0. Amny A. Yaskohwww.holisticheotih.com onero2 Page 1 The Role of Excitotoxins in Autistic Type Behavior Dr. Amy A. Yasko Introduction Ihave boon researching and working with inflammatory pathways in the body since my doctoral work at Albany Medical College. | have always felt that itis critical to understand why something is happening in order to make informed choices directed at correcting the imbalance. | believe very strongly that the pathway of excitotoxin damage as described brilliantly by Dr. Russel Blaylock, definitely leads to neurological inflammation. In applying the knowledge of this process to my work with individuals who have ALS, Parkinson's, MS and Alzheimer's, | have had considerable success in reversing symptoms of these diseases. More recently, | have used and extended the concepts of excitotoxin damage as they pertain to autism. | have found that by understanding the process that leads to the type of neurological inflammation that we know as "autism", | am able to make significant strides in helping these children. The following represents what | believe is ‘occurring thus far with respect to the process of neurological inflammation that results in autistic like behavior. It is a work in progress, and does not answer every question with regard to autistic type neurological inflammation, It does however, provide an explanation for many of the observed behaviors and symptoms that are associated with autism, a framework from which to help reverse many of these traits, and a rationale for why many of the currently utilized therapies are effective, Although | have never met, nor corresponded with Dr. Russell Blaylock, | thank him for his explanation and description of excitotoxin damage. It is from using, and extending his insights that | have been able to successfully touch and change many lives that have been afflicted with neurological inflammation.Dr. Amy A Yoskohwrusholsticheatin.com enero2 Page 2 Overview Through her consulting practice, Dr. Amy Arrow Yasko has worked with a large number of individuals with neurological inflammation. This includes individuals with ALS, MS, Parkinson's Disease, Alzheimer's Disease, and autism. Dr. Amy has found that the program se has implemented to successfully break the cycle of neurological inflammation with other types of neurological disorders is useful in helping to reverse the neurological inflammation that manifests as autism. In addition, she has had success in reversing symptoms of Crohn's disease, which has been postulated to occur via chronic measles infection as is often seen with autism. Dr. Amy views autism as a subset of neurological inflammation, and as such has applied a variation of the approach that she has utilized with these other inflammatory disorders to the type of neurological inflammation that results in autistic like behavior. While autism has a variety of similarities to other forms of neurological inflammation (Parkinson's, ALS, MS, and Alzheimer's), it clso has unique features that contribute to the autistic type of inflammation. Basically, Dr. Amy approaches neurological inflammation in general with a three-step program which can be implemented simultaneously. First, itis critical to remove excitotoxin triggers from the system. This involves closely monitoring food and supplement intake to avoid excitotoxins. Excitotoxins are neurotransmitters such as glutamate or aspartate that can excite the nerves to death when their levels are not regulated properly. Excess excitotoxins cause an imbalance in the flow of calcium, Which leads to activation of a complex inflammatory cascade, release of inflammatory mediators, and ultimately causes the death of neurons. Foods or supplements that, contain excitotoxins include MSG (monosodium glutamate), glutamic acid, glutamine, nutrasweet, aspartate, aspartame, and cysteine. Mercury and aluminum can also serve to trigger glutamate release. Next, it is important to stop the inflammatory process created by the excitotxin triggers. This is achieved with a number of supplements known to mitigate inflammatory mediators. Finally, the third stage is to repair the damage, generate new neurons, and support the liver. This is accomplished with a number of supplements, which serve as antioxidants as well as to help increase glutathione levels, restore liver function,0, Amy A. Yasko/swrw.holisicheolth.com enero2 Page 3 promote nerve growth, restore vitamin K levels, decrease glutamate levels, and balance GABA levels. Dr. Amy has found that in working with autistic neurological inflammation in particular, there are additional factors to consider. These include dealing with potentially chronic viral, bacterial, and yeast infections in the body (which can generate release of additional inflammatory mediators}, balancing the acid/alkaline ratio and restoring normal flora to the Gl tract, and meial toxicity (which also generates excitotoxin damage). There are several underlying factors that may predispose certain individuals to autistic type neurological inflammation, Those include persons of blood type O, (and to a lesser extent blood type A), early recurrent streptococcal infections, excess stomach acid, predominantly male sex, early multiple vaccinations, and well above normal intelligence. There may also be a correlation with a familial history of liver dysfunction/disease, vitamin K deficiency, acid reflux, and autoimmune problems. Excitotoxins Glutamate is the main excitatory neurotransmitter in the body. It is essential for learning, and for both short-term and long-term memory. It is also the precursor to the inhibitory neurotransmitter, GABA. GABA is ¢ calming neurotransmitter, and is essential for speech. Problems occur if the normal process of regulation of glutamate malfunctions and if toxic levels of this excitatory neurotransmitter build