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Summary

Of the research available up to May 2008, that which seems to have particularly worried US government officials regarding the link between vaccines and autism was the Portuguese study published in Autumn 2007.  [See Mitochondrial Disorder References below].  Subsequent research also increased that cause for concern.

The clinical "vaccines-to-autism" case of Hannah Poling appears to be just one example of what is shown by the recent research to be caused by a biological mechanism.  That mechanism is indicated by current research to account for 20% of cases of autistic spectrum disorders (ASDs) and be triggered by vaccines. 

It is also suggested that a broadening of the base of research could show that for all cases of ASDs and of symptoms of ASDs, the likely figure affected is nearer 65-75%.   So this is of some significance.

Whilst this seems likely to account for a good proportion of cases, it does not account for all cases of ASDs.  There is further good research indicating other and/or related mechanisms at work (see more below).  The fact there is a "spectrum" of disorders strongly suggests there is more than one mechanism.

Grateful thanks for his pro bono assistance in preparing this briefing memorandum are due to Professor Jeff Bradstreet MD, MD(H) FAAFP, Adjunct Professor of Pediatrics, Southwest College of Naturopathic Medicine, International Child Development Research Centre, Melbourne, FL 32934, USA.

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Why Vaccines Can Cause Autism

The Hannah Poling case is an example of the following:-

• mitochondria convert food into energy so that cells in the body can function
• if the mitochondria in the cells in children's bodies do not work properly, they can exhibit symptoms which "look like"/are autism/ASD
• oxidative stress can damage the mitochondria so they do not work or do not work properly
• glutathione protects against oxidation
  
• autistic children seem to lack glutathione
  
• viruses cause oxidation, including viruses in vaccines

But also:-

• recent research shows that mitochondrial disorder in autistic children is as common as 20 percent of cases
• that clearly concerned US government experts
  
• it is also believed by some researchers that if the intake of subjects was broadened to include other biomarkers of oxidative stress, the figure could be as high as 65-75% of autistic children who have this problem, but we do not have those data at this point.
  

For detailed references for the above:-

• follow this link Mitochondrial Disorder References.

For a more detailed explanation for the layman:-

• see this explanation by Johns Hopkins neurologist and father of Hannah Poling, Dr Jon Poling:-

Child's case shifts autism debate Atlanta Journal Constitution,  USA - 11 Apr 2008

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The Hannah Poling Case

Hannah Poling's clinical condition (Jon Poling is her father, a John's Hopkins neurologist and one of the authors):-

"Developmental Regression and Mitochondrial Dysfunction in a Child With Autism" Volume 21, Number 2, February 2006)  - Abstract - PDF

The authors' state :-

"Young children who have dysfunctional cellular energy metabolism therefore might be more prone to undergo autistic regression between 18 and 30 months of age if they also have infections or immunizations at the same time. Although patterns of regression can be genetically and prenatally determined, it is possible that underlying mitochondrial dysfunction can either exacerbate or affect the severity of regression. Abnormalities of oxidative phosphorylation can be developmental and age related and can normalize with time."

And the legal case was formally conceded by US government experts confirming:-
"At the July 19, 2000 examination, "CHILD" received five vaccinations - DTaP, Hib, MMR, Varivax, and IPV. Id. at 2, 11."

"Medical personnel at the Division of Vaccine Injury Compensation, Department of Health and Human Services (DVIC) have reviewed the facts of this case, as presented by the petition, medical records, and affidavits. After a thorough review, DVIC has concluded that compensation is appropriate in this case.

In sum, DVIC has concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations CHILD received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder. Therefore, respondent recommends that compensation be awarded to petitioners in accordance with 42 U.S.C. § 300aa-11(c)(1)(C)(ii)."

Full text is here:

The Vaccine-Autism Court Document Every American Should Read - David Kirby - Huffington Post - February 26, 2008

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Other Mechanisms

In addition to cases like Hannah Poling, these areas will have to be addressed. 

There is good research to show that:-

• ASD is a condition resulting from an encephalopathy (a degenerative disease of the brain) eg.

