Attention Freddd: MTHFS deficiency

[richvank]

Hi, Freddd.

I've been thinking about your body's intolerance of folinic acid and of vegetable-based folates. Vegetables contain folinic acid as well as methylfolate, and lettuce, spinach, carrots and peppers contain significant amounts of folinic acid. I suspect that it is the intolerance of folinic acid that causes your body to be intolerant of vegetable-based folate, also.

Here's what I suspect accounts for this. I suspect that you have an inherited deficiency in the enzyme methenyltetrahydrofolate synthetase (MTHFS). This is the only enzyme known to catalyze a reaction with folinic acid. If you have a deficiency in this enzyme, and you consume folinic acid, it will build up in your cells. The problem with this is that folinic acid normally acts as a regulator of folate metabolism by inhibiting enzymes in this metabolism. In particular, it inhibits the serine hydroxymethyltransferase (SHMT) enzyme, which normally is the main enzyme that converts tetrahydrofolate to 5,10 methylene tetrahydrofolate, which in turn is the substrate for making methylfolate.

So, a deficiency in MTHFS will allow folinic acid to rise, and this will inhibit SHMT, which will lower 5,10 methylene tetrahydrofolate, and thus will also lower production of methylfolate, which is needed by methionine synthase in the methylation cycle.

I think this can explain why folinic acid has been so devastating to you and why its effects are so persistent, once you have ingested it. It builds up, because the enzyme that normally controls its level by converting it to 5,10 methylene tetrahydrofolate is deficient. It stays high for a long time for the same reason. When it is high, it suppresses the SHMT reaction, which lowers the natural production of methylfolate, which then inhibits methionine synthase and partially blocks the methylation cycle.

This would also explain why you have had to take such high dosages of methylfolate, especially if you have taken some folinic acid or vegetable-based folates, which contain folinic acid. The reason is that your normal production of methylfolate has been inhibited, so that you have to supply it exogenously. I suspect that in addition, your tetrahydrofolate is probably high, because it is the product of the methionine synthase reaction, and if SHMT is inhibited, that will tend to inhibit the conversion of THF to 5,10 methylene THF, so that THF would probably rise. High THF will likely exert backpressure (product inhibition) on the methionine synthase reaction, so that it is necessary to add more methylfolate to drive it at a normal rate.

I think it would be very interesting to see the results of a methylation pathways panel on you. This panel measures a range of folate forms, and I think it would give some unusual results in your case.

Best regards,

Rich

 

[richvank]

Hi, Freddd.

One more thing:

After I wrote the post above, I began to wonder how your cells are able to make new DNA, because the thymidine needed must be made using 5,10 methylene THF, and with your SHMT enzyme shut down by high folinic acid, the 5,10 methylene THF would be low.

But then it hit me. You take a high dosage of methyl B12. This supplies a lot of methyl (1-carbon) groups. By taking high dosages of both methylfolate and methyl B12, you overdrive your methyation cycle. This causes the glycine N-methyl transferase reaction to kick in in order to drain off the excess methyl groups by converting glycine to sarcosine. The sarcosine is then used to convert THF to 5,10 methylene THF in lieu of the SHMT reaction, which is shut down by the high folinic acid. The result is that you are able to use methyl B12 to supply 1-carbon groups to form 5,10 methyene THF, and that gives you the substrate for making thymidine and hence DNA for making new cells. Very cool!

I've also been thinking about your bad response to folic acid supplementation. Folic acid is converted by the DHFR reaction into THF. This is not much of a help, because if the SHMT reaction is blocked, this will not form 5,10 methylene THF, and hence will not form methylfolate for the methionine synthase reaction in the methylation cycle. In fact, if THF goes high, it may encourage formation of methenyl THF, and that in turn can be converted into folinic acid, which will further suppress the SHMT reaction.

I think all of this fits together pretty well. However, it doesn't explain your inability to make use of hydroxo B12 or your problems with glutathione and its precursors. To explain those features, I think I still have to invoke a mutation in the B12 intracellular processing enzymes, such as CblC. That would mean that there are two mutations, one in the B12 metabolism and one in the folate metabolism. This seems like a rare combination. I haven't found a MTHFS deficiency reported in the literature. It does seem that that is the situation though.

Best regards,

Rich

 

[Freddd]

Hi Rich,

Very very interesting.

After I wrote the post above, I began to wonder how your cells are able to make new DNA, because the thymidine needed must be made using 5,10 methylene THF, and with your SHMT enzyme shut down by high folinic acid, the 5,10 methylene THF would be low.

