UMLS:C0004352 - FACTA Search

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

Proper bodily response to environmental toxicants presumably requires proper function of the xenobiotic (foreign chemical) detoxification pathways. Links between phenotypic variations in xenobiotic metabolism and adverse environmental response have long been sought. Metabolism of the drug S-carboxymethyl-L-cysteine (SCMC) is polymorphous in the population, having a bimodal distribution of metabolites, 2.5% of the general population are thought to be nonmetabolizers. The researchers developing this data feel this implies a polymorphism in sulfoxidation of the amino acid cysteine to sulfate. While this interpretation is somewhat controversial, these metabolic differences reflected may have significant effects. Additionally, a significant number of individuals with environmental intolerance or chronic disease have impaired sulfation of phenolic xenobiotics. This impairment is demonstrated with the probe drug acetaminophen and is presumably due to starvation of the sulfotransferases for sulfate substrate. Reduced metabolism of SCMC has been found with increased frequency in individuals with several degenerative neurological and immunological conditions and drug intolerances, including Alzheimer's disease, Parkinson's disease, motor neuron disease, rheumatoid arthritis, and delayed food sensitivity. Impaired sulfation has been found in many of these conditions, and preliminary data suggests that it may be important in multiple chemical sensitivities and diet responsive autism. In addition, impaired sulfation may be relevant to intolerance of phenol, tyramine, and phenylic food constituents, and it may be a factor in the success of the Feingold diet. These studies indicate the need for the development of genetic and functional tests of xenobiotic metabolism as tools for further research in epidemiology and risk assessment.
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PMID:Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus on sulfur-dependent detoxification pathways. 871 48

The advances in medical technology during the last four decades has provided evidence for an underlying neurological basis for autism. The etiology for the variations of neurofunctional anomalies found in the autistic spectrum behaviors appears inconclusive as of this date but growing evidence supports the proposal that chronic exposure to toxic agents, i.e., xenobiotic agents, to a developing central nervous system may be the best model for defining the physiological and behavioral data found in these populations. A total of 20 subjects (15 males and 5 females) who received a formal diagnosis of autism by a developmental pediatrician, pediatric neurologist, or licensed psychologist were included. The mean age for the sample was 6.35 yrs offnge = 3-12 years). This study employed several measures that collectively would provide evidence of burden levels of xenobiotic agents and abnormal liver detoxication processes. These included: (1) Glucaric Acid Analysis, (2) blood analyses for identification of specific xenobiotic agents, and (3) Comprehensive Liver Detoxification Evaluation. Kolmogorov-Smirnov testing for a chi-square and Normal distribution of the Glucaric Acid finding indicates that each of these distributions is significantly different from expected distributions (p < .01). It is most noteworthy that of the 20 cases examined for this study, 100% of the cases showed liver detoxication profiles outside of normal. An examination of 18 autistic children in blood analyses that were available showed that 16 of these children showed evidence of levels of toxic chemicals exceeding adult maximum tolerance. In the two cases where toxic chemical levels were not found, there was abnormal D-glucaric acid findings suggesting abnormal xenobiotic influences on liver detoxication processes. A proposed mechanism for the interaction of xenobiotic toxins with immune system dysfunction and continuous and/or progressive endogenous toxicity is presented as it relates to the development of behaviors found in the autistic spectrum.
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PMID:Autism: xenobiotic influences. 966 46

