Shikimate pathway amino acid deficiency in ALS causes death - Specially designed nutritional product can help

Dedication - Norma Leger 

August 19, 1963 to November 16, 2017

Forever in my heart, my beautiful sister

https://www.facebook.com/debwot/notes?lst=1215147006%3A1215147006%3A1573895996

The queued 3 minutes of my video is from August 2016 about.  Little did I know I had discovered what likely killed my sister, shikimate pathway amino acid deficiency caused by dysbiosis and gross lactobacillus species dysregulation.  Had I known more about how essential correct ratios of single essential amino acids are to health and life expectancy, I sincerely believe I would still have a sister.  Learn from this and fight back so others can still have a mother, father, sister, brother, daughter, son, husband, wife, or friend, whatever relationship brings you to ALS, https://youtu.be/bb7KmiIs0Kc?t=1351,

The most important issues in ALS, watch 3 minutes starting with leaky gut.

Mark Manchester is ALS reversal #41 on Bedlack's list and he used a product called Leap2BFit.

Here’s my declaration: The purpose of my journey in ALS is to be here and give the reasons why Mark’s protocol is the single most important protocol to research and consider. My belief is so strong, I believe that we are at the beginning of the biggest healing revolution in ALS history and it is founded on my research efforts trying to synthesize what the research is telling us in ALS, my sister’s test results, my interaction with pALS and quantitative reports from pALS showing improvement at what I believe to be an unprecedented level in the ALS community.

Mark’s protocol is a scoop of leap2bfit with 1/4 teaspoon of l-serine on an empty stomach (at least 3 hours after your last meal) twice per day and wait at least 30 minutes before eating.  Leap2BFit is sold at leapxx.com.

Leap2BFit is a patented formulation of single amino acids with well research highly bioactive cofactors on the metabolic pathways. The amino acid ratio was formulated by applying stoichiometrically calculated ratios of amino acid use in the metabolic pathways.

What this means to a person with chronic illness and poorly functioning mitochondria is that body has the best chance of using these nutrients without being prevented because of the lack of energy to move chemical reactions forward. Indeed, if you actually study ALS, really study it, you find a ton of metabolites backed up and not moving forward past an enzyme that needs ATP energy to make that reaction move forward. The adenosine to inosine[1] reaction is a very good example of this problem. Another example is that there is systemic changes at the molecular and cellular level in ALS[2] and that’s reactions not happening to prevent those changes so these are backlogged reactions that the body lacks the ability to complete that all require energy and the correct nutrients. And then energy issues in ALS are extremely well documented[3].

They talk about hypermetabolism in ALS, and that’s what it looks like when you see huge calories going in and the body isn’t keeping up, weight is lost and muscles shrink, but with damaged mitochondria the body switches from getting energy from the efficient Krebs cycle to the inefficient glycolysis, and the difference in energy yield and efficiency is massive[4]. So Leap2BFit is a formulation that is designed to circumvent the energy backlogged reactions because it has the least possible energy conversion required by the body to have reactants available and it is taken on an empty stomach, so the body has the most ATP energy available because it is not using it on digestion.  The body does triage and Leap2BFit is a massively well designed nutritionally dense product that a body full of sick mitochondria can make use of where it is needed the most.

Being an absorbable supplement is an important part of the formulation, and the correct ratio of amino acids is important. In the diagram below you see a massive decline in life expectancy in mice when they do not have the necessary amino acids.  The mice to not survive to adulthood with insufficient essential amino acids.  The light and dark green graph lines are very important.  They represent the same protein source, but one is a complex protein and the other is the same ratio of amino acids as single amino acids.  When the amino acids are single, the mice live longer, even on a poorly designed protein for their health.  This study shows that longest life span is from a balanced ratio of essential amino acids.  Leap2BFit has that, but it also has amino acids required to support tissue repair, such as the gut, the blood brain barrier, neuro and fine vascular tissues, and it has many of the most highly bioavailable cofactors required for those metabolic reactions to happen.

Percentage of mice's survival according to diet. From left to right, mice without essential amino acids and with only 30% of the amino acids did not survive long. The light green and dark green and the same protein, but with the light green the body digested the amino acids and with the dark green the protein was broken into free amino acids and the mice lived longer with the free amino acids. The blue is from a standard rodent commercial diet and the red is free essential amino acids. [5]

ALS has serious mitochondria injury in the liver[6].  This study through labs found a "high incident of mild liver dysfunction," but it also took electron microscope pictures of the mitochondria and these findings are anything but mild:

•(1) bizarre giant mitochondria;
•(2) intramitochondrial paracrystalline inclusions;
•(3) disorganization of the lamellar structure of rough endoplasmic reticulum;
•(4) increased numbers of smooth endoplasmic reticulum; and/or
•(5) parasinusoidal fibrosis.