But then it hit me. You take a high dosage of methyl B12. This supplies a lot of methyl (1-carbon) groups. By taking high dosages of both methylfolate and methyl B12, you overdrive your methyation cycle. This causes the glycine N-methyl transferase reaction to kick in in order to drain off the excess methyl groups by converting glycine to sarcosine. The sarcosine is then used to convert THF to 5,10 methylene THF in lieu of the SHMT reaction, which is shut down by the high folinic acid. The result is that you are able to use methyl B12 to supply 1-carbon groups to form 5,10 methyene THF, and that gives you the substrate for making thymidine and hence DNA for making new cells. Very cool!

Making cells because of DNA transactions is a KEY indicator for me that I am not in folate deficiency. It stops at the drop of a hat and can start up again just as quickly. It's very binary, on-off, not graded. So with the glutathione induced folate deficiency the cell reproductiion shut down within hours, cheilitis burn in 8 hours and IBS two days after, and lots of symptoms that occur only after a sustained slower severe deficiency came on within days. The folinic acid form took a couple of weeks to get to the cell reproduction shutdown and then IBS followed the cheilitis by 2 days, just as it does with folic acid or glutathione. It just took longer for the folinic acid to build up to the initial shutdown point. Then it lasted longer after I discontinued it. If one looks at the diagram of these b12-folate reactions, if it is drawn assuming hydroxycbl or cyanocbl there is a different cycle than if it is drawn assuming mb12 in the first place. There are a lot of alternative pathways in many of these things to get around missing items. Often the favored one is the least expensive in terms of energy or rare resources or preferred for some other reason.

I think all of this fits together pretty well. However, it doesn't explain your inability to make use of hydroxo B12 or your problems with glutathione and its precursors. To explain those features, I think I still have to invoke a mutation in the B12 intracellular processing enzymes, such as CblC. That would mean that there are two mutations, one in the B12 metabolism and one in the folate metabolism. These seems like a rare combination. I haven't found a MTHFS deficiency reported in the literature. It does seem that that is the situation though.

I think you are missing on the glutathione. There was only one common factor tying all 10 who tried it together and all had a similar response, they were all successful on the active b12/Metafolin protocol. If they had not had success, they would be more likely to still have the deficiency symptoms glutathione causes in the first place and hence no change, no detrimental response. The side effects of cerefolin with NAC reflect the "NAC DETOX reaction" which are also folate deficiency symptoms which are reversed by Metafolin but they didn't recognize it since how could it be that when taking cerefolin. Metanx and Deplin don't have those side effects since they don't have NAC. These glutathione and NAC "detox" reactions are way too common to be some rare mutation.

For the inability to utilize cyanocbl or hydroxcbl, they don't supply the methyl groups needed for the alternate pathway with the paradoxical folate deficiency. CblC is much more complete than my results which did not result in MCV> 100. It is rare to discover CblC in adults since the kids usually die if not treated as children. Hydroxcbl works for some and the rest die even if treated. I never had "failure to thrive" or anything like that. My body's failure with cyanocbl was partial.

Of the group of other diseases that have low CSF cobalamin, MS is the one with the pattern of frequent remission and then worsening as those with paradoxical folate deficiency. It also is the one that has elevated CSF Hcy and normal CSF MMA

I do agree that there are some genetic factors present. There is the folate problem. There is some problem with dealing with inactive cobalamins but not the same problems as the Cbl X diseases. And finally I appear to have the same low CSF cobalamin as others with CFS/FMS. Each of my 3 children inherited various degrees of these 3 problems.

 

[richvank]

Hi Rich,

Very very interesting.

***Hi, Freddd.

***Thanks for the response.

After I wrote the post above, I began to wonder how your cells are able to make new DNA, because the thymidine needed must be made using 5,10 methylene THF, and with your SHMT enzyme shut down by high folinic acid, the 5,10 methylene THF would be low.

But then it hit me. You take a high dosage of methyl B12. This supplies a lot of methyl (1-carbon) groups. By taking high dosages of both methylfolate and methyl B12, you overdrive your methyation cycle. This causes the glycine N-methyl transferase reaction to kick in in order to drain off the excess methyl groups by converting glycine to sarcosine. The sarcosine is then used to convert THF to 5,10 methylene THF in lieu of the SHMT reaction, which is shut down by the high folinic acid. The result is that you are able to use methyl B12 to supply 1-carbon groups to form 5,10 methyene THF, and that gives you the substrate for making thymidine and hence DNA for making new cells. Very cool!

Making cells because of DNA transactions is a KEY indicator for me that I am not in folate deficiency. It stops at the drop of a hat and can start up again just as quickly. It's very binary, on-off, not graded.

***It sound like a very good indicator of intracellular folate availability in your case.

So with the glutathione induced folate deficiency the cell reproductiion shut down within hours, cheilitis burn in 8 hours and IBS two days after, and lots of symptoms that occur only after a sustained slower severe deficiency came on within days.