Similar to many complex autoimmune diseases, genetic and environmental factors including diet, infection and xenobiotics play a critical role in the development of autism. In this study, we postulated that infectious agent antigens such as streptokinase, dietary peptides (gliadin and casein) and ethyl mercury (xenobiotic) bind to different lymphocyte receptors and tissue enzyme (DPP IV or CD26). We assessed this hypothesis first by measuring IgG, IgM and IgA antibodies against CD26, CD69, streptokinase (SK), gliadin and casein peptides and against ethyl mercury bound to human serum albumin in patients with autism. A significant percentage of children with autism developed anti-SK, anti-gliadin and casein peptides and anti-ethyl mercury antibodies, concomitant with the appearance of anti-CD26 and anti-CD69 autoantibodies. These antibodies are synthesized as a result of SK, gliadin, casein and ethyl mercury binding to CD26 and CD69, indicating that they are specific. Immune absorption demonstrated that only specific antigens, like CD26, were capable of significantly reducing serum anti-CD26 levels. However, for direct demonstration of SK, gliadin, casein and ethyl mercury to CD26 or CD69, microtiter wells were coated with CD26 or CD69 alone or in combination with SK, gliadin, casein or ethyl mercury and then reacted with enzyme labeled rabbit anti-CD26 or anti-CD69. Adding these molecules to CD26 or CD69 resulted in 28-86% inhibition of CD26 or CD69 binding to anti-CD26 or anti-CD69 antibodies. The highest % binding of these antigens or peptides to CD26 or CD69 was attributed to SK and the lowest to casein peptides. We, therefore, propose that bacterial antigens (SK), dietary peptides (gliadin, casein) and Thimerosal (ethyl mercury) in individuals with pre-disposing HLA molecules, bind to CD26 or CD69 and induce antibodies against these molecules. In conclusion, this study is apparently the first to demonstrate that dietary peptides, bacterial toxins and xenobiotics bind to lymphocyte receptors and/or tissue enzymes, resulting in autoimmune reaction in children with autism.
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PMID:Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. 1461 20

Causes and contributing factors for autism are poorly understood. Evidence suggests that prevalence is rising, but the extent to which diagnostic changes and improvements in ascertainment contribute to this increase is unclear. Both genetic and environmental factors are likely to contribute etiologically. Evidence from twin, family, and genetic studies supports a role for an inherited predisposition to the development of autism. Nonetheless, clinical, neuroanatomic, neurophysiologic, and epidemiologic studies suggest that gene penetrance and expression may be influenced, in some cases strongly, by the prenatal and early postnatal environmental milieu. Sporadic studies link autism to xenobiotic chemicals and/or viruses, but few methodologically rigorous investigations have been undertaken. In light of major gaps in understanding of autism, a large case-control investigation of underlying environmental and genetic causes for autism and triggers of regression has been launched. The CHARGE (Childhood Autism Risks from Genetics and Environment) study will address a wide spectrum of chemical and biologic exposures, susceptibility factors, and their interactions. Phenotypic variation among children with autism will be explored, as will similarities and differences with developmental delay. The CHARGE study infrastructure includes detailed developmental assessments, medical information, questionnaire data, and biologic specimens. The CHARGE study is linked to University of California-Davis Center for Children's Environmental Health laboratories in immunology, xenobiotic measurement, cell signaling, genomics, and proteomics. The goals, study design, and data collection protocols are described, as well as preliminary demographic data on study participants and on diagnoses of those recruited through the California Department of Developmental Services Regional Center System.
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PMID:The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. 1683 68

Porphyrins are derivatives formed in the heme synthesis pathway and porphyrins afford a measure of xenobiotic exposure. The steps in the heme pathway most vulnerable to heavy metal inhibition are uroporphyrin decarboxylase (UROD) and coproporphyrinogen oxidase (CPOX) reactions. Mercury toxicity was associated with elevations in urinary coproporphyrin (cP), pentacarboxyporphyrin (5cxP), and precoproporphyrin (prcP) (also known as keto-isocoproporphyrin) levels. Two cohorts of autistic patients in the United States and France had urine porphyrin levels associated with mercury toxicity. A prospective study of urinary porphyrin testing at LabCorp (United States) and the Laboratoire Philippe Auguste (France) involving 71 autism spectrum disorder (ASD) patients, neurotypical sibling controls, and general population controls was undertaken. ASD patients had significant elevations in urinary levels of cP, 5cxP, and prcP relative to controls, and > 50% of ASD patients had urinary cP levels more than 2 standard deviations above the mean values for neurotypical sibling controls. Significant reductions in urinary 5cxP and cP levels were observed in ASD patients following chelation. A significant correlation was found between urinary porphyrins measured at LabCorp and those measured at the Laboratoire Philippe Auguste on individual ASD patients. The established developmental neurotoxicity attributed to mercury and biochemical/genomic evidence for mercury susceptibility/toxicity in ASDs indicates a causal role for mercury. Urinary porphyrin testing is clinically available, relatively inexpensive, and noninvasive. Porphyrins need to be routinely measured in ASDs to establish if mercury toxicity is a causative factor and to evaluate the effectiveness of chelation therapy.
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PMID:A prospective study of mercury toxicity biomarkers in autistic spectrum disorders. 1788 29

