Glutathione Depletion in Autism and the Spin-off for CFS By Rich Van Konynenburg

(This was taken from several posts Rich made on CFSResearch and CFSExperimental in April, 2005. Thanks for his permission to re-organize and post them)

  • Glutathione and Autism
  • Glutathione, Mercury and CFS
  • An Autism – CFS Connection?
  • Hope for the Future?
  • Background: A Short Course on Gene Mutations.

Glutathione and Autism

I want to notify everyone here about some developments that I think are significant.

About two weeks ago, on April 2, Dr. S. Jill James of the University of Arkansas gave a talk at the Experimental Biology 2005 conference in San Diego on the research she and he coworkers have done on autism. Recently published research by S. Jill James and coworkers showed that there were abnormalities in several of the substances involved with the methionine cycle (also called the methylation cycle) and the transsulfuration pathway in children with autism. These are important in the synthesis of glutathione, which was found to be about 80% depleted in children with autism. Accordingly, Dr. James and coworkers investigated SNPs in these children in various enzymes and other proteins associated with this cycle and pathway, and they found abnormally high prevalences of SNPs in the genes coding for catechol-O-methyltransferase (COMT), transcobalamin II, and glutathione S-transferase M1.

The enzyme catechol-O-methyltransferase catalyzes one of the reactions that breaks down epinephrine (adrenaline) and norepinephrine (noradrenaline). A mutation in this enzyme that slows the rate of this reaction would have the effect of allowing epinephrine to rise to higher concentrations and to have a longer lifetime. Since epinephrine has been found in animal experiments to decrease the rate of production of glutathione in the liver as well as to decrease the rate of chemical reduction (recycling) of oxidized glutathione, it seems likely that a COMT SNP would tend to deplete glutathione.

Transcobalamin II is the principal protein that binds vitamin B12 after it is absorbed in the small intestine, and carries it in the blood to the various tissues in the body for their use. A mutation in this protein could decrease the transport of vitamin B12, which is used in the methionine cycle to convert homocysteine to methionine. This could also perturb the synthesis of glutathione.

The enzyme glutathione S-transferase M1 is one of a family of enzymes that conjugates (links) glutathione to particular toxins to make them more water-soluble, so they can be removed from the body. This is part of Phase II detoxification. The M1 enzyme has been found in a German study to be more highly mutated in people who are sensitive to thimerosol, which is the mercury-containing preservative used in some vaccines. Thus, a mutation in this enzyme might make it more difficult for a person to use glutathione to remove mercury from their body, and thus make them more susceptible to mercury toxicity.

Dr. James suggested that autism occurs when there is a combination of a certain genetic makeup and an environmental insult that interacts with it. In autism, this environmental insult may be mercury, as from the thimerosol in vaccines, which many autism parents have suspected to be involved in causing autism in their children. As most readers will know, the body uses glutathione to rid itself of mercury. In children who are less able to maintain their glutathione levels for genetic reasons, mercury may be more toxic.

(An organization has recently been formed promoting the uses of mercury chelation using transdermal DMPS to combat autism in children.  You can access it as http://www.generationrescue.org).

Glutathione, Mercury and CFS

The significance of all this for CFS, in my opinion, is that since glutathione is known to be depleted in many PWCs, and many are found to be elevated in mercury, it is possible that they may have SNPs in one or more of these same proteins. There are several reasons to suspect that there is a genetic susceptibility in many cases of CFS, and such SNPs may account for it.

The Great Smokies Diagnostic Lab, in their Genovations testing, currently offers characterization of panels of SNPs in several enzymes and proteins suspected to be important for particular diseases. No prescription is required for such characterization. The Great Smokies representative at the recent OHM meeting told me that they are planning to offer tests for individual SNPs, not as panels, in the near future, and this will decrease the cost to people who are interested in only certain ones. They are also planning to add characterizations of more SNPs in different enzymes as the tests for them become commercially available. He told me that they expect that there will be growth in the number of tests of SNPs involving detoxification, because the drug companies are now being required by the FDA to take account of the different responses that different people have to drugs, because of mutations in the enzymes involved with detoxification. I think that there could be a helpful spin-off from this for PWCs, since problems with detox appear to be a feature of many cases of CFS.

