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1.
Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dtsz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder. 相似文献
2.
Jessica Lasky-Su Tobias Banaschewski Jan Buitelaar Barbara Franke Keeley Brookes Edmund Sonuga-Barke Richard Ebstein Jacques Eisenberg Michael Gill Iris Manor Ana Miranda Fernando Mulas Robert D Oades Herbert Roeyers Aribert Rothenberger Joseph Sergeant Hans-Christoph Steinhausen Eric Taylor Kaixin Zhou Margaret Thompson Philip Asherson Stephen V Faraone 《Neuropsychopharmacology》2007,62(9):985-990
BACKGROUND: Previous research found an association between single nucleotide polymorphisms (SNPs) in the promoter region of DRD4 and statistically derived phenotypes generated from attention-deficit/hyperactivity disorder (ADHD) symptoms. We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals. METHODS: Four SNPs were genotyped in and around DRD4 in 2631 individuals in 642 families. We developed a quantitative phenotype at each SNP by weighting nine inattentive and nine hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, the screening procedure implemented in PBAT was used to select and test the five SNPs/genetic model combinations with the greatest power to detect an association for DRD4. RESULTS: One of the four SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = .02). A rank ordering of the correlation between each of the ADHD symptoms and the quantitative phenotype suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; however, including inattentive symptoms was necessary to achieve a significant result. CONCLUSIONS: This study partially replicated a previous finding by identifying an association between rs7124601 and a quantitative trait generated from ADHD symptoms. The rs7124601 is in linkage disequilibrium (LD) with the SNPs identified previously. In contrast to the previous study, this finding suggests that both hyperactive-impulsive and inattentive symptoms are important in the association. 相似文献
3.
James L. Kennedy Elizabeth A. Billett Fabio M. Macciardi Massimiliano Verga Thomas J. Parsons Herbert Y. Meltzer Jeffery Lieberman Janet A. Buchanan 《American journal of medical genetics. Part A》1995,60(6):558-562
Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex, and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied. © 1995 Wiley-Liss, Inc. 相似文献
4.
Arthur Robinson 《American journal of medical genetics. Part A》1994,53(3):264-273
The dopamine hypothesis of schizophrenia proposed that dopaminergic pathways are involved in the etiology of the disease. In particular, interest among psychiatrists has focused on the D2 receptor because of its affinity to antipsychotic drugs. Recently a new dopamine receptor gene has been cloned, and named the dopamine D3 receptor. The D3 receptor is a potential site for antipsychotic drug action and may be involved in the pathophysiology of schizophrenia. We have carried out a linkage study between the susceptibility gene for schizophrenia and polymorphism of the dopamine D3 receptor gene in two Japanese pedigrees. The LOD scores were negative for, all genetic models and for all affective status at a recombination fraction θ = 0. Linkage of DRD3 has been excluded for the model 1 (dominant model) and the model13 (recessive model). The LOD score was - 3.43 at θ = 0 for model 1 (dominant model) and broad definition of affected status. These results were consistent with previous studies. © 1994 Wiley-Liss, Inc. 相似文献
5.
Liu Yang Tao Li Claudia Wiese Lars Lannfelt Pierre Sokoloff Chong T. Xu Zhong Zeng Jean-Charles Schwartz Xiehe Liu Hans W. Moises 《American journal of medical genetics. Part A》1993,48(2):83-86
The D3 dopamine receptor gene is an important candidate gene for schizophrenia, since (because of its almost exclusive expression in the limbic system) it combines the dopamine receptor hypothesis with the limbic system hypothesis of schizophrenia. A BalI restriction fragment length polymorphism of the D3 dopamine receptor gene has been typed in 107 schizophrenic patients and 98 normal controls from Sichuan (China). With regard to alleles or genotypes, no significant differences were obtained between controls from Europe and China, between patients and controls, and between patient subgroups and controls. These results indicate a lack of association between schizophrenia and the D3 dopamine receptor gene in our sample. Our findings are at variance with reports of a significant excess of homozygosity at the D3 dopamine receptor gene in schizophrenic patients from Wales (United Kingdom) and Alsace (France). In conclusion, further studies will be needed with larger samples of patients from Wales and Alsace as well as with samples of different racial groups to prove or disprove the initial positive association between schizophrenia and genotypes of the D3 dopamine receptor gene. © 1993 Wiley-Liss, Inc. 相似文献
6.
Alessio Squassina Matthew Lanktree Vincenzo De Luca Umesh Jain Marilee Krinsky James L. Kennedy Pierandrea Muglia 《Neuroscience letters》2008
Several lines of evidence from neuroimaging, pharmacology and genetics support the involvement of the dopaminergic system in the etiology of Attention Deficit Hyperactivity Disorder (ADHD). Previous candidate gene studies have investigated the association between a dinucleotide (CA)n repeat polymorphism, located 18.5 kb from the start codon of the DRD5 gene, and ADHD. Association between the 148 bp allele and ADHD has been reported in some studies, however replication of the finding has not been consistent. We tested for an association between the (CA)n repeat and adult ADHD in a sample comprised of 119 families with adult ADHD probands and 88 unrelated adult ADHD cases with a corresponding number of controls matched for age, ethnicity and sex. In the family sample we found a non-significant trend for association between the 148 bp allele and ADHD (Z = 1.91, p = 0.055). An excess of non-transmissions was detected for the 150 and 152 bp alleles (Z = −2.26, p = 0.023; Z = −2.20, p = 0.028). Quantitative analysis performed using the Brown Attention Deficit Disorder Scale (BADDS) showed association between the 150 bp allele and lower total score (p = 0.011), and lower effort (p = 0.008), activation (p = 0.008) and attention (p = 0.01) cluster scores. We did not replicate association findings in the case–control group, likely due to the lack of statistical power of this sample. Our findings add to the literature suggesting DRD5 (CA)n repeat has a modest effect in modulating susceptibility to adult ADHD but further studies are required. 相似文献
7.
