Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autistic disorder (OMIM 209850) is a disease with a significant genetic component of a complex nature.(1) Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region (15q11-13) have been described in several individuals with autism.(1) For this reason, markers across this region have been screened for evidence of linkage and association, and a marker (155CA-2) in the gamma-aminobutyric acid type-A receptor beta3 subunit gene (GABRB3) has been associated in one study(2) but not others.(3-5) We completed an association analysis with 155CA-2 using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). We also used four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) localized within 150 kb of 155CA-2. The use of multi-allelic TDT (MTDT) (P < 0.002), as well as the TDT (P < 0.004), demonstrated an association between autistic disorder and 155CA-2 in these families. Meiotic segregation distortion could be excluded as a possible cause for these results since no disequilibrium was observed in unaffected siblings. These findings support a role for genetic variants within the GABA receptor gene complex in 15q11-13 in autistic disorder.
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PMID:Association between a GABRB3 polymorphism and autism. 1192 Jan 58

We report a female child with tetrasomy of the 15q11-q13 chromosomal region, and autistic disorder associated with mental retardation, developmental problems and behavioral disorders. Combining classical and molecular cytogenetic approaches by fluorescence in situ hybridization technique, the karyotype was demonstrated as 47,XX,+mar.ish der(15)(D15Z1++,D15S11++,GABRB3++,PML-). Duplication of the 15q proximal segment represents the most consistent chromosomal abnormality reported in association with autism. The contribution of the GABA receptor subunit genes, and other genes mapped to this region, to the clinical symptoms of the disease is discussed.
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PMID:Tetrasomy 15q11-q13 identified by fluorescence in situ hybridization in a patient with autistic disorder. 1206 63

This paper describes the use of a GABA-transaminase agonist for the treatment of infantile autism. An approximate one third reduction of GABA and ammonia levels for an autistic patient with noticeable improvement of verbal/language skills and a reduction of repetitious ritualistic self-stimulatory behavior (stimming) was observed. A reduction of the plasma GABA (by administrating a GABA-T agonist, Imipramine) probably results in more axon(s)-to-oligodendrocyte signaling in the corpus callosum and it is postulated that this could result in a reduction of the autistic features for the patient.
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PMID:Use of a GABA-transaminase agonist for treatment of infantile autism. 1216 Jun 95

The role of secretin as a classical hormone in the gastrointestinal system is well-established. The recent debate on the use of secretin as a potential therapeutic treatment for autistic patients urges a better understanding of the neuroactive functions of secretin. Indeed, there is an increasing body of evidence pointing to the direction that, in addition to other peptides in the secretin/glucagon superfamily, secretin is also a neuropeptide. The purpose of this review is to discuss the recent data for supporting the neurocrine roles of secretin in rodents. By in situ hybridization and immunostaining, secretin was found to be expressed in distinct neuronal populations within the cerebellum and cerebral cortex, whereas the receptor transcript was found throughout the brain. In the rat cerebellum, secretin functions as a retrograde messenger to facilitate GABA transmission, indicating that it can modulate motor and other functions. In summary, the recent data support strongly the neuropeptide role of secretin, although the secretin-autism link remains to be clarified in the future.
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PMID:Secretin as a neuropeptide. 1239 59

Cohen has illustrated that extremely high Gamma-aminobutyric acid (GABA) levels in the urine and blood and high plasma ammonia were observed for an autistic male child diagnosed with infantile autism. GABA is a major inhibitory neurotransmitter of the mammalian brain and the enzyme responsible for catabolism is GABA-Transaminase (GABA-T). Elevated levels of ammonia in the plasma results in a decrease in the efficiency for the GABA-T enzyme and this results in higher GABA concentrations after regulation in the liver. It is postulated that a link between plasma ammonia and plasma GABA exists where the concentration of GABA in the plasma is directly related to the ammonia plasma concentration. A ratio of approximately 0.30 (plasma ammonia/GABA) is a consistent finding for normal subjects and for subjects with infantile autism and liver diseases such as hepatic encephalopathy.
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PMID:The significance of ammonia/gamma-aminobutyric acid (GABA) ratio for normality and liver disorders. 1244 21

Angelman syndrome is a severe neurodevelopmental disorder with cognitive impairment and neurological deficits. It results from a maternal deletion of human chromosome 15q11-13 containing two candidate genes E6-P ubiquitin-protein ligase (UBE3A) and GABA(A) receptor beta3 subunit (GABRB3), the latter of which has been also linked to autism. To clarify the potential role of GABA(A) beta3 subunit-containing inhibitory receptors in these disorders, we applied ligand autoradiography on brain sections from mice with inactivated GABRB3 or maternal UBE3A genes. Binding of GABA(A) receptor channel ([(35)S]t-butylbicyclophosphorothionate) and benzodiazepine ([(3)H]Ro 15-4513) site ligands was reduced in selected brain regions of the beta3-deficient mice as compared to controls, while the UBE3A-deficient mice failed to show reduced GABA(A) receptors. The results, suggesting two different pathophysiological mechanisms, are in agreement with positron emission tomography results from Angelman syndrome patients of the corresponding genetic backgrounds.
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PMID:Mouse models of Angelman syndrome, a neurodevelopmental disorder, display different brain regional GABA(A) receptor alterations. 1267 42