When particular SNPs are found, it is often possible to compensate for them by increasing the intake of particular vitamins, minerals, or other substances that may support the particular reactions involved as either cofactors for the enzyme, or as substrates for the reaction (Substrates are reactants that are changed into products by the reaction). Dr. Bruce Ames and colleagues at U.C.Berkeley have argued that these mutations are the basis for the observed benefits of megadosing particular nutrients by particular people.

In the case of the autism work of Dr. James and coworkers, they found that increasing the intake of vitamin B12 (methylcobalamin),folinic acid (the active form of folic acid) and trimethyglycine (also known as betaine) was effective in bringing the glutathione level up to normal in children with autism.

An Autism – Chronic Fatigue Syndrome Connection? Advances in the understanding of autism are continuing to occur at a rapid pace, and there continues to be more evidence found that autism and CFS have a lot in common, in my opinion. At the 4th International Meeting for Autism Research Boston in April 2005, David Amaral et al. reported finding a 20 percent higher number of B lymphocytes in children with autism, compared to normals. Judy Van de Water et al. reported lower levels of cytokines in children with autism compared to normals, after antigen provocation. I haven’t been able to find out yet which cytokineswere obsered to be lower. Combined with earlier research on the immune system and autism, the work of Amaral et al. suggests a Th2 shift and a suppression of cell-mediated immunity in autism, as is frequently found in CFS.

Here are some of the other features that have been reported in the past to be found in autism, which are also found in CFS:

  • Oxidative stress
  • Toxicity and sensitivity to toxins, especially mercury
  • Gastrointestinal problems, including dysbiosis, leaky gut, and problems with casein and gluten.
  • Coagulation problems
  • Sleep disorders
  • HPA axis dysfunction
  • Abnormalities in sulfur metabolism

Researchers at UCLA are homing in on gene mutations associated with autism. S. Jill James and colleagues have already reported on some single-nucleotide polymorphisms that are associated with problems in methylation and detox, involving sulfur metabolism.

There was also work reported in Boston by David Amaral on proteomics, i.e. the concentrations of various proteins in the blood, in kids with autism compared to normals. Big differences were found in a large number of proteins. I don’t think this kind of work has been reported yet in CFS, but I think it will be done soon, since Eleanor Hanna at the NIH told me at their workshop two years ago that she thought this is where the answers will lie in CFS research, and she is in charge of CFS research there.

The common denominator and root cause of many of the observed features that these two disorders have in common appears to be glutathione depletion. As I have said earlier, the differences between autism and CFS appear to be caused by glutathione becoming depleted earlier in life in the kids with autism, before the brain has been fully developed, while in CFS the glutathione depletion occurs later.

Because of the prominent symptoms in autism related to lack of proper brain development, which are not found in CFS, I think that in the past researchers have not paid attention to the similarities. But once glutathione depletion was found to be present in both, the picture really has seemed to come together.

Hope for the Future?

I think that this is very exciting. I think that there could very well turn out to be many parallels between autism and CFS. The difference may be that autism occurs when glutathione depletion occurs early in life, while CFS occurs later in life, after the brain has had a chance to develop.

I think that CFS research will benefit from these developments in autism. This talk got wide news coverage around the world. The autism parents are highly motivated, and many have resources. They are politically organized and capable of exerting considerable clout. I expect an increase to occur in research into glutathione depletion and into testing for relevant SNPs. I think this can only help CFS research, since I believe that glutathione depletion is very important in CFS as well.

All this is happening at the same time that a breakthrough has occurred in cystic fibrosis research that also involves glutathione (by Valerie Hudson at BYU in Utah). In cystic fibrosis, it appears that cells have difficulty in exporting glutathione. There is another highly motivated set of parents associated with this disease, and I expect that they will also be promoting research into glutathione.

We all know how difficult it has been to get scientific interest and funding for research into CFS. I think we are now about to benefit from spin-offs from research into these other diseases. I think that this is a very interesting turn of events.

I suggest that everyone with CFS keep their eye on autism research. It is going great guns now, and I strongly suspect that much of what they find out in terms of genetic variations and basic biochemistry is going to apply to CFS pretty directly. The big differences are going to be in things involved with the lack of proper brain development in autism and the effects of that, which are not found in CFS. But the rest should be applicable. Stay tuned!

