|• Metal-Metabolism and Autism
• Metallothionein Promotion Therapy
• Metallothionein Promotion Nutrients
|• The Pfeiffer MT Promotion protocol
• Zinc & Copper Imbalances
What are these? What role do they play in therapy? What benefits may manifest for the ASD patient? The content below should provide some indication. If you have any queries, do not hesitate to contact us.
Malfunctioning of metallothionein protein (MT) has been associated with expression of autism spectrum disorders (William Walsh, Anjum Usman), resulting in impaired brain development and extreme sensitivity to toxic metals and other substances. This is often unnoticed in infancy and early childhood.
MT is the primary system for managing cadmium (Cd), mercury (Hg), and other toxic metals. It 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.
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 the squamous epithelial cells in the intestines. The roles of the various MT proteins and isoforms are not well enough understood and are the subject of intensive research.
MT functioning involves:
• The induction of thionein,
• The "pre-loading" of Zinc (Zn) atoms, and
• Redox reactions in which Zn may be displaced by other metals.
MT proteins are induced by Zn, Cu (Copper), Cd, and other toxic as well as nutrient metals. In addition, MT can be induced by injury, emotional stress, and/or nuclear radiation and is thus 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.
A study of 503 autism-spectrum patients, showed abnormal levels of copper and zinc in blood (p<0.0001) indicating malfunctioning of metallothionein (MT) proteins. The magnitude of unbound copper provides a reliable indication of the degree of metallothionein function (or dysfunction) in humans.
It thus appears as if the most likely explanation for severe metal-metabolism dysfunctions probably lies in the function of the group of proteins known as the metallothioneins. Genetic errors in the gene coding for the various proteins, or having certain genes "turned off" by influences on the promoter regions on either side of the genes themselves, would suggest to be the only two explanations for the dysfunction of this group of proteins.
Stimulating the Production of Metallothionein Proteins
PCR (Polymerase Chain Reaction) studies of the gene coding for the various metallothionein proteins in autistic spectrum disorders have been negative (Segal, et al, accepted for publication). This would indicate that there is nothing wrong with these genes themselves, but the production of MT has somehow been "turned off" by other genetic and/or environmental factors.
Thus, by using substances known already found in the medical literature to stimulate the production of metallothionein proteins, it should therefore be possible to restore the function of the complete protein system. 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.
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.
Consequences of MT Malfunction in a Newborn
The expected consequences of malfunctioning MT during gestation or early infancy are consistent with several classic symptoms of autism and may represent, [one of the, or even the] underlying cause of autism.
The following has been observed in newborns, which is also associated with MT malfunction:
• Abnormal Cu (Copper) and Zn (Zinc) levels in the blood and 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 the MT's protective detoxification of heavy metals function.
• 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 some toxic metal overload or under-secretion.
With malfunctioning MT proteins, a foetus 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 associated with heavy metal toxicity. If the foetus/infant receives no mercury exposure, even with severely compromised MT function, no mercury overload problems are manifested. At low mercury exposure rates, those with the most severely compromised MT function are adversely affected, but with higher amounts of early mercury exposure, also those with less severely dysfunctional MT systems will also be adversely affected.
MT and Neuronal Development: Maturation of the Brain & the Timing of Environmental Insults
As MT is directly involved in neuronal development and maturation of the brain and G.I. tract, the timing of environmental insults is thus critically important. It appears as if by age three, these two systems may have sufficiently matured so that environmental toxins can no longer provoke autism.
Autism Can Be Caused by Early Exposure to Neurotoxins Such As Mercury
There is now also evidence that autism 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 sulphur amino acid abnormality, along with a myriad of other genetic and/or environmental insults.
New therapies aimed at elimination of existing heavy metals, and stimulation of metallothionein production should help the children currently affected by dysfunctional MT systems. (This dependent on their age at the initiation of therapy in those children).
Recent developments have been made to promote metallothionein (MT) in the G.I. tract, brain, and elsewhere. William Walsh (Ph.D.) and staff at the Pfeiffer Treatment Centre in Naperville, Illinois developed this protocol for the induction of metallothionein. This 2 phase protocol is based on 1,200 published articles describing MT synthesis, activation, and redox mechanisms.