• "We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably
  in cerebellum of autistic patients. .... CSF showed a unique proinflammatory profile ..... Our findings indicate that innate neuroimmune reactions play a pathogenic role in an undefined proportion of autistic patients, suggesting that future therapies might involve modifying neuroglial responses in the brain. ...... Because this neuroinflammatory process appears to be associated with an ongoing and chronic mechanism of CNS dysfunction, potential therapeutic interventions should focus on the control of its detrimental effects and thereby eventually modify the clinical course of autism."  -  Vargas, Nascimbene, Krishnan, Zimmerman, Pardo: Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism - Annals of Neurology Vol 57 No 1 January 2005

• "Oxidative stress, brain inflammation, and microgliosis have been much documented in association with toxic exposures including various heavy metals...the awareness that the brain as well as medical conditions of children with autism may be conditioned by chronic biomedical abnormalities such as inflammation opens the possibility that meaningful biomedical interventions may be possible well past the window of maximal neuroplasticity in early childhood because the basis for assuming that all deficits can be attributed to fixed early developmental alterations in neural architecture has now been undermined." - Martha Herbert, MD, PhD [Harvard University] Large Brains in Autism: The Challenge of Pervasive Abnormality. The Neuroscientist, Volume 11, Number 5, 2005.  

• encephalopathies are normally caused by an infection (90% of the time), and most often we will expect a viral infection

• this is well known and accepted
• eg.  rubella viral infection has long been a known and well accepted cause of autism ever since the US rubella pandemic of 1964 (numerous references available if needed)
• live rubella virus is found in rubella vaccines

• measles virus can similarly be a source of such infection, including from measles vaccine
• it is known to cause inflammatory encephalitis and be a persistent immune trigger
  

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Heavy Metals and Other Environmental Toxins

The role of environmental toxins a significant aspect, including heavy metals and other toxins.  It is not covered here at this time and may be covered on a later occasion.  The information here was prepared primarily as a briefing document on mitochondrial disorders and to explain why vaccines are implicated in causing autism in association with mitochondrial disorders.

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Mitochondrial Disorder References
(most recent first)

Portuguese Study:-

Concerns amongst US officials were raised regarding mitochondrial disorder prevalence in autistic children by this large Autumn 2007 study of 332,808 portuguese children:-

Epidemiology of autism spectrum disorder in Portugal: prevalence, clinical characterization, and medical conditions
Developmental Medicine & Child Neurology, 2007

Abstract: The objective of this study was to estimate the prevalence of autistic spectrum disorder (ASD) and identify its clinical characterization, and medical conditions in a paediatric population in Portugal. A school survey was conducted in elementary schools, targeting 332 808 school-aged children in the mainland and 10 910 in the Azores islands. Referred children were directly assessed using the Diagnostic and Statistical Manual of Mental Disorders (4th edn), the Autism Diagnostic Interview–Revised, and the Childhood Autism Rating Scale. Clinical history and a laboratory investigation was performed. In parallel, a systematic multi-source search of children known to have autism was carried out in a restricted region. The global prevalence of ASD per 10 000 was 9.2 in mainland, and 15.6 in the Azores, with intriguing regional differences. A diversity of associated medical conditions was documented in 20%, with an unexpectedly high rate of mitochondrial respiratory chain disorders.

And these are not isolated papers - numerous studies indicating large numbers of autistic children could be affected:-

This very recent paper (April 2008) gives us 20% and it is using narrow biochemical markers:-

[IN1-1.004] Oxidative Phosphorylation (OXPHOS) Defects in Children with Autistic Spectrum Disorders
John Shoffner, Lauren C. Hyams, Genevieve N. Langley, Atlanta, GA  -  Sunday, April 13, 2008 2:45 PM
Platform Session: Integrated Neuroscience: Autism (2:00 PM-3:15 PM)

