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Autism spectrum disorder

Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old.

Epidemiology

Clustering of Autism in California 1993–2001 – This spatial clustering map shows a small area North of Los Angeles, where there is a cluster of children born with autism. Here, children are at four times greater risk for autism than children living in other parts of California. The risk is still present after adjusting for a number of factors. Source: Yap et al.

The prevalence of autism in the United States has increased significantly over the past twenty years. Using information from state birth records and case records of patients affiliated with the California Department of Health Services, Bearman and colleagues estimate that approximately 25 percent of the increased prevalence of autism observed in California between 1992 and 2005 is due to changes in how autism is diagnosed.1)

Dr. Bearman and colleagues recently published that there are certain geographical areas of California where babies are more likely to develop autism (see right). The authors point out that localized “clusters” of autism suggests that environmental factors such as increased public awareness and local advocacy may play a role. However, clusters of disease may just as well suggest autism is caused by a communicable infection such as the slow-growing chronic infection described by the Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop..

Evidence of infectious cause

Growing evidence exists to conclude that autism spectrum disorder is driven by microbial pathogens.

Unique microbial populations

Persistent co-infections are generally a sign of an immune system disabled by the Th1 pathogensThe community of bacterial pathogens which cause chronic inflammatory disease - one which almost certainly includes multiple species and bacterial forms.. It's telling to note that there remains no conclusive evidence for any single kind of virus always present in patients with autism.

  • Patients with autism tend to suffer from severe gastrointestinal problems and have different bacteria in their GI tract. In a 2005 Paracho et al. study, the fecal flora of ASD patients contained a higher incidence of Clostridium histolyticum bacteria than that of healthy children.2)
Ratio of selected urinary metabolite concentrations to that of urinary creatinine between children with autism, their siblings, and controls. Key: *, ***, indicates a significant difference at p < 0.05, 0.001 confidence levels, respectively.
  • According to Nicolson et al.: “A large subset of ASD [autism spectrum disorder] patients shows evidence of bacterial and/or viral infections.” 3) He reports that his team found conclusive evidence of Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in ASD patients.
  • Nicolson's team also showed that autistic children had several urinary metabolites that were highly significant as compared to controls (see right).4) This study confirms other work that children with ASD have unique microbial populations and further suggests that ASD could be clinically diagnosed using a urine test.

Other evidence

  • Familial aggregationOccurrence of a given trait shared by members of a family (or community) that cannot be readily accounted for by chance. of other chronic inflammatory diseases – In one large-scale study, schizophrenia was more common among mothers and fathers of autistic children compared to controls. Depression and personality disorders were more common among case mothers but not fathers.5) A John's Hopkins study found that mothers with celiac disease and rheumatoid arthritis have higher incidence of having children with autism. A connection was also identified for children with a family history of type 1 diabetes.6)
  • Autistic symptoms appear following infection reactivation – One paper described two cases of children who at first developed normally, but before the age of three developed autistic symptoms following the reactivation of a chronic oto-rhinolaryngologic infection“7)
  • Autoantibodies – In a 2009 study, a significant proportion of autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine.8) A second study found high levels of anti-nuclear antibodies in the blood serum of Egyptian autistic children.9) The Marshall Pathogenesis explains so-called “autoantibodies” as antibodies generated in response to pathogenic bacterial cells that have been destroyed as a result of an active immune response.
  • Temporary remission of symptoms during fever – A Johns Hopkins research team has documented how children with ASD exhibit fewer characteristic autistic behaviors during fever, a change which was unrelated to fever severity.10) This provocative change in behavior may be due to the fact that acute infections such as those which cause fevers may temporarily delay immunopathologyA temporary increase in disease symptoms experienced by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed.. In the absence of immunopathology, autistic children display less behaviors characteristic of autism and consistent with die-off of chronic bacteria.
  • Prenatal infection and autism – A population-wide study from Denmark spanning two decades of births indicates that infection during pregnancy increases the risk of autism in the child. Hospitalization for a viral infection, like the flu, during the first trimester of pregnancy triples the odds. Bacterial infection, including of the urinary tract, during the second trimester increases chances by 40 percent.11)

Patient interviews

Doreen V. (patient's mother)

autism, ADHD, depression, severe anxiety, chronic fatigue syndrome (CFS)

Read the interview


Interviews of patients with other diseases are also available.

