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Summary of Defeat Autism Now! (DAN!) October 2001 Conference

By James Adams (parent)

Published in this site by written permission of the author, Prof. James Adams

First, many thanks to Bernie Rimland, Maureen Odonnell, Sid Baker and Jon Pangborn for all their efforts in organizing the conference and the new DAN! Protocol. The new version of the DAN! Treatment protocol is available from the Autism Research Institute, 4182 Adams Ave, San Diego, CA 92116 for $20. It is authored by Jon Pangborn, Ph.D., and Sidney Baker, M.D. It is a major revision, and is now 161 pages.

Summary of Friday’s Advanced Practitioner’s Session:

(There was also a new parent session and another practitioner’s session)

Opioid Peptides: Karl Reichelt, Ph.D., presented a summary of many years of work by himself and others on the role of opioid peptides in autism. Protein is made of peptides, which are made of amino acids. Basically, his lab and several others have published many articles in the scientific literature on their findings of unusual proteins and peptides in the urine of people with autism. Those proteins and peptides come from casein (dairy) and gluten (wheat and related grains), and they have an opioid-like effect on the brain, with a potency several times that of morphine. The peptides enter the blood due to 2 major biological flaws: 1) a failure of the digestive track to fully digest/break-down the casein and gluten molecules into amino acids, and 2) a “leaky gut” which allows the undigested proteins/peptides to pass into the blood stream. The failure of the gut to properly digest the proteins is apparently due to a lack of peptidases (digestive enzymes), which he hypothesizes could be due to genetic defects (other speakers also discussed environmental and nutritional causes). Recent work by Dr. Cade (1999) found antibodies (IgA) to gluten and casein in the mucous membranes of 12 of 44 people with autism. These opioid peptides can have many behavioral and physical effects, and could cause many of the symptoms of autism.

A single-blind, 2-year study found that children with autism improved on a gluten-free, casein-free (GFCF) diet, but regressed if the diet was stopped. A recent 2001 study by Cade found that digestive enzymes helped, but were only half as effective as a GFCF diet. Currently, the best labs have about a 5-10% false negatives and positives, so he recommends everyone with autism try a GFCF diet.

Summary: Gluten and casein, from dairy and wheat, appear to have an opioid-effect in autism, so a trial of total avoidance is strongly recommended.

Immunology – Dr. Gupta gave a very detailed talk on immunological abnormalities in autism. Basically, the immune system is composed of T cells (to fight viruses and fungi), B cells (to fight bacteria), Natural Killer cells. T cells consist of TH1 and TH2 cells. In autism, there is a major shift from TH1 to TH2. The decrease in TH1 may explain the increased susceptibility to viral and fungal infections in autism. The increase in TH2 may explain the increased autoimmunity, such as his findings of antibodies to myelin basic protein (MBP) and neuronal axonal filaments in the brain. Also, there is an increase in tumor necrosis factor (TNF) in autism, which could lead to decreased blood flow into the brain, a loss of Purkinje cells (often found on autopsy), alterations in neurotransmitters and neuropeptides, and possibly demyelination, as found in multiple sclerosis (MS). The decrease in TH1 could explain the “leaky gut” in autism, due to more viruses causing the lymphoid cells to multiply rapidly (as found by Dr. Wakefield in many cases), and causing more peptide absorption (as found by Dr. Reichelt and others). Mercury could also play an important role, as it can poison mitochondria (the part of every cell that produces energy), and it can denature DNA, alter membrane permeability, induce autoimmunity, and cause apoptosis (cell death). In a test-tube, very low (micromolar) concentrations of thimerosoal were found to cause cell death, and the addition of glutathione was found to block thimerosal and reduce cell death. One possible therapy for autism is intravenous Immunoglobulin, which can neutralize bacteria and viruses and promote phagocytes to attack bacteria and fungi.

Summary: In autism, there is a major change in the immunological system, making people with autism vulnerable to bacteria, fungi, and viruses, and causes the immune system to attack the body (autoimmunity). Mercury is a possible cause of this.

