Defective Functioning of Metallothionein Protein (MT) and Toxic Metal Sensitivity, Pfeiffer Treatment Clinic, Dr

Defective Functioning of Metallothionein Protein (MT) and Toxic Metal Sensitivity, Pfeiffer Treatment Clinic, Dr. W. Walsh et al, www.flcv.com/ptcmt.html

Introduction: Defective Functioning of Metallothionein Protein (MT)

Dr. William Walsh and Dr. Anjum Usman have discovered that defective functioning of metallothionein protein (MT) is a distinctive feature of autism. This abnormality results in impaired brain development and extreme sensitivity to toxic metals and other environmental substances. This disorder is often unnoticed in infancy and early childhood until aggravated by a serious environmental insult.

In a study of 503 autism-spectrum patients, the authors found abnormal levels of copper and zinc in blood (p<0.0001) indicating defective functioning of metallothionein (MT) proteins. Also, calculation of unbound copper provides a reliable indication of the degree of metallothionein function (or dysfunction). In humans, MT proteins regulate blood levels of these trace minerals, detoxify mercury and other heavy metals, and assist in neuronal development. The expected consequences of defective MT during gestation or early infancy are consistent with several classic symptoms of autism. It appears that defective functioning of MT proteins may represent the underlying cause of autism.

Consequences of MT Malfunction in a Newborn

It is very interesting to examine the consequences of MT malfunction in a newborn:

Abnormal Cu and Zn levels in blood and in hippocampus

Impaired neuronal development, especially in the first 30 months of life, which could result in incomplete maturation of the G.I. tract and brain.

Loss of MT's protective detoxification of heavy metals

MT is the primary system for managing cadmium, mercury, and other toxic metals. MT has an extraordinary affinity for these heavy metals and the resultant proteins (cadmium MT, mercury MT, etc.) effectively sequester the toxic metals and render them relatively innocuous.

Impaired immune function

Immature GI tract

Since the above factors closely resemble classic symptoms of autism, it is logical to conclude that the root cause of autism may be an error of metal-metabolism involving MT followed by victimization by a toxic metal.

The most likely explanation for the severe metal-metabolism dysfunction lies in the function of a group of proteins known as metallothioneins. Genetic errors in the genes coding for the various proteins or having the genes "turned off" by influences on the promoter regions on either side of the genes themselves would be the only two explanations for dysfunction of this group of proteins.

Stimulating the Production of Metallothionein Proteins

PCR (Polymerase Chain Reaction) studies of the genes coding for the various metallothionein proteins in autistic spectrum disorders have been negative (Segal, et al, accepted for publication). This means there is nothing wrong with these genes themselves, but the production of metallothionein proteins has somehow been "turned off" by other genetic and possibly environmental factors. Thus, by using items known already found in the medical literature to stimulate the production of metallothionein proteins, it should be possible to restore function to this entire system of proteins, thus allowing the restoration of function of these proteins. This should allow the body to naturally rid itself of accumulated heavy metals, help the GI tract to mature, and correct the immune system impairments.

With defective MT proteins, a fetus or infant is not able to efficiently excrete heavy metals to which he/she has been exposed. These heavy metals, if not excreted, lead to problems with heavy metal toxicity. If the fetus/infant receives no mercury exposure, even with severely compromised MT function, no problems result. At low mercury exposure rates, only those with the most severely compromised MT function are adversely affected. But, with higher and higher amounts of early mercury exposure, those with less severely dysfunctional MT systems will be adversely affected.

What Has Been Observed: Vaccinations, Mercury & Autism

This is exactly what has been observed over the past 10 to 15 years. In the 1950's infants received 25 to 50 mcg mercury via vaccinations. The autism rate in the 1950's was about 2 in 10,000. The addition of another DPT vaccine in early infanthood became commonplace in the 1970's, and a small rise in the autism incidence rate was noted. In 1988, infants began receiving a Hib vaccination at 2,4, and 6 months, each vaccine containing 25 mcg of mercury. Then, in 1991, the hepatitis B vaccine was "mandated", with the first vaccination given within a few days of birth and 2 additional vaccines given during the 1st 6 months of life. Each hepatitis B vaccine contained 12.5 mcg Hg.

