A Framework For Understanding: The Biomedical Presentation Of Children With Autism

Emerging science supports the concept that central nervous system changes underlying autism are, in part, created by micronutrient deficiencies, excessive immunological responses and loss of immune tolerance to certain foods and chemicals. This presentation seeks to provide a framework for understanding this emerging paradigm, and will summarize a range of treatment approaches that correspond to each area of the framework. An emerging paradigm supports the concept that adverse genetic-environmental interaction is contributing to the pathophysiology of individuals diagnosed with autism spectrum disorders.  Toxicants, including heavy metals such as mercury, arsenic, and chromium 6, and chemicals, including volatile organic compounds produced by industry and engines, have been implicated in the etiology of autism and the worsening of micronutrient deficiencies, immunological abnormalities, gastrointestinal inflammation, and neurological pathology.  This presentation will define a framework for understanding this emerging paradigm, focusing on the evidence basis for the presence of a connected stream of pathology, linking adverse genetic-environmental interaction to dysfunction of the metalloprotein and methylation systems necessary for heavy metal and chemical detoxification.  Disruption of the detoxification systems of the body will be noted to contribute to a deficiency of critical micronutrients, such as zinc, selenium, essential fatty acids, calcium, magnesium, and B vitamins, and micronutrient deficiency will be related to dysfunction of the immune system (inmmune dysregulation) seen in many children with autism.  For example, zinc sufficiency is required for normal T cell (immune "generals") and B cell (antibody producer) communication, and lack of total body zinc often leads to excessive immune production of antibodies and inflammatory mediator proteins.  The presence of immune dysregulation will be associated with gastrointestinal and central nervous system inflammation.  Gastrointestinal abnormalities, including dysbiosis, abnormal sets of bacteria present in the small and large intestine, will be noted to produce chemical mediation that can potentially induce mitochondrial dysfunction, decreasing the energy production of neurons and their supporting structures, oligodendrocytes.  This series of pathophysiological events leads to inflammation of high metabolism areas of the developing brain, including the right prefrontal cortex that is highly critical in the development of attachment, facial recognition, and the time linked integration of other cortical areas, and the dominant hemisphere's Wernicke's and Broca's areas, responsible for language understanding and production, respectively.  Inflammation of the brain is a contributor to the decreased cortical integration noted to be present in children with autism.

The relationship between genetic and environmental interaction can be illustrated by the effects of mutational change on the PONS gene responsible for paroxonase function in the body, that is critical for detoxifying pesticides.  Sets of children and their parents with PONS gene mutations studied in the United States had far higher rates of diagnosis with autism and multiple sclerosis than comparison children and parents with PONS gene mutations who lived in Italy, where exposure to pesticides is far lower than in the United States.  Children who live near very busy roadways, with subsequent increased exposure to hydrocarbons, have increased rates of autism diagnosis compared to their peers who live much further away from busy roads, on multiple recent studies.  Mothers who lived within 100 meters of agricultural fields sprayed by pesticides had 10 times the rate of children diagnosed with autism than their peers in one study.  The association between genetic mutation and toxin accumulation is supported by recent studies that have strongly implicated copy number variant changes of the human genome (areas of duplication and deletion of regions of certain chromosomes) in participation in the pathophysiology leading to autism.  Numerous copy number variants affect genes that are critical in heavy metal and chemical detoxification, providing additional possible mechanisms for relationships between genome changes and detoxification dysfunction.

Several studies have supported the presence of zinc deficiency in children with autism, which may be secondary to less than ideal functioning of genes coding for metalloproteins.  Zinc and selenium, along with a protein called glutathione, are critical mediators of the metallothionein pathways essential for heavy metal detoxification.  Recent  studies have supported the presence of significantly different oxidized/reduced glutathione ratios being present in children with autism compared to controls, indicating altered functioning of a pathway critical for both heavy metal and chemical detoxification in children with autism.

Immunological abnormalities in children with autism are clearly documented in the literature, involving excessive antibody production, complement deposition, Natural Killer Cell activity, and mast cell degranulation.  Micronutrient deficiency and toxin accumulation have adverse effects on bone marrow, thymus, and other immune tissue functioning, and leukopenia, thrombocytopenia, eosinophilia and monocythemia are more often found in children with autism than controls.  Excessive tendency to produce antibodies leads to the phenomenon of increased cross reactive antibody production.  For example, the immune system's tendency to produce increased IgG antibodies to gluten, leads to increasing antibody production against the cerebellar vermis (the front of the cerebellum critical for cognitive changing of attentional focus and coordination), as the surface of the cerebellar vermis has a protein "signature", called an epitope, that is very similar to the epitope found on gluten.  A subset of children with autism appear to have increased gastrointestinal inflammation either localized to one location or present diffusely.  Loss of immune tolerance to certain proteins, such as casein, gluten, and soy, may mediate excessive intestinal inflammation in a subset of children with autism, and may contribute to decreased appropriate breakdown of proteins and less absorption of micronutrients through the villi of the small intestine.  The common presence of abnormal intestinal flora, dysbiosis, leads to less production of zinc dependent enzymes necessary for full breakdown of numerous proteins.  Several possible pathophysiological mechanisms for mitochondrial dysfunction are present in the literature, including excessive release of propionic acid from dysbiotic bacteria, that malaffect carnitine pathways in the mitochondria of the cells of the central nervous system.

Each of these proposed pathophysiological mechanisms have treatment options which will be reviewed.  Detoxification pathways can be enhanced by the provision of zinc and selenium, and nutrients that increase the production of reduced glutathione.  Immune dysregulation can be modulated with provision of zinc, essential fatty acids, and the careful use of probiotics, healthy bacteria that heal dysbiosis, improve intestinal immune and enzymatic functioning and decrease the production of cross reactive antibodies that can adversely affect brain function.  Food proteins that induce cross reactive antibody formation, such as caseins and glutens, can be decreased in the diet, and European based literature supporting such a diet in certain children with autism will be reviewed.  The necessity of supplementing children who are on casein and gluten free diets with a selected sets of micronutrients and food sources will be noted.  The use of folinic acid to augment chemical detoxification, and mitochondrial enhansing nutrients, such as Coenzyme Q 10 and acetyl-l-carnitine, will be discussed.  Overall, a basic framework for understanding the subset of children with autism affected by detoxification, immunological, gastrointestinal, and mitochondrial function abnormalities will be supplied, and the evidence basis for sound nutritional supplementation and the avoidance of certain food proteins for a period of time will be summarized.