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)

Platelet monoamine oxidase activity was measured in 9 autistic subjects and 9 controls. There were no significant differences in the rates of metabolism of 5-hydroxytryptamine, dopamine or tyramine between the two groups, although the rate of metabolism of tyramine was more rapid than 5-hydroxytryptamine or dopamine within each group. It is concluded that the data presented do not support the view that measurement of platelet monoamine oxidase can be used as a biochemical index to aid in the clinical diagnosis of infantile autism.
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PMID:Platelet monoamine oxidase in children with infantile autism. 118 19

Fenfluramine, an anorexigenic drug, lowers serotonin (5-hydroxytryptamine) and 5-hydroxyindoleacetic acid levels in brain, spinal fluid, and blood, and has been used as a treatment for autism. Fenfluramine's mode of action is unknown. We present evidence from chromatography and nuclear magnetic resonance spectroscopy that fenfluramine selectively binds the serotonin and 5-hydroxyindoleacetic acid precursor, 5-hydroxytryptophan. The mode of binding may have general applications for the understanding of drug activity, receptor binding, and for the design of specific antagonists to aromatic compounds.
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PMID:Fenfluramine binds 5-hydroxytryptophan. 620 Dec 40

Whole blood and urinary levels of serotonin (5-hydroxytryptamine; 5-HT) and the derivative urinary 5-hydroxyindoleacetic acid (5-HIAA) were measured in normal and autistic subjects. An association was tested between autism and a marker coding for the 5-HT2A serotonergic receptor gene. Significant group (high urinary 5-HT and low whole blood 5-HT in autism) and age effects (urinary 5-HT decrease with age) were found. Moreover, whole blood 5-HT levels were correlated with clinical state. No differences in allele and genotype frequencies for the 5-HT2A receptor marker were found in this autistic population compared with age-matched healthy students.
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PMID:Serotonin and autism: biochemical and molecular biology features. 895 59

The serotonin system has been implicated as a factor in some cases of autism since the finding in 1961 of elevated serotonin (5-hydroxytryptamine) levels in the blood of patients with autism. This has been clarified as elevation in the platelet content of serotonin. Subjects with elevated whole blood serotonin levels have been shown to have elevated platelet serotonin transport into platelets and decreased serotonin 5-HT2 receptor binding. Most individuals with autism who are treated with potent serotonin transporter inhibitors have a reduction in ritualistic behavior and aggression. Reduction of central nervous system serotonin, induced by acute tryptophan depletion, causes a worsening of stereotyped behavior. Recent developments in the molecular biology of serotonin receptors are reviewed.
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PMID:The serotonin system in autism. 905 96

Tetrahydrobiopterin (BH(4)) cofactor is essential for various processes, and is present in probably every cell or tissue of higher organisms. BH(4) is required for various enzyme activities, and for less defined functions at the cellular level. The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase. Based on gene cloning, recombinant expression, mutagenesis studies, structural analysis of crystals and NMR studies, reaction mechanisms for the biosynthetic and recycling enzymes were proposed. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I, the expression of which may be under the control of cytokine induction. In the liver at least, activity is inhibited by BH(4), but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory protein. The enzymes that depend on BH(4) are the phenylalanine, tyrosine and tryptophan hydroxylases, the latter two being the rate-limiting enzymes for catecholamine and 5-hydroxytryptamine (serotonin) biosynthesis, all NO synthase isoforms and the glyceryl-ether mono-oxygenase. On a cellular level, BH(4) has been found to be a growth or proliferation factor for Crithidia fasciculata, haemopoietic cells and various mammalian cell lines. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia. Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer's disease, Parkinson's disease, autism and depression, have been suggested to be a consequence of restricted cofactor availability.
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PMID:Tetrahydrobiopterin biosynthesis, regeneration and functions. 1072 95

Autism is a pervasive developmental disorder that is aetiologically and clinically heterogeneous. Twin and family-genetic studies provide evidence for strong genetic components. An international consortium using an affected sib pair strategy has found a promising linkage to a region on chromosome 7. In 10 to 15% of cases autism is due to associated medical conditions that affect normal brain functioning. Postmortem studies on small case series report cellular abnormalities in the limbic system and cerebellum. Between 10 and 20% of individuals with autism have macrocephalia, which is in accordance with magnetic resonance imaging (MRI) findings of an increased total brain tissue volume and enlargement most prominent in the occipital and parietal lobes. The most robust and well replicated neurobiological abnormality in autism is an elevation of whole blood serotonin (5-hydroxytryptamine; 5-HT) found in over 30% of patients. Pharmacological interventions with serotonin reuptake inhibitors or with atypical neuroleptics that block both dopamine (D2) and serotonin (5-HT2) receptors seem to offer clinical benefit and merit further study.
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PMID:Autism: current theories regarding its pathogenesis and implications for rational pharmacotherapy. 1093 59

Serotonin (5-hydroxytryptamine, 5-HT) appears to play a role in the pathophysiology of a range of neuropsychiatric disorders, and serotonergic agents are of central importance in neuropharmacology. Genes encoding various components of the 5-HT system are being studied as risk factors in depression, schizophrenia, obsessive-compulsive disorder, aggression, alcoholism, and autism. Recently, pharmacogenetic research has begun to examine possible genetic influences on therapeutic response to drugs affecting the serotonin system. Genes regulating the synthesis (TPH), storage (VMAT2), membrane uptake (HTT), and metabolism (MAOA) of 5-HT, as well as a number of 5-HT receptors (HTR1A, HTR1B, HTR2A, HTR2C, and HTR5A), have been studied and this initial research is reviewed here. After a brief introduction to serotonin neurobiology and a general discussion of appropriate genetic methodology, each of the major 5-HT-related genes and their encoded proteins are reviewed in turn. For each gene, relevant polymorphisms and research on functional variants are discussed; following brief reviews of the disorder or trait association and linkage studies, pharmacogenetic studies performed to date are covered. The critical and manifold roles of the serotonin system, the great abundance of targets within the system, the wide range of serotonergic agents-available and in development-and the promising preliminary results suggest that the serotonin system offers a particularly rich area for pharmacogenetic research.
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PMID:Pharmacogenetics and the serotonin system: initial studies and future directions. 1113 68