***I suggest that what happened here was that glutathione reacted with the methyl B12 to produce glutathionylcobalamin. It is reported in the literature that glutathione will react with other forms of B12, and that it is a rapid reaction. Normally, the B12 processing enzymes in the cells can utilize this to reform methylcobalamin. However, in your case, they do not seem to be able to do so, and I think there is a genomic cause for this. The details of this part of the B12 processing pathway have not yet been completely worked out by the researchers, so I can't identify a particular enzyme as being responsible, but I suspect that this pathway will be sorted out pretty soon. Anyway, this would shut down the availability of methyl B12 in your case, and since I'm suggesting that that is the source of the one-carbon groups to form 5,10-methylene THF, hence thymidine, and hence DNA in your case, it follows that your body's inability to make new cells would result from the shutdown in availability of methyl B12, and I think it is understandable that it could be sudden.

The folinic acid form took a couple of weeks to get to the cell reproduction shutdown

***O.K. It may have taken some time for the folinic acid to build up in the cells enough to inhibit the SHMT enzyme significantly.

and then IBS followed the cheilitis by 2 days, just as it does with folic acid or glutathione.

***O.K., that probably reflects the lifetime of the enterocytes. The old ones will serve a couple of days before being sloughed off. If there aren't enough new ones to replace them, the gut will start to have problems.

It just took longer for the folinic acid to build up to the initial shutdown point.

***O.K.

Then it lasted longer after I discontinued it.

***I think that would be consistent with not having high enough activity of the MTHFS enzyme, because it's the only one that can catalyze reactions with folinic acid. You may have a version that is present but very slow, so that eventually it does lower the folinic acid, but it takes time to do that.

If one looks at the diagram of these b12-folate reactions, if it is drawn assuming hydroxycbl or cyanocbl there is a different cycle than if it is drawn assuming mb12 in the first place.

***Normally, if just obtained orally, all the forms of cobalamin pass through the same sequence in the cells. The beta ligand is removed first, and then methyl B12 and adenosyl B12 are formed in the amounts needed by the cells. If larger dosages of methyl B12 are injected or taken sublingually, apparently it is able to diffuse into the cells and bypass the normal processing, based on your experience. I don't think the researchers have studied this process. It's somewhat surprising to me that a water-soluble molecule this large would be able to diffuse significantly through the lipid membranes, but apparently it does. Maybe it makes use of some of the pores or channels. I think this would be a very interesting thing to study, and it could have a lot of benefit, by placing your type of treatment on a sound scientific footing, which might make it more acceptable to the biomedical community, and thus enable it to help many more people.

There are a lot of alternative pathways in many of these things to get around missing items. Often the favored one is the least expensive in terms of energy or rare resources or preferred for some other reason.

***You're right. There is redundancy in the system that can often be exploited in cases where it is necessary to do so. I think the mechanism I suggested involving use of sarcosine to transfer methyl groups from methyl B12 in the methylation cycle over to form 5,10-methylene THF in the folate metabolism is one example of that.

I think all of this fits together pretty well. However, it doesn't explain your inability to make use of hydroxo B12 or your problems with glutathione and its precursors. To explain those features, I think I still have to invoke a mutation in the B12 intracellular processing enzymes, such as CblC. That would mean that there are two mutations, one in the B12 metabolism and one in the folate metabolism. These seems like a rare combination. I haven't found a MTHFS deficiency reported in the literature. It does seem that that is the situation though.

I think you are missing on the glutathione.

***Maybe so. Maybe it isn't a CblC mutation. As I noted above, it must be a problem with whatever enzyme normally removes glutathione from cobalamin so that it can be converted to methyl B12. This seems to be the step that isn't working properly. It has been published that a glutathione transferase reaction is normally used in the intracellular processing of B12, in the step that removes the methyl group from incoming methyl B12. So there must normally be a step that goes on to remove the glutathione, but this hasn't been specifically identified yet.

There was only one common factor tying all 10 who tried it together and all had a similar response, they were all successful on the active b12/Metafolin protocol. If they had not had success, they would be more likely to still have the deficiency symptoms glutathione causes in the first place and hence no change, no detrimental response. The side effects of cerefolin with NAC reflect the "NAC DETOX reaction" which are also folate deficiency symptoms which are reversed by Metafolin but they didn't recognize it since how could it be that when taking cerefolin. Metanx and Deplin don't have those side effects since they don't have NAC. These glutathione and NAC "detox" reactions are way too common to be some rare mutation.

***This is puzzling to me. As I understand what you are saying, these ten people had been on methylfolate and methyl B12 and had improved, and then they switched to CerefolinNAC and they went downhill with symptoms indicative of folate deficiency. Is that right? If so, then yes, it looks as though the added NAC is what caused these problems. Do you know what dosage of CerefolinNAC they used? Each caplet contains 600 mg of