Also, over the past 10 to 15 years, the practice of giving RhoGAM injections to Rh-negative women has undergone a dramatic change. In the early 1980's an Rh-negative woman meeting the criteria for RhoGAM administration received the injection immediately after birth of the child. The current recommendations now include routine administration of RhoGAM (in women meeting the criteria) at 28 weeks gestation, after amniocentesis, and (with some obstetricians) if any spotting occurs during pregnancy. The amounts of mercury contained in RhoGAM injections vary with the manufacturer, but most contain about 25 mcg Hg. Thimerosal-free RhoGAM injections are now available.

The current autism incidence rate is now 1 in 150 children. Even those epidemiologists who contended that the rise is simply due to better diagnosis have conceded that the increase is indeed real and is quite alarming (IMFAR Conference, 2001, San Diego).

Click here to see a chart showing the cumulative mercury exposure received during infanthood by birth year (weighted by compliance rates) and the DSM-IV autism incidence rate in California (the only state in which each child suspected of having a developmental delay must be evaluated by a central agency with unchanged criteria over the last 10 years). Note that the incidence rates reflect only full-fledged DSM-IV autism and not lesser diagnoses such as PDD/NOS. (rate prop. to cum. exposure level)

MT and Neuronal Development: Maturation of the Brain & the Timing of Environmental Insults MT is directly involved in neuronal development and maturation of the brain and G.I. tract, and the timing of environmental insults are critically important. By age three, these systems may have sufficiently matured so that environmental toxins can no longer provoke autism.

There are four primary types of MT protein: MT-I and MT-II are found in cells throughout the body, with MT-Ill restricted primarily to the brain and MT-IV to squamous epithelial cells in the intestines. The roles of the various MT proteins and isoforms are not well understood and are the subject of intensive research.

MT functioning involves (1) induction of thionein, (2) "pre-loading" with Zn atoms, and (3) redox reactions in which Zn may be displaced by other metals. MT proteins are induced by Zn, Cu, Cd, and other toxic and nutrient metals. In addition, MT can be induced by injury, emotional stress, and/or nuclear radiation and is an important anti-oxidant system in the body. A primary mechanism for Zn loading and metal binding is the glutathione (GSH), glutathione disulfide (GSSH) redox couple.

Evidence that Autism Can Be Caused by Early Exposure to Neurotoxins Such As Mercury

There is now evidence that autism/PDD can be caused by a biochemical abnormality, which disables MT protein accompanied by early exposure to neurotoxins such as mercury. Mechanisms with the potential for disrupting MT functioning include severe Zn depletion, impaired synthesis of GSH, toxic metal overload, a pyrrole disorder, and a sulfur amino acid abnormality, along with a myriad of other genetic and/or environmental insults.

The discovery of disordered metal-metabolism in autism may lead to early identification of autism-prone children, prevention of regressive autism, and improved therapy outcomes.

Also, the ongoing elimination of thimerosal from infant vaccines (as recommended by both the FDA and AAP starting in 1999) and from RhoGAM injections (a more recent development) should result in much lower autism incidence rates in the coming years. We should start noticing the decline in 2 to 3 years as the children born in 2000-2001 approach the ages at which autism is most commonly diagnosed.

The new therapies aimed at elimination of existing heavy metals and the induction of the production of metallothionein should help the children currently affected, dependent on age at the initiation of therapy in those children found to have dysfunctional MT systems. www.healing‑arts.org/children/holmes.htm

Amy S. Holmes, M.D.

March 5, 2002 References:

· Walsh, W.J., Usman, A., and Tarpey, J.; Disordered Metal Metabolism In a Large Autism Population, Proceedings of the Amer. Psych. Assn.; New Research: Abstract NR109, New Orleans, May, 2001. (www.hriptc.org/)

· Walsh, W.J., Usman, A., Tarpey, J., and Kelly, T.; Metallothionein and Autism, Second Edition, Pfeiffer Treatment Center, Naperville, IL (2002).