OBJECTIVE: To retrospectively survey patients with autistic spectrum disorders that were evaluated clinically for mitochondrial disease and to assess the clinical and laboratory features of this group of patients. BACKGROUND: Autism is a developmental disorder characterized by disturbance in language, perception and socialization. A variety of biochemical, anatomical and neuroradiographical studies imply a disturbance of brain energy metabolism in autistic patients. Recent studies confirmed the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. (J Autism Dev Disord, 2006. 36:1137) Although rare, Mecp2 mutations can produce autistic features and the mouse model has significant mitochondrial defects. (Mol Cell Biol, 2006. 26: 5033) Additional genetic defects associated with mitochondrial dysfunction include inverted 15q11-13 duplication (Complex III defect) (Ann Neurol, 2003,53,801), A3243G mutation (mitochondrial transfer ^{RNALeucine(UUR)} gene, mtDNA depletion(J Pediatr, 2004,144,81), G8363A mutation (mitochondrial transfer RNA^Lysine gene. (J Child Neurol, 2000,15,357). DESIGN/METHODS: Retrospective analysis of 37 children with autistic spectrum disorders. Clinical, biochemical, metabolic, and genetic data is assessed. RESULTS: Twenty four children (65%) had skeletal muscle OXPHOS defects: Complex I (16), Complex I and Complex III (5), Complex III (1), Complex I and Complex IV (2). Thirteen (35%) had normal skeletal muscle OXPHOS enzyme activities for Complexes I-IV. Clinical, metabolic, protein chemistry, and sequencing of coding regions of the mitochondrial DNA will be reported. CONCLUSIONS/RELEVANCE: Most children with autistic spectrum disorders do not have recognizable abnormalities on a broad range of imaging, metabolic and genetic studies. However, a subset of patients do harbor significant defects in oxidative phosphorylation function. Complex I abnormalities are the most frequently encountered defect. Recognition of these children is important for understanding how genes that produce autistic spectrum disorders impact mitochondrial function. Supported by: Horizon Molecular Medicine.
Category - Neurogenetics and Gene Therapy

Mitochondrial Energy-Deficient Endophenotype in Autism
American Journal of Biochemistry and Biotechnology 4 (2): 198-207, 2008
J. Jay Gargus and Faiqa Imtiaz
Department of Physiology and Biophysics and Department of Pediatrics, Section of Human Genetics, School of Medicine, University of California, Irvine, Arabian Diagnostics Laboratory, King Faisal Specialist Hospital and Research Centre

Abstract: While evidence points to a multigenic etiology of most autism, the pathophysiology of the disorder has yet to be defined and the underlying genes and biochemical pathways they subserve remain unknown. Autism is considered to be influenced by a combination of various genetic, environmental and immunological factors; more recently, evidence has suggested that increased vulnerability to oxidative stress may be involved in the etiology of this multifactorial disorder.

Furthermore, recent studies have pointed to a subset of autism associated with the biochemical endophenotype of mitochondrial energy deficiency, identified as a subtle impairment in fat and carbohydrate oxidation. This phenotype is similar, but more subtle than those seen in classic mitochondrial defects. In some cases the beginnings of the genetic underpinnings of these mitochondrial defects are emerging, such as mild mitochondrial dysfunction and secondary carnitine deficiency observed in the subset of autistic patients with an inverted duplication of chromosome 15q11-q13. In addition, rare cases of familial autism associated with sudden infant death syndrome (SIDS) or associated with abnormalities in cellular calcium homeostasis, such as malignant hyperthermia or cardiac arrhythmia, are beginning to emerge. Such special cases suggest that the pathophysiology of autism may comprise pathways that are directly or indirectly involved in mitochondrial energy production and to further probe this connection three new avenues seem worthy of exploration: 1) metabolomic clinical studies provoking controlled aerobic exercise stress to expand the biochemical phenotype, 2) high-throughput expression arrays to directly survey activity of the genes underlying these biochemical pathways and 3) model systems, either based upon neuronal stem cells or model genetic organisms, to discover novel genetic and environmental inputs into these pathways.

Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment
American Journal of Biochemistry and Biotechnology 4 (2): 208-217, 2008
Daniel A. Rossignol, J. Jeffrey Bradstreet, International Child Development Resource Center,

Abstract: Classical mitochondrial diseases occur in a subset of individuals with autism and are usually caused by genetic anomalies or mitochondrial respiratory pathway deficits. However, in many cases of autism, there is evidence of mitochondrial dysfunction (MtD) without the classic features associated with mitochondrial disease. MtD appears to be more common in autism and presents with less severe signs and symptoms. It is not associated with discernable mitochondrial pathology in muscle biopsy specimens despite objective evidence of lowered mitochondrial functioning. Exposure to environmental toxins is the likely etiology for MtD in autism. This dysfunction then contributes to a number of diagnostic symptoms and comorbidities observed in autism including: cognitive impairment, language deficits, abnormal energy metabolism, chronic gastrointestinal problems, abnormalities in fatty acid oxidation, and increased oxidative stress. MtD and oxidative stress may also explain the high male to female ratio found in autism due to increased male vulnerability to these dysfunctions.

Biomarkers for mitochondrial dysfunction have been identified, but seem widely under-utilized despite available therapeutic interventions. Nutritional supplementation to decrease oxidative stress along with factors to improve reduced glutathione, as well as hyperbaric oxygen therapy (HBOT) represent supported and rationale approaches. The underlying pathophysiology and autistic symptoms of affected individuals would be expected to either improve or cease worsening once effective treatment for MtD is implemented.


Bridging from Cells to Cognition in Autism Pathophysiology: Biological Pathways to Defective Brain Function and Plasticity
American Journal of Biochemistry and Biotechnology 4 (2): 167-176, 2008
Matthew P. Anderson, Brian S. Hooker and Martha R. Herbert

Departments of Neurology and Pathology, Harvard Medical School/Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, High Throughput Biology Team, Fundamental Science Directorate, Pacific Northwest National Laboratory, Pediatric Neurology/Center for Morphometric Analysis, Massachusetts General Hospital/Harvard Medical School, and Center for Child and Adolescent Development, Cambridge Health Alliance/Harvard Medical School

Abstract: We review evidence to support a model where the disease process underlying autism may begin when an in utero or early postnatal environmental, infectious, seizure, or autoimmune insult triggers an immune response that increases reactive oxygen species (ROS) production in the brain that leads to DNA damage (nuclear and mitochondrial) and metabolic enzyme blockade and that these inflammatory and oxidative stressors persist beyond early development (with potential further exacerbations), producing ongoing functional consequences. In organs with a high metabolic demand such as the central nervous system, the continued use of mitochondria with damaged DNA and impaired metabolic enzyme function may generate additional ROS which will cause persistent activation of the innate immune system leading to more ROS production. Such a mechanism would self-sustain and possibly progressively worsen. The mitochondrial dysfunction and altered redox signal transduction pathways found in autism would conspire to activate both astroglia and microglia. These activated cells can then initiate a broad-spectrum proinflammatory gene response. Beyond the direct effects of ROS on neuronal function, receptors on neurons that bind the inflammatory mediators may serve to inhibit neuronal signaling to protect them from excitotoxic damage during various pathologic insults (e.g., infection). In autism, over-zealous neuroinflammatory responses could not only influence neural developmental processes, but may more significantly impair neural signaling involved in cognition in an ongoing fashion. This model makes specific predictions in patients and experimental animal models and suggests a number of targets sites of intervention. Our model of potentially reversible pathophysiological mechanisms in autism motivates our hope that effective therapies may soon appear on the horizon.


Ng F, Berk M, Dean O, Bush AI.

Oxidative stress in psychiatric disorders: evidence base and therapeutic implications.

Int J Neuropsychopharmacol. 2008 Jan 21;:1-26 [Epub ahead of print]

PMID: 18205981 [PubMed - as supplied by publisher]


Oxidative Stress in Autism: Elevated Cerebellar 3-nitrotyrosine Levels
American Journal of Biochemistry and Biotechnology 4 (2): 73-84, 2008
Elizabeth M. Sajdel-Sulkowska, - Dept of Psychiatry, Harvard Medical School

A marker for oxidative stress was 68.9% higher in autistic brain issue than controls (a statistically significant result), while mercury levels were 68.2% higher.

" The preliminary data suggest a need for more extensive studies of oxidative stress, its relationship to the environmental factors and its possible attenuation by antioxidants in autism.”

Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M.

How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis.

Neurotoxicology. 2008 Jan;29(1):190-201. Epub 2007 Oct 13.

Behav Brain Res. 2007 Jan 10;176(1):149-69. Epub 2006 Sep 1.

Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders.

MacFabe DF, Cain DP, Rodriguez-Capote K, Franklin AE, Hoffman JE, Boon F, Taylor AR, Kavaliers M, Ossenkopp KP.

The Kilee Patchell-Evans Autism Research Group, Department of Psychology, Division of Developmental Disabilities, University of Western Ontario, Social Science Centre, London, Canada.

Clinical observations suggest that certain gut and dietary factors may transiently worsen symptoms in autism spectrum disorders (ASD), epilepsy and some inheritable metabolic disorders. Propionic acid (PPA) is a short chain fatty acid and an important intermediate of cellular metabolism. PPA is also a by-product of a subpopulation of human gut enterobacteria and is a common food preservative. We examined the behavioural, electrophysiological, neuropathological, and biochemical effects of treatment with PPA and related compounds in adult rats. Intraventricular infusions of PPA produced reversible repetitive dystonic behaviours, hyperactivity, turning behaviour, retropulsion, caudate spiking, and the progressive development of limbic kindled seizures, suggesting that this compound has central effects. Biochemical analyses of brain homogenates from PPA treated rats showed an increase in oxidative stress markers (e.g., lipid peroxidation and protein carbonylation) and glutathione S-transferase activity coupled with a decrease in glutathione and glutathione peroxidase activity. Neurohistological examinations of hippocampus and adjacent white matter (external capsule) of PPA treated rats revealed increased reactive astrogliosis (GFAP immunoreactivity) and activated microglia (CD68 immunoreactivity) suggestive of a neuroinflammatory process. This was coupled with a lack of cytotoxicity (cell counts, cleaved caspase 3' immunoreactivity), and an increase in phosphorylated CREB immunoreactivity. We propose that some types of autism may be partial forms of genetically inherited or acquired disorders involving altered PPA metabolism. Thus, intraventricular administration of PPA in rats may provide a means to model some aspects of human ASD in rats.

Arch Pediatr Adolesc Med. 2007 Apr;161(4):356-61.

Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype.

Williams TA, Mars AE, Buyske SG, Stenroos ES, Wang R, Factura-Santiago MF, Lambert GH, Johnson WG.

Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
OBJECTIVE: To test whether polymorphisms of the glutathione S-transferase P1 gene (GSTP1) act in the mother during pregnancy to contribute to the phenotype of autistic disorder (AD) in her fetus. DESIGN: Transmission disequilibrium testing (TDT) in case mothers and maternal grandparents. SETTING: Autistic disorder may result from multiple genes and environmental factors acting during pregnancy and afterward. Teratogenic alleles act in mothers during pregnancy to contribute to neurodevelopmental disorders in their offspring; however, only a handful have been identified. GSTP1 is a candidate susceptibility gene for AD because of its tissue distribution and its role in oxidative stress, xenobiotic metabolism, and JNK regulation. PARTICIPANTS: We genotyped GSTP1*G313A and GSTP1*C341T polymorphisms in 137 members of 49 families with AD. All probands received a clinical diagnosis of AD by Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule-Generic testing. MAIN OUTCOME MEASURES: Association of haplotypes with AD was tested by the TDT-Phase program, using the expectation-maximization (EM) algorithm for uncertain haplotypes and for incomplete parental genotypes, with standard measures of statistical significance. RESULTS: The GSTP1*A haplotype was overtransmitted to case mothers (P = .01 [P = .03 using permutation testing]; odds ratio, 2.67 [95% confidence interval, 1.39-5.13]). Results of the combined haplotype and genotype analyses suggest that the GSTP1-313 genotype alone determined the observed haplotype effect. CONCLUSIONS: Overtransmission of the GSTP1*A haplotype to case mothers suggests that action in the mother during pregnancy likely increases the likelihood of AD in her fetus. If this is confirmed and is a result of a gene-environment interaction occurring during pregnancy, these findings could lead to the design of strategies for prevention or treatment.

Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism. BMC Genet. 2006 Feb 10;7:8.

Buyske S, Williams TA, Mars AE, Stenroos ES, Ming SX, Wang R, Sreenath M, Factura MF, Reddy C, Lambert GH, Johnson WG.

Departments of Statistics and Genetics, 110 Frelinghuysen Rd, Rutgers University, Piscataway, NJ 08854, USA.

BACKGROUND: Certain loci on the human genome, such as glutathione S-transferase M1 (GSTM1), do not permit heterozygotes to be reliably determined by commonly used methods. Association of such a locus with a disease is therefore generally tested with a case-control design. When subjects have already been ascertained in a case-parent design however, the question arises as to whether the data can still be used to test disease association at such a locus. RESULTS: A likelihood ratio test was constructed that can be used with a case-parents design but has somewhat less power than a Pearson's chi-squared test that uses a case-control design. The test is illustrated on a novel dataset showing a genotype relative risk near 2 for the homozygous GSTM1 deletion genotype and autism. CONCLUSION: Although the case-control design will remain the mainstay for a locus with a deletion, the likelihood ratio test will be useful for such a locus analyzed as part of a larger case-parent study design. The likelihood ratio test has the advantage that it can incorporate complete and incomplete case-parent trios as well as independent cases and controls. Both analyses support (p = 0.046 for the proposed test, p = 0.028 for the case-control analysis) an association of the homozygous GSTM1 deletion genotype with autism.

 
Oxidative Stress in Autism
Pathophysiology, 2006.
Abha Chauhan, Ved Chauhan 2006 Aug;13(3):171-81. Epub 2006 Jun 12.

This study provides an overview of the evidence supporting the link between oxidative stress and autism.

"Upon completion of this article, participants should be able to: 1. Be aware of laboratory and clinical evidence of greater oxidative stress in autism. 2. Understand how gut, brain, nutritional, and toxic status in autism are consistent with greater oxidative stress. 3. Describe how anti-oxidant nutrients are used in the contemporary treatment of autism."

J Toxicol Environ Health B Crit Rev. 2006 Nov-Dec;9(6):485-99.

Evidence of toxicity, oxidative stress, and neuronal insult in autism.

Kern JK, Jones AM.

Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9119, USA.
According to the Autism Society of America, autism is now considered to be an epidemic. The increase in the rate of autism revealed by epidemiological studies and government reports implicates the importance of external or environmental factors that may be changing. This article discusses the evidence for the case that some children with autism may become autistic from neuronal cell death or brain damage sometime after birth as result of insult; and addresses the hypotheses that toxicity and oxidative stress may be a cause of neuronal insult in autism. The article first describes the Purkinje cell loss found in autism, Purkinje cell physiology and vulnerability, and the evidence for postnatal cell loss. Second, the article describes the increased brain volume in autism and how it may be related to the Purkinje cell loss. Third, the evidence for toxicity and oxidative stress is covered and the possible involvement of glutathione is discussed. Finally, the article discusses what may be happening over the course of development and the multiple factors that may interplay and make these children more vulnerable to toxicity, oxidative stress, and neuronal insult.
PMID: 17090484 [PubMed - indexed for MEDLINE]

 

James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, Cutler P, Bock K, Boris M, Bradstreet JJ, Baker SM, Gaylor DW.

Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141(8):947-56

 

Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC.

Increased excretion of a lipid peroxidation biomarker in autism.

Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):379-84.


McGinnis WR.
Oxidative stress in autism.   - Copy attached
Altern Ther Health Med. 2005 Jan-Feb;11(1):19.

Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins.

Chauhan A, Chauhan V, Brown WT, Cohen I. Life Sci. 2004 Oct 8;75(21):2539-49

NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314, USA.