Prodigies, autism, and the interactome

As described in Psychology Today, autism and being a prodigy are closely related:

Ruthsatz found that both the first-degree families of individuals with autism and the first-degree families of prodigies in her sample displayed three out of five common traits of autism: impaired social skills, impaired ability to switch attention, and heightened attention to detail. This intrigued her, so she decided to look for autism in her current sample of prodigies.

Lo and behold, while about one in every 88 children in the United States is diagnosed with autism, four out of the eight prodigies in the current study had family members who either had an autism diagnosis or had a first- or second-degree relative with an autism diagnosis. Additionally, three of the prodigies had already been diagnosed with autism, and as a group they showed higher levels of autistic traits compared with a control group consisting of people weren't prodigies (but scored only slightly higher than those with high-functioning autism, or Asperger's.

This may be a case where the exact interaction among microbes, known as the interactome, may contribute both to illness as well as exceptional cognitive abilities.

Read More

Notes and comments

<DiseaseHierarchy>

Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes.

Jyonouchi H, Geng L, Streck DL, Toruner GA. J Neuroimmunol. 2011 Jul 29. [Epub ahead of print] http://www.sciencedirect.com/science/article/pii/S0165572811001913

Innate/adaptive immune responses and transcript profiles of peripheral blood monocytes were studied in ASD children who exhibit fluctuating behavioral symptoms following infection and other immune insults (ASD/Inf, N=30). The ASD/Inf children with persistent gastrointestinal symptoms (ASD/Inf+GI, N=19), revealed less production of proinflammatory and counter-regulatory cytokinesAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. with stimuli of innate immunityThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease. and marked changes in transcript profiles of monocytes as compared to ASD/no-Inf (N=28) and normal (N=26) controls. This included a 4-5 fold up-regulation of chemokines (CCL2 and CCL7), consistent with the production of more CCL2 by ASD/Inf+GI cells. These results indicate dysregulated innate immune defense in the ASD/Inf+GI children, rendering them more vulnerable to common microbial infection/dysbiosis and possibly subsequent behavioral changes.

“The analysis of more than 600 three-year-olds with an older autistic sibling found that almost one in five of them had an autism spectrum disorder, which includes Asperger's syndrome and similar conditions” http://www.reuters.com/article/2011/08/15/us-autistic-kids-idUSTRE77E0OW20110815

With the exception of fibrotic tissue deposited in the organs by years of disease, we have seen the body exhibit a miraculous ability to heal itself. The adults have recovered their brains, their memories, their cognition, decades of their lives. I don't see why we shouldn't expect the same phenomena of neuro-regeneration in children. There is one child, Matt, who has indeed exhibited such a recovery.

Trevor Marshall, PhD

From Trevor, “Brain autoantibodies found in AUTISM”:

Ann Clin Psychiatry. 2009 Jul-Sep;21(3):148-61.

Phenotypic expression of autoimmuneA condition or disease thought to arise from an overactive immune response of the body against substances and tissues normally present in the body autistic disorder (AAD): a major subset of autism.

Singh VK.

Brain State International Research Center, Scottsdale, AZ 85260, USA.vj1000s@yahoo.com

BACKGROUND: Autism causes incapacitating neurologic problems in children that last a lifetime. The author of this article previously hypothesized that autism may be caused by autoimmunity to the brain, possibly triggered by a viral infection. This article is a summary of laboratory findings to date plus new data in support of an autoimmune pathogenesis for autism. METHODS: Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay. RESULTS: Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)–salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants–a marker of systemic inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.. CONCLUSIONS: The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy. The author has advanced a speculative neuroautoimmune (NAI) model for autism, in which virus-induced autoimmunity is a key player. The latter should be targeted by immunotherapy to help children with autism.

PMID: 19758536

From Amy:

Very interesting. I had also found this study:

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TBD-4VB6KTF-B&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_searchStrId=1021423445&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3f27b32cf2776353b0c363891b3fbef5