up in the synaptic junctions. The brain requires sufficient levels of oxygen and energy to remove excess glutamate, However, glutamate release leads to the release of insulin, which results in decreased glucose levels. The amount of glucose in the brain regulates the removal of excess glutamate from the synapses. Therefore, a drop in blood glucose disrupts this removal process and allows the build up of toxic glutamate. In fact, conditions of hypoglycemia, or low calorie/starvation conditions induce the release of glutamate and reduce the ability to remove excess levels of glutamate from the brain. This excess glutamate depletes glutathione. Glutathione is one of the most powerful antioxidants found in theDr. Amy A Yasko/wwn holslichealih.com enn6r02 Poge a body and helps to protect neurons from damage. Glutatione depletion consequently leads to the death of additional neurons. Glutamate has six different types of receptors to which it can bind in the brain. One of these receptors, the NMDA receptors, is tied to calcium transport as its mode of action. In the case of the NMDA receptors, the release of excess glutamate triggers an inflammatory cascade that results in the death of neurons by the major influx of calcium into the nerve until it results in neural cell deeth. Normal levels of calcium result in normal neuron functioning. However, excessive levels of calcium make it impossible for the neuron to rest; the neuron continues to fire without stopping, causing the release of inflammatory mediators, the release of more glutamate, thus resulting in more calcium influx. The high intracellular levels of calcium also lead to high levels of nitric oxide and peroxynitrite, causing damage to the energy producing apparatus of the cells. Magnesium is able to modulate the calcium flow, as is zinc. However, zinc is a double- edged sword as it is also able to activate glutamate release via the non-NMDA. glutamate receptors. Although these receptors are called "glutamate receptors", any of the excitatory amino acids are able to bind to the receptors and cause excitotoxin damage. The toxic potential of these excitatory amino acids has been suggested to be proportional to their ability to excite neurons. These excitatory amino acids include glutamate, aspartate, and to a lesser extent cysteine and homocysteine. Glutamate and aspartate are common as food additives as well as naturally occurring components of a large number of foods. In cells, glutamate and aspartate can be synthesized from each other. The two main food additives that are sources for excitotoxins are MSG (monosodium glutamate) and aspartame (nutrasweet), High levels of glutamate and aspartate are found naturally in protein rich foods, including very high levels in wheat gluten, and milk casein. While these amino acids are necessary for normal brain function, excess mounts of them create a wide range of bodily damage. Body systems that have been affected by glutamate toxicity include effects on white blood cells (elevations in the levels of eosinophils,), effects on blood vessels (causing migraines and reduced regulation of blood pressure), and inhibition of the conversion of glutamate to GABA.Dr. Amy A. Yosko/wwnw.hotstichealin.com eneio2 Page S In addition, high levels of excitatory amino acids, and low levels of glutathione have been associated with a number of neurodegenerative disorders. The sites in the brain that have been reported to be damagec by excitotoxins include the hypothalamus, the hippocampal neurons, and the Purkinje naurons, among others. Notably, damage to the Purkinje neurons has been associated with autistic type behavior. Excess levels of glutamate have been definitely implicated in a range of neurodegenerative diseases, including Aizhe mer's disease, Parkinson's disease, Huntington's chorea, stroke, Multiple sclerosis, and ALS. In the case of autism, irregularities related to glutamate have been observed. In addition, glutamate, glutamic acid and aspartate and aspartic acid were found to be elevated in individuals exhibiting autistic behavior relative to controls. While there have been reports that the density of AMPA-type glutamate receptors is decreased in autism, this may be due to receptor recycling as a function of glutamate binding rather than an actual lack of receptors. Cells are constantly in the process of selecting and recycling receptors. Recycling occurs, and is more complex in neurons. In neurons recycling is complicated by the fact that internalized proteins have the possibility of returning to their surface of origin or to a second plasma membrane domain. This would seem likely in this case, for although the receptor density was decreased, the mRNA levels of glutamate AMPA receptors were significantly increased in autism. Predisposing Factors to Excitotoxin Damage Children with autistic type behavior have often been described as exceedingly intelligent, even to the extreme point of being considered savants in particular areas. Dr. Tsien and his collaborators have demonstrated a correlation between glutamate receptors and superior ability in learning and nemory. By overproducing a component of one of the glutamate receptors they were able to increase the level of glutamate binding. This was the first demonstration of a relationship between increased glutamate/glutamate receptors and higher intelligence. The down side of the enhanced level of glutamate was an increased risk of stroke and seizure activity. This work suggests a potential correlation between inteligonce and glutamate levels. It alsoDr, Amy A. Yosko/wwn.hofsichealth.com enej02 Pages points to the potential increased susceptibility to excitotoxin damage due to excess glutamate/glutamate receptor activity as a corsequence of enhanced intelligence. ‘Autistic type behavior is four times moe common in males