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 behaviour 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. The rate of formation of new synaptic connections declines rapidly with age, and early intervention is thus 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 slower 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. (Behavioural therapies, which shower the brain with impulses and promote neuronal development, are especially recommended in conjunction with Metallothionein Promotion therapy.)
It should be noted that each molecule of MT requires 7 atoms of zinc (Zn) for proper functioning.) Aggressive preloading with Zn and augmenting nutrients is thus usually followed by the cautious, gradual introduction of MT promotion nutrients. (Premature synthesis of MT at intestinal mucosa can temporarily prevent Zn transport into the bloodstream, resulting in severe irritability).
MT proteins are composed of 14 amino acids and zinc. Many ASD patients are unable to efficiently cleave dietary proteins into the individual amino acids needed for MT synthesis. The nutrient formulation provides these 14 amino acids, in the proportion found in MT. Large amounts of cysteine is required for MT synthesis and can be supplied in the form of oral glutathione (GSH), which breaks down in the G.I. tract with minimal side effects.
The equilibrium constants for binding of MT to heavy metals are remarkably large; with the net result that Zn-MT becomes a "magnet" for toxic metals.
The MT-promotion therapy is recommended only for patients with disturbed metal metabolism. Key laboratory tests also 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/d. 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 a full evaluation include blood counts, tests of liver and kidney functions, as well as an evaluation of thyroid function. Because of the high prevalence of elevated ammonia levels in patients with autism/PDD and related disorders, testing plasma ammonia is highly recommended prior to treatment
In addition, 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.
Metallothionein Dysfunction may be treated by a 2-step approach: (See more in next section -Pfeiffer protocol)
Step 1 -Primer
• Gut Clean-up - Restoring balanced levels of friendly bacteria and reduce overgrowths of unfriendly organisms such as Clostridia and yeast.
• Supporting Nutrients – Augmentation of exact nutrients as determined by testing
• Reduction of elevated plasma ammonia (if necessary)
• Aggressive zinc pre-loading
• DMSA only, 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 the Zn dosage. Prior to Phase 2, the plasma zinc levels should be greater than 100 mcg/dL, 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 (kgs) plus 15-20 mg. For example, an 18kg child would receive 25-27 mg/day during Phase 1. In addition, it is suggested that the following augmenting nutrients be given with the Zn:
-Pyridoxal-5-Phosphate, Manganese Gluconate, and Vitamins C and E. Taurine may be used for patients with seizure tendencies.
Phase 2: -Blended compounds
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. Continuation of casein/gluten-free diets, probiotics, the Metabolic Primer, and other ongoing therapies is recommended.
The advantage of MT induction over DMSA/LA medication is that it does not promote large overgrowths of unfriendly organisms in the intestines so often associated with the use of lipoic acid. If the patient is responding well on DMSA/LA with no overgrowths of unfriendly organisms, then it may be best to continue 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.
The functionality levels of diagnosed ASD patients are by definition associated with a spectrum. This would advocate that any response to treatment, and the treatment regime itself, could vary from patient to patient. It has been suggested that an imbalance, or poor state of equilibrium, between Copper (Cu) and Zinc (Zn) and a severe Zinc deficiency could indicate a metallothionein (MT) disorder.
In a 2001 presentation to the American Psychiatric Association, Dr. William J. Walsh of the Pfeiffer Treatment Centre* suggested a potential link between metallothionein disorders and autism. Walsh concluded:
"The absence of Cu and Zn homeostasis and severe Zn deficiency are suggestive of a metallothionein (MT) disorder. MT functions include neuronal development, detoxification of heavy metals, and immune response. Many classic symptoms of autism may be explained by a MT defect in infancy including G.I. tract problems, heightened sensitivity to toxic metals, and abnormal behaviours. These data suggest that an inborn error of MT functioning may be a fundamental cause of autism."
*See Zinc & Copper Imbalances: Immense Biochemical Implications by Michael McEvoy 05/12/2012 below, or click on the image.