Additional Resources

· The Chelation of Mercury in the Treatment of Autism, by Amy Holmes, M.D.

www.healing‑arts.org/children/holmes.htm

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· Heavy Metal Detoxification and Metallothionein Promotion, by Amy Holmes, M.D.

Heavy Metal Detoxification and Metallothionein Promotion

Background:

Recent developments have been made to promote metallothionein (MT) in the G.I. tract, brain, and elsewhere. This protocol is based on 1,200 published articles describing MT synthesis, activation, and redox mechanisms. A total of 22 nutrients that enhance MT production were identified and tested in informal clinical trials involving staff and volunteer autism families.

We found that aggressive zinc loading must precede full-scale MT Promotion therapy for best results. Each molecule of MT requires 7 atoms of zinc (Zn) for proper functioning. Premature synthesis of MT at intestinal mucosa can temporarily prevent Zn transport into the bloodstream, resulting in severe irritability. Our best clinical outcomes were achieved using a two-phase protocol:

Preloading with Zn and augmenting nutrients, followed by:

Cautious, gradual introduction of MT promotion nutrients.

William Walsh, Ph.D. and staff at the Pfeiffer Treatment Center in Naperville, Illinois developed the protocol for the induction of metallothionein production itself.

The advantage of MT induction itself over DMSA/LA is that it does not promote the large overgrowths of unfriendly organisms in the intestines so often associated with the use of lipoic acid. If a child is doing well on DMSA/LA with no overgrowths of unfriendly organisms, then it may be best to stick with this treatment, however if a child is found to have large overgrowths of unfriendly organisms at initial evaluation or experiences overgrowths of these organisms once lipoic acid is added, it is probably best to use the protocol of MT induction instead.

MT Promotion Nutrient

The scientific literature clearly indicates that most of the body's MT is induced by zinc, with glutathione (GSH) needed for loading apo-MT with zinc and glutathione disulfide (GSSH) required for redox exchange. Selenium and the GSH/GSSH redox couple enhance

delivery of Zn to cells

sequestering of mercury and other heavy metals

The equilibrium constants for binding of MT to heavy metals are remarkably large; with the net result that Zn-MT is a "magnet" for these toxic metals.

MT proteins are composed of 14 amino acids and zinc. Many autism-spectrum patients are unable to efficiently cleave dietary proteins into the individual amino acids needed for MT synthesis. Our formulation provides all 14 amino acids, in the proportion found in MT. The large amounts of cysteine required for MT synthesis can be supplied in the form of oral GSH which breaks down in the G.I. tract with minimal side effects.

The HRI Pharmacy has patented various MT-promotion formulations in order to ensure that they will be widely available at low cost. Because of risks associated with improper use, these formulations will be available by prescription to medical professionals, but not to the general public.

The various MT-promotion formulations are available only from the HRI Pharmacy. The original prescription written by your physician must be mailed to the HRI Pharmacy directly. It cannot be called or faxed into the pharmacy.

Clinical Testing Procedure

MT-promotion therapy is recommended only for patients with disturbed metal metabolism. Key laboratory tests include serum copper, plasma zinc, and serum ceruloplasmin. In healthy individuals, the Cu/Zn ratio usually ranges between 0.8 and 1.2, and the amount of free copper (unbound by ceruloplasmin) ranges from 5 to 25 mcg/dL. In addition, the presence or absence of symptoms of copper overload and zinc deficiency can also aid diagnosis. Meaningful assays require acid-etched trace-metal-free sample tubes and avoidance of trace mineral supplements for 24 hours before sampling.

Other essential tests required for full evaluation include blood counts, tests of liver and kidney functions, along with an evaluation of thyroid function. Testing plasma ammonia is highly recommended prior to treatment because of the high prevalence of elevated ammonia levels in patients with autism/PDD and related disorders.

Also, a full evaluation of intestinal microflora, including both stool comprehensive parasitology (aerobic bacteria, yeast, and parasites) and urine organic acid test is recommended prior to the initiation of any therapy.

Other tests that may be useful include plasma sulfate and plasma reduced glutathione levels prior to the initiation of therapy.

Treatment for Patients Found to Have Metallothionein Dysfunction

A good trial of the gluten-free, casein-free diet (at least 6 months) is highly recommended. The best source of information about this diet is the book written by Lisa Lewis, Ph.D., Special Diets for Special Kids.

