Autism and Schizophrenia subgroup related to blockage by toxic exposures of enzymes processing gluten and casein, B. Windham (Ed), 2014    

(affects at least 65% of autistic children (100)) (overlaps with other mechanisms documented in (110))

I.               Gluteomorphins (glia) and Casomorphins

Traditional bread produces compounds called gluteomorphins. And as their name implies, these compounds engage opioid receptors in your brain – the same receptors triggered by drugs like morphine and heroin. Very similar compounds, called casomorphins, are found in cheese.  wheat – including so-called “healthy” whole wheat – spikes your blood sugar more than most foods. That’s because most of the carbohydrates in wheat are in the form amylopectin A which is unique because of how rapidly it is transformed to glucose. According to research published in the American Journal of Clinical Nutrition (2), eating just two slices of whole wheat bread spikes your blood sugar more than drinking a can of soda, eating a candy bar or helping yourself to six teaspoons of table sugar. But it is not just one single protein in wheat that causes reactions in people (3). Gluteomorhin (Gliadorphin) is a peptide that is seven amino acids long.  DPP IV is used in two different steps of gliadorphin metabolism as it cleaves peptides which have proline in the second position. In the first step, DPP IV cleaves the tyr – pho segment off the beginning of the gluteomorphin peptide. This leaves a peptide with the sequence gln – pro – gln – pro – phe and DPP IV acts a second time to cleave the gln – pro, leaving gln – pro – phe.  the remaining gln – pro – phe tripeptide is an inhibitor of DPP IV. Instead of being acted on a third time by this enzyme, this tripeptide actually inhibits the action of DPP IV. This results in the inactivation of DPP IV and an impaired ability to break down further gluteomorphins. As a result, gluteomorphins may build up to high levels because of the inhibitory effect of the gln – pro – phe tripeptide on DPP IV. (3b)

 

Gluteomorphins result from incomplete digestion of the gluten protein (29). This impaired ability to fully digest gluten is caused by inadequate levels of the enzyme that cleaves gluteomorphin peptides into smaller peptides. This enzyme is called dipeptyl peptidase IV, these peptides are opioid-like compounds that behave much like morphine in the brain. Another peptide similar in both structure and effect to gliadorphin is caseomorphin, also a morphine-like compound that results from incomplete breakdown of casein, a milk protein found in many dairy products. DPP IV also acts on caseomorphin, which is also a seven amino acid peptide with proline in the same positions. Caseomorphin metabolized by DPP IV meets the same fate as gliadorphin. After being cleaved twice, a tripeptide with proline in the center position remains, which inhibits DPP IV just like the tripeptide that results from gluteomorphin metabolism. Caseomorphin is also picked up on opioid receptors in the brain and produces similar mind-altering effects and withdrawal symptoms. (4a) Because casein can cause the same production of morphine-like compounds, a dairy free diet is often also recommended for children with autism and can greatly reduce symptoms in children for whom caseomorphin is playing a role (29). Children with autism have abnormal leakage from the gut of gliadorphin (29); and abnormally high levels of gliadorphin have been found in the urine of autistic children via mass spectrometry testing (2).

The DPP IV enzyme does not just catalyze gluteomorphins. It is also a regulator of many other peptides processes in the body and a deficiency of DPP IV can interfere with the action of these peptides(29a). Some relate to digestion directly, including Peptide YY, Pancreatic polypeptide and Substance P. Other peptides that rely on DPP IV regulate immune function and inflammatory response, including Neuropeptide Y and Interleukens 1b, 2, 3, 5, 8, 10, 11 and 13. Depressed levels of DPP IV may lead to problems with these peptides being activated and deactivated. In addition to autism, other mental illnesses are associated with altered levels of DPP IV, in some cases elevated and in others depressed. For example, low levels of DPP IV are found in people suffering from major depression (5a& and also in alcoholics, including recovered alcoholics who have been abstinent from alcohol for some time. (5b) Low levels are also commonly found in celiac disease, (5c) rheumatoid arthritis, (5d) and anorexia. (5e) Conversely, high levels of DPP IV are found in patients with schizophrenia. (5b)

Gelatin, especially hydrolyzed gelatin, has been shown to trigger autistic symptom in susceptible children. The MMR vaccine has been shown to be a potent inhibitor of DPP IV due to its hydrolyzed gelatin content. Hydrolysis results in tripeptides with proline in the second position, similar to the tripeptides that result from gluteomorphin metabolism that inhibit DPP IV (29a). Opiate-blocking drugs like naltrexone can decrease the severity of autistic symptoms. Because naltrexone blocks the effects of opioids on the brain and gluteomorphins behave like opioids to exacerbate autistic symptoms, naltrexone appears to alleviate symptoms of autism by blocking opioids from acting on the brain. (6)

Genetic deficiencies in DPP IV may contribute to the formation of gluteomorphins. Autistic children are thought to be deficient in DPP IV, which leads to high levels of gluteomorphins in children who consume gluten. Gluteomorphins have also been found in the urine of autistic children. Because gluteomorphins are made from dietary gluten and inhibit DPP IV, which may already be low in autistic children, a gluten free diet is often recommended for autistic children and can reduce autistic symptoms considerably(29a).