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME) in some countries, is a debilitating disease with a constellation of multi-system dysfunctions primarily involving the neurological, endocrine and immune systems. While substantial information is available concerning the complex dysfunction-associated symptoms of CFS, environmental origins of the disease have yet to be determined. Part of the dilemma in identifying the cause(s) has been the focus on biomarkers (hormones, neurotransmitters, cytokines, infectious agents) that are contemporary with later-life CFS episodes. Yet, recent investigations on the origins of environmental diseases of the neurological, endocrine, reproductive, respiratory and immune systems suggest that early life toxicologic and other insults are pivotal in producing later-life onset of symptoms. As with autism and childhood asthma, CFS can also occur in children where the causes are certainly early-life events. Immune dysfunction is recognized as part of the CFS phenotype but has received comparatively less attention than aberrant neurological or endocrine function. However, recent research results suggest that early life immune insults (ELII) including developmental immunotoxicity (DIT), which is induced by xenobiotics, may offer an important clue to the origin(s) of CFS. The developing immune system is a sensitive and novel target for environmental insult (xenobiotic, infectious agents, stress) with major ramifications for postnatal health risks. Additionally, many prenatal and early postnatal neurological lesions associated with postnatal neurobehavioral diseases are now recognized as linked to prenatal immune insult and inflammatory dysregulation. This review considers the potential role of ELII including DIT as an early-life component of later-life CFS.
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PMID:Possible role for early-life immune insult including developmental immunotoxicity in chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME). 1833 82

Two recent studies, from France (Nataf et al., 2006) and the United States (Geier & Geier, 2007), identified atypical urinary porphyrin profiles in children with an autism spectrum disorder (ASD). These profiles serve as an indirect measure of environmental toxicity generally, and mercury (Hg) toxicity specifically, with the latter being a variable proposed as a causal mechanism of ASD (Bernard et al., 2001; Mutter et al., 2005). To examine whether this phenomenon occurred in a sample of Australian children with ASD, an analysis of urinary porphyrin profiles was conducted. A consistent trend in abnormal porphyrin levels was evidenced when data was compared with those previously reported in the literature. The results are suggestive of environmental toxic exposure impairing heme synthesis. Three independent studies from three continents have now demonstrated that porphyrinuria is concomitant with ASD, and that Hg may be a likely xenobiotic to produce porphyrin profiles of this nature.
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PMID:An investigation of porphyrinuria in Australian children with autism. 1870 27

Early-life immune insults (ELII) including xenobiotic-induced developmental immunotoxicity (DIT) are important factors in childhood and adult chronic diseases. However, prenatal and perinatal environmentally induced immune alterations have yet to be considered in depth in the context of autism and autism spectrum disorders (ASDs). Numerous factors produce early-life-induced immune dysfunction in offspring, including exposure to xenobiotics, maternal infections, and other prenatal-neonatal stressors. Early life sensitivity to ELII, including DIT, results from the heightened vulnerability of the developing immune system to disruption and the serious nature of the adverse outcomes arising after disruption of one-time immune maturational events. The resulting health risks extend beyond infectious diseases, cancer, allergy, and autoimmunity to include pathologies of the neurological, reproductive, and endocrine systems. Because these changes may include misregulation of resident inflammatory myelomonocytic cells in tissues such as the brain, they are a potential concern in cases of prenatal-neonatal brain pathologies and neurobehavioral deficits. Autism and ASDs are chronic developmental neurobehavioral disorders that are on the rise in the United States with prenatal and perinatal environmental factors suspected as contributors to this increase. Evidence for an association between environmentally associated childhood immune dysfunction and ASDs suggests that ELII and DIT may contribute to these conditions. However, it is not known if this linkage is directly associated with the brain pathologies or represents a separate (or secondary) outcome. This review considers the known features of ELII and DIT and how they may provide important clues to prenatal brain inflammation and the risk of autism and ASDs.
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PMID:Potential for early-life immune insult including developmental immunotoxicity in autism and autism spectrum disorders: focus on critical windows of immune vulnerability. 1882 24