Autism may involve an autoimmune pathogenesis in a subgroup of patients. The frequency of anti-nuclear antibodies in 80 autistic children and their relationship to a family history of autoimmunity were studied, compared with 80 healthy, matched children. Children with autism had a significantly higher percent seropositivity of anti-nuclear antibodies (20%) than healthy children (2.5%; P < 0.01). Fifty percent of anti-nuclear antibody-seropositive autistic children had an anti-nuclear antibody titer of ≥1:640 (very high positive); 25%, ≥1:160 (high positive); and the remaining 25%, 1:80. All anti-nuclear antibody-seropositive healthy children had anti-nuclear antibody titers of 1:80. A family history of autoimmunity was significantly higher in autistic children (47.5%) than healthy controls (8.8%; P < 0.001). Anti-nuclear antibody seropositivity was significantly higher in autistic children with a family history of autoimmunity than those without such history (36.8% and 5%, respectively; P < 0.001). Anti-nuclear antibody seropositivity had significant positive associations with disease severity, mental retardation and electroencephalogram abnormalities. Autoimmunity may play a role in a subgroup of children with autism. Further studies are warranted to assess anti-nuclear antibody seropositivity, other markers of autoimmunity (e.g., brain-specific autoantibodies), and the role of immunotherapy in children with autism.

From Trevor:

“Misfolded Proteins Linked to Autism Disorders”

http://www.medicalnewstoday.com/articles/200742.php

This lines up with research described at DMM2008, where it was revealed that Prions were only infectious in the presence of a chronic inflammatory disease. It seems that there are a lot of misfolded proteins, not just prions, which result from the inflammatory disease process.

Singh, V. K. (2009). “Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism.” Ann Clin Psychiatry 21(3): 148-161. 19758536

BACKGROUND: Autism causes incapacitating neurologic problems in children that last a lifetime. The author of this article previously hypothesized that autism may be caused by autoimmunity to the brain, possibly triggered by a viral infection. This article is a summary of laboratory findings to date plus new data in support of an autoimmune pathogenesis for autism. METHODS: Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay. RESULTS: Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)–salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants–a marker of systemic inflammation. CONCLUSIONS: The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy. The author has advanced a speculative neuroautoimmune (NAI) model for autism, in which virus-induced autoimmunity is a key player. The latter should be targeted by immunotherapy to help children with autism.

Mostafa, G. A. and N. Kitchener (2009). “Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children.” Pediatr Neurol 40(2): 107-112. 19135624

Autism may involve an autoimmune pathogenesis in a subgroup of patients. The frequency of anti-nuclear antibodies in 80 autistic children and their relationship to a family history of autoimmunity were studied, compared with 80 healthy, matched children. Children with autism had a significantly higher percent seropositivity of anti-nuclear antibodies (20%) than healthy children (2.5%; P < 0.01). Fifty percent of anti-nuclear antibody-seropositive autistic children had an anti-nuclear antibody titer of > or =1:640 (very high positive); 25%, > or =1:160 (high positive); and the remaining 25%, 1:80. All anti-nuclear antibody-seropositive healthy children had anti-nuclear antibody titers of 1:80. A family history of autoimmunity was significantly higher in autistic children (47.5%) than healthy controls (8.8%; P < 0.001). Anti-nuclear antibody seropositivity was significantly higher in autistic children with a family history of autoimmunity than those without such history (36.8% and 5%, respectively; P < 0.001). Anti-nuclear antibody seropositivity had significant positive associations with disease severity, mental retardation and electroencephalogram abnormalities. Autoimmunity may play a role in a subgroup of children with autism. Further studies are warranted to assess anti-nuclear antibody seropositivity, other markers of autoimmunity (e.g., brain-specific autoantibodies), and the role of immunotherapy in children with autism.

J Child Neurol. 2006 Jun;21(6):444-9.High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression. Sokol DK, Chen D, Farlow MR, Dunn DW, Maloney B, Zimmer JA, Lahiri DK. Department of Neurology, Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, IN 46202, USA. dksokol@iupui.edu Abstract Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased alpha-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found. PMID: 16948926

Ear infections and autism Readers of this thread will know that I have suggested that my son’s apparent regressive autism at age 20 months was precipitated by an ear infection (otitis media). I wrote a few posts on this some time back and Trevor has indicated that too many beta-lactam antibiotics (e.g. penicillin) can cause bacteria to morph into more virulent L-formsDifficult-to-culture bacteria that lack a cell wall and are not detectable by traditional culturing processes. Sometimes referred to as cell wall deficient bacteria. and cause a pathogenic microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms. to develop in a person. This could explain why some infants suffer a severe and apparently sudden regression after being given too much penicillin as infants to treat ear infections which is standard medical practice for treating such ear infections. Amy has written on this too.

