Hi Rich,
And again, each of adb12 and mb12 has their own effects and both are improved with methylfolate. If you have any ideas on this I would be very interested in hearing them. If you have any ideas of how to improve these reponses I would be very interested.
Hi, freddd.
As you probably know, the main fuel for the brain is glucose, and the secondary fuel is ketones. As you probably also know, when a person does not have enough adenosylcobalamin in their mitochondria, methylmalonate and propionate rise, because the pathway that normally feeds them into the Krebs cycle at succinyl Co A is partially blocked.
Below is an abstract of a paper describing a study in rats in which elevated methylmalonate and propionate were found to block the metabolism of the ketones by the brain. This would take away one of the main sources of fuel for the cells of the brain. I suggest that this is the reason you obtain better brain function from your high-dose supplementation of adenosylcobalamin, given that you have a genetic mutation that prevents the normal formation of adenosylcobalamin in the cells.
As you probably know, glucose normally first passes through the glycolysis chain in the cytosol of the cells, and is converted to pyruvate. Pyruvate then normally enters the mitochondria and is converted to acetyl-CoA, which enters the "top" of the Krebs cycle. In CFS, because the methylation cycle is partially blocked due to an intracellular functional deficiency of methylcobalamin and 5-methyl tetrahydrofolate, glutathione becomes depleted. The partial methylation cycle block and the depletion of glutathione are linked in a vicious circle mechanism.
(I'm not totally clear on the mechanism of this vicious circle, but the synthesis glutathione is downstream in the sulfur metabolism from the methylation cycle, and we have good evidence now in both autism and CFS that a partial block in the methylation cycle is linked to depletion of glutathione. So it's an experimentally observed phenomenon, even though I don't think anyone completely understands its mechanism yet.)
At any rate, the depletion of glutathione causes a rise in concentrations of oxidizing free radicals, which are produced as a normal part of oxidative metabolism in the mitochondria, but are normally taken care of by the antioxidant enzyme system, of which glutathione serves as the basis. There is abundant evidence of elevated oxidative stress in both CFS and autism.
When the oxidizing free radicals rise, they react with the enzymes that have iron-sulfur clusters, deactivating a fraction of these enzymes. One of these enzymes is aconitase, which lies early in the Krebs cycle, after citrate. This puts a partial block at this point in the Krebs cycle. Since the pathway for the overall metabolism of glucose must pass through this enzyme, the result is that the functional deficiency of methylcobalamin partially blocks the use of glucose for fuel by the cells, including the cells of the brain. The evidence for the partial block at aconitase comes from the urine organic acids test results that I have reviewed from many people with CFS, which often show a bottleneck between citrate and the following Krebs metabolites.
Succinyl CoA lies beyond aconitase in the Krebs cycle, so that the injection of the ketones pathway into the latter part of Krebs cycle is not impacted by the partial block at aconitase. I suggest that even though there is a partial block at aconitase, it is still possible to get some energy to drive ATP synthesis by injecting substrates at succinyl CoA and utilizing only the latter part of the Krebs cycle. I think this is why adenosylcobalamin is able to help with ATP production, even though low glutathione due to a partial methylation cycle block is still causing a partial block at aconitase. The point is that the Krebs cycle is not a closed cycle. Things can come in and out of it at various points in the cycle.
The result of all this is that methylcobalamin affects the use of glucose for fuel by the brain, while adenosylcobalamin affects the use of ketones. I suggest that when you supplement both at high dosages, you help feed both of the brain's fuels into the Krebs cycle, thus raising the rate of production of ATP, which is needed to drive the membrane ion pumps in the neurons, as well as other reactions in the neurons and the other cells of the brain.
I suggest that the reason you experience separate benefits from these two forms of B12 is that your cells are not able to interconvert them because of the genetic mutation in your intracellular B12 processing enzymes.
I think it is possible (and there is some evidence for this in the literature) that the relative use of glucose and ketones as fuel may differ for the neurons and the glial cells (such as the astrocytes), and this may also be involved in your differing responses to the two forms of B12. Furthermore, I think there could be differences between different major parts of the brain in terms of their relative use of these two fuels, and that may also be contributing to the differing effects on mental clarity that you experience from these two B12 forms.
I don't currently see how adenosylcobalamin could interact directly with 5-methyl tetrahydrofolate in your case. In cases in which the cells are able to interconvert the forms of B12, I suggest that the availability of sufficient 5-methyl tetrahydrofolate would make the use of methylcobalamin more efficient, so that more of the B12 resources could be directed toward synthesis of adenosylcobalamin. Thus, there would be an indirect interaction between 5-methyl THF and adenosylcobalamin. But I don't know of a direct connection between 5-methyl THF and adenosyl B12.