Sulfation: Susan Owens substituted for Rosemarie Waring, and presented Dr. Waring's data on sulfate in autism. Basically, people with autism were found to excrete roughly twice as much sulfate in their urine, so that they had only 1/5 the normal level of sulfate in their bodies. Sulfur is an essential mineral, and is needed for many functions in the body. AIDS patients have also been found to exhibit a loss of sulfur in their urine, leading to a loss of extracellular sulfated structures in the brain. This has not yet been investigated in autism, but may be the same. In AIDS patients, treatment with N-acetyl cysteine was found to be beneficial.

In autism, TNF (tumor necrosis factor) is elevated, which can inhibit the conversion of cysteine to sulfate.

Low sulfur levels could cause many problems.

· Sulfur is needed to sulfate the hormone CCK, which stimulates oxytocinergic neurons to release oxytocin. So, a lack of sulfur could explain the low oxytocin levels found in autism, which is important for socialization.

· Sulphate is important for detoxification of metals and other toxins.

· Sulphation requires activated sulfate, which requires magnesium.

· Boys excrete more sulfur than girls, so they may be more susceptible to sulfation problems.

· Wakefield's group found that the ileum of the intestine lacks sulfur, which would lead to a leaky gut.

· Sulphate is needed to release pancreatic digestive enzymes.

· Many enzymes would be impaired if sulfur levels were low.

· The perineuronal nets around neurons, which modulate their function, are primarily composed of chondroitin sulfur. Low sulfur would thus yield less modulation of neurons

· The hepatitis B vaccine was found to inhibit sulphation chemistry for one week in typical people.

Summary: Almost all people with autism have very low levels of sulfur in their blood, which could cause many of the problems associated with autism. Sulfur could be replaced by Epsom salt baths, sulfate creams (now available from Kirkman labs), or possibly with cysteine or n-acetyl cysteine (but Pangborn has concerns about the use of cysteine or n-acetyl cysteine). Since sulfate leaves the blood in 4-8 hours, it should be used at least 1x/day, and possibly more often.

Mercury: Jim Laidler discussed the latest statistics from the US Dept of Education on the number of people with autism, which show a 10-fold increase in the number of people with autism over the last 7 years. Also, they show that, unlike other disabilities, the number of people with autism is heavily skewed towards the younger ages (twice as many in the 6-11 as the 12-17 group).

Some similarities between autism and mercury toxicity include restriction of visual field (tunnel vision), autoimmune abnormalities, and many other symptoms.

Mercury detoxification is best done with DMSA. Chlorella and cilantro should be avoided because, although they gather mercury from the environment, they do not bind mercury as strongly as human tissue, so they will tent to release mercury into humans. DMSA can best be used on a 3 day on, 11 day off cycle, with dosing every 8 hours (4 hours vs. 8 does not seem to make much difference). DMSA may cause some fatigue or irritability, since it seems to cause GI dysbiosis temporarily. DMSA does not transport mercury into the brain. Once DMSA has lowered the level of heavy metals, alpha lipoic acid can be added on the days of DMSA, and will increase excretion of mercury. Doses for alpha lipoic acid can start at 1-3 mg/kg-day, and increase up to 10 mg/kg-day. Chelation should be stopped either when metal excretion is not detectable, or when no further improvements are observed. Since some people with autism improve on DMSA even when little metal is being excreted, DMSA may be having other effects, such as acting as a powerful antioxidant, removing cysteine, or binding to gliotoxin (a toxin from yeast that affects neurons).

He also discussed the possible connection between the NMDA (n-methyl d aspartate) receptor and autism. Blockage of that receptor could cause reduced pain, tunnel vision, inability to shift attention, auditory problems, repetitive behaviors, dilated pupils, and language problems. The reason is that it controls pruning of brain cells during development, modulates pain, and modulates dopamine and serotonin.

Summary: The increase in the number of people with autism could be explained by mercury in vaccines. Many symptoms of autism could be explained by mercury toxicity. DMSA, followed by DMSA and alpha lipoic acid, are effective in decreasing mercury levels, and can improve the symptoms of autism in some cases.

