This Is MS Multiple Sclerosis Community: Knowledge & Support

Hi Annesse,

The glucose metabolism stuff would be interesting.

I was more interested in the thyroid receptors; particularly PPAR, RAR,LAR and VDR plus RXR.

No worries.

Regards

Hi Scott1~Sorry, I realized that was not what you were asking after I made the post. I considered erasing it, but thought it was relevant to the rest of the discussion, so decided to leave it. I haven't done any research on the thyroid receptors. The building blocks for thyroid receptors are amino acids though, right? Depending on how they are synthesized and what amino acids are used could make them relevant to our discussion on protease.


The inability to bind and transport vitamin B12, especially across the blood-brain barrier, will explain two more symptoms of MS; optic neuritis and nystagmus. Nystagmus is involuntary, rapid repetitive movements of the eyes. The following abstract shows the connection to nystagmus and lack of vitamin B12. It is entitled, "Downbeat nystagmus indicates cerebellar or brain-stem lesions in vitamin B12 deficiency".
http://www.ncbi.nlm.nih.gov/pubmed/3487624

Here is some information on B12 and optic neuropathy.
http://www.medlink.com/medlinkcontent.asp The following information is a quote from the link.

"An unusual but well documented manifestation of cobalamin deficiency is optic neuropathy. This may present as a subacutely progressive decrease in visual acuity with a cecocentral scotoma (ie, a scotoma obscuring central vision and enlarging the blind spot). The condition known as tobacco-ethanol amblyopia is similar, and may, at least in part, depend on cobalamin deficiency. A case of the Charles Bonnet syndrome (visual hallucinations in a person with marked visual impairment) has been described (Bourgeois et al 2010)."

The following study shows that B12 deficiency is directly linked to white matter lesions. It states in the results, "Poorer vitamin B12 status was significantly associated with greater severity of white matter lesions, in a concentration-related manner." It also states in the conclusion, "These results indicate that vitamin B12 in the NORMAL range is associated with severity of white matter lesions, especially periventricular lesions."

http://www.ncbi.nlm.nih.gov/pubmed/18977824

If the white matter lesions found in MS are due to a B12 deficiency, then the other diseases we have identified with white matter lesions should have a B12 deficiency as well. We have shown that CFS patients have white matter lesions and a B12 deficiency.

We have also identified Sjogren's patients as having white matter lesions. In the next study entitled, "Iron and vitamin deficiencies, endocrine and immune status in patients with primary Sjogren's syndrome," it is shown that Sjogren's patients are deficient in vitamin B12. They were also found to be deficient in iron and have an increased risk of developing hypothyroidism (30%), just as with the other diseases we have been discussing.

http://www.ncbi.nlm.nih.gov/pubmed/11495189

We have shown that lupus patients have white matter lesions. They have also been found to have a vitamin B12 deficiency. The following information states that a 2004 study published in "Rheumatology International" found that serum vitamin B12 deficiencies in patients with lupus were "much higher" than in controls.

http://www.livestrong.com/article/47837 ... ith-lupus/

Celiac's disease, diabetes, and Alzheimer's patients also have been shown to have severe vitamin B12 deficiencies and all of these diseases have white matter lesions as well. Here is some more information on the presence of white matter lesions and the diagnosis of MS.

http://braindiseases.wordpress.com/2008 ... resent-ms/

The Krebs Cycle

The Krebs cycle is a series of chemical reactions that occur within the matrix of the mitochondria. The main goal of the Krebs cycle is to produce energy. Essentially, the cycle involves converting the potential energy of nutrients into the readily available energy of adenosine triphosphate (ATP). The Krebs cycle is essential for the oxidative metabolism of glucose and other simple sugars. Thousands of times a second, one turn of the cycle turns a glucose fragment into carbon dioxide and water, just as if it had been burnt in a flame.

Succinyl-CoA is an important intermediate in the Krebs cycle. Vitamin B12 serves as a cofactor for the enzyme methylmalonyl-CoA mutase, which converts L-methylmalonyl-CoA into succinyl-CoA. Succinyl-CoA can then enter the Krebs cycle. Therefore, vitamin B12 is an essential component for the completion of the Krebs cycle. This is why vitamin B12 is called the “energy vitamin.” We have previously discussed the importance of CoQ10 in the Krebs cycle and why a lack of phenylalanine would lead to a deficiency in CoQ10. A lack of these essential nutrients would lead to a failure in the Krebs cycle.