Metallothioneins are proteins whose purposes are to metabolise and regulate metals. There are at least ten known closely related metallothionein proteins expressed in the human body. In humans, large quantities are synthesized primarily in the liver and kidneys, however they have been found at a number of other sites as well. Its production is dependent on availability of the dietary minerals zinc and selenium, and the amino acids histidine and cysteine. Mammals possess genes for four subfamilies of metallothionein, the ubiquitous MT-1 and MT-2, the brain specific MT-3 and the squamous epithelium specific MT-4.
A genetic metallothionein (MT) weakness is consistent with:
• Casein/gluten intolerance
• Presence of dense, undeveloped brain cells evident in autopsy studies
• Hypersensitivity to mercury & other toxic metals
• High autism incidence after thalidomide
• Hypersensitivity to vaccines
• Poor immune function
• Low stomach acid
• Higher incidence in males
• Taste/texture sensitivities,
• Tendency for yeast overgrowth
• Leaky gut
• Behaviour problems
Measurements of MT-levels, as well as zinc, have been used to indicate zinc deficiency. MT increases rapidly after zinc supplementation and decreases if the diet is deficient in zinc. The zinc from plasma proteins begins to be used up when the body stores are depleted. When plasma zinc levels are below 33 mcg/dL, skin-rash, abdominal pain, diarrhoea, loss of appetite and a reduced sense of taste and smell can occur.
The Pfeiffer Treatment Centre has developed a nutrient therapy to promote metallothionein in the gastrointestinal tract, brain and elsewhere. Each molecule of MT requires 7 atoms of zinc to function properly. Aggressive supplementation with zinc and augmenting nutrients must precede any attempt to promote MT for best results.
Supplementation for at least 4 to 8 weeks is recommended, but it can be up to 6 months or more. Sensitive patients may require a gradual build up of zinc dosages. It is also important to remember that Primer must never be taken on an empty stomach, as this may cause nausea (even though zinc is best absorbed on an empty stomach). Premature synthesis of MT at the intestinal mucosa can temporarily prevent zinc transport into the blood, which can result in severe irritability.
The Pfeiffer MT Promotion protocol is a 2 stage process:
1. Preloading zinc and co-factors (Primer)
2. Metallothionein promoting nutrients (Promoter)
-The Primer contains (per daily dose): Zinc Picolinate 50mg, Pyridoxine-5-phosphate 25mg (active vitamin B6), Pyridoxine HCL (B6) 50mg,Manganese Gluconate 7.5mg, Vitamin E 100mg (Mixed tocopherols), Ascorbate activity (Vitamin C) as Magnesium Ascorbate 300mg, and Magnesium (Ascorbate) 22mg. These doses are standard and can be adapted to suit individual needs.
The Promoter provides the building blocks of the (MT) protein. The idea of this supplement is to boost MT function in a natural way, thus allowing the body to then detoxify (or chelate) itself naturally. This may also self-correct some of the other dysfunctions that are present based on MT abnormalities. Many ASD children use this supplement with anecdotal evidence of positive effects.
MT proteins are made up of 14 amino acids and zinc. Many ASD patients are unable to efficiently cleave dietary proteins into the individual amino acids needed for the MT synthesis. The Promoter formulation provides all 14 amino acids, in the proportions found in MT proteins. The large amounts of cysteine required for MT synthesis are provided in the form of oral glutathione (GSH) which breaks down in the gastrointestinal tract with minimal side effects. Glutathione and Selenium (also in the Promoter) enhance the delivery of zinc to the cells, and the sequestering of mercury and other heavy metals.
Glutathione is a tripeptide, (i.e. a peptide consisting of three amino acids – cysteine, glutamic acid and glycine, joined together by peptide bonds) and is the most powerful naturally occurring antioxidant in human cells.
-The Promoter contains (per 175mg capsule): Glutathione (Reduced) 100mg, Selenium 10mcg, Serine (L) 13.7mg, Lysine (L) 17.85mg, Alanine (L) 8.4mg, Glycine (L) 5.8mg, Threonine (L) 4.3mg, Proline 3.5mg, Aspartic Acid 4.25mg, Asparagine 2.75mg, Glutamic Acid 6mg, Methionine (L) 3.15mg, Glutamine (L) 2.2mg, Isoleucine 2mg, Valine (L) 1.1mg. The Promoter Capsules are also available in 87.5mg and 350mg.