Lab Tests: Jon Pangborn discussed biochemical types of autism. These include:

· PKU variants: may involve dihydrobipterin-to-tetrahydrobiopterin (DPR or DHR reductase)

i. Phenylalanine -> Tyrosine

ii. Tryptophan -> 5-HTP -> Serotonin

· Fragile X: may involve deficiency of deoxyuridine to deoxythymidine transformation due to 5,10 methylene THF dysfunction

· Histidinemia: Histidine -> 5-Formimino THF

· Adenylosuccsinate Lyase Deficiency

i. Adenylosuccate -> AMP + Fumarate

ii. Purine synthesis decreased before formation of inosine

· 5-PRPP Synthesis Deficient: - initial and rate limiting step for purine synthesis; 5-PRPP also needed for pyrimidine synthesis

· Inosine Phosphate Dehydrogenase Weakness

i. Inosine phoshate -> guanine phosphate, which makes biopterin

· Lesch-Nyhan Disease

i. Hypoxanthine -> Inosine Phosphate

ii. Increase in uric acid and oxidants

· Purine autism – adenosine deaminase deficiency

· DPPIV weakness – adenosine deaminase binding protein (CD 26) – inability to digest casein and gluten

For each of the disorders listed above, he provided a flow chart of how each of them can affect metabolism. He also listed specific lab tests for Hyperphenlyalaninemia / uria, Histidineemia, Fragile X, Rett, Lesch-Nyhan Syndrome, and Purine Autism.

He briefly discussed the many factors that could weaken DPPIV, the enzyme need to digest gluten and casein, and he mentioned an open (non-blinded) study of EnZymAid and how it helped improve several symptoms of autism.

Finally, he gave examples of typical findings in elemental analyses of packed red blood cells and hair, amino acid testing, detox profiles, comprehensive digestive stool analyses, yeast sensitivity, bacterial sensitivity, and fatty acid analysis. This is all discussed in more detail in the new DAN! Protocol, which he co-authored.

Treatments: Woody McGinnis (from Practitioner Training session 1):

Autism and ADHD are similar, with multiple underlying problems, and the gut and nutrition are of paramount importance. There has been extensive reports in the literature of GI problems. In particular, 85% of children suffering from night awakening were found to have reflux esophagitis – stomach acid rose into their esophagus when they lay down, burning it.

GI problems lead to poor nutrient digestion and absorption, a leaky gut, microbial overgrowth, and possibly altered signaling to the brain (80% of vagus nerves go from gut to head).

Low zinc can lead to low stomach acid, which is critical for digestion. 45% of people with ADHD have low stomach acid, and probably similar for autism.

Greater oxidative stress is common. Hence, give vitamins C, E, A, zinc, selenium, and taurine. Both the gut and brain are very sensitive to oxidative stress.

To help with detoxification, give B6, B12, folate, Mg, zinc, selenium, lipoic acid, and methionine.

Possible treatments include: diets (GFCF, low sugar, organic (esp. meat), purified water, no Nutrasweet), digestive enzymes, probiotics, vitamin/mineral supplements (esp. zinc and C), cod liver oil (for vitamin A and D), fish oil and evening primrose oil (for omega 3 and omega 6 fatty acids), anti-viral medications, secretin, DMSA/alpha lipoic acid (to remove heavy metals), and bethanecol (helps intestinal mucosa, stimulates digestive enzymes).

Recommends full nutritional assay. This includes checking stool pH (easy at home), IgE or IgG food testing, and urinary pyroles (25% of autistics have bad toxin; Vitamin Diagnostics is one possible lab).

For constipation problems, recommends magnesium citrate, fiber, vitamin C, and bethanecol.

Glutamine can be great to feed intestine, but avoid if blood ammonia high.

Extra: Jeff Bradstreet

First, Jeff unveiled his plans to create an integrated campus facility to treat the biological, behavioral, and nutritional needs of people with autism. He hopes to raise $20-$30 million in private funds to create it.

Then he began discussing the biological problems in autism and how to treat them. First, he explained that vaccines and vaccine additives can shift the immune system from TH1 to TH2. In some cases these additives are added specifically to stimulate antibody production, but in the case of autism it may overstimulate it, causing autoimmunity problems.