Mitochondria are essential for healthy liver function and this study is showing there's a massive mismatch between what labs are showing and very damaged mitochondria in the liver in ALS.  If you were to have cancer in the liver and they were able to cut it out, they could cut out half your liver and it would grow back.  The body protects the liver first because removing harmful substances is essential to survive.  If you were to go through the weight of literature on mitochondria you find tiny looking problems causing massive problems all over the place, so why studying the liver and the damaged mitochondria has failed to receive further study has been to the peril of pALS.

Norma Leger liver problem 2 months ahead of any neurological symptoms.

Norma Leger liver test results at time neurologist tells her to "look up ALS."

My sister had a test showing a severe isolated problem with the liver two months ahead of feeling any neurological symptoms and by the time she was told to look up ALS a year later, all liver function looked normal through testing.  GGT catabolizes reduced glutathione to cysteine and glycine and this begs the question, what event happened in the body to require this and what was the body doing?  The liver and the damaged mitochondria are grossly understudied in ALS.  Few pALS have a capture of test results around their trigger event in testing like my sister's test.

The mitochondria in the motor neurons[7] are injured.  Actual motor neuron death happens quite late in the disease process and this study showed that the mitochondrial degeneration was an important early event.  In particular, "The absence of massive motor neuron death at the early stages of the disease indicates that the majority of motor neurons could be rescued after clinical diagnosis."  From Amy Jaramillo's treatment method, www.bodyscience.life/als, we learned that amino acid injections can build the muscle to once again reach the nerves.  From Mark Manchester's reversal, his observation was that muscles that had stopped fasciculating had fasciculations return as the muscle returned, and he has found that now that muscle use has returned, the fasciculations are again declining.  It is generally believed that these fasciculations represent the dying of motor neurons, but the motor neuron research cited and Mark Manchester's reversal experience suggests that belief needs to be re-examined.

The amino acid imbalance in ALS is so serious, it has been considered a biomarker for ALS[8].  PALS are not routinely tested for amino acid issues, but we did testing on my sister with Genova's nutreval test, www.gdx.net/product/nutreval-nutritional-test-plasma.  The amino acid issues in the research is consistent with what my sister’s test results showed. Additionally, I wrote one of the researchers of the amino acid biomarker paper and my belief that pALS were deficient in amino acids in the shikimate pathway and he wrote back that he believe that I was correct and they had designed a study to conclusively demonstrate this, but the project fell apart and the research never went forward.

Norma Leger's test results showed low amino acids from the shikimate pathway which are methionine, phenylalanine, tryptophan, and tyrosine. Taurine is another essential amino acid not in the shikimate pathway that is low and is related to eye issues, but that's a topic for another post. The body can make the nonessential amino acids, but conversion requires ATP energy.  This test was two years after the bad liver test, April 2016.

My research video produced August 2016 identified 3 of the most important issues in ALS,  the microbiome shift, the leaky gut, and the amino acid deficiencies that come as a result of the pathogenic biofilms in the gut that crowd out the microbes you need and instead you have an overgrowth of microbes that are stealing your essential amino acids and other nutrients. https://youtu.be/bb7KmiIs0Kc?t=1351.

Specially formulated single amino acids formulas, as in proteases not required, increase mitochondria density in mice[9].  This is an extremely important study that has been ignored to peril of pALS.  Long term supplementation of a specifically formulated amino acid supplement resulted in "increased number and volume of mitochondria."  This is very important.  Our cells are actually two organisms in one, the mitochondria being a self-replicating independent organelle with its own DNA.  When you see "increased number" that means the mitochondria have replicated.  Many strategies in ALS have looked at how to band-aid sick and dysfunctional mitochondria to help them limp along and work longer and these strategies have had marginal short term success before rapid deterioration and ultimate failure.  This study shows that specifically developed amino acid formulations with specific ratios help healthy mitochondria to replicate, and this should allow the body to dispose of sick mitochondria which is why I believe it to be a superior strategy to helping the mitochondria.

Specially formulated amino acids on mitochondrial density is documented in the research [9].