than females. This gender related susceptibility to autistic behavior may also be mediated by glutamate and GABA levels. Dr. McCarthy and her collaborators have studied the role of glutamate and GABA in brain differentiation between males and females. Overall, they have found greater levels of neuronal excitation in the brains of developing males than in females, and that these differences are related to glutamate and GABA neurotransmission. These differences are medulated by testosterone, with levels of glutamate and GABA being twice as high in the male brain as compared to the female brain during early development, During puberty there are also gender-associated differences in glutamate and GABA. Glutamate and GABA levels have been shown to be related to the release of lutenizing hormone. In addition, fluctuations in GABA levels have been implicated in symptoms of PMS. Itis possible to speculate that higher levels of these neurotransmitters in developing males makes them more susceptible to excitotoxin damage, leading to autistic behavior. Conversely, females may have a secondary pathway for glutamate /GABA that is menstrual cycle related. This fallback pathway could protect females from over expression and excitotoxin damage to the glutamate/GABA system. Vitamin K Deficiency/Sugar Deregulation In all cases of neurological inflammation leading to autistic behavior there seems to be an initial insult to the system, which results in a reduction of normal flora in the intestinal tract, with a subsequent loss of Vitamin K. Most often this seems to occur as a result of chronic streptococcal ear infections, the antibiotic use that follows, and a lack of re-population of the intestines with normal flora. Alternatively, or in addition, excess stomach acid and insufficient bile (due to decreased liver function) creates a situation of relative acid excess and acid pH in the intestinal tract. (Ingestion of glutamate, as MSG, itself has been reported to cause excess acid and heartburn.) This would create an environment that is conducive to yeast, E.coli and streptococcal overgrowth and non- ideal for normal protective bacterial flora. This imbalance in normal flora can be further exacerbated by the excitotoxin glutamate. Excess glutamate has been shown to increase the survival of enterohemorrhagic E.coli, particularly under acidic conditions.Dx. Amy A Yasko/wen holtichealin.com en6r02 Page 7 While Vitamin K is a fat-soluble vitamin, itis not stored like the other fat-soluble vitamins; consequently it needs to be absorbed on a daily basis. Normally this occurs when the bacteria in the GI tract process leafy greens. If however, the normal flora of the Gl tract has been disturbed there will be a Vitamin K deficiency. Most likely, all children are born deficient in Vitamin K, as it does not cross the placenta. Vitamin K is essential for clotting, to prevent excessive bruising and bleeding, for bone and teeth health, for sugar regulation, and hence to control hypoglycemic related anxiety attacks. One of the highest levels of vitamin K in the body is in the pancreas, which is critical for sugar regulation in the body. Most children suffering from autistic behavior seem to have imbalances in their ability to tolerate sugars. In addition to the brain, the other area of the body that is able to concentrate the excitotoxin glutamate is the pancreas, which would result in further damage to the pancreas and sugar regulation. Vitamin K serves a role to react enzymatically with glutamate and calcium, to ensure proper placement of the calcium where it belongs in bone and teeth. In addition, Vitamin K is a cofactor for the conversion of glutamate to gamma carboxyglutamate. Lack of vitamin K would then create a cycle of deregulation in the glutamate/caicium pathway leading to further neurological inflammation. Glutamate also leads to the release of insulin, which results in decreased blood sugar levels. While glutamate serves a vital function as an excitatory neurotransmitter, if excess glutamate is not removed from the synapses between the nourons it can be toxic to the neurons. The amount of glucose in the brain regulates the removal of excess glutamate from the synapses. Therefore, a drop in blood glucose disrupts this removal process and allows the build up of toxic glutamate. One can see the cascade of events that occurs, beginning with excess ingested glutamate, that can bind to glutamate receptors in the pancreas, which then causes an increase in insulin, decreasing the blood level of glucose, that in turn prevents the removal of excess glutamate in the synapses. resulting in neurotoxicity from ingested glutamate. This creates the roller coaster of high/low glutamate and sugar without the proper regulation of this process by nutrients such as vitamin K.Dr. Amy A. Yasko/wunw.holisicheatth.com ener2 Page 8 Blood Type/ Streptococcal Infection The A-B-O system for blood typing is dependent on the blood group antigens that are expressed on the outer surface of an individuals’ red blood cells. Those with blood type A have NAC-gal (n-acetyl galactosamine) as the predominant blood group antigen, and those with type B have galactose as their primary antigen. Those with blood type O have fucose as a predominant antigenic determinant on their red blood cells. In addition, fo a lesser extent the NAC-glu (n-acetyl glucosamine) antigen would be accessible to the immune system in those with blood type O due to the limited carbohydrate antigen on the surface of type 0 red blood cells. It is necessary for the body to discern the difference between self and non-self, and to prevent the immune system from attacking self. As a consequence of this "tolerance" to self, those with blood type O would have a higher tolerance to NAC-glu, and would not have as high a natural tolerance to NAC-gal and