For more information about Primers and Promoters and the Pfeiffer MT Promotion protocol please contact us.
by Michael McEvoy 05/12/2012
The status of zinc and copper levels may have profound implications for many people. Much has been written about the significance of these two trace elements for many, many years. Many health conditions may be directly caused by abnormal zinc and copper levels. With all of the recent attention given to methylation status, gene mutations, MTHFR (Methylenetetrahydrofolate reductase), and the associated neurological and mental/behavioral disorders that may ensue, zinc and copper status remains a pivotal ratio in these regards. While zinc toxicity and copper deficiency are possible, the subject of this article is on the more common imbalance: copper toxicity and zinc deficiency.
The Physiological Roles Of Zinc(Zn) & Copper(Cu)
Zinc and copper are antagonists. The balance between these two trace elements is an example of the effects of biological dualism. While zinc toxicity is possible, far more common is zinc deficiency and copper toxicity. Both zinc and copper play essential roles in the body, and there can be a number of causes for why imbalances ensue. It may be easier to identify the roles that zinc doesn't play in the body, than the roles it does play. Zinc is an essential trace element that activates several hundred enzymatic reactions. These reactions are fundamental to life and biological activity.
Some of the activities that zinc are involved in:
• DNA & RNA synthesis
• Gene expression
• Nervous system function
• Immune function & immune signaling such as cell apoptosis
• Neuronal transmission
• Brain function
• Zinc possesses powerful anabolic activities in the cells
• Formation of zinc proteins known as "zinc fingers"
• Zinc is essential for blood clotting and platelet formation
• Zinc is involved in Vitamin A synthesis
• Folate is made available through zinc enzyme reactions
• Along with copper, Zinc makes up the antioxidant enzyme system, ZnCu superoxide dismutase
• Steroidal hormone synthesis
• Growth & development of children
• Testosterone and semen formation
• The highest concentration of zinc is found in the male prostate gland
Copper is an essential trace element serving many important functions as well. However, copper is well documented to induce several toxic effects in the body, when elevated. Because copper is a pro-oxidant when free and unbound, it can quickly generate free radicals. The major sources for copper toxicity are: exposure to industrial forms of copper such as copper pipes, copper cookware, birth control, exposure to copper-based fungicides. Diets high in copper and low in zinc may play a role in copper toxicity. Pyrrole disorder, which causes depletion of zinc, may result in elevated levels of copper.
Some of the essential roles copper plays in the body:
• Connective tissue formation
• ATP synthesis
• Iron metabolism
• Brain health via neurotransmitter synthesis
• Gene transcription
• Synthesis of the antioxidant superoxide dismutase
• Skin pigmentation
• Nerve tissue: myelin sheath formation
• Copper tends to rise when estrogen is dominant
Perhaps one of the first reports that zinc and copper imbalances play a role in human health and disease was their detection in mental disorders made by Carl Pfeiffer, MD, PhD. Dr. Pfeiffer identified a condition known as pyrrole disorder, sometimes referred to as pyrroluria or "mauve factor".
As it turns out, pyrrole disorder is a major biochemical imbalance in many people with chronic illnesses such as chronic Lyme disease, autism, schizophrenia, depression, bi-polar, and chronic fatigue syndrome. Pyrroles are a byproduct of hemoglobin synthesis. Apparently, some individuals are more predisposed towards producing higher amounts of pyrroles. When pyrroles are excessive, they irreversibly bind to zinc and vitamin B6, causing their excretion. Consequently, it is common that once zinc levels become depleted, copper levels tend to rise.
Problems associated with copper toxicity include: pyrrole disorder, estrogen dominance, schizophrenia, depression, anxiety disorder, chronic fatigue, migraines, liver toxicity, thyroid conditions, chronic candida yeast infections, PMS, to name a few. Some research has even implicated copper toxicity with Alzheimer's Disease and with cardiovascular disease. Perhaps one of the primary mechanisms through which copper toxicity can damage tissues is through its initiation of oxidative stress and free radical formation. Free copper ions that are not bound to copper proteins such as ceruloplasmin, are pro-oxidants, and are highly reactive.