The body’s main source of energy comes from the complete oxidation of glucose to carbon dioxide and water via the Krebs cycle. Fatigue, exhaustion, exercise intolerance, and brain fog are all directly related to impaired energy production.

Glucose is the only fuel normally used by brain cells. Because neurons cannot store glucose, they depend on the bloodstream to deliver a constant supply. Neurons, the cells that communicate with each other, have a high demand for energy because they’re always in a state of metabolic activity. Even during sleep, neurons are still hard at work repairing and rebuilding their structural components. A lack of glucose would lead to mental confusion or lack of mental clarity. This is commonly known as “brain fog.” Researchers at Mount Sinai School of Medicine have found that patients with Alzheimer’s disease have lower glucose utilization in the brain than those with normal cognitive function. They discovered that mice with impairment in brain cell energy production developed signs of Alzheimer’s disease such as cognitive defects and memory impairment.

Exercise intolerance is a common feature of autoimmune disease. In the abstract, “Chronic fatigue syndrome and mitochondrial dysfunction,” researchers discuss the connection to exercise intolerance and impaired mitochondrial glucose metabolism. They state, “What happens if some part of these cellular metabolic pathways goes wrong? If the mitochondrial source of energy is dysfunctional many disease symptoms may appear including the symptoms of CFS.”

The researchers continue, “Suppose that the demand for ATP (adenosine triphosphate) is higher than the rate at which it can be recycled. This happens to athletes during the 100 meters sprint. The muscle cells go into anaerobic metabolism where each glucose molecule is converted into 2 molecules of lactic acid. This process is very inefficient (5.2% energy production compared to the 100% of complete oxidation) and can last for only a few minutes. The increased acidity leads to muscle pain. Also, when the concentration of ADP (adenosine diphosphate) in the cytosol increases and the ADP cannot be recycled quickly enough to ATP, another chemical reaction takes place. This becomes important if there is any mitochondrial dysfunction. Two molecules of ADP interact to produce one of ATP and one of AMP (adenosine monophosphate). The AMP cannot be recycled and thus half of the potential of ATP is lost. This takes some days to replenish and may account for the post-exertional malaise symptom experienced by patients.” The researchers also state, “There is considerable evidence that mitochondrial dysfunction is present in some CFS patients. Muscle biopsies studied by electron microscopy have shown abnormal mitochondrial degeneration.”

Multiple sclerosis patients also have impaired glucose metabolism. In the abstract, “Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression,” the researchers state, “As extra-mitochondrial glucose metabolism increases with impaired mitochondrial metabolism of glucose, these findings implicate mitochondrial dysfunction in the pathogenesis of MS disease progression.”

Impaired glucose metabolism also plays a major role in diabetes. Insulin secretion from the pancreatic islet cells requires ATP. The abstract, “ Interaction between Mitochondria and the Endoplasmic Reticulum: Implications for the Pathogenesis of Type 2 Diabetes Mellitus,” states, “ Type 2 diabetes mellitus is characterized by impaired insulin secretion from pancreatic B-cells. In addition, insulin-responsive tissues, such as muscle, liver, and adipose tissue, exhibit insulin resistance. A number of findings suggest that both of these major features of type 2 diabetes are associated with mitochondrial dysfunction… “The study found that, “mitochondrial dysfunction in BAT (brown adipose tissue) appears to be linked to impaired thermogenesis and energy expenditure, contributing to the development of obesity and insulin resistance in adult humans.”

Impaired glucose metabolism is a common occurrence in autoimmune disease, as is evidenced by the following study titles.

“Lowered cerebral glucose utilization in amyotrophic lateral sclerosis”

“Cerebral Blood Flow and Glucose Metabolism in Hypothyroidism: A Positron Emission Tomography Study”

“Fluctuating cognitive abnormalities and cerebral glucose metabolism in neuropsychiatric systemic lupus erythematosus”

Interesting and a half. Great aunt passed away from type 1 diabetes, my mom has psoriasis, I do to and ms. I always knew there was some connection.