This video by Dr Douglas Wallace really helped me to understand that in disease mitochondrial dysfunction usually precedes illness as 90% of the energy comes from the mitochondria so if they are not working, you start to get a backlog of poorly functioning enzymes because of lack of energy, and indeed, in ALS, there is evidence everywhere of poorly functioning enzymes.  Individual genetics determine the nature of the disease by which enzymes work poorly in poor energy environments, but improving the production of ATP energy by increasing healthy mitochondria helps enzymes that are the first to show problems in a poor energy environment.

So to further understand the importance and perhaps the source of the amino acid deficiency, you need to look at gut biogeography, have some understand of gut microbes.

From: Gut biogeography of the bacterial microbiota.[10]

So the lactobacillacea are predominantly manganese oxidizing microbes[11,12].  Borrelia Burdorferi is also manganese oxidizing[13], and its cellular division time is quite slow [14].  The lactobacillus species, being manganese oxidizing, also have slow cellular division rates [15].  The difference in cellular division rate and considering if a microbe is iron or manganese oxidizing simply isn't given the consideration of how this manifests in disease.  The lactobacillaceae need a head start in their cellular division and the manganese they require is delivered to the small small intestine via the bile duct.

Iron fortification is unnatural and poorly tested.  An infant study suggests that fortifying with iron messes up the bifidobacteria.  Other iron oxidizing microbes over populate and this study suggests to me that the overpopulation of iron oxidizing microbes is sequestering iron for its cellular division at the expense of the much needed bifidobacteria [16].  When digestion is required for the release of iron, the cellular division rate of the iron oxidizing microbes slower than when there is an abundance of iron and somehow the iron oxidizing bifidobacteria do better.  Iron fortified infant formula resulted in 11 to 19 points of lower IQ in children who had high iron and it only increased IQ by 3 to 5 points in children with low iron [17].  Other studies show the lowest IQ in children with the highest manganese in drinking water [18], with a 6 point difference between the highest and lowest levels of manganese in drinking water.  There is much higher ALS associated with well water, [19] and well water tends to have higher levels of manganese.

Norma Leger's gut health test show inability to culture lactobacillus and low bifidobacterium

Back to the lactobacillus species.  My sister's gut health tests approximately two years after first symptoms show no culture and very low bifidobacterium.  For the lactobacillus it means the levels were too low to culture.  The bifidobacterium and lactobacillus species are essential to each other in the gut.  Patients with chronic fatigue syndrome were given a lactobacillus casei supplement for two months and both the lactobacillus and the bifidobacteria increased [20].

In ALS there is high manganese up the spine [21, 22, 23].  The way manganese metabolism is supposed to work is the manganese is fed into the small intestine from the bile and then there is active transport of unused manganese back to the liver.    With healthy levels of lactobacillus manganese is used up for cellular division and eliminated through the stool.  Without lactobacillus using manganese manganese recycling can increase the levels of manganese beyond what is safe for the liver and it gets sent out via the vagus nerve resulting in the high manganese up the spine.  Lactobacillus species make GABA, acetylcholine, lactic acid, tyramine, phenylethylamine, tryptomine, and serotonin [24], which are all are risk for deficiency without lactobacillus.  With the missing bifidobacterium that require the lactobacillus to thrive, you have a reduction in "the production and/or liberation of B vitamins, antioxidants, polyphenols, and conjugated linoleic acids ... as well as preservation of gut barrier functions and protection against pathogens by producing bacteriocins, decreasing luminal pH by the production of acids and blocking the adhesion of pathogens to intestinal mucosa." [25]

Another problem from low lactobacillus is the lack of amino acids from the shikimate pathway being produced at the lining of the gut.  The lactobacilli have "conserved multiple tandem repeats of aromatic residues and glycines that anchor to the bacterial cell surface by binding the choline residues of wall teichoic acids and lipoteichoic acids." [26]  Glycine is a glyphosate analog, and glyphosate is a patented antimicrobial agent [27] that disrupts the shikimate pathway which is present in lactobacillus, [28].  So this is a number of problems from perhaps a problem with the glycine for anchoring the lactobacillus in the first place, and then because lactobacillus are supposed to be anchored to the lining of the gut, they are probably also supposed to be a guaranteed source of shikimate pathways amino acids right at the lining of the gut.