Autism, an incurable neurodevelopmental brain disorder, is a complex psychopathology in which the affected individual cannot effectively self-regulate their sensory inputs toward coherent and focused motor outputs. There have been many hypotheses as to the etiology of autism - genetics, neurotransmitter imbalances, early childhood immunizations, xenobiotic and teratogenic agents, and maternal infection; the disorder can perhaps be studied best under the field of "Psychoneuroimmunology", which analyzes systemic and psychopathologies from an integrated approach through the combined effects of the nervous, immune, and endocrine systems. Using principles of psychoneuroimmunology along with previously established but yet un-linked scientific principles and observations, this paper proposes a neuroimmune-based mechanistic hypothesis for the etiology of autism that connects elevated levels of maternal pro-inflammatory cytokines to autistic symptoms in her offspring through a logical sequence of events. While both researchers and clinicians often note correlations between pro-inflammatory cytokine levels and autistic symptoms in affected individuals, no specific mechanism has been documented that logically and directly connects the two. I propose that pro-inflammatory cytokines arising from maternal inflammation, infection, and, possibly, autoimmunity, pass through the placenta; enter the fetal circulation; cross the fetal blood-brain barrier (BBB); and cause aberrant neuronal growth and plasticity within the fetal brain via a "cytokine-storm". Microglia and astrocyte stimulation lead to a positive-feedback loop that also facilitates the development of a chronic inflammatory environment within the fetus, pre-disposing it to lifelong comorbid psychiatric and systemic pathologies. Such a mechanism could account for many of the observed symptoms and behaviors of autistic individuals such as hyper-sensitivity to environmental stimuli, object fixation, echolalia, repetitive physical behaviors, chronic enterocolitis, autoimmune disease, and, at the extreme, savantism. The thiazolidinedione pioglitazone (and possibly rosiglitazone), a non-steroidal anti-inflammatory drug (NSAID), which is commonly used to lower blood glucose levels and associated inflammatory markers in patients with diabetes, and histamine receptor blockers, as well as monitoring and limiting sucrose-containing foods, might prove to be effective preventative therapies for the development of autism in the fetus for pregnant women displaying either a cytokine-induced depression or other elevated systemic inflammatory state conditions.
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PMID:A proposed mechanism for autism: an aberrant neuroimmune response manifested as a psychiatric disorder. 2142 Dec 90

Our understanding of the vast collection of microbes that live on and inside us (microbiota) and their collective genes (microbiome) has been revolutionized by culture-independent "metagenomic" techniques and DNA sequencing technologies. Most of our microbes live in our gut, where they function as a metabolic organ and provide attributes not encoded in our human genome. Metagenomic studies are revealing shared and distinctive features of microbial communities inhabiting different humans. A central question in psychiatry is the relative role of genes and environment in shaping behavior. The human microbiome serves as the interface between our genes and our history of environmental exposures; explorations of our microbiomes thus offer the possibility of providing new insights into our neurodevelopment and our behavioral phenotypes by affecting complex processes such as inter- and intra personal variations in cognition, personality, mood, sleep, and eating behavior, and perhaps even a variety of neuropsychiatric diseases ranging from affective disorders to autism. Better understanding of microbiome-encoded pathways for xenobiotic metabolism also has important implications for improving the efficacy of pharmacologic interventions with neuromodulatory agents.
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PMID:The mind-body-microbial continuum. 2148 46

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