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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis--with the pedigree disequilibrium test and the family-based association test--and for genotypic and haplotypic association analysis--with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.
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PMID:Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism. 1608 Jan 14

Disruption of gamma-aminobutyric acid (GABAergic) interneuron development during the embryonic and early postnatal periods can have profound neurological and behavioral consequences. Hepatocyte growth factor/scatter factor (HGF/SF) has been identified as an important molecular cue that may guide the movement of interneurons from their birthplace in the ganglionic eminences (GE) to their final resting place in the neocortex. In vitro studies demonstrate that decreased HGF/SF bioactivity in pallial and subpallial tissues is associated with a reduction in the number of cells migrating out of GE explants. The uPAR knockout mouse provides a unique opportunity to study the effects of interneuron disruption in vivo. uPAR-/- mice have reduced HGF/SF bioactivity in the GE during the period of interneuron development and a concomitant 50% reduction in the number of GABAergic interneurons seeding frontal and parietal regions of the cerebral cortex. Behaviorally, these mice display an increased susceptibility to seizures, heightened anxiety, and diminished social interaction. This article discusses the commonalities between the functional defects seen in uPAR-/- mice and those of humans with developmental disorders, such as epilepsy, schizophrenia, and autism. It is suggested that disruption of GABAergic interneuron development may represent a common point of convergence underlying the etiologies of many of these developmental disorders.
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PMID:Disruption of interneuron development. 1620 92

Significant progress has been made in the search for underlying pathophysiologic mechanisms in autism over the past 50 years. The cause of the disorder, however, remains largely unknown. This article reviews neurochemical contributions to the pathophysiology of autism with a focus on monoamines, glutamate/gamma-aminobutyric acid systems, and neuropeptides. As these efforts move forward, it will be important to begin to integrate genetic studies with those involving neuroimaging and postmortem research in each of these 3 areas, as well as with pharmacologic treatment approaches.
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PMID:Neurochemistry in the pathophysiology of autism. 1640 Nov 45

Autistic regression seems to occur in about a quarter of children with autism. Its cause is unknown. Late-onset autistic regression, that is, after 2 years of age, shares some features with catatonic regression. A working hypothesis is developed that some children with autistic regression suffer from early-onset catatonic regression. This hypothesis cannot be answered from current data and is difficult to address in clinical studies in the absence of definite markers of autistic and catatonic regression. Treatment implications are theoretical and involve the potential use of anticatatonic treatments for autistic regression. Focus is on electroconvulsive therapy (ECT)--an established but controversial treatment that is viewed by many, but not all, as the most effective treatment for severe, life-threatening catatonic regression. Clinical trials of ECT in early- or late-onset autistic regression in children have not been done yet. The effects of electroconvulsive seizures--the experimental analogue of ECT--should also be tested in gamma-aminobutyric acid-ergic animal models of autistic regression, autism, catatonia, and other neurodevelopmental disorders. Purkinje cell survival and neurogenesis are putative outcome measures in these models.
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PMID:Are autistic and catatonic regression related? A few working hypotheses involving gaba, Purkinje cell survival, neurogenesis, and ECT. 1669 91

We have compiled significant linkage results from 20 genome scans for the autism syndrome disorder (ASD) and 2 for catatonia in schizophrenia (SZ). Localization of the markers has been updated across the studies using the same cytological (Genetic Location Database), physical (National Center for Biological Information), and genetic (Marshfield) maps. Eight autosomal chromosomes (1, 2, 3, 7, 9, 13, 15, and 17) showed significant linkages with ASD, and one with catatonia (15). Chromosome 15 was further characterized for SZ genome scans (N = 4) since catatonia was observed in SZ patients, for candidate genes for ASD and catatonia, and for the numerous chromosomal rearrangement and abnormalities associated to ASD. From these results, we observed that four potential susceptibility regions for ASD could be observed on chromosome 15 at 15q11-q13, 15q14-q21, 15q22-q23, and 15q26, respectively. All the four regions were shared between ASD and SZ, with 15q15-q21 being also shared with catatonia. Strong candidate genes, such as gamma-aminobutyric acid receptor B3, A5, and G3, have shown associations with ASD at 15q11-q13 susceptibility region where the majority of the chromosomal rearrangements are also found. On the other hand, negative association results were observed at 15q14-q21 susceptibility region for catatonia with the genes encoding the zinc transporter SLC30A4, the cholinergic receptor nicotinic alpha polypeptide 7, and the delta-like 4 Drosophila. Further, fine mapping and candidate gene analyses are needed to highlight potential common genes between ASD and catatonia for this chromosome.
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PMID:Shared susceptibility region on chromosome 15 between autism and catatonia. 1669 97

