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

This paper attempts to view the autistic syndrome in the context of a disorder of brain development. The authors review some of the known or suspected causes of the autistic syndrome: maternal rubella, metabolic diseases, and heredity. Some basic principles of cellular neuroanatomy and chemical neurotransmission are sketched. The stages of human brain development from neurulation through histogenesis, cell migration, and elaboration of dendritic trees and axonal projections are described. The authors conclude that there are a limited number of developmental loci that could be disrupted and lead to the autistic syndrome, and that these most probably occur in the end stages of neuronal development, after the migrating neurons have reached their final place in the brain and have begun to elaborate communicative processes. Finally, the authors speculate on how neurochemical disturbances might alter end stage neuronal differentiation leading to the pathology of infantile autism.
J Autism Dev Disord 1982 Jun
PMID:Intrinsic and extrinsic determinants of neuronal development: relation to infantile autism. 612 37

Infantile autism is a syndrome of unknown aetiology and unknown neuro-anatomic substrate. The authors report a histological study of the brain of a well-documented 16-year-old female with autistic syndrome and severe mental retardation, using direct microscopic examination of the whole brain. The major findings are low brain weight, a thin corpus callosum and ventricular dilatation. No abnormalities were found in the hippocampus or cerebellum. Excessive axonal elimination during brain development is hypothesized. The relations of hypothetical developmental events with the clinical features of autistic syndrome are discussed.
 ...
PMID:Neuropathological study of a case of autistic syndrome with severe mental retardation. 863 17

Oligodendrocyte-myelin glycoprotein (OMgp) is expressed on the surface of oligodendrocytes and neurones and is thought to inhibit axonal regeneration after brain injury in adult, like Nogo and myelin-associated glycoprotein (MAG). We previously observed that the OMgp gene locus on chromosome 17 could be associated with autism, a developmental disorder. The aim of the present study was to characterise the developmental expression of OMgp mRNA in the central nervous system. First we determined the rat OMgp gene sequence and compared it with the human and mouse sequences. Several regions, putative sites for the fixation of transcription factors, are conserved between these three species in the unique intron of this gene. Using quantitative and semi-quantitative RT-PCR, we studied OMgp gene expression in rat brain during post-natal development. We found that OMgp mRNA expression was developmentally regulated, with a peak of expression in the late stages of myelination. We observed a similar profile in oligodendrocyte cultures, in absence of neurones, suggesting that OMgp mRNA expression by oligodendrocytes was independent of axonal influence. Our observations suggest that OMgp is a late marker of myelination, which could be implicated in the arrest of oligodendrocyte proliferation, arrest of myelination or compaction of myelin.
 ...
PMID:The oligodendrocyte-myelin glycoprotein gene is highly expressed during the late stages of myelination in the rat central nervous system. 1293 13

Recent studies have highlighted novel functions of a group of cell adhesion molecules during nervous system development. Members of this protein family are characterized by an extracellular domain with sequence homology to cholinesterases and include the neuroligins, synaptic cell adhesion molecules recently implicated in autism, and neurotactin, a cell surface receptor involved in axonal pathfinding. Although these proteins have a structural organization similar to the enzyme acetylcholinesterase, the cholinesterase domain lacks enzymatic activity and functions as a protein-protein interaction motif. This protein family provides a striking example of how the function of a catalytically active domain has evolved to mediate receptor-ligand interactions that regulate morphogenetic processes during development of the nervous system.
 ...
PMID:Making connections: cholinesterase-domain proteins in the CNS. 1458 2

Rett syndrome (RTT) is a severe neurodevelopmental disorder with features of autism that results from mutation of the gene encoding the transcriptional repressor methyl-CpG binding protein (MECP2). The consequences of loss of a transcription factor may be complex, affecting the expression of many proteins, thus limiting understanding of this class of diseases and impeding therapeutic strategies. This is true for RTT. Neither the cell biological mechanism(s) nor the developmental stage affected by MECP2 deficiency is known. In vivo analysis of the olfactory system demonstrates that Mecp2 deficiency leads to a transient delay in the terminal differentiation of olfactory neurons. This delay in maturation disrupts axonal targeting in the olfactory bulb, resulting in abnormal axonal projections, subglomerular disorganization, and a persistent reduction in glomerular size. These results indicate a critical cell biological function for Mecp2 in mediating the final stages of neuronal development.
 ...
PMID:The transcriptional repressor Mecp2 regulates terminal neuronal differentiation. 1534 42

The Smith-Lemli-Opitz syndrome is a mental retardation/malformation syndrome with behavioral components of autism. It is caused by a deficiency in 3beta-hydroxysteroid-Delta7-reductase (DHCR7), the enzyme required for the terminal enzymatic step of cholesterol biosynthesis. The availability of Smith-Lemli-Opitz syndrome mouse models has made it possible to investigate the genesis of the malformations associated with this syndrome. Dhcr7 gene modification (Dhcr7-/-) results in neonatal lethality and multiple organ system malformations. Pathology includes cleft palate, pulmonary hypoplasia, cyanosis, impaired cortical response to glutamate, and hypermorphic development of hindbrain serotonergic neurons. For the current study, hindbrain regions microdissected from gestational day 14 Dhcr7-/-, Dhcr7+/- and Dhcr7+/+ fetuses were processed for expression profiling analyses using Affymetrix oligonucleotide arrays and filtered using statistical significance (S-score) of change in gene expression. Of the 12,000 genes analyzed, 91 were upregulated and 98 were downregulated in the Dhcr7-/- hindbrains when compared to wild-type animals. Fewer affected genes, representing a reduced affect on these pathways, were identified in heterozygous animals. Hierarchical clustering identified altered expression of genes associated with cholesterol homeostasis, cell cycle control and apoptosis, neurodifferentiation and embryogenesis, transcription and translation, cellular transport, neurodegeneration, and neuronal cytoskeleton. Of particular interest, Dhcr7 gene modification elicited dynamic changes in genes involved in axonal guidance. In support of the microarray findings, immunohistochemical analyses of the netrin/deleted in colorectal cancer axon guidance pathway illustrated midline commissural deficiencies and hippocampal pathfinding errors in Dhcr7-/- mice. The results of these studies aid in providing insight into the genesis of human cholesterol-related birth defects and neurodevelopmental disorders and highlight specific areas for future investigation.
 ...
PMID:Immunohistochemical and microarray analyses of a mouse model for the smith-lemli-opitz syndrome. 1628 Jun 35