Essential amino acids tryptophan, tyrosine and phenylalanine are produced by lactobacillus, which is supposed to adhere to glycine residues in the lining of the gut.  My sister showed no growth in her lactobacillus culture and tested very low for the the amino acids lactobacillus can produce.
https://www.genome.jp/kegg-bin/show_pathway?lpl01230

Another problem associated with low lactobacillus is that some species are protective against aluminum-induced neural injuries [29].  Aluminum has been shown to cause motor neuron deficits and degeneration [30.]  The metal concentrations in the spine paper [22] shows higher aluminum up the spine in ALS which may be related to the loss of protection from the lactobacillus species.  So, dysbiosis and low lactobacillus have significant research showing serious problems that are found in ALS.

My sister's testing also showed a serious problem with biotoxins, which can be produced from mycoplasma and/or candida infections.  The microbes she was missing are essential to keep candida under control.  The damage to health from gliotoxin is massive [31, 32, 33, 34, 35, 36, 37, 38, 39].

Norma's May 2016 Realtime laboratories mycotoxin panel report showed 3 times acceptable level of ochratoxin A, just in the positive range for aflatoxin and trichothecene and a massive 21 time the acceptable level of gliotoxin.

Dr Dioguardi's amino acid work and its application to ALS is completely under appreciated, understudied and not applied.  The understanding of this amino acid work was applied to the development of Leap2BFit.  Basically in ALS as far as the amino acids are concerned, there is a net loss happening in the muscle.  The paper, Wasting and the Substrate-to-Energy Controlled Pathway:  A Role for Insulin Resistance and Amino Acids, [40] is a masterpiece explaining the importance of stoichiometrically calculated ratios of amino acid required by humans with attention paid to the other energy required to prevent catabolism, and this basic concept of treatment has not been applied to pALS.  I doubt very much that neurologist are familiar with any of this work, and Dr Dioguardi's graph (above) from other work [5] shows that single amino acids of even poorly designed proteins extend life over proteins that require digestion.

So what figure 1 from the wasting paper shows is that the body cannot make proteins from carbohydrates or lipids once they are broken down.  In ALS there is hypermetabolism [41, 42].  The Dioguardi paper explains how this works and is "characterized by lowest efficiency in energy production per mole of oxygen consumed," which to me in another definition for hypermetabolism and process likely involved in the muscle wasting in ALS.

Leap2BFit was designed applying knowledge of the importance of amino acid ratios, amino acids required to build basic barriers like the gut barrier and the blood brain barrier, both of which are compromised in ALS.  It was designed with the knowledge that poorly functioning mitochondria leave a body in chronic energy deficiency, so cofactors, precursors and beneficial botanicals to support essential metabolic reactions have been added in the highest researched bioavailable form, as per the 8 patented ingredients added, quatrefolic, theracurmin, alphasize, serinaid, curcumin complex, selenium select, menaQ7, and turmacin.  Each of these ingredients have a wealth of research showing that they have health benefits, and they are combined with the specially designed amino acid formulation.  There is also other vitamins and minerals added that also support the metabolic reactions.  The product was designed to have everything the body needs to move essential metabolic reactions forward and to not need to burn energy to convert say on amino acid to another.  The body needs the least possible energy to help itself with this formulation.

General comments about using Leap2BFit...

So for some general comments around ALS and successfully using this product, well, there is also that serious problem with the microbiome shift. When the body has the proper nutrition you are supposed to get diarrhea when you have bad microbes as that is how the body is built to eliminate them. There is actually research out there showing people do better with eliminating infection when this is allowed to run its course, but care needs to be taken to ensure electrolytes and fluids are replaced. My sister worked hard at taking probiotics and I realized far too late that she did not understand this. A few times she tried things that I thought should help and she had huge gut reactions and diarrhea and she would get so mad at me, and she thought she was losing her probiotic microbes that she’d worked so hard at taking. She also didn’t know that the stuff growing in her gut was putting out massive levels of metabolites to kill her probiotic microbes. Her gut health tests showed “no culture” for her lactobacillus species and she poured those into her body, but her tests also showed the lactobacillus inhibitors. A month later she wrote that she was feeling the best she’d felt in a long time. I believed what we had done had helped her, but the immediate thing she felt was a significant herx reaction, and this is where harmful microbes release endotoxins and they do make you feel sick. And then once you feel better, your gut is working somewhat better, for a while. So bad gut health comes with all kinds of awful kickback when you are attempting to fix it. Elimination through diarrhea might actually be an easier way to deal with it.

