencies only in western and eastern Asia. To pursue this pattern, we report here new frequency data for 37 populations. Most of our data are from South and Southeast Asia and confirm that there is a low frequency of this allele in the region between eastern and western Asia. The distribution suggests that the derived allele increased in frequency independently in western and eastern Asia after humans had spread across Eurasia

Impairment of visually guided associative learning in children with Tourette syndrome

The major symptoms of Tourette syndrome are motor and vocal tics, but Tourette syndrome is occasionally associated with cognitive alterations as well. Although Tourette syndrome does not affect the majority of cognitive functions, some of them improve. There is scarce evidence on the impairment of learning functions in patients with Tourette syndrome. The core symptoms of Tourette syndrome are related to dysfunction of the basal ganglia and the frontostriatal loops. Acquired equivalence learning is a kind of associative learning that is related to the basal ganglia and the hippocampi. The modified Rutgers Acquired Equivalence Test was used in the present study to observe the associative learning function of patients with Tourette syndrome. The cognitive learning task can be divided into two main phases: the acquisition and test phases. The latter is further divided into two parts: retrieval and generalization. The acquisition phase of the associative learning test, which mainly depends on the function of the basal ganglia, was affected in the entire patient group, which included patients with Tourette syndrome with attention deficit hyperactivity disorder, obsessive compulsive disorder, autism spectrum disorder, or no comorbidities. Patients with Tourette syndrome performed worse in building associations. However, the retrieval and generalization parts of the test phase, which primarily depend on the function of the hippocampus, were not worsened by Tourette syndrome