Friday, October 7, 2011

Methylation Pathways

Easy to understand videos explaining methylation pathways:
Below are links to videos by Dr. Neil Rawlins and Dr. Amy as well as a link to and excerpts from articles explaining the Methylation Cycle. The first article is from one of Generation Rescue's bloggers, Dr. Jerry. It explains the Meth Cycle in easy to understand terms as well as a brief overview of supplementation used to correct it. I've added hyperlinks to other pages in my blog to help explain further as it relates to DS. And yet another explanation is linked at the end.

Here are videos explaining it by Dr Neil Rawlins:

Part 1

Part 2

Part 3

Part 4
Dr. Amy’s presentation, “Mutations & Methylation” may still be available online at

The second article is by Steven Wm. Fowkes which explains the same process, just in greater, more technical detail.

Let’s Talk About…Methylation, Glutathione, and Vitamin B12
May 25 2011
Here are excerpts:
...A “pathway” merely describes a factory that produces a product.  The Methylation factory produces glutathione similar to the way a Ford Factory produces pick up trucks.  Just like a truck factory requiring numerous steps to  produce a finished product, the Methylation factory has lots of steps required before producing the finished product: glutathione. 
Glutathione is very important in maintaining and restoring physical  health, and even mental health.   We know that children with autism [and Down syndrome -Andi] tend  to have lower levels of glutathione when compared to neurotypical  children... 
Glutathione is essential for protecting cells from toxins -- it is our master anti-oxidant and seems to play in FOCUS, CONCENTRATION, AND LANGUAGE.
We can actually increase our body’s ability to produce glutathione….even if we are genetically challenged!  Dr. Jill James proved that we can increase the production of glutathione by supplying  our Methylation factories with necessary key ingredients. 
Methyl B12 : this is vitamin B12 in its “methyl” form.  It can be given with a nose spray, subcutaneous injection, or orally.  It seems to work best for some in a nose spray (if the child tolerates it) or subcutaneous injection.  Dosing is variable based on age and weight, and how you are going to administer it (intranasal or  subcutaneous). 
Vitamin B6 : aides in the production of glutathione. 
Folic Acid: this is a B vitamin that works as a  cofactor in the Methylation factory.  This can be combined in the B12  injection or in the nasal spray.  For some children this can be rather  activating and can cause hyperactivity, and thus will have to be  removed. (Folinic Acid, or Metafolin are better types) 
Dimethylaminoethanol: also known as DMG.  DMG also supports the Methylation pathway as a “methyl donor”. 
Trimethylglycine: also known as TMG.  TMG is DMG  plus another methyl group. Again, we are trying to provide the assembly  line of the factory an “incentive” to make more glutathione. 
Methionine: an amino acid that can be considered the “chassis” or the starting molecule that can eventually be transformed to glutathione 
N-acetyl cysteine: also known as NAC.  This is precursor for cysteine and glutathione
In addition to providing supplements to aid in the production of glutathione, you can also supplement glutathione directly.  It can be given as an IV infusion, inhaled with a nebulizer, rubbed in as a cream, and orally (which I usually do not recommend since it seems to enhance the growth of yeast). 
Improving the function of the Methylation pathway impacts many functions of the cell, right down to how DNA is read. What the parents report, and what we are commonly after, is the improvement of language! It appears that when we improve glutathione production, many children can make significant improvements with focus, concentration and language.
Excerpt from Nutritional Intervention in Down’s Syndrome by Steven Wm. Fowkes

This article covers a metabolic disturbance and nutritional interventions targeted to ameliorate those disturbances.

Methylation Pathways

Down syndrome individuals exhibit significant disturbances in methylation pathways (see Figure 1). The over-expression of cystathionine beta-synthase (located on the 21st chromosome) causes homocysteine to be converted into cysteine (reaction 2) at an accelerated rate [Chadefaux, 1985]. This conversion requires serine. One of the signs of increased cystathionine beta-synthase enzyme activity is a systemic depletion of serine reserves. Indeed, the vast majority of untreated Down’s individuals show serum serine levels at the low end or below the low end of the normal range.

Serine is also used to fuel the folic acid cycle (Figure 1, cycle B). The shortage of serine impairs the production of methyl tetrahydrofolate (Me-THF), which is required to recycle homocysteine to methionine (reaction 1). With an insufficiency of Me-THF, more homocysteine goes down the cystathionine pathway to be converted into cysteine instead of being recycled into methionine. This undercuts methylation metabolism.

Methionine is required for the production of S-adenosylmethionine (SAM), the “active methyl donor” that is a vital part of countless metabolic reactions throughout the body. The under-activity of the folate cycle coupled with overactivity of the cystathionine pathway diverts the homocysteine from the SAM cycle (see Figure 2). In other words, the almost-closed cycle is opened and homocysteine drains into the cysteine pool.

Many parents have reported cognitive and behavioral improvements after supplementation with methyl donors (DMAE (Dimethylaminoethanol), choline, DMG and betaine) and methylation catalysts (folic acid and Vitamin B6 and B12). SAM itself has also been used to treat children with attention-deficit disorders.

Although methylation pathways are usually deficient in Down’s syndrome, some degree of moderation is required not to overdrive the folic acid cycle (Figure 1, Cycle B). In Dr. Peters study of folic acid in Down’s syndrome, approximately ten percent of the children exhibited excessive hyperactivity and/or irritability when given 20 mg folic acid (50 times the adult RDA). In a recent version of MSB Plus compounded by Nutrichem Pharmacy (which normally includes 45 mg vitamin B6, 45 mcg B12, 1 mg folic acid, 200 mg serine, 75 mg methionine and 75 mg cysteine), an increase of folate to 3 mg (7.5 times RDA) and methionine to 275 mg (approximately the RDA) resulted in a substantial number of children exhibiting extreme irritability and hyperactivity behaviors. The symptoms reversed in days with discontinuation of the additional folate and methionine, but this experience should encourage moderation when supplementing methyl donors and methylation co-factors.

It is not known whether the disturbances in serine, folate and methylation metabolism are fundamentally due to cystathionine beta-synthase overactivity or whether they may also be due to impaired digestion and malabsorption of associated vitamins, minerals and amino acids. An experiment is being designed using trisomy-16 mice to investigate the influence of digestive stimulation on metabolic imbalances that might give us some clues.

Here's another explanation of the methylation cycle:

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