Candida albicans is a pathogenic yeast normally present in small quantities in the intestines. In healthy individuals, candida levels are kept at bay by beneficial bacteria. But when those friendly bacteria are low or wiped out by antibiotic use, candida can proliferate out of control. One common result of a candida overgrowth is a reduction in hydrochloric acid production in the stomach, called hypochlorhydria. Adequate levels of hydrochloric “stomach acid” are necessary for the beginning stages of protein digestion. Without adequate stomach acid, proteins like gluten and casein may not be digested properly. Strong stomach acid initiates a series of digestive cascades that turn on many other digestive processes. Pepsin, which is also required to digest proteins like gluten, relies on adequate stomach acid for activation. If stomach acid is inadequate, pepsin is not activated, and gluten metabolism suffers. Another component of digestion that relies on adequate stomach acid is the secretion of pancreatic enzymes like secretin that help digest food. When stomach acid is low, these enzymes are not released into the small intestine to help with digestion and the ability to digest proteins like gluten is impaired.

A third cause of impaired protein digestion is dysbiosis, an unhealthy condition in the intestines. Dysbiosis can lead to overgrowths like candida and also plays a direct role in the final stages of gluten breakdown which takes place lower in the intestines. Imbalances in gut flora inhibit the body’s ability to cleave short gluteomorphin peptides into their individual amino acids.

II.          Enzymatic Inhibition by mercury (and other toxic metals)

 

A direct mechanism involving mercury’s inhibition of cellular enzymatic processes by binding with the hydroxyl radical (SH) in amino acids appears to be a major part of the connection to allergic/immune reactive conditions (15-23,28,36,47,51,98). For example mercury has been found to strongly inhibit the activity of xanthine oxidase(16) and dipeptyl peptidase (DPP IV) which are required in the digestion of the wheat protein gluten or the milk protein casein (15,17,19,20,22a,24,-26,31,98, 105) - the same protein that is cluster differentiation antigen 26  (CD26) which helps T lymphocyte activation. CD26 or DPPIV is a cell surface glycoprotein that is very susceptible to inactivation by mercury binding to its cysteinyl domain. Mercury and other toxic metals also inhibit binding of opioid receptor agonists to opioid receptors, while magnesium stimulates binding to opioid receptors (15). Studies involving a large sample of patients with autism, schizophrenia, or mania found that over 90 % of those tested had high levels of the milk protein beta-casomorphine-7 in their blood and urine and defective enzymatic processes for digesting milk protein (24,25,27), and similarly for the corresponding enzyme needed to digest wheat gluten (24,26). Like casein, gluten breaks down into molecules with opioid traits, called gluteomorphine. As with caseomorphin, it too can retain biological activity if the enzymes needed to digest it are not functioning properly.

Proteins in bovine milk are a common source of bioactive peptides. The peptides are released by the digestion of caseins and whey proteins (105).  In vitro the bioactive peptide beta-casomorphin 7 (BCM-7) is yielded by the successive gastrointestinal proteolytic digestion of bovine beta-casein variants A1 and B, but this was not seen in variant A2 or in goat’s milk. In hydrolysed milk with variant A1 of beta-casein, BCM-7 level is 4-fold higher than in A2 milk.  Variants A1 and A2 of beta-casein are common among many dairy cattle breeds. A1 is the most frequent in Holstein-Friesian (0.310–0.660), Ayrshire (0.432–0.720) and Red (0.710) cattle. In contrast, a high frequency of A2 is observed in Guernsey (0.880–0.970) and Jersey (0.490–0.721) cattle (105). In children with autism, most of whom have been found to have been exposed to high levels of toxic metals through vaccines, mother’s dental amalgams, or other sources; higher levels of BCM-7 is found in the blood (24-26).  

BCM-7 appears to play a significant role in the aetiology of human diseases including diabetes, immune, neurological, and cardiovascular (105,106). Epidemiological evidence from New Zealandclaims that consumption of beta-casein A1 is associated with higher national mortality rates from ischaemic heart disease. It appears that the populations that consume milk containing high levels of beta-casein A2 have a lower incidence of cardiovascular disease and type 1 diabetes. Beta-casomorphin-7 has opioid properties including immunosuppression, which account for the specificity of the relation between the consumption of some but not all beta-casein variants and diabetes incidence.  BCM-7 has also been suggested as a possible cause of sudden infant death syndrome (SIDS). In addition, neurological disorders, such as autism and schizophrenia, appear to be associated with milk consumption and a higher level of BCM-7 (105,106).