Shinichiro Nanko Akira Ueki Mineko Hattori Xiao Y. Dai Tsukasa Sasaki Rimmei Fukuda Kazuhiko Ikeda Hajime Kazamatsuri 《American journal of medical genetics. Part A》1994,54(4):361-364
Parkinson's disease is thought to be caused by a combination of unknown environmental, genetic, and degenerative factors. Evidence from necropsy brain samples and pharmacokinetics suggests involvement of dopamine receptors in the pathogenesis or pathophysiology of Parkinson's disease. Genetic association studies between Parkinson's disease and dopamine D2, D3 and D4 receptor gene polymorphisms were conducted. The polymorphism was examined in 71 patients with Parkinson's disease and 90 controls. There were no significant differences between two groups in allele frequencies at the D2, D3, and D4 dopamine receptor loci. Our findings do not support the hypothesis that susceptibility to Parkinson's disease is associated with the dopamine receptor polymorphisms examined. © 1994 Wiley-Liss, Inc. 相似文献
8.
Evidence for an Association of the Dopamine D5 Receptor Gene on Age at Onset of Attention Deficit Hyperactivity Disorder 总被引:3,自引:0,他引:3
J. Lasky-Su J. Biederman N. Laird M. Tsuang A. E. Doyle J. W. Smoller C. Lange S. V. Faraone 《Annals of human genetics》2007,71(5):648-659
The purpose of this study was to determine whether the single nucleotide polymorphisms (SNPs) within candidate genes for attention deficit hyperactivity disorder (ADHD) are associated with the age at onset for ADHD. One hundred and forty-three SNPs were genotyped across five candidate genes ( DRD5 , SLC6A3 , HTR1B , SNAP25 , DRD4 ) for ADHD in 229 families with at least one affected offspring. SNPs with the highest estimated power to detect an association with age at onset were selected for each candidate gene, using a power-based screening procedure that does not compromise the nominal significance level. A time-to-onset analysis for family-based samples was performed on these SNPs to determine if an association exists with age at onset for ADHD. Seven consecutive SNPs surrounding the D5 dopamine receptor gene ( DRD5 ), were associated with the age at onset for ADHD; FDR adjusted q-values ranged from 0.008 to 0.023. This analysis indicates that individuals with the risk genotype develop ADHD earlier than individuals with any other genotype. A haplotype analysis across the 6 significant SNPs that were in linkage disequilibrium with one another, CTCATA , was also found to be significant (p-value = 0.02). We did not observe significant associations with age at onset for the other candidate loci tested. Although definitive conclusions await independent replication, these results suggest that a variant in DRD5 may affect age at onset for ADHD. 相似文献
9.
The current study used a variable- and person-centered approach to examine whether a DRD4 polymorphism explained within-individual differences in frequency of marijuana use from adolescence into emerging adulthood. Data were analyzed from 1897 respondents from the genetic subsample of the National Longitudinal Study of Adolescent Health (Add Health) at waves I (ages 13–17), II (ages 14–18), and III (ages 21–25). Latent class growth model results revealed that marijuana use was characterized by four trajectories (non-users/experimenters, increasers, desisters, and chronic users), and that the DRD4 polymorphism differentiated increasers from non-users/experimenters. Overall, the results suggested that the DRD4 polymorphism may be relevant to differences in the developmental trajectories of marijuana use. 相似文献
10.
《Journal of neurogenetics》2012,26(4):209-217
AbstractOrganizational inefficiency and inattention are speculated to be the reason for executive deficit (ED) of ADHD probands. Even with average IQ, probands often perform poorly due to higher inattention. Pharmacotherapy, cognitive behavioural therapy, and counselling provide only symptomatic relief. Several candidate genes showed involvement with ADHD; the most consistent are dopamine receptor 4 (DRD4) and solute carrier family 6 member 3 (SLC6A3). We analyzed association of rarely investigated DRD4 and SLC6A3 variants with ADHD core traits in Indo-Caucasoid probands. ED, inattention, organizational efficiency, and IQ were measured by Barkley Deficit in Executive Functioning-Child & Adolescent scale, DSM-IV-TR, Conners’ Parent Rating Scale-revised, and WISC respectively. Target sites were analyzed by PCR, RFLP, and/or Sanger sequencing of genomic DNA. DRD4 variants mostly affected inattention while SLC6A3 variants showed association with IQ. Few DRD4 and SLC6A3 variants showed dichotomous association with IQ and inattention. DRD4 Exon3 VNTR >4R showed negative impact on all traits excepting IQ. Inattention showed correlation with attention span, organizational efficiency, and ED, while IQ failed to do so. We infer that IQ and attention could be differentially regulated by dopaminergic gene variants affecting functional efficiency in ADHD and the two traits should be considered together for providing better rehabilitation. 相似文献