And from YEARS ago:

http://www.aarda.org/infocus_article.php?ID=28

The Common Thread by Noel Rose, MD

Hi Annese,

Have you looked at glyceraldehyde-3-phosphate dehydrogenase?

Regards

Hi Scott1,

No, but if it is a valid finding in any of these conditions, I have never not been able to trace it very directly back to protease. I just looked quickly at how it is produced and please correct me if I am wrong (I very well could be), it is a byproduct of tryptophan and thiamin (B1).

We have shown that MS patients lack tryptophan and if you are deficient in B12, you will not be able to absorb B1, it will be excreted in your urine. This would explain the findings of low levels of glceraldehyde-3-phosphate in MS.

Hi Annesse,

I have another idea but keep going. I won't distract your train of thought. Your posts are interesting.

Regards,

Many autoimmune sufferers react negatively to chemicals and sun exposure. As part of the autoimmune process, sun sensitivity is due to a disorder called porphyria. Porphyria is caused by a deficiency of one of the components needed to make a substance in the body called heme.

Heme is a red pigment composed of iron linked to a chemical called protoporphyrin. Heme has many important functions in the body. Heme is found in the largest amounts in the blood and bone marrow in the form of hemoglobin within the red blood cells. Hemoglobin gives blood its red color and carries oxygen to every part of the body. As a component of proteins in the liver, heme has many functions, including breaking down hormones, drugs, and other chemicals.

The body makes heme mostly in the bone marrow and liver. The process of making heme is called the heme biosynthetic pathway. Each step of the process is controlled by one of eight enzymes. If any one of the eight enzymes is deficient, the pathway is disrupted. As a result, porphyrin, or its chemical precursors, may build up in body tissues and cause illness.

Porphyrins can accumulate in the skin and cause photosensitivity. Exposure to the sunlight may cause symptoms such as redness, rash, itching, burning, blistering, and swelling. Once triggered, an episode can escalate and cause even more toxic porphyrins to build up in the tissues, leading to even more serious illness.

The first component in the heme pathway is Succinyl-CoA. Without B12, the body would not be able to produce Succinyl-CoA (Vitamin B12 serves as a cofactor for the enzyme methylmalonyl-CoA mutase, which converts L-methylmalonyl-CoA into succinyl-CoA) and this would lead to a failure in the entire heme pathway, just as in the Krebs Cycle.

Once our bodies produce heme, it goes on to become an essential component of our bodies first line of defense against chemicals and environmental pollutants; a powerful enzyme detoxification system called cytochrome P450.

The cytochrome P450 system detoxifies all sorts of different chemicals that we eat and breathe, including drugs, carcinogens formed in cooking, and poisonous compounds in plants. For instance, cytochrome P450 is the reason doctors tell you not to drink grapefruit juice when taking certain medications. Grapefruits contain a flavinol molecule that inhibits cytochrome P450 enzymes. This would slow down the detoxification of the drug and might cause it to have a stronger effect than intended.

The cytochrome P450 enzyme system also plays an essential role in hormone synthesis. It converts cholesterol into pregnenolone, which then gets converted into other hormones like estrogen, testosterone, cortisol, and DHEA. A defect in the cytochrome P450 enzyme system would account for the abnormal hormone levels found in autoimmune disease. For instance, the following study states that "low DHEA levels have been implicated in chronic fatigue syndrome, and low DHEA levels are found in lupus and rheumatoid arthritis." It also states, "lower levels of DHEA and its sulfated compound, DHEAS, have been demonstrated in MS patients.."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910465/

The following study found that about half of the patients with MS had low estrogen.
http://www.ncbi.nlm.nih.gov/pubmed/6786955

The active site of cytochrome P450 contains a heme iron center, and therefore, cytochrome P450 enzymes are hemoproteins. A failure in the heme biosynthetic pathway would also result in a failure of the cytochrome P450 enzyme detoxification system.