Another problem is there is a lot of tissue damage in ALS, which includes the lining of the gut, the muscles, the liver, the bone, the blood brain barrier, etc.. The body can not possibly be detoxing probably because of all of those damaged mitochondria, so get some of these systems working again by fixing mitochondria, and toxins the body’s tucked away in the least harmful form to you are going to need to be eliminated to actually restructure that tissue. But think of those damaged mitochondria as a pile of cement blocks blocking the entry and exit door, so it is difficult to get that stuff out and it is difficult to get the good stuff back in. As the liver repairs mitochondria, it is actually chipping and hammering away at those cement blocking and opening up that pathway. When a person with cancer has half their liver cut out, it grows back in about six months. Well, repairing those liver mitochondria is similar to trying to grow back a liver. It is going to take time, and moving the crap out can come with side effects. Turning the mitochondria back on in places they haven’t hardly worked at all can come with side effects. If you are full of aluminum from vaccines, well, the body might start working on trying to get rid of it and that might not feel good.

There are strategies being consider in clinical trials designed to prevent mitochondrial programmed cell death and I think the body programs the cell death for a reason and it isn’t making the mitochondria health and eventually they will too unhealthy to work. Amino acids is promoting new mitochondrial growth.

Here’s the thing, triage is prioritizing the most important things, and they body has done that in ALS, maintaining brain function, and in my sister’s case, she lost things like estrogen production ahead of ALS, and there were just signs of her body going out of balance. So the body knows how to heal and what it is most important and given the correct tools, in this case amino acids and cofactors designed to promote mitochondrial growth, and the body will tirage what it needs to do to help you. Mark’s most dramatic improvement came in his second year of using leap2bfit and l-serine. Mark may have also done other things earlier that helped to change something that need to be changed.

I’ve chatted with other pALS showing benefit, and quantifiable benefit. I’ve seen pALS videos showing fasciculations from say a year or two ago, and none today and feeling back to normal. I’ve seen video of pALS that could not move limbs moving them again.  Mark Manchester still has fasciculations but he says there are becoming less and less as time goes by. I’ve seen pALS self-report improved ALSFRS test scores in pALS organized trials using Leap2BFit and L-serine.

So to me, with my research and my understanding of ALS and the pALS that are report and showing quantifiable improvements I believe there is more hope for pALS and all pALS because of what this research is showing.

I have also seen pALS with extremely strong and painful reactions.  One of these pALS stopped after 3 weeks, added a number of other strategies (ibudilast, CuATSM, Nadir's protocol, Rick Simpson's Oil), and resumed Leap2BFit and is showing considerable improvements now.  Diet needs to be worked on, ensuring that elimination pathways are open (poop at least once per day, 3 times is better), and other supplements may be required.

It can not be ignored that Mark Manchester took Leap2BFit mixed with food once per day for a year before switching to twice per day, and he also has a supplement protocol that helps with digestion, liver function and probiotics, and these may have contributed to his remarkable reversal, from 4 years on a vent to walking again.  So it was two years of taking Leap2BFit before Mark Manchester had his surgery to remove his trache.

The body did not get sick overnight and there is a ton of structural repair that needs to happen, with the liver, the fine vascular tissue, the mitochondrial division, etc.  The body does triage best.

Mark Manchester's ALS reversal is the biggest new in ALS history because the body is actually repairing itself with this strategy.

Mark's charity, themanchesterproject.org, has gifted about 500 pALS with 2 months of Leap2BFit and L-serine and half the pALS that responded to a survey reported feeling benefits.  A second survey is being planned.

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Further reading...

Pathobiont release from dysbiotic gut microbiota biofilms in intestinal inflammatory diseases: a role for iron?  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-018-0495-4

Iron and Virulence in the Family Enterobacteriaceae, https://www.tandfonline.com/doi/pdf/10.3109/10408418809104468

Manganese-induced sex-specific gut microbiome perturbations in C57BL/6 mice https://www.sciencedirect.com/science/article/pii/S0041008X17302648

Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1−/Δ7 mice https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408808/

R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease http://jem.rupress.org/content/214/12/3507

Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants https://gut.bmj.com/content/64/5/731

Children have higher levels of glyphosate than their parents. https://sacramento.cbslocal.com/2019/07/24/weed-killer-roundup-kids-epa-higher-levels-parents/#.XcXSjhMdnSk.twitter

GTT - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388159/

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