galactose as would those with blood types of A or B. Similarly, those with blood type A would have a higher "self-tolerance" to NAC-gal. The major carbohydrate antigenic determinants on the surface of the streptococcus bacteria are predominantly NAC-glu and NAC-gal. As a consequence, persons with blood type O and type A would have an initial greater natural tolerance to infection from streptococcal bacteria. After repeated exposure to the streptococcus bacterium, an immune response would finally be mounted, and targeted against the antigenic. determinants on the bacterium. When this happens the immune cells of the body inadvertently launch an autoimmune attack uson body tissue with antigenic determinants that are similar to the antigen on the surface of the streptococci. This reaction to the NAC-glu and NAC-gal on the surface of the streptococci could also lead to an autoimmune type reaction against the NAC-glu/gal in the Gl tract. This process has been recognized since the middle 1980's and is known as molecular mimicry. The excessive shedding of NAC-glu and NAC-gal, otherwise referred to as GAG has been described and well characterized by others. Suffice to say that the shedding of GAGs in the Gl tract is enhanced with immune activation and inflammation. Following infection and/or inflammation, the body would need to replace GAGs that have been lis would lead to undersulfated GAGs in the Gl tract along with the deficiency of other sulfur shed, as well as to sulfate them. If there is a sulfur deficiency in the body,Di. Amy A. Yosko/wwnw.hotstichoalin.com enero2 Page? related proteins in the body. Nitric oxide has been shown to inhibit sulfation of GAGs, High levels of nitric oxide are a consequence of excitotoxin damage. Generally, bacteria elicit a B cell mediated immune response, and viruses elicit a T cell mediated immune response. However, a large number of extracellular toxins are elaborated by streptococci, all of which have the ability to nonspecifically stimulate T cells. Therefore once an immune response is mounted against streptococcus it would involve both T cell and B cells resulting in a major inflammatory reaction, One particular extracellular enzyme produced by streptococcus is a sulfhydryl protease. This protease is capable of cleaving sulfhydryl groups and may lead to a deficiency of available sulfur containing moieties in the body following streptococcal infection. These sulfhydryl groups are involved in the binding and elimination of heavy metals in the body. Streptococcal infection is also known to lead to elevated levels of the inflammatory cytokines NFKB and TNF alpha. In addition, the level of TNF alpha is inversely correlated with glutathione levels. Consequently, high TNF alpha levels as a result of streptococcal infection would result in decreases in glutathione levels. Streptococcal infection is also associated with a wide variety of behavioral disturbances. High levels of TNF alpha (as a result of streptococcal infection) have been implicated in Tourettes syndrome, facial tics, obsessive compulsive behavior, and schizophrenia. On a related note, lithium (the most popular prescription drug for treating the mood swings associated with manic, or bipolar depression) has been demonstrated to act by protecting the brain from over stimulation by glutamate. Excessive levels of glutamate have also been implicated in drug craving and in addictive behavior. Consequently, the net results of streptococcal infection are depletion of Vitamin K levels, decreased glutathione levels, decreased sulfhydryl protein levels, over stimulation of the immune system, increased TNF alpha levels (which trigger OCD, facial tics, etc.), potential autoimmune responses and inflammatory reactions against the GAGs in the GI tract. Blood Type/Gluten & Casein The various blood groups are also related to the observed sensitivity to certain foods. According to Dr. Peter D'Adamo, those with type O and type A blood are particularly sensitive to diary products. Those with Type O blood are also extremely sensitive to wheat.i, Amy A. Yosko/werw.holstichealin.com enej02 Page 10 The sugar in milk, lactose, is comprised of galactose along with glucose. Type O blood and type A would be less tolerant of galactose groups than would be type B blood; this could explain the diary intolerance noted by D'Adamo. Both type A and O blood create antibodies to the galactose sugar in milk, as the body would be designed to reject anything that looks like type B blood in the system, Those with type B blood would be tolerant to the galactose, as it would be seen as "self." Both type O and Type A persons would potentially mount an immune response to the galactose in milk, leading to an inflammatory reaction. Wheat germ agglutinin (WGA, derived from wheat) is known to bind NAC-glu, and in doing so causes an inflammatory cascade. In those with type O blood this would create binding to both blood cells (as blood type O has an accessible NAC-glu moiety) as well as a reaction in the intestinal tract, as the intestinal tract is lined with a mixture of sulfated NAC-gal and NAC-glu. When the WGA binds to intestinal cells it changes the permeability characteristics of these cells. This change in permeability results in a translocation of the gut bacteria to the periphery, as well as overgrowth of bacteria and a change in the normal flora of the gut. WGA\is also able to cause an increase in various inflammatory mediators in the immune cells leading to an inflammatory cascade in the gut. Both inflammatory mediators, as well as nitric oxide production have been shown to inhibit sulfate incorporation into NAC-glu and NAC-gal.. Nitric oxide and inflammatory mediators are produced as part of an inflammatory cascade, and in response to excitotoxins. While those with blood type A should be more tolerant