Next, he discussed the etiology of autism in the following series:

1) autistic enterocolitis creates an abnormal environment for bad bacteria, yeast, and parasites

2) Mercury exposure alters the type of microorganisms in the gut (also occurs when DMSA is used to excrete mercury)

3) In his small study, he found that on a DMSA challenge test, autistic children excrete 5x as much mercury as normal children (8.63 mcg per 24 hr, vs. 1.48 mcg per 24 hr). Thus, either they were exposed to high amounts and/or they have a limited ability to excrete it. The mercury can have many effects, including completely inhibiting the DPPIV, needed to digest gluten and casein.

4) In terms of nutritional abnormalities:

a. Zn deficiency exists in 90% of autistic children

b. Cu excess exists in 90%

c. Calcium and magnesium deficiencies are common

d. Omega 3 deficiency exists in nearly 100%

e. Fiber deficiency exists in nearly 100%

f. Antioxidant deficiency exists in nearly 100%

5) The damaged GI tract causes poor protein digestion. This results in:

a. Deficiency of essential amino acids

b. Extra food for bad bacteria, causing high levels of ammonia (a toxin) – substances that reduce ammonia may reduce brain fog (alpha keto glutaric acid is one option)

c. Gluten and casein peptides, which act as opioids

d. Undigested proteins causing allergic reactions in gut and blood

He also listed treatment options for various disorders. These include:

Treatment for Viral Infections:

Monolaurin: ¼ tsp., 3x/day: active vs. measles, HHV-6, pathogenic bacteria; seemed to have helped 2 kids

Treatment for Weakened Immune System

· Zinc: 20-200 mg

· Selenium: 100-200 mcg

· Beta-glucan (activates macrophages, the part of the blood that eats foreign matter)

· Caution: easily becomes rancid, so make sure you get a good brand

· IP-6 (from Enzymatic Therapy): activates Natural Killer cells; 1-2/day on empty stomach

· Transfer Factor: from Chisolm

· Oral immune globulin – prescription only

Treatment for Mercury and other Heavy Metals

(See Consensus Treatment for Metal Detoxification for Children with Autism)

· DMSA: but it can cause temporary regression, possibly by the undigested amount feeding gut bacteria

· Alpha Lipoic Acid: but caution, it can make some children worse

· Glutathione: oral, transdermal, or intravenous

· Colostrums (Kirkman's Super Colostrum Gold)

· Monolaurin

· Vancomycin or flagyl – to fight bad bacteria

· Fiber (Miralax is one option)

· Reduce sugars

· Eat vegetables

· Essential fatty acids

Treatment for Protein Maldigestion:

· morselation: chew food into smaller pieces, so more surface area for digestion

· Digestive Enzymes: options include EnzymAid, Creon, others for all meals/snacks

Treatment for Ammonia Excess

· It is a neurotoxin. To test for it, ship blood only on dry ice.

· To treat it, follow treatment for protein maldigestion. Also, reduce/eliminate glutamine. Finally, use alpha keto glutaric acid, 100-300 mg, 2x/day

Treatment for Nutritional Deficiencies

· Multivitamin/mineral supplement

· Essential fatty acids

· High-quality food (no junk food, soda, etc)

· Eat smaller portions, more frequently

Treatment for Food Allergies

· Test for food allergies at a lab like Immunolabs – remove allergic foods

· Rotation diet (don’t eat the same thing)

· Digestive enzymes

· IV Immunoglobulin and mercury detoxification may help

Treatment for Detoxification:

· Oral sulfur: taurine, glucosamine sulfate, MSM, n-acetyl cysteine

· Transdermal magnesium sulfate (Kirkman), Epsom salt baths

· Glutathione – transdermal or IV

· Milk Thistle – to support liver

Summary:

1) gut damage creates breeding ground for bad bacteria and fungi

2) mercury causes GI problems

3) many nutritional deficiencies exist

4) poor protein digestion causes nutritional deficiencies and food for bad bacteria

Effective treatments for the above conditions exist and can help.

Also, at the meeting Kirkman Laboratories distributed a free 176 page Guide to Intestinal Health in Autism Spectrum Disorder. You can request a copy from Kirkman Labs, 1-888-KIRKMAN.

Day 2:

Yeast Treatments: Sidney Baker:

Dr. Baker discussed the importance of first evaluating the severity of each symptom on a simple scale (3=mild, 6=moderate, 9=severe, 12=incapacitating), and then trying different treatments and evaluating their effect. Ie, treat the child, not the tests.