A Short Course on Gene Mutations - (in response to a question from CFSFMExperimental Rich gave a short introduction to genes and gene mutations)

The cells in the body carry out their various functions by means of a large number of different biochemical reactions. The rates of these reactions must be controlled in order to coordinate the overall operation of the cell. This control is most often carried out by enzymes, which serve as catalysts for the reactions.

Enzymes are a type of protein, and they are assembled by the cell as strings of amino acids. The particular sequence of amino acids foreach enzyme is coded in the gene for that enzyme, made of DNA and located in the nucleus of the cell.

DNA consists of a long double-helix molecule that incorporates a sequence of nucleotides, each made up of one of four bases (thymine, guanine, adenine or cytosine), a sugar ring (deoxyribose) and a phosphate group. A particular sequence of three nucleotides in the DNA molecule codes for each different amino acid to be placed in the
enzyme.

The rate of an enzyme-controlled biochemical reaction depends on the concentration of the particular enzyme that is present (number of enzyme molecules per unit volume) and the efficiency in promoting the reaction of the particular form of the enzyme that is present.

The concentration depends on “gene expression,” i.e. the degree to which the gene code for that particular enzyme has been translated into making enzymes.

The particular form of the enzyme that is produced depends on whether mutations have occurred in the gene that code for the enzyme. A mutation involves a change in the sequence of nucleotides in the DNA, and it can be caused by a variety of things, including ionizing radiation, toxins and viruses. Mutations occur originally in the DNA in the sperm or ova of a particular person. From there, they are propagated to the descendents of that person, and they become part of the DNA of every nucleated cell in the body, including the germ cells that they pass on to their offspring. We inherit mutations from our father and mother, and we propagate them on to our offspring.

If we have inherited a particular mutation from only one of our parents, we are said to be heterozygous for the corresponding allele (version) of the enzyme. If we got the same mutation from both our parents, we are said to be homozygous for that allele. If an allele is of the type that can cause observed effects (phenotype) in a person who is only heterozygous in that allele, it is called a dominant allele. If it is necessary to be homozygous in a particular allele in order to observe phenotypic expression, then it is called a recessive allele. In the case of dominant alleles, if only one parent is heterozygous in it, half the offspring will show the phenotypic effect. In the case of recessive alleles, if one parent is heterozygous in it, they are called a carrier. In order for offspring to manifest an observable (phenotypic) effect from a recessive allele, both parents must be carriers of that allele, and even then, on the average, only one out of four of their offspring will manifest the observable effect.

There are several possible types of mutation. Some mutations render the enzyme completely nonfunctional. If this enzyme is essential for life, such a mutation is fatal. Other mutations cause the affected enzyme to be less efficient than the normal form of the enzyme, in varying degrees, depending on the particular mutation.

One class of mutations is called “single nucleotide polymorphisms “or SNPs. In this class, only one nucleotide has been changed in the normal gene for a particular enzyme. This results in a change of one amino acid in the enzyme that is made from this coded pattern, out of perhaps hundreds or thousands in the sequence of amino acids making up the enzyme. If a person has a particular SNP, all the copies of the particular enzyme that is coded for by the gene that has this SNP will have this one amino acid changed from the normal enzyme. Depending on where in the sequence this change has been made, it can have a large or a small effect on the enzymes efficiency in promoting its particular biochemical reaction.

The entire human genome is currently thought to code for about 25,000 or 30,000 different proteins. Over 1.5 million different SNPs have been found in the entire human genome. We all have some of them. It’s just a question of which ones we have. The differences between the set of SNPs that each of us has are important factors that determine biochemical individuality. Among many other things, these differences give us different susceptibilities to various diseases and toxicities.

Because of the progress in understanding the human genome and the biotechnology of gene chips, it is now possible to characterize SNPs on a large scale at a relatively low cost. As a result, many studies have been conducted and others are currently underway to study the prevalence of particular SNPs in people who develop various diseases. In choosing which of the many SNPS to study in connection with a particular disease, it is helpful if the pathogenesis is understood, so that the particular reactions that might be important can be known, and hence SNPs in the particular enzymes for these reactions can be sought. Correlations have been found for many diseases, and if the pathogenesis of a particular disease is understood, it is often possible to understand why a particular SNP would make a person more vulnerable to the disease. Conversely, if the pathogenesis is not understood, SNP correlations can provide clues about the particular reactions that may be involved in the pathogenesis.

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