In a previous post, freddd, you encouraged me to visit the B12 deficiency thread on the "wrong diagnosis" website to look into the success that people there have experienced from your treatment protocol. I was happy to see that people there had benefited, and I think that you were able to do some very good things for some of them. However, here's my problem: I can't tell how many of these people actually had chronic fatigue syndrome, which is what I am specializing in, and to which this forum is devoted. In my view, B12 deficiency is not the same as chronic fatigue syndrome, and I think the formal case definitions would support me in that view. As I've acknowledged in the past, your treatment protocol is capable of helping people who have a wide variety of B12 problems, since it bypasses the normal absorption, transport and processing of B12 in the body. As such, it does help people who have a partial methylation cycle block as a result of the vicious circle mechanism that is present in CFS. But I claim, based on clinical experience, that it is not necessary to use methylcobalamin and adenosylcobalamin to help these people, because their cells are capable of converting between the various forms of B12 to satisfy their needs for the two active coenzyme forms.
I know that you have cited the experience of many people from this other website, in terms of the need to use high dosages of both these coenzyme forms in order to achieve successful results, and have applied this experience to chronic fatigue syndrome cases. However, I question the relevance of this part of the experience, because I don't see evidence that these other folks actually had CFS, as opposed to other B12-related problems, such as pernicious anemia or transcobalamin deficiency, or, as in your case, genetic mutation of the intracellular B12 processing enzymes. As far as I know, most people who have CFS do not have these other problems, based on the fact that CFS is defined as an acquired, rather than a lifelong disorder, and the observation that most are helped by hydroxocobalamin.
As I've reported in the past, the simplified treatment protocol, which uses hydroxocobalamin rather than the coenzyme forms methylcobalamin and adenosylcobalamin, has been found to help at least two-thirds of the people with CFS who have tried it. I realize that you have suggested that the reason that the other nearly one-third do not respond to this treatment is that hydroxocobalamin is "inactive." I think that that might be a possible explanation for some of those with CFS who do not respond, but I also think that some don't respond for other reasons, such as lack of enough of the vitamin and mineral cofactors, lack of high enough levels of the amino acids that are needed, or high body burdens of toxic heavy metals, which are known to be able to block enzymes in this part of the metabolism. So I would say that it is far from proven that the non-response of this nearly one-third is due to the "inactivity" of hydroxocobalamin, as you have repeatedly claimed. I have studied some of the nonresponding cases in detail with lab testing, and I have identified cases in which it appears that one of these other factors is involved in the nonresponse. Until we have more measured data, I don't think it is justified to make the claim that all of the nonresponse is due to "inactivity" of hydroxocobalamin.
I'm bringing these things up not to pour cold water on your efforts, but just to try to clarify the issues as well as we can at this point. I can't say that I know what the optimum protocol is for treating CFS. It may be that some people need to go a bit more slowly, while others will do better by "pushing through" the symptoms by continuing with high dosages. I can't say. It may depend on the sizes of their body burdens of toxins.
I think we still have a lot to learn about this. I appreciate being able to interact with you about these things in an objective way.
Rich
Biochem Med Metab Biol. 1991 Feb;45(1):56-64.
Effects of methylmalonate and propionate on uptake of glucose and ketone bodies in vitro by brain of developing rats.
Dutra JC, Wajner M, Wannmacher CF, Dutra-Filho CS, Wannmacher CM.
Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Methylmalonate (MMA) and propionate effects on glucose and ketone body uptake in vitro by brain of fed and 30-hour-fasted 15-day-old rats were studied. In some experiments cerebrum prisms were incubated in the presence of glucose and either MMA or propionate in Krebs-Ringer bicarbonate buffer, pH 7.0. In others, the incubation medium contained beta-hydroxybutyrate (HBA) or acetoacetate (AcAc) instead of glucose. We verified that MMA increased glucose uptake by brain of fasting animals, whereas propionate had no effect. In addition, MMA diminished HBA but not AcAc incorporation into brain prisms, whereas propionate provoked a diminished utilization of both ketone bodies by brain. The in vitro effect of MMA and propionate on brain and liver beta-hydroxybutyrate dehydrogenase activity was also investigated. It was shown that MMA but not propionate significantly inhibited this activity. Rats were also injected subcutaneously three times with a MMA buffered solution, and the in vivo effects of MMA on the above-mentioned parameters assessed. Results from these experiments confirmed the previously found in vitro MMA effects. Methylmalonic acidemic patients accumulate primarily methylmalonate and secondarily propionate and other metabolites in their tissues at levels comparable to those we used in our assays. Most patients who survive early stages of the disease show a variable degree of neuromotor delay. Since glucose and sometimes ketones are the vital substrates for brain metabolism, it is possible that our findings may contribute to a certain extent to an understanding of the biochemical basis of mental retardation in these patients.
PMID: 2015109 [PubMed - indexed for MEDLINE]