to WGA in terms of their blood cells than those with type O blood, they would be equally susceptible to the inflammatory effects of WGA in the gut and tc lactose/galactose related inflammatory issues. In addition to blood type related issues, wheat, casein, and hydrolyzed yeast are concentrated sources of glutamate. Wheat gluten is 43% glutamate and milk casein is 23% glutamate. Browers yeast, hydrolyzed yeast, and yeast extracts are considered definite sources of MSG. Consequently, a diet that is high in casein, gluten, and yeast would exacerbate a system that is already overwhelmed with excess excitotoxins. The opioid excess theory suggests that the problem with casein and gluten stems from the fact that casein will break down in the stomach to produce a peptide known as casomorphine, and gluten breaks down to gluteomorphine. These partially digestedDi. Any A. Yoskofwww.holisticheaiih.com onero2 Page " proteins derived from gluten and casein are proposed to react like opioids in the brain and in so doing reduce pain, induce pleasure and intensify or cause many of the symptoms of autism. This theory would still be consistent with an involvernent of the glutamate receptors in autistic type behavior. The NMDA receptor has a binding site for PCP (phencyclidine), or “angel dust". At non-anesthetic doses PCP produces behavioral effects in common with several other drugs including opiates. It produces a dissociative state in which patients are generally unresponsive and perceive no pain. This would suggest a relationship between opioids and the action of glutamate at the NMDA receptor. Vaccines/Virus Itmay be that the lack of normal flora in the gut, as well as already elevated levels of the inflammatory mediator TNF, and depletion of glutathione and sulfhydryl containing proteins due to streptococcal infection set up a predisposing condition for problems with certain vaccines. To further exacerbate the condition, it has been found that the tetanus toxin, from the DPT vaccine can cause the lining of the intestinal tract to peel, leading to diarrhea as well as creating a lack of normal flora. The subsequent vaccination of children with these predisposing conditions, with a live virus, such as the MMR vaccine, may allow an otherwise attenuated and nonviral strain to create an infectious situation by populating the gut. The gut would normally be protected by normal flora and sulfated NAC-glu molecules so that this would not occur. However, given the predisposing conditions one could end up with the chronic measles infection that has been described by Wakefield. The disturbance in the gut in conjunction with insufficient bile (due to decreased liver function) creates a situation of potentially relative acid excess and acid pH in the intestinal tract. This would create an environment that is conducive to yeast, E.coli, and streptococcal growth and non-ideal for normal protective bacterial flora. The imbalance in normal flora and pH would lead to problems with fatty acid absorption and yeast overgrowth as is seen with many of these children, Measles virus is capable of causing neurological inflammation, adding to the inflammatory process already in place with the overproduction of TNF. if the pancreas is not functioning optimally (lack of vitamin K, and too much glutamate in the pancreas)Ds, Amy A. Yasko/wenw holtichealih.com ener02 Page 2 then the inflammatory mediators will become glycosylated (have sugars linked onto them), which then calls in more inflammatory mediators to the site. In addition to vaccine issues associated with potential chronic viral infection, there is the issue of the preservatives themselves that are used to maintain the stability of injected substances. The preservatives can contain free glutamate as gelatin, which would directly trigger excitotoxin damage. Other preservatives include thimerosal (a meroury derivative), phenol, and aluminum. In the case of aluminum, it has been shown that the entry of aluminum into the brain is enhanced when it is coupled to glutamate. Aluminum, once in the brain, is able to trigger additional excitotoxin release and damage, During the course of vaccination and the body's immune response to the intended antigens, the body may also mount an immune response to the other substances (including mercury, phenol and aluminum) that are injected simultaneously with the antigen. This phenomenon would be similar to a hapten-carrier mediated immune reaction, which is well known and characterized in immunology. This may explain issues that some autistic children have with the lasting immune reactions to the preservatives used in vaccines. Mercury is a particular problem, aside from its potential antigenicity. Mercury, if it is not quickly eliminated from the system becomes tightly bound to sulfhydryl containing enzymes, resulting in a decrease in sulfur containing proteins in the body- including glutathione and the MT proteins. In addition, decreases in glutathione-S-transferase result in further decreased expression of MT. Mercury has also been shown to further activate the inflammatory process by triggering glutamate release in the pancreas and the brain which would have the same effect as excitotoxin damage in the brain triggered by MSG. Another complicating factor in the who'e vaccine process is the common practice of acetaminophen (i.e.tylenol) administration prior to, and following vaccination of children. Acetaminophen has been shown to deplete glutathione levels, which are critical for detoxification in the body. Between acetaminophen administration and mercury it would lead to a severe depletion of already low glutathione levels. The suggested positive rationale behind vaccination is to prevent more serious. disease from active acute naturally acquired infections. However, many of the potential effects of acute