 

The studies also found high levels of Ig A antigen specific antibodies for casein, lactalbumin and beta-lactoglobulin and IgG and IgM for casein.   Beta-casomorphine-7 is a morphine like compound that results in neural disfunction (24,25), as well as being a direct histamine releaser in humans and inducing skin reactions (14,21,25c).  Similarly, many also had a corresponding form of gluten protein with similar effects (24,26).   Elimination of milk and wheat products and sulfur foods from the diet has been found to improve the condition of ASD children (100,28, etc.).  A double- blind study using a potent opiate antagonist, naltrexone (NAL), produced significant reduction in autistic symptomology among the 56% most responsive to opioid effects (28).  The behavioral improvements were accompanied by alterations in the distribution of the major lymphocyte subsets, with a significant increase in the T-helper-inducers and a significant reduction of the T-cytotoxic-suppressors and a normalization of the CD4/CD8 ratio.   Studies have found mercury causes increased levels of the CD8 T-cytotoxic-suppressors (29).   As noted previously, such populations of patients have also been found to have high levels of mercury and to recover after mercury detoxification (23,11,22a,30,40,96,100).  As mercury levels are reduced the protein binding is reduced and improvement in the enzymatic process occurs(22a,11,96).

II.  Lactose Intolerance

Lactose (milk sugar), which is a major component of milk, is a disaccharide sugar made up of the simple sugars glucose and galactose (1).  Lactase is an enzyme which facilitates digestion of lactose.  Over 50% of non-Caucasians are lactose intolerant, to a significant degree and about 20% of Caucasians. Infants are most lactose tolerant but lactase activity declines dramatically over time so that by adulthood to about 5 to 10 % of the level of infants. Only a relatively small percentage of people retain enough lactase activity to absorb significant amounts of lactose throughout their adult life (1). Lactose intolerance results in undigested lactose in the intestines which often causes gas, bloating, abdominal discomfort, and proliferation of bacteria in the intestines. In addition to inhibiting the enzymes required to digest milk casein and whey, chronic mercury exposure in animals has also been found to inhibit lactase and glucose-6-phosphatase needed to digest lactose and other polysaccharides (31). Thus, chronic exposure to mercury and toxic metals also increases lactose intolerance and digestion problems of carbohydrates in general.  Digestive problems have been found to commonly be improved by reducing chronic mercury and toxic metal exposures. 

Lactose intolerance can also be alleviated to some degree by supplemental enzymes, using fermented milk products such as yogurt or kefir, or using only small amounts of milk products spread throughout the day (1). 

    A new study has found that there has been a significant increase in another gluten related condition in the last 50 years –celiac disease (32). The researchers showed that the presence of undiagnosed celiac disease was 4 to 4.5-fold greater in the more recent subject group compared to an earlier Warren Air Force Base group.  This study indicates that the rise in the prevalence of celiac disease over the last 50 years is not simply due to increased awareness and better diagnostic tests for this condition. Additionally, the fact that the mortality rate of undiagnosed celiac disease is almost 4-fold higher than for those without the condition suggests that screening for celiac disease instead of waiting for a patient to complain of symptoms may be warranted. A positive test result should be confirmed before undergoing a gluten-free diet. The study authors concluded, “During 45 years of follow-up, undiagnosed celiac disease was associated with a nearly 4-fold increased risk of death. The prevalence of undiagnosed celiac disease seems to have increased dramatically in the United States during the past 50 years.” Studies have also found that untreated celiac disease can result in infertility, spontaneous abortions, and birth defects, along with other reproductive system problems (10). 

       Altered porphyrins by mercury exposure is another mechanism that mercury has been shown to cause problems and symptoms seen in autism (7,9c). Mercury has been well documented to cause neurological, mood and behavioral problems for children and others(8,9, etc.) Mercury also has additive and synergistic effects with other toxic metals and toxins so lower exposure levels of each can produce significant damage (9). Susceptibility factors also reduce some people’s ability to detoxify mercury and other toxins, making some more affected by toxic exposures.

The papers discussed here show some of the ways that mercury can cause or be a factor in autism and other neurological conditions.

References

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(10) Dr. Sheila Crowe,   Division of gastroenterology and hepatology in the department of medicine at the University of Virginia, New York Times February 3, 2010

 

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& rest in (110)  http://www.myflcv.com/kidshg.html