Autism is a neurological disorder of childhood with poorly understood etiology and pathology. We compared lipid peroxidation status in the plasma of children with autism, and their developmentally normal non-autistic siblings by quantifying the levels of malonyldialdehyde, an end product of fatty acid oxidation. Lipid peroxidation was found to be elevated in autism indicating that oxidative stress is increased in this disease. Levels of major antioxidant proteins namely, transferrin (iron-binding protein) and ceruloplasmin (copper-binding protein) in the serum, were significantly reduced in autistic children as compared to their developmentally normal non-autistic siblings. A striking correlation was observed between reduced levels of these proteins and loss of previously acquired language skills in children with autism. These results indicate altered regulation of transferrin and ceruloplasmin in autistic children who lose acquired language skills. It is suggested that such changes may lead to abnormal iron and copper metabolism in autism, and that increased oxidative stress may have pathological role in autism.

Clin Chim Acta. 2003 May;331(1-2):111-7.

Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism.

Söğüt S, Zoroğlu SS, Ozyurt H, Yilmaz HR, Ozuğurlu F, Sivasli E, Yetkin O, Yanik M, Tutkun H, Savaş HA, Tarakçioğlu M, Akyol O.

Department of Biochemistry, Faculty of Medicine, Inönü University, Pasakosku Mahallesi 11, Sok. Ozkaracalar Apt. No: 42/4, Malatya 44200, Turkey.
BACKGROUND: There is evidence that oxygen free radicals play an important role in the pathophysiology of many neuropsychiatric disorders. Although it has not been investigated yet, several recent studies proposed that nitric oxide (NO) and other parameters related to oxidative stress may have a pathophysiological role in autism. METHODS: We assessed the changes in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and thiobarbituric acid-reactive substances (TBARS) levels in plasma as well as NO levels in red blood cells (RBC) in patients with autism (n=27) compared to age- and sex-matched normal controls (n=30). RESULTS: In the autistic group, increased RBC NO levels (p<0.0001) and plasma GSH-Px activity (p<0.0001) and unchanged plasma TBARS levels and SOD activity were detected. CONCLUSIONS: These findings indicate a possible role of increased oxidative stress and altered enzymatic antioxidants, both of which may be relevant to the pathophysiology of autism.
PMID: 12691871 [PubMed - indexed for MEDLINE]


Investigation of antioxidant enzymes in children with autistic disorder.

Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T. Prostaglandins, Leukotrienes and Essential Fatty Acids Volume 67, Issue 5, November 2002, Pages 341-343

GATA Child and Adolescent Psychiatry Department, Etlik, Ankara, Turkey.
Impaired antioxidant mechanisms are unable to inactivate free radicals that may induce a number of pathophysiological processes and result in cell injury. Thus, any abnormality in antioxidant defence systems could affect neurodevelopmental processes and could have an important role in the etiology of autistic disorder. The plasma levels of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), and erythrocyte levels of GSH-Px were investigated in 45 autistic children and compared with 41 normal controls. Levels of erythrocyte SOD, erythrocyte and plasma GSH-Px were assayed spectrophotometrically. Activities of erythrocyte SOD, erythrocyte and plasma GSH-Px in autistic children were significantly lower than normals. These results indicate that autistic children have low levels of activity of blood antioxidant enzyme systems; if similar abnormalities are present in brain, free radical accumulation could damage brain tissue.

Mitochondria, Oxidative Stress and Neurodegeneration
Microglial Cells in Culture Express a Prominent Glutathione System for the Defense against Reactive Oxygen Species
Johannes Hirrlinger, Jan Mirko Gutterer, Lothar Kussmaul, Bernd Hamprecht, Ralf Dringen Dev Neurosci 2000;22:384-392
Selected Papers from the 4th International Conference on Brain Energy Metabolism, Eynsham Hall/Oxford (UK), August 14-18, 1999