viral infection appear to be similar to the observed issues seen withDi, Amy A. Yasko/wonw.hotsichealih.com enero2 Poge 13 autistic type of neurological inflammation and from glutamate excitotoxicity. Natural acute measles, mumps and rubella infections have been known to have potentially serious repercussions including brain damage, deafness, and blindness. An interesting finding is that studies have shown that excessive glutamate can cause both hearing problems and extreme photosensitivity, in addition to neurotoxicity. In the case of the MMR vaccine, justification for vaccination has come from the suggestion of associations between viral infestion and diabetes. In the case of rubella virus, it has already been shown to be associated with diabetes. Babies infected with the rubella virus in their mother’s womb, who are born with congenitally acquired rubella syndrome, often develop Type | diabetes. One study concluded that rubella virus can infect pancreatic islet cells and that the infection can severely reduce levels of secreted insulin. Like rubella, mumps disease has been strongly associated with the development of Type 4 diabetes. Similar to rubella virus, the mumps virus can infect pancreatic islet cells. It has been found that 85% of children with Type | diabetes have antibodies against the enzyme that converts glutamic acid into GABA (the GAD enzyme, or glutamic acid decarboxylase). Therefore, natural infection from the MMR viruses is associated with diabetes, where one sees issues with sugar regulation and excesses of glutamate. Again, many of the potential effects of acute viral infection appear to be similar to the observed issues s2en with autistic type of neurological inflammation, and from glutamate excitotoxicity Vitamin A deficiency is often noted in chronic viral infection, as well as in many children with autistic type behavior. Caution should be used in supplementing with vitamin A, as there is also an underlying liver dysfunction that is seen in children with autistic type behavior. An intrinsic hepatotoxicity with excess vitamin A has been noted in treating liver disease that is associated with a vitamin A deficiency. In some cases of liver dysfunction vitamin A supplementation has been found to hasten, rather than alleviate liver disease, in spite of vitamin A deficiencies. Heavy Metals/PST & MT Detoxification/Liver The liver is probably one of the most important organs in the body when it comes to health. The liver is the site for carbohydrate, fat and protein metabolism, storage of vitamins and minerals, and regulatory mechanisms for blood sugar and hormone levels. Bile production, which is necessary for elimination reactions, also takes place in thei. Amy A. Yasko/werw.holisicheatth.com enero2 Page u liver. In addition, and perhaps most importantly, the liver is the site for detoxification of the body. A central problem in the treatment of autism is the function and health of the liver. Ifthe liver is healthy, it can make sufficient enzymes for the efficient detoxification of the body. The liver contains high levels of enzymes, and enzyme systems that are required for detoxification processes. The liver contains one of the highest levels of glutathione. Glutathione is one of the most powerful antioxidants found in the body. Glutathione is essential for both the phase I and phase II detoxification systems of the liver. Phenol~ sulphotransferase (PST) is another sulfur-containing enzyme that detoxifies leftover hormones and toxic molecules, as well as food dyes and chemicals. Metallothioneins are sulfur containing proteins that scavenge free radical and regulate metals. In the case of autistic children, almost 100% have low PST enzyme levels. Both the PST enzymatic detoxification system as well as glutathione require sulfur. The metallothioneins, MT proteins that are involved in heavy metal detoxification in the body, are also sulfur-containing proteins. This lack of sulfur seems to be a central problem with children exhibiting autistic behavior. A central theme in the current treatment of autism seems to be the removal of heavy metals. While this is useful, heavy metal toxicity appears to be a consequence of the underlying problem and not the problem itself. High extracellular levels of the excitotoxin glutamate cause the extrusion of intracellular cysteine- resulting in glutathione depletion. Low levels of magnesium also result in decreased levels of glutathione, as does infection or inflammation that cause elevations in TNF alpha. The heavy metal toxicity may be secondary to the lack of sulfur/glutathione detoxification systems; this heavy metal toxicity then triggers further excitotoxin release which creates a continuous cycle of inflammation and depletion of antioxidants and detoxification proteins. ‘The function and health of the liver and pancreas appear to be at the center of many of the health issues seen in these child‘en. If the liver is healthy it can make sufficient glutathione. The PST enzymatic detoxification system, the MT proteins, as well as glutathione require sulfur. While sulfur-containing supplements are useful as chelating agents, it is more likely that the primary role they are serving is to supply sulfur for glutathione, the PST enzyme system, for taurine, and as antioxidants. DMSA is commonly used to help to chelate heavy metals and for detoxification with childrenDt. Amy A. Yaskohwww.holisticheatih.com onero2 Page 18 exhibiting autistic behavior. DMSA may be helpful as it serves as a source of sulfur although there are less potentially harmful sources of sulfur). However, it is important to realize that DMSA has been shown to trigger the inflammatory mediator TNF alpha 80 it would be important to use caution and to actively use agents that reduce inflammation when using this protocol. GABA/Speech/CCK/Secretin