Step 1

Gut Clean-up - restore good levels of friendly bacteria and reduce overgrowths of unfriendly organisms such as Clostridia and yeast

Supporting Nutrients - exact nutrients determined by testing

Reduction of elevated plasma ammonia (if necessary)

Aggressive zinc pre-loading

DMSA alone until very little mercury, lead or tin is excreted in urine (if necessary)

· Step 2 - MT Promotion Protocol

Phase 1: Zinc Loading: Aggressive supplementation with Zn and augmenting nutrients for 4 to 8 weeks is recommended. Sensitive patients may require gradual build-up of Zn dosage. Plasma zinc levels should be greater than 100 mcg/dL prior to Phase 2 to minimize irritability side effects. Zinc dosages vary with body weight. A helpful rule of thumb for small patients is to provide a daily mg dosage of Zn equal to weight (lbs) plus 15-20 mg. For example, a 40 lb child would receive 55-60 mg/day during Phase 1. In addition, we recommend the following augmenting nutrients be given with the Zn: Pyridoxal-5-Phosphate, Manganese Gluconate, and Vitamins C and E. Also, Taurine may be used for patients with seizure tendencies. We have developed a compounded supplement for Phase 1, which we call the "Metabolic Primer".

Phase 2: After Phase 1 is completed, GSH, Se, and the 14 amino-acid constituents of MT are introduced gradually, as tolerated. These nutrients are available in a compounded blend called the MTP supplement. Continuation of casein/gluten-free diets, probiotics, the Metabolic Primer, and other ongoing therapies is recommended.

Objectives of MT-Promotion Therapy

Promotion of the MT protein system is expected to provide many benefits to autism-spectrum patients, including:

elimination of toxic metals

protection against future toxic exposures

normalization of the G.I. tract

improved behavior control

improved immune function

enhanced development of brain neurons and synaptic connections

The first 5 benefits may be attainable in the first year of treatment, regardless of the patient's age. However, the rate of formation of new synaptic connections declines rapidly with age, and early intervention is critically important for development of speech, cognitive advancement, etc. Great patience is needed in treatment of older children who can be expected to progress at a relatively slow rate. For example, it may require years for a 10 year old to achieve the same cognitive progress achieved by a 2 year old in a few weeks. Behavioral therapies, which shower the brain with impulses and promote neuronal development are especially recommended in conjunction with MT Promotion therapy.

Amy S. Holmes, M.D.

March 5, 2002

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·Metal-Metabolism and Autism, by Amy Holmes, M.D.

·Detoxification for Heavy Metals as a Treatment for Autism, by Lewis Mehl-Madrona, M.D., Ph.D.

·Discussions and new information on this topic are ongoing on our Autism Web-Forum.

·Articles by Bill Walsh and other important information from the Health Research Institute and Pfeiffer Treatment Center website.

·All About Vaccines and Childhood Immunizations: In this new very comprehensive and extensive section on vaccines we will continually update you in a balanced manner regarding the many new studies and controversies regarding vaccinations and the possible risks involved, especially concerning developmental delays and neurometabolic disorders in children. We discuss and review the theories and data surrounding vaccine complications, vaccine-induced neuropathies, public policy concerns, the mercury and thimerosal controversy, autoimmunity, and the possible realtionship between vaccinations and autism spectrum disorders.

·The Autism Biomedical Discussion Group has been created for the discussion of research and biomedical interventionsas they apply to the investigation and treatment of autistic spectrum disorders. Topics of discussion include immunology, endocrinology, gastrointestinal issues, allergies, metabolic and mitochondrial issues, exposure to neurotoxins, vaccine injury, dietary and nutritional protocols, medications, and other areas pertinent to diagnostics and treatment protocols for individuals with autism

·Detoxification for Heavy Metals as a Treatment for Autism, by Lewis Mehl-Madrona, M.D., Ph.D.

·Discussions and new information on this topic are ongoing on our Autism Web-Forum

·Articles by Bill Walsh and other important information from the Health Research Institute and Pfeiffer Treatment Center website