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder characterized by an inborn error of the catabolism of the inhibitory neurotransmitter GABA. Because of the deficiency of SSADH, the final enzyme of the GABA degradation pathway, the substrate, succinic semialdehyde, is shunted towards production of 4-hydroxybutyric acid (gamma-hydroxybutyric acid). Elevations of gamma-hydroxybutyric acid can be detected in the physiologic fluids of patients with SSADH deficiency, and forms the mainstay of diagnosis. The clinical features of SSADH deficiency include nonspecific neurologic manifestations such as mental retardation/developmental delay, absent speech, hypotonia, nonprogressive ataxia, features of autism or pervasive developmental delay, developmental language delay (dyspraxia, receptive, and expressive delays), and occasionally, seizures. Although the metabolic pathway has been established, it is not known whether insufficient GABA and/or excess gamma-hydroxybutyric acid contribute to the disease phenotype. Pharmacological therapy in patients with this disorder has been limited to vigabatrin, an anticonvulsant that blocks GABA transaminase. This review will discuss therapeutic options in SSADH deficiency, on the basis of patient experience, and preliminary work using a murine model. Finally, a discussion of adjunctive therapies will be included.
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PMID:Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency. 1289 56

Autism is increasingly diagnosed, but therapeutic options are limited in many children. ECT is considered as a safe, effective, and life-saving treatment in people of all ages who suffer from affective disorders, acute psychosis, and, in particular, catatonia. There are recent speculations that certain types of autism may be the earliest expression of catatonia and that both disorders have identical risk factors. Therefore, ECT may improve autism and, if started early enough, may prevent further development of autistic symptoms in some children. The use of ECT in autism has never been systematically assessed. There have been two large ECT studies in children in the 1940s. Autism was not assessed in these studies because the autistic syndrome was just then being recognized as a separate entity. Findings from these studies add little to the hypothesis that ECT may be effective in autistic children, but attest to the safety and feasibility of ECT in children. Another limitation is the use of older ECT techniques. What may well be the greatest deterrent to use ECT in autism is widespread anti- ECT sentiment not only among the public but within the medical community as well. All child specialists--psychiatrists, neurologists, psychologists, and developmental pediatricians--should independently review the feasibility, potential, and risk of using ECT in autism. Unless anti-ECT prejudice can be overcome, it is unlikely that any ECT trial in autism is forthcoming. Research areas that may support the hypothesis that ECT is effective in autism should be pursued. First, any link between autism and catatonia should be further explored in clinical and biochemical studies. A GABA theory of autism and catatonia may be pivotal. Second, the role of abnormal GABAA receptor subunit genes in autism and catatonia should be further assessed. Candidate loci for autism and catatonia have been found on the long arm of chromosome 15 where three GABAA receptor subunits genes are located. The GABAA receptor beta 3 subunit gene (GABRB3) was the leading candidate gene for a subgroup of autism in two independent studies. Third, a novel genetic mouse model of autism should be tested. Mutant mice with a targeted deletion of the GABRB3 gene have a complete deficit of the beta 3 subunit of the GABAA receptor. This knockout mouse model seems promising to study developmental effects of altered GABAA receptor function as it relates to certain developmental disorders including autism.
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PMID:Could ECT be effective in autism? 1578 May 21

Repetitive behaviors (such as circling) are one of the defining features of autism. The substantia nigra (SN) is involved in circling. We used unilateral SN pars reticulata (SNR) infusions of the GABA agonist muscimol to induce circling and deoxyglucose autoradiography mapping in adult and postnatal day (PN) 15 male and female rats to determine its substrates. In adults, muscimol infusions in posterior SNR induced a higher circling rate than in anterior SNR, after which males displayed faster circling than females. In contrast, PN15 female rats circled faster than PN15 male rats. Autoradiograms demonstrated age- and sex-specific alterations of deoxyglucose uptake in the SN pars compacta (SNC) associated with highest circling rates. The data suggest that there is a close relationship of the GABAergic SNR and dopaminergic SNC in the induction of circling; there is a topographic organization of the SNR in terms of circling behavior and associated deoxyglucose uptake, which is dependent on age and sex.
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PMID:Circling behavior and [14C]2-deoxyglucose mapping in rats: possible implications for autistic repetitive behaviors. 1568 63

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


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