Another issue with children with this tyoe of neurological inflammation is the lack of /or slow development of speech. The calming neurotransmitter, GABA is essential for speech. GABA neurons damp the propagation of sounds so that a distinction can be made between the onset of a sound and background noise. (GABA is often used to help restore speech in individuals who have suffered strokes.) In addition to its’ effect on the intestinal lining, the tetanus toxin from the DPT vaccine attacks the Purkinje cells of the brain (which are known to be decreased in attistic children), These cells are involved in the production of GABA. In addition, the amino acid taurine (another sulfur containing amino acid) is itself involved in neurotransmission, and also helps to elevate the level of GABA. Taurine levels would also be depleted under conditions of low sulfation. Normally, excess levels of the excitotoxin glutamate can convert to GABA. There ‘seems to be a disconnect in this process for autistic children so that the excitatory neurotransmission is high (stims) and the calming neurotransmission is low (lack of speech), where again, one sees the need for sulfur containing proteins or amino acids in this process. The chronic measles infection proposed by Wakefield may be related to this disconnect between glutamate and GABA. Active measles infection (as opposed to chronic) can lead to Type | diabetes. In Type | diabetes the body makes antibodies against the enzyme that converts glutamate to GABA. It is possible to speculate that chronic measles infection may also affect this enzyme. The Gl tract also appears to be involved in this aspect of the pathology. In an ideal situation, following the digestion of food in the stomach by HCL, the HCL is dumped into the small intestine, stimulating the release of several proteins. These include gastric inhibitory peptide (GIP), secretin, and cholecystokinin (CCK). GIP slows the release of acid into the intestinal tract, secretin stimulates the pancreas to0. Amy A. Yaskohmww.holisticheciih.com onero2 Page 6 release bicarbonate to neutralize the acid, and CCK stimulates the gall bladder to release the bile (made by the liver) into the intestines to neutralize the acid and help digest fats. |f, however, the pancreas and the liver are in a weakened state, this ideal situation will not occur, particularly in those with blood type © who naturally produce additional stomach acid or in those with a history of excess acid. Instead, the HCL is stil dumped into the small intestine; however, these three proteins will not be released properly. This results in a situation where the intestinal tract will become more acidic due to lack of released bile, and result in an environment that is more conducive to growth of yeast, E.coli, and streptococcus, rather than normal intestinal flora. In addi absorption of fat-soluble nutrients (.e.vitamins A, D, and K), and a sub-optimal amount of secretin and CCK to trigger communication with the brain, Decreased levels of CCK in the brain are related to “idiopathic environmental n, there will be inadequate digestion of fats, consequently a decrease in intolerance". This is a psychological disorder that is characterized by impairment of normal social and vocational functioning and is also correlated with anxiety and panic. This condition is reminiscent of some of the socialization issues seen in children with autistic type behavior. Similar to CCK, the hormone secretin is found in the brain as well as the Gl tract. Secretin has been shown to cross the blood/brain barrier. It is postulated that secretin that crosses over into the brain as well as secretin that is released by Purkinje cells in the brain may regulate cells nearby to produce GABA. In addition, secretin appears to activate neurons in the amygdala, an area of the brain that integrates social and emotional stimuli While it has not yet been implicated directly in autistic type behavior, Neuropeptide Y is another peptide that is abundant in both the brain and the GI tract. In the brain it is involved in regulation of appetite, anxiety and blood pressure. In the Gl tract Neuropeptide Y is involved in the regulation of pancreatic secretions and gut motility. Neuropeptide Y has been reported to suppress glutamate and antagonize the effects of glutamate. The milk protein casein is a major food source of glutamate, and casein free diets have been found to be helpful in autistic children. However, the milk protein casein and whey are powerful stimulators of CCK. Diets deficient in casein and whey could lead to imbalances in CCK levels in the Gl tract, necessitating additional stimuli for CCK.Dt. Amy A. Yoskofwww.holistichectth.com sner02 Pogo ” Secretin has been shown to potentiate the levels of CCK induced enzymes, and this may be an additional benefit associated with its use. Ona related note, endocannabinoids have analgesic effects on the brain that function via a different pathway than opioids. Endocannabinoids in the brain suppress the release of both CCK and GABA. Endocannabinoids synthesis in the brain is. activated by glutamate receptors. According to current research done at NeuroGenesis, low levels of opioids, caused by stress, also result in low levels of GABA. In addition, low levels of opioids are correlated with high dopamine levels and low serotonin levels. Conclusion Excessive levels of glutamate have definitely been implicated in a number of diseases that involve neurological inflammation. This includes Parkinson's disease, Alzheimers's disease, Huntington's chorea, Multiple sclerosis, and ALS. In addition, glutamate induced neurotoxicity is indicated in stroke, brain injury, heart disease, schizophrenia, and bipolar disorder. In reviewing the predisposing factors, as well as the sequence of events that lead to autistic type