My rheumatologist told me she thought I had Porphyria, but I've never been properly tested whilst ill or biopsied the suspected rash, so we may never know. I can't drink alcohol, take contraceptives, and in more recent years I've had two brain events, both exactly two weeks after a common dental anaesthetic, and whilst I was also mildly iron overloaded. So I'm familiar with the P450 cytochrome system. In my case it seems to be a "cup runneth over" situation. I can get away with small amounts of these things, but large doses and combinations of triggers seem to set me off.
I think the final crux was the mild iron overload combined with the lidocaine, it tipped me off the deep end for a few years, and I became quite chronic.
All processed through the P450 system.
It's something to think about.
I would love some day to get genetically tested for porphyria, in fact it's a goal for me.
Thanks for all your information.

Hi Bethr~

One of the most amazing things I have learned through all of this is that not just the symptoms of all of these diseases can be traced back to missing enzymes, but the triggers as well. PEDD (Pancreatic Enzyme Deficiency Disease) is a pathway, and anytime something interrupts this pathway, you will see symptoms of autoimmune disease. The PEDD pathway is proteins-B12-enzymes.

Anaesthetics can interrupt this pathway by blocking B12. For instance, I have a fibromyalgia differential list in my book. There are 45 conditions and diseases on this list that share many of the same symptoms of fibromyalgia. One of the conditions on the list is dysbarism. Dysbarism can be seen in scuba divers. On the surface, it does not seem that dysbarism could possibly be connected to the autoimmune pathway and yet the symptoms mimic those of fibromyalgia-enough to it being placed on the fibromyalgia differential list.

Webster's Dictionary gives the definition of dysbarism as, "A reaction to a sudden change in environmental pressure, such as rapid exposure to the lower atmospheric pressures of high altitudes. It is marked by symptoms similar to those of decompression sickness." Webster's dictionary continues, "Nitrogen narcosis-Nitrogen comprises 79% of the air breathed by aerobic organisms, but at surface pressures it has no sedating effect. At greater depths, however, nitrogen affects the brain in precisely the same way as Nitrous oxide (also known as laughing gas)."

"Nitrous oxide inactivates the cobalamin form of B12 by oxidation. Symptoms of B12 deficiency, including sensory neuropathy, myelopathy, and encephalopathy, can occur within days or weeks of exposure to nitrous oxide anesthesia in people with subclinical vitamin B deficiency. Recovery can be slow and incomplete" according to http://www.wellness.com. (Every one of the 45 conditions on the fibromyalgia differential list can be traced back to the "pathway" in just the same way)

This link on CFS states, "The disorder is known sometimes to occur or worsen after anaesthetics," and provides 3 studies as evidence.
http://www.cfids-cab.org/freds/cfs.htm

You also mention alcohol intolerance. The enzyme responsible for the detoxification of alcohol is called alchohol dehydrogenase. Even under normal conditions, women make about 25% less of alcohol dehydrogenase than men. Alcohol dehydrogenase uses two molecular "tools" to perform its function, one of which is zinc. (We have shown that MS patients lack zinc and why.)

In the study, "Dietary zinc-deficiency and its recovery responses in rat liver cytosolic alcohol dehydrogenase activities" it was concluded, "These results suggest that rat live cytosolic ADH activity was clearly related to dietary zinc levels."

Here are some more examples of different triggers that can interfere with the Protein-B12-Enzyme pathway.

Certain medications can cause lupus. This is known as drug-induced lupus. Most cases are associated with procainamide (Pronesty), hydralazine (Apresaline), and quinidine (Quinaglute). All of these drugs are ENZYME INHIBITORS. They would interrupt the enzyme part of the pathway.

Pesticide use has been associated with an increased risk of autoimmune disease as the following link shows.
http://www.arthritistoday.org/news/bug- ... pus007.php
Pesticides are poisons and most poisons work by specific inhibition of enzymes. In fact, the very dictionary definition of a poison is that it kills enzymes.

The first mass outbreak of CFS in this country can also be traced back to a disruption in the enzyme portion of the pathway. In the abstract, "Chronic Fatigue, Fluoride and Heavy Metals" Dr. Cheney, a well known CFS researcher, found that the area (South Lake Tahoe) contained high levels of fluoride in the water (due to the fact that it is in a volcanic zone) and linked the outbreak to these levels. In fact, even today, South Lake Tahoe water reports have specific caution for immune compromised persons not to drink the water.
Dr. Cheney put this in his report: "Fluoride is a potent enzyme poison due to its affinity toward trace minerals."