I would not, however, restrict a theory to explain the aetiology of autism to solely this - too much vitamin D in infant formula as well as an acquired microbiota from parents and/or siblings or pets needs to be thrown into the mix of factors (as has been discussed on this thread).

I want to bring folks attention to a recent study that purports to demonstrate that the traditional practice of prescribing antibiotics to infants is to be generally supported see http://www.nejm.org/doi/pdf/10.1056/NEJMoa0912254.

This study was done to address the concerns that abxs are being over-prescribed to infants when viral infections could be causal rather than bacteria and the worry about more bacteria-resistant species being created by over‑prescription.

This study shows no awareness of the issue raised by others before us that over-prescription could be causing cases of ASD. It was actually a mother of an autistic child, Ellen Bolte, who first raised a concern that her son’s autistic regression occurred after frequent courses of antibiotics produced diarrhoea in her son before catastrophic ASD set in. The NEJM study acknowledges that diarrhoea is routinely observed in many children given abxs for OM. Indeed, 6 children in the study group were taken off the abx protocol because of this – the children contracted a clostridium dificile infection. I wonder if any of these children became autistic.

Bolte speculated that the gut’s protective microflora can be disturbed by abxs and this could permit even more virulent clostridia than clostridium dificile bacteria to multiply and possibly cause ASD through a gut-brain connection – see http://www.ncbi.nlm.nih.gov/pubmed/9881820.

Bolte’s idea was taken up by Sidney Finegold who has many Pub med citations (see http://www.ncbi.nlm.nih.gov/pubmed/20603222

http://www.ncbi.nlm.nih.gov/pubmed/17904761 and

http://www.ncbi.nlm.nih.gov/pubmed/12173102

I believe Finegold is an eminent microbiologist who is still pursuing this idea since the late 1990s when Bolte’s paper was first published.

In addition to this, a PubMed paper by Joan Fallon also discussed a possible link between Augmentin, the abx used in the NEJM study, and autism see http://www.ncbi.nlm.nih.gov/pubmed/15607562

None of these papers were cited in the NEJM study. I grant that these papers are about speculations as to a possible link between abx administration and autism rather than established fact. Nonetheless, I think it is pretty poor for the NEJM authors not to have acknowledged these studies (to say nothing of an MP view of the causes of ASD).

Regrettably, none of these studies have an awareness of the Marshall concept of a pathogenic microbiota disrupting vitamin D metabolism and thence gene expression and thence ASD.

Incidentally, one child of the 12 studied by Andrew Wakefield who developed regressive ASD and gastrointestinal disease as infants in his ‘controversial’ study did so after an ear infection as compared to the MMR jab.

John

Nature. 2011 May 25. [Epub ahead of print]Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, Mill J, Cantor RM, Blencowe BJ, Geschwind DH. Source Program in Neurogenetics and Neurobehavioral Genetics, Department of Neurology and Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1769, USA. Abstract Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder.

PMID: 21614001

Identical twins reveal role of environmental factors in autism

http://bit.ly/nMpHAp

References

1)
Diagnostic change and the increased prevalence of autism.
King M, Bearman P
Int J Epidemiol38p1224-34(2009 Oct)
2)
Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.
Parracho HM, Bingham MO, Gibson GR, McCartney AL
J Med Microbiol54p987-91(2005 Oct)
4)
Urinary Metabolic Phenotyping Differentiates Children with Autism from Their Unaffected Siblings and Age-Matched Controls.
Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK
J Proteome Resp(2010 May 13)
5)
Parental psychiatric disorders associated with autism spectrum disorders in the offspring.
Daniels JL, Forssen U, Hultman CM, Cnattingius S, Savitz DA, Feychting M, Sparen P
Pediatrics121pe1357-62(2008 May)
6)
Association of family history of autoimmune diseases and autism spectrum disorders.
Atladóttir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton WW, Parner ET
Pediatrics124p687-94(2009 Aug)
10)
Behaviors associated with fever in children with autism spectrum disorders.
Curran LK, Newschaffer CJ, Lee LC, Crawford SO, Johnston MV, Zimmerman AW
Pediatrics120pe1386-92(2007 Dec)
11)
Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders.
Atladóttir HO, Thorsen P, Østergaard L, Schendel DE, Lemcke S, Abdallah M, Parner ET
J Autism Dev Disord40p1423-30(2010 Dec)
home/diseases/autism.txt · Last modified: 06.12.2017 by sallieq
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