behavior, the involvement of glutamate, or other excitotoxins is a thread that winds its way through all of these factors, From the standpoint of predisposing factors, excess glutamate is correlated with intelligence, as well as early gender differences in neurological development. Imbalances in the Gl tract and the normal flora balance can be exacerbated by glutamate. Vitamin K, a key vitamin in the pancreas is itself involved in glutamate enzymatically. Two of the major food issues for children with autistic type behavior are casein and gluten. Both of these food proteins are high in natural glutamate. In addition, the glutamate receptor has a binding site that should allow for opioid-like molecules to interact (similar to PCP). If the issue with casein and gluten is their opioid generated derivatives this would still involve the glutamate receptor, Vaccines can contain free glutamate, and metals that are components of vaccine preparations are able to trigger glutamate release. Imbalances in the conversion of glutamate to GABA have been noted as the sequelae of measles/mumps/rubella viral infections and low levels of GABA are related to speech difficulties,Di, Amy A. Yoskohwwwholistichealih.com enero Poge 18 Although this paper does not answer every question with regard to autistic type neurological inflammation, it does present a relationship between excess glutamate, excitotoxin damage, and many of the behaviors and symptoms associated with autistic type neurological inflammation. Taken together with the evidence for glutamate and excitotoxin damage in other types of neurological inflammation, it would be remiss not to consider the involvement of glutamate when working with children who present with autistic type neurological inflammation. In addition, this paper has also touched upon other previously unmentioned factors that are worth considering as contributing to autisic type neurological inflammation including the involvement of streptococcal infections, blood type, and lack of GABA.Dr. Amy A Yasko/wwwholstichealih.com en6r02 Page 9 Appendix Definite Sources of MSG © Hydrolyzed Protein * Sodium Caseinate or Calcium Caseinate © Autolyzed Yeast or Yeast Extract * Gelatin © Hydrolyzed Oat Flour © Glutamic acid © Monosodium glutamate Possible sources of MSG © Textured Protein * Carrageenan or Vegetable Gum Seasonings or Spices Flavorings or Natural Flavorings * Chicken, Beef, Pork, Smoke Flavorings * Bouillon, 3roth or Stock Barley Malt, Malt =xtract, Malt Flavoring Whey Protein, Whey Protein Isolate or Concentrate © Soy Protein, Soy Protein Isolate or Concentrate © Soy Sauce or Extract Other sources of MSG ¢ MSG is found in most of the food prepared by major fast-food chains * Binders and fillers for medications, nutrients, and supplements, both prescription and non-prescription, and some fluids administered intravenously in hospitals, may contain MSG. © According to the manufacturer, Varivax-Merck chicken pox vaccine (Varicella Virus Live), contains L-monosodium glutamate and hydrolyzed gelatin both of which contain processed free glutamic acid (MSG) * MSG is used as a plant "growth enhancer" (AuxiGro) that is sprayed on growing crops. AuxiGro Plant Metabolic Primer contains 29.2% by weight, pharmaceutical grade, L-glutamic acid, * The most common source of MSG is molasses or sugar beet or cane. ¢ MSG and Aspartame(nutraswee!) are found in everything from soups, sauces, and juice to frozen entrees, candy, cigarettes, and anything with seasonings (e.g., potato chips, meat, ice cream)Dr. Amy A. Yasko/www.holiticheali.com eni6r02 Page 20 Sources of Aspartate,aspartame,aspartic acid « Aspartic acid, found in aspartame (NutraSweet) ordinarily causes MSG type reactions in MSG sensitive people * Aspartame (Nutrasweet), aspartic acid,aspartate are used to sweeten many prepared foods, as a tabletop sweetener, sources include: * cocoa mix, topping mix yogurt-type products shake mix cereal gelatin mix instant breakfast mix frozen novelties milk flavor additives wine coolers chewable multivitamins carbonated soft drinks fruit syrups powdered soft drinks puddings and pie fillings fruit juice drinks instant coffee and tea mixes refrigerated tea ready-to-eat gelatin chewing gum frozen desserts refrigerated flavored milk beverages breath mints over-the-counter pharmaceuticals fruit spreads & toppingsDi. Amy A. Yosko/wnu.holtichealih.com ones02 Page a Free and Bound Glutamate in Natural Products Glutamate can be found in two forms: The "bound" form is linked with other amino acids to form proteins, whereas the "fre" form is not linked to other amino acids. Glutamate occurs naturally in protein-containing foods; the level of glutamate in food varies greatly, but is high in foods such as tomatoes, cheese (particularly parmesan cheese), milk, mushrooms, fish, peas and many vegetables. All plants contain large amounts of glutamate. Food item Fioo Glutamic Acid Free Aspartic Acid (mg/1005) (mg/1009) Tomato | 740.0 35.0 Fresh tomato juice 260.0 60.0 Processed tomato juice [ 230.0 60.0 Grapefruit, white meat I 115) a7 Grapefruit juice 186 730.0 ‘Orange juice 210 89.0 Nectarine, fruit 9.0 200.0 Peach juice 320 212.0 Plum, yellow fruit 79 185.0 Prunes (California) 74a 185.5 Prunes, dry 786 518.4 Grape, red Malaga 784.0 2 Grape juice I 258.0 768 Strawberry 44.4 60.4 Potato 702.0 5 Broccoll 176.0 00 Parmesan Cheese 7,200.0 ~ Gruyere Cheese 7,050.0 60.0 Mushroom (Psalfota campestis) 180.0 30.0 From: Giacometi, T. 1979. Free and bound glutamate in natural products, pp. 26-34. In, Filer, L.J., Jr. ot al. (eds.), Glutamic Acid: Advances in Biochemistry and Physiology, Raven Press, New York, NY.3 Amy A Yoskorwvaichoatincom enej02 Page Food item ‘Bound Glutamate (mgi1009) Parmesan Cheese 9.847 Eggs 7,583 ‘Chicken 3,309) Duok 3,636. 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