Chronic exposure to mold has been linked to conditions such as MS. http://www.mold-help.org/content/view/582/
The following abstract states,"it is most likely that mycotoxins interrupt the structure and function of vitamin B12."
http://www.ncbi.nlm.nih.gov/pubmed/17982599

Aspartame would be an example of something that would affect the protein part of the pathway.
Aspartame is a dipeptide molecule produced by joining phenylalanine and aspartic acid. We have shown that MS patients lack phenylalanine, so why would ingesting phenylalanine from aspartame lead to an increased risk of MS and other autoimmune disease?

Phenylalanine is an essential amino acid found in high protein foods. The lack of phenylalanine in MS is due to the inability to digest proteins. If you lack the ability to digest proteins, you would also not be able to properly metabolize the components of those proteins-amino acids. For instance, gluten is a protein. If someone has celiac disease, would it be wise for them to avoid gluten, but take components of the gluten into their bodies? Would they not also react to the components of gluten? The study entitled, "Intermediary Metabolism of Phenylalanine and Tyrosine in Diffuse Collagen Diseases" found that when the amino acids, phenylalanine and tyrosine, were given to lupus patients, the amino acids "unfailing aggravated both clinical signs and laboratory data of collagen disease."

Speaking of gluten, there is a high correlation of gluten intolerance associated with autoimmune disease. This would need to be explained as well. First, gluten is a protein and autoimmune sufferers lack the enzymes to digest proteins.

Just as with the other diseases we have been discussing, celiac disease patients also lack vitamin B12. This is indicative that they are also unable to digest other proteins and not just gluten. An important function of vitamin B12 is repairing damaged, flattened microvilli (little fingers in the intestinal tract that are damaged in patients with gluten intolerance).
http://www.celiac.com/articles/807/1/Lo ... Page1.html

How did the 'staff of life' become something we should be concerned about eating? What has changed? Not just the wheat itself, but the way bread is made. Our ancestors, and virtually all pre-industrialized peoples, soaked or fermented their grains before making them into porridge or breads. Through scientific research, we are now able to understand why and how it all works. The sourdough process transforms or breaks down food components in flour into a simpler form that is more easily digested. A diet high in unfermented whole grains, particularly high-gluten grains like wheat, puts an enormous strain on the digestive system.

Why did we stop making bread the traditional way? Convenience and money are both factors. Sourdough yeast lives forever if you take care of it. Once you have it, and you can easily get some from a friend that bakes sourdough bread, you never have to buy it again. So, where's the money in that? Fleischmann's first engineered "yeast that would die" around the 1860s as a convenience. Sourdough yeast takes longer to rise. The changeover became complete in the 1980s, when instant yeast was introduced.

What if the gluten was properly fermented through? Would someone who is gluten intolerant or even someone with Celiac disease actually be able to consume fermented bread, with no toxic effects? The study entitled “Sourdough bread made from wheat and nontoxic flours and started with selected lactobacilli is tolerated in celiac sprue patients” showed that even someone with celiac disease can eat bread with no toxic effects, as long as the bread is properly fermented. In the study, sourdough bread was made from 30% wheat and mixture of oat, millet, and buckwheat flours. The bread was fed to 17 patients with celiac disease with no negative consequences. However, when the same 17 patients were fed the bread make with baker’s yeast, 13 patients showed “a marked alteration in intestinal permeability.

In an additional study entitled “Safety for patients with celiac disease of baked goods made of wheat flour hydrolyzed during food processing” celiac patients were fed a 60-day diet of baked goods made from wheat flour manufactured with sourdough lactobacilli and fungal proteases. They also experienced no ill effects. Notice the use of protease in this study. This is additional evidence that if we have sufficient enzymes to properly digest all of our proteins, we will be able to release amino acids, iron, zinc, vitamin B12, carry protein-bound calcium, metabolize vitamin D, etc. We will be able to do all of this and not experience any "toxic effects".