The immunopathogenesis of autism is presented schematically in Fig. 1. Two main immune dysfunctions in autism are immune regulation involving pro-inflammatory cytokines and autoimmunity. Mercury and an infectious agent like the measles virus are currently two main candidate environmental triggers for immune dysfunction in autism. Genetically immune dysfunction in autism involves the MHC region, as this is an immunologic gene cluster whose gene products are Class I, II, and III molecules. Class I and II molecules are associated with antigen presentation. The antigen in virus infection initiated by the virus particle itself while the cytokine production and inflammatory mediators are due to the response to the putative antigen in question. The cell-mediated immunity is impaired as evidenced by low numbers of CD4 cells and a concomitant T-cell polarity with an imbalance of Th1/Th2 subsets toward Th2. Impaired humoral immunity on the other hand is evidenced by decreased IgA causing poor gut protection. Studies showing elevated brain specific antibodies in autism support an autoimmune mechanism. Viruses may initiate the process but the subsequent activation of cytokines is the damaging factor associated with autism. Virus specific antibodies associated with measles virus have been demonstrated in autistic subjects. Environmental exposure to mercury is believed to harm human health possibly through modulation of immune homeostasis. A mercury link with the immune system has been postulated due to the involvement of postnatal exposure to thimerosal, a preservative added in the MMR vaccines. The occupational hazard exposure to mercury causes edema in astrocytes and, at the molecular level, the CD95/Fas apoptotic signaling pathway is disrupted by Hg2+. Inflammatory mediators in autism usually involve activation of astrocytes and microglial cells. Proinflammatory chemokines (MCP-1 and TARC), and an anti-inflammatory and modulatory cytokine, TGF-beta1, are consistently elevated in autistic brains. In measles virus infection, it has been postulated that there is immune suppression by inhibiting T-cell proliferation and maturation and downregulation MHC class II expression. Cytokine alteration of TNF-alpha is increased in autistic populations. Toll-like-receptors are also involved in autistic development. High NO levels are associated with autism. Maternal antibodies may trigger autism as a mechanism of autoimmunity. MMR vaccination may increase risk for autism via an autoimmune mechanism in autism. MMR antibodies are significantly higher in autistic children as compared to normal children, supporting a role of MMR in autism. Autoantibodies (IgG isotype) to neuron-axon filament protein (NAFP) and glial fibrillary acidic protein (GFAP) are significantly increased in autistic patients (Singh et al., 1997). Increase in Th2 may explain the increased autoimmunity, such as the findings of antibodies to MBP and neuronal axonal filaments in the brain. There is further evidence that there are other participants in the autoimmune phenomenon. (Kozlovskaia et al., 2000). The possibility of its involvement in autism cannot be ruled out. Further investigations at immunological, cellular, molecular, and genetic levels will allow researchers to continue to unravel the immunopathogenic mechanisms' associated with autistic processes in the developing brain. This may open up new avenues for prevention and/or cure of this devastating neurodevelopmental disorder.
 ...
PMID:Immunological findings in autism. 1651 56

CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3beta. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.
 ...
PMID:Pten regulates neuronal arborization and social interaction in mice. 1667 86

There is strong evidence for the importance of genetic factors in idiopathic autism. The results from independent twin and family studies suggest that the disorder is caused by the action of several genes, possibly acting epistatically. We have used cDNA microarray technology for the identification of constitutional changes in the gene expression profile associated with idiopathic autism. Samples were obtained and analyzed from 6 affected subjects belonging to multiplex autism families and from 6 healthy controls. We assessed the expression levels for approximately 7,700 genes by cDNA microarrays using mRNA derived from Epstein-Barr virus-transformed B lymphocytes. The microarray data were analyzed in order to identify up- or downregulation of specific genes. A common pattern with nine downregulated genes was identified among samples derived from individuals with autism when compared to controls. Four of these nine genes encode proteins involved in biological processes associated with brain function or the immune system, and are consequently considered as candidates for genes associated with autism. Quantitative real-time PCR confirms the downregulation of the gene encoding SEMA5A, a protein involved in axonal guidance. Epstein-Barr virus should be considered as a possible source for altered expression, but our consistent results make us suggest SEMA5A as a candidate gene in the etiology of idiopathic autism.
 ...
PMID:Constitutional downregulation of SEMA5A expression in autism. 1702 46

Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro- and macro-scopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas.
 ...
PMID:Modeling early cortical serotonergic deficits in autism. 1703 75


1 2 3 4 5 6 7 8 9 10 Next >>