To obtain information on the glutathione metabolism of microglial cells, the content of glutathione and activities of enzymes involved in the defense against peroxides were determined for microglia-rich cultures from rat brain. These cultures contain approximately 90% microglia cells as determined by immunocytochemical staining for glial markers, by the phagocytosis activity of the cells and by the production of superoxide after stimulation of the cells with phorbolester. For these cultures, a glutathione content of 41.2 ± 11.2 nmol/mg protein and a specific activity of glutathione reductase of 15.2 ± 3.2 nmol/(min × mg protein) were determined. These values are significantly higher than those found for astroglial or neuronal cultures. In addition, with 68.7 ± 23.5 nmol/(min × mg protein), the specific activity of glutathione peroxidase in microglial cultures was 78% higher than in cultured neurons. The specific catalase activity of microglial cultures was less than 40% that of astroglial or neuronal cultures. Microglial cultures contain only marginal amounts of oxidized glutathione. However, on application of oxidative stress by incubation of microglial cultures with hydrogen peroxide or with the superoxide-producing hypoxanthine/xanthine oxidase system, cellular glutathione was rapidly oxidized. These results demonstrate that microglial cells have a prominent glutathione system, which is likely to reflect the necessity for self-protection against reactive oxygen species when produced by these or surrounding brain cells.

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Other Mechanisms - Some Sample References

Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: The results of a parent survey 2008; 12; 293 Autism, Stephen T. Schultz, Hillary S. Klonoff-Cohen, Deborah L. Wingard, Natacha A. Akshoomoff, Caroline A. Macera and Ming Ji

This paper funded by the National Autistic Society associates autism with use of  paracetamol after MMR vaccination.  In the light of the prior papers this indicates the children respond to the infection with fever, which is then treated at home with paracetamol (eg. Calpol).  As prior papers have noted, the response to an infection (eg introduced by vaccine) is implicated in triggering the mitochondrial condition or an encephalopathy.

 Possible Immunological Disorders in Autism: Concomitant Autoimmunity and Immune Tolerance
The Egyptian Journal of Immunology, 2006
Maha I. Sh. Kawashti, Omnia R. Amin Nadia G. Rowehy

Microbiology Department, Faculty of Medicine (For Girls), Al Azhar University, Cairo, Egypt, Psychiatry Department, Faculty of Medicine, Cairo University, Cairo, Egypt and Serology Lab King Fahad General Hospital, Jeddah, K.S.A.

Abstract: Autism is a pervasive developmental disorder that affect children early in their life. Immunological disorders is one of several contributing factors that have been suggested to cause autism. Thirty autistic children aged 3-6 years and thirty non-autistic psychologically-free siblings were studied. Circulating IgA and IgG autoantibodies to casein and gluten dietary proteins were detected by enzyme-immunoassays (EIA). Circulating IgG antibodies to measles, mumps and rubella vaccine (M.M.R) and cytomeglovirus were investigated by EIA. Results revealed high seropositivity for autoantibodies to casein and gluten: 83.3% and 50% respectively in autistic children as compared to 10% and 6.7% positivity in the control group. Surprisingly, circulating anti-measles, anti-mumps and anti-rubella IgG were positive in only 50%, 73.3% and 53.3% respectively as compared to 100% positivity in the control group. Anti-CMV IgG was positive in 43.3% of the autistic children as compared to 7% in the control group. It is concluded that, autoimmune response to dietary proteins and deficient immune response to measles, mumps and rubella vaccine antigens might be associated with autism, as a leading cause or a resulting event. Further research is needed to confirm these findings.

Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141(8):947-56.


Immunity,neuroglia and neuroinflammation in autism
Carlos, Vargas, Zimmerman International Review of Psychiatry, December 2005;17(6):485 –495
Summary
Autism is a complex neurodevelopmental disorder of early onset that is highly variable in its clinical presentation.Although the causes of autism in most patients remain unknown,several lines of research support the view that both genetic and environmental factors influence the development of abnormal cortical circuitry that underlies autistic cognitive processes and behaviors.The role of the immune system in the development of autism is controversial.Several studies showing peripheral immune abnormalities support immune hypotheses,however until recently there have been no immune findings in the CNS. We recently demonstrated the presence of neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism,findings that support the view that neuroimmune abnormalities occur in the brain of autistic patients and may contribute to the diversity of the autistic phenotypes.The role of neuroglial activation and neuroinflammation are still uncertain but could be critical in maintaining,if not also in initiating,some of the CNS abnormalities present in autism.A better understanding of the role of neuroinflammation in the pathogenesis of autism may have important clinical and therapeutic implications.