The blueprints for the assessment, treatment, and future study of catatonia in autism spectrum disorders (ASDs), which are submitted in this chapter aim to increase early recognition and treatment of catatonia in ASDs, show the urgency of controlled treatment trials, and increase collaborative and interdisciplinary research into the co-occurrence of these two enigmatic disorders. Catatonia should be assessed in any patient with ASDs when there is an obvious and marked deterioration in movement, pattern of activities, self-care, and practical skills, compared with previous levels, through a comprehensive diagnostic evaluation of medical and psychiatric symptoms. A formal diagnosis should be ascertained using ASD specific criteria for catatonia that takes into account baseline symptoms like muteness, echophenomena, stereotypy, negativism, or other psychomotor abnormalities. Any underlying medical and neurological conditions should be treated, and culprit medications or other substances that may cause catatonia should be eliminated. Separate treatment blueprints are presented for mild, moderate, and severe catatonia, featuring combinations of a psychological approach developed by Shah and Wing and medical treatments that have shown efficacy in catatonia: lorazepam challenge, lorazepam trial, lorazepam continuation, and bilateral electroconvulsive therapy (ECT). These treatment modalities in themselves are well established. Side effects and complications are known and manageable. Legal, ethical, and practice guidelines governing all treatment aspects should be followed. The treatment blueprints should be viewed as best estimates pending future controlled studies. The blueprint for the future study of catatonia in ASDs describes promising clinical and preclinical research avenues. Longitudinal studies need to assess the possible effect of early recognition and adequate treatment of catatonia in ASDs in order to avoid the impairment associated with chronicity. Effects of current and new anticatatonic treatments should be examined in experimental models of autism and catatonia. Finally, the role of gamma-aminobutyric acid (GABA) dysfunction in autism, catatonia, and abnormal stress responses in these disorders should be further assessed.
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PMID:Blueprints for the assessment, treatment, and future study of catatonia in autism spectrum disorders. 1669 3

The gamma-aminobutyric acid (GABA) receptor genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11-q13 have been major candidates for susceptibility genes for autism, a neurodevelopmental disorder with a complex genetic etiology. In this study, we first investigated the association between the GABA receptor genes and autism in a Japanese population by analyzing 11 single nucleotide polymorphisms (SNPs). Intron 3 of GABRB3 was densely mapped because the previous studies observed the association of the microsatellite 155CA-2 located in the region. We observed no significant difference in allelic frequencies or genotypic distributions of the 11 SNPs between patients and controls. A permutation test showed no significant global differences in estimated haplotype frequencies between patients and controls. Analysis after confining the subjects to males showed similar results. Thus, this study provides no positive evidence of an association between the GABA receptor genes and autism in a Japanese population. However, in a SNP (rs3212337) located near the microsatellite 155CA-2, a significant deviation from the Hardy-Weinberg equilibrium was observed in patients (p = 0.029, corrected for multiple testing). This finding may suggest further studies around the markers for more definitive conclusions.
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PMID:No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population. 1795 31

Since there is a strong correlation between tuberous sclerosis and autism, we used a tuberous sclerosis model (Eker rat) to test the hypothesis that the increased regional cerebral O(2) consumption in the Eker rat might be associated with autism. We also examined whether this increased cerebral O(2) consumption was related to changes in the activity of the gamma-aminobutyric acid (GABA) inhibitory system. Young (4 weeks) male control Long Evans (n=14) and Eker (n=14) rats (70-100g) were divided into control and bicuculline (1mg/kg/min for 2 min then 0.1mg/kg/min for 13 min, GABA(A) receptor antagonist) treated animals. Cerebral regional blood flow ((14)C-iodoantipyrine) and O(2) consumption (cryomicrospectrophotometry) were determined in isoflurane anesthetized rats. We found significantly increased basal O(2) consumption in the cortex (6.3+/-0.7 ml O(2)/min/100g Eker vs. 5.1+/-0.2 ml O(2)/min/100g control), hippocampus and cerebellum, but not the pons. Regional cerebral blood flow was also elevated in the cortex and hippocampus in Eker rats at baseline, but cerebral O(2) extractions were similar. Bicuculline significantly increased O(2) consumption in the cortex (6.5+/-0.3) and all other regions of the control rats, but had no effect on cortex (5.9+/-1.5) or other regions of the Eker rats. Cerebral blood flow followed a similar pattern. In conclusion, Eker rats had significantly elevated cerebral O(2) consumption and blood flow, but this was not affected by GABA receptor blockade. This suggested a reduced activity of the GABA(A) receptor in the brains of Eker rats. This may have important implications in the treatment of autism.
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PMID:Cerebral O(2) consumption in young Eker rats, effects of GABA blockade: implications for autism. 1828 78

Gamma-aminobutyric acid A (GABA(A)) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the expression of four GABA(A) receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann's Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABA(A) receptor subunit expression in the three brain areas. Our results demonstrate that GABA(A) receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism.
J Autism Dev Disord 2009 Feb
PMID:GABA(A) receptor downregulation in brains of subjects with autism. 1882 Oct 8

Autism is a neurodevelopmental disorder that is often comorbid with seizures. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in brain. GABA(B) receptors play an important role in maintaining excitatory-inhibitory balance in brain and alterations may lead to seizures. We compared levels of GABA(B) receptor subunits GABA(B) receptor 1 (GABBR1) and GABA(B) receptor 2 (GABBR2) in cerebellum, Brodmann's area 9 (BA9), and BA40 of subjects with autism and matched controls. Levels of GABBR1 were significantly decreased in BA9, BA40, and cerebellum, while GABBR2 was significantly reduced in the cerebellum. The presence of seizure disorder did not have a significant impact on the observed reductions in GABA(B) receptor subunit expression. Decreases in GABA(B) receptor subunits may help explain the presence of seizures that are often comorbid with autism, as well as cognitive difficulties prevalent in autism.
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PMID:Expression of GABA(B) receptors is altered in brains of subjects with autism. 1900 45


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