He mentioned GFCF diets, anti-fungal treatments, vitamin/mineral supplements, and essential fatty acid supplements.

He especially discussed an unusual anti-fungal treatment, saccharomyces boulardi (available from 1-800-426-2831), which is a yeast that attacks other yeast. It produces lactic acid that promotes good flora. As with any effective anti-fungal, it can cause a die-off reaction (when the yeast die all their toxins are released at once), and activated charcoal (from a pharmacy, 4x/day) can help absorb those toxins. He also listed several nonprescription anti-fungal treatments, including capryllic acid, undecelynic acid, citrus seed extract, oil of oregano, and garlic. Both organic acid tests and stool tests can sometimes be contradictory and misleading.

He mentioned that high methylmalonic acid is an indicator of vitamin B12 deficiency, and recommends B12 injections in those cases (absorption of B12 is very low in the digestive tract). Only Vitamin Diagnostics has a good direct test for B12 test. B12 injections can help within hours to days.

Secretin – Walter Herlihy (RepliGen)

Initial collection of parental reports by the Autism Research Institute (Bernie Rimland) helped them determine that a single infusion of secretin seemed to help for 3-5 weeks.

In order to win FDA approval for secretin, there are three phases of testing. For secretin, Phase 1 (safety) and Phase 2 (establish dosing) have been completed. They are now hoping to start Phase 3 (statistical proof of efficacy).

In reviewing the Phase 1 trials, most of them were small, so that although they showed some improvement the results were not statistically significant. However, pooling all of the results into a meta-analysis did show a positive benefit of secretin.

In the phase 2 trials, 126 patients at 5 labs were involved in a double-blind, placebo-controlled study including 3 infusions. The results of the two standardized tests (GARS and CARS) showed only minor improvement, and were not statistically significant. Clinical Global Impressions (CGI, a very simple 1-7 scale rating whether they became better or worse) was rated by parents and by professionals. The parents results showed a 0.43 improvement on the scale compared to controls, which was statistically significant, but the professionals found only a 0.22 improvement, which was not statistically significant. The ADOS test, which has become the gold standard for assessing severity of autism, found some improvement, but again not statistically significant. The MacArthur Language Inventory found a small effect of secretin, but it was not statistically significant. Finally, there was an evaluation of GI function, but there was no difference between the children who received the placebo vs. the secretin.

However, analysis of stool samples found that many of the children had abnormal levels of chymotrypsin (29% had low levels) or calprotectin (26% had elevated levels). These abnormalities seemed to result in more day-to-day variation in behavior, and made it harder to evaluate. So, the data was re-analyzed without those children, leaving 64 children to be analyzed. Those results were more positive, and statistically significant results were found in the data was then re-analyzed to only count children who did not have chymotrypsin or calprotectin abnormalities in the stool, as those seemed to cause a lot of day-to-day variation in behavior. In this case, the CGI-parent and CGI-professional scores, the ADOS, and the MacArthur Language Inventory all showed statistically significant results.

In addition, his lab searched for opioid peptides, but did not find any in the 120 patients that they investigated, which is a curious contradiction with work by Reichelt, Cade, Shattock, and several other researchers who have found them.

Conclusion: The phase II study showed some statistically significant benefit for secretin, especially when considering only the subset of children who did not have chymotrypsin or calprotectin abnormalities. The benefits included language, but did not include GI function.

Disordered Metal Metabolism: William Walsh first discussed his data on 503 children with autism, which found an elevated Cu: Zinc ratio in nearly all the children. Specifically, 85% had very high Cu: Zinc ratios, 8% were receiving zinc supplements and had only moderate imbalances, 6% has a severe pyrole disorder (indicating severe zinc depletion), and only 4 of the 503 children did not have a serious Cu: Zinc imbalance. The average Cu: Zinc ration was 1.63 in autism, vs. 1.15 in the controls, and was highly statistically significant (p<0.0001). This is a very important finding from a very large study.