Neonatal Borna disease virus (BDV) infection of the rat's brain produces neurodevelopmental damage similar to some pathological and clinical features of human developmental disorders, e.g., autism and schizophrenia. Since BDV-infected rats exhibited an inhibition of postnatal weight gain, the present study sought to evaluate a contribution of nutritional status to virus-induced neurodevelopmental injury. We compared neuroanatomical, neurochemical, and behavioral alterations following neonatal BDV infection and rearing in the oversized litters in Fischer344 rats on postnatal day (PND) 26. Despite a comparable weight gain inhibition, different patterns of brain pathology, alterations in brain monoamine systems, and behavioral deficits were observed in the BDV-infected rats compared to the malnourished rats. While no appreciable cell injury was noted in the brains of the malnourished rats, a significant loss of Purkinje cells (PC) and early signs of degeneration of the hippocampal dentate gyrus were found in the BDV-infected rats. Both neonatal BDV infection and postnatal malnourishment increased tissue concentrations of serotonin [5-hydroxytryptamine (5-HT)] in the hippocampus. In contrast, increased turnover of 5-HT in the cortex and hippocampus and elevated turnover of dopamine (DA) in the striatum were found in the malnourished rats only, suggesting that different pathogenic mechanisms might underlie monoamine disturbances in virus-infected and malnourished rats. The observed dissimilar neuroanatomical and neurochemical abnormalities might explain the different responses to novelty in the BDV-infected and malnourished rats. Compared to the control rats, the BDV-infected rats exhibited novelty-induced hyperactivity, while no differences in locomotion were noted between the control and malnourished rats. Taken together, the present data indicate that virus-associated inhibition of postnatal weight gain is unlikely to account for the major BDV-associated neurodevelopmental alterations that seem to be due to specific effects of neonatal BDV infection.
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PMID:Postnatal weight gain inhibition does not account for neurobehavioral consequences of neonatal Borna disease virus infection. 1463 36

The biological causes of autism are unknown. Since the early 1960s, the most consistent pathophysiological finding in autistic individuals has been their statistically elevated blood 5-hydroxytryptamine (5-HT, serotonin) levels. However, many autistic individuals have normal blood 5-HT levels, so this finding has been difficult to interpret. The serotonin transporter (SERT) controls 5-HT uptake by blood platelets and has been implicated in autism, but recent studies have found no correlation between SERT polymorphisms and autism. Finally, autism is considered a brain disorder, but studies have so far failed to find consistent serotonergic abnormalities in autistic brains. A simple mathematical model may account for these paradoxes, if one assumes that autism is associated with the failure of a molecular mechanism that both regulates 5-HT release from gut enterochromaffin cells and mediates 5-HT signaling in the brain. Some 5-HT receptors may play such a dual role. While the failure of such a mechanism may lead to consistent abnormalities of synaptic transmission with no alteration of brain 5-HT levels, its effects on blood 5-HT levels may appear paradoxical.
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PMID:Serotonergic paradoxes of autism replicated in a simple mathematical model. 1569 91

Serotonin (5-hydroxytryptamine, 5-HT) is an amine neurotransmitter derived from tryptophan and is important in brain systems regulating mood, emotional behavior, and sleep. Selective serotonin reuptake inhibitor (SSRI) drugs are used to treat disorders such as depression, stress, eating disorders, autism, and schizophrenia. It is thought that these drugs act to prolong the action of 5-HT by blocking reuptake. This may lead to decreased 5-HT content in the nerve fibers themselves; however, this has not previously been directly demonstrated. We have studied the effects of administration of two drugs, imipramine and citalopram, on levels of 5-HT in nerve fibers in the murine brain. Quantitative analysis of the areal density of 5-HT fibers throughout the brain was performed using ImageJ software. While a high density of fibers was observed in mid- and hind-brain regions and areas such as thalamus and hypothalamus, densities were far lower in areas such as cortex, where SSRIs might be thought to exert their actions. As anticipated, imipramine and citalopram produced a decline in 5-HT levels in nerve fibers, but the result was not uniform. Areas such as inferior colliculus showed significant reduction whereas little, if any, change was observed in the adjacent superior colliculus. The reason for, and significance of, this regionality is unclear. It has been proposed that serotonin effects in the brain might be linked to changes in glutamatergic transmission. Extracellular glutamate levels are regulated primarily by glial glutamate transporters. Qualitative evaluation of glutamate transporter immunolabeling in cortex of control and drug-treated mice revealed no discernable difference in intensity of glutamate transporter immunoreactivity. These data suggest that changes in intracellular and extracellular levels of serotonin do not cause concomitant changes in astroglial glutamate transporter expression, and thus cannot represent a mechanism for the delayed efficacy of antidepressants when administered clinically.
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PMID:Quantitative analysis of immunolabeling for serotonin and for glutamate transporters after administration of imipramine and citalopram. 1585 94


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