Empirical research from clinicians, indicates that there are different types of copper imbalances. For example, if there is a lot of free, unbound copper present, this may cause a situation of nutritive copper deficiency. Another copper imbalance is when high pyrroles depress zinc levels, and copper levels concomintantly rise. If high pyrroles are present, B6 will also be lost in high amounts. In a general but very real sense, all forms of copper excess will affect zinc status, due to the dualistic nature of zinc and copper.
Copper & Estrogen
It has been known for many years that copper can cause a rise in estrogen, and conversely estrogen may raise copper. Estrogen dominance has been extensively studied in its role in breast cancer development. One possible, critical role that can cause estrogen to become carcinogenic is through its oxidation induced by copper. Once oxidized, estrogen forms volatile hydroxyl radicals and the associated DNA damage and "mutagenesis".
As mentioned previously, pyrrole disorder will directly depress zinc status, causing high levels of its excretion. When zinc is lost, copper rises. Because of their essential roles in neurotransmitter synthesis, low zinc and high copper levels can directly effect cognition, behavior and thought processes. Zinc has been studied in biochemical reactions involving calcium-driven, synaptic neurotransmission, as well as in glutamate/GABA balance and with limbic brain function.
Zinc & Reproduction
Zinc is essential for steroidal hormone synthesis, and is a well known catalyst for testosterone synthesis, as well as leutinizing hormone. Zinc has demonstrated its ability to prevent miscarriage and toxicity during pregnancy. The male prostate gland reportedly contains the highest concentration of zinc in the body.
Zinc & Brain Function
Much attention has been given to excitotoxicity, such as the effects induced by MSG (monosodium glutamate). Excess stimulation of the excitatory neurotransmitter glutamate, may cause severe physical and psychological reactions in certain individuals. Zinc has been studied for its ability to enhance GABA (glutamate's antagonistic neurotransmitter) activity and to suppress excess glutamate.
Studies on mice demonstrated that when depleted of zinc for two weeks, the mice developed seizures, most likely due to GABA deficiencies and glutamate excess.
There is an emerging body of evidence that demonstrates that Alzheimer's disease may involve copper toxicity and zinc deficiency. Not only can excess copper cause zinc depletion, but so can excess lead.
The hippocampus, a major part of the limbic brain, records memories and is responsible for processing meaningful experiences. Numerous studies site that if hippocampal cells are deprived of zinc, the hippocampal cells die. In addition to hippocampus cell death induced by zinc deprivation, the amygdala, the other major limbic gland experiences cell death as well, when deprived of zinc.
Testing Zinc & Copper Status
What are the best methods for testing zinc and copper? The jury is still out on this one. However, it seems that if zinc status in serum or plasma is tested, the same should be performed on copper values. Additionally, reliance upon laboratory reference ranges has very limited value, due to the fact that reference ranges are derived from statistical averages, and not necessarily optimum functioning levels.
RBC (red blood cell) measurements of minerals is believed to be a very accurate indicator of the cells' carrying capacity of a particular nutrient. Hair Tissue Mineral Analysis (HTMA) is a valid way to monitor zinc and copper activity. According to clinical observations made by William Walsh, PhD, when HTMA zinc levels are depressed, they correlate very well with low plasma levels. According to Walsh, and other clinicians, elevated HTMA levels of zinc may also indicate a problem, due to excess zinc leaving the body. Although it is my opinion that serum or plasma values should be concomitantly tested, especially if there is reason to suspect a zinc/copper imbalance, such as in the case of pyrrole disorder, chronic fatigue, lyme disease, a behavioral disorder or mental illness.
Michael McEvoy has a private nutritional consulting practice. He works with clients nationally and internationally. Learn more about his nutritional consulting services and programs by contacting him: http://metabolichealing.com/contact/
Jing Qian and Jeffrey L. Noebels, Department of Neurology, Baylor College of Medicine, Houston, Texas "Exocytosis of Vesicular Zinc Reveals Persistent Depression of Neurotransmitter Release during Metabotropic Glutamate Receptor Long-Term Depression at the Hippocampal CA3–CA1 Synapse"
'Nutrient Power: Heal Your Biochemistry & Heal Your Brain", William Walsh, PhD
'Mental & Elemental Nutrients', Carl C Pfeiffer, MD, PhD
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