Walsh hypothesizes that the Cu: Zinc imbalance could be due to a defect in metallothionein function, since metallothionein proteins regulate Cu and Zinc levels. The primary functions of metallothionein include: development of brain neurons; cell transcription; regulation of Cu and Zinc; detoxification of heavy metals; maturation of GI tract; powerful antioxidant; immune function; deliver of zinc to cells. It is the primary defense of the body against heavy metals. If a defect in metallothionein exists, it could be due to a genetic impairment or due to environmental damage.

There are four metallothionein proteins:

MT-I and MT-2 are present in all cells throughout the brain and periphery

MT-III is a neuronal growth inhibitor found primarily in brain

MT-IV is found primarily in skin and GI tract.

A defective metallothionein could explain many of the symptoms of autism, including sensitivity to heavy metals, zinc depletion and copper overload, reduced stomach acid, incomplete breakdown of proteins. Since metallothionein production is enhanced by estrogen and progesterone during early development, females will be better protected than males against heavy metals.

Researchers studied a MT-knockout mouse (a mouse without any metallothionein) and found that it had a very weakened immune system and had a high incidence of seizures.

The activity of metallothionein is primarily enhanced by zinc, glutathione, selenium, and n-acetyl cysteine. Of secondary benefit are vitamins B6, A, C, D, E, genistein, biochanin A, and glucorticoids.

In Wilson's disease, copper overload can be treated by removing excess copper and long-term zinc therapy. This may also help in autism, and may lead to reduced GI problems, improved behavior and cognition, and reduced vulnerability to heavy metals. His lab (Pfeiffer Labs) is investigating nutritional interventions to promote metallothionein and thereby reduce symptoms of autism.

However, there are no commercial lab tests for metallothionein, and the children with autism did not have their metallothionein levels tested.

Also, their lab found that 45% of children with autism were undermethylated (needed folate and DMAE), whereas 15% were overmethylated.

Conclusion: In a very large and important study of 503 children with autism, a very high Cu: Zinc ratio was found. This could have a wide-reaching effect since copper and zinc play many roles in the body. It is hypothesized that the Cu: Zn imbalance is due to a defect in metallothionein, and such a defect could explain many of the biochemical abnormalities in autism. Nutritional interventions with zinc and other supplements are recommended for treating this imbalance.

Paul Shattock (AKA Robert Redbird):

Paul humorously discussed the great increase in the incidence of autism, which now affects 1 in 150 children. He thinks it is due to a combination of a genetic susceptibility and an increase in an environmental toxin(s). These could include vaccines, pesticides, dietary changes, gut dysbioses, heavy metals, plasticizers, toxic fumes, food additives, and drug residues in food and water.

In his studies of the urine of people with autism, they often find peptides that are similar to opioids, several times as potent as morphine. Opioids are known to decrease sociability, decrease memory and learning ability, increase stereotopy and hyperactivity, cause constipation and lower body temperature. These peptides could interfere with the central nervous system, and affect many functions, including perception, cognition, behaviors, mood, emotions, CNS development, immune system, and gut function.

Based on the levels of one type of peptide (IAG), there seem to be two types of autism:

Type 1: elevation in many peptides, including IAG

Type 2: elevation in many peptides, but normal IAG

Type 2 is the more recent type, and occurs about 10% of the time in the UK and 50% in the US, suggesting it is due to vaccine exposure which is more recent and higher in the US. Type 2 children tend to be more social, have unusual thirst, have an abnormal gait, and have bowel problems.

Elevated IAG levels are also found in Gulf War veterans.

Freeman had found dermorphin, a peptide 2000x more potent than morphine, in some children with autism.

Waring had found that people with autism had only 1/5 as much sulfur in their blood as normal, which could cause several problems, including:

1) neurotransmitters not being processed after use

2) reduced ability to eliminate metals

3) leaky gut

4) proliferation of yeast in gut

Organophosphate pesticides act by blocking enzymes in insects, and may also affect enzymes in humans and IAG levels.

Sunderland treatment protocol (available at www.osiris.sunderland.ac.uk/autism)

1) test for celiac disease and amino acids

2) vitamin/mineral supplements

3) GFCF diet, and keep a food diary to determine if other foods should be avoided

4) Test vitamin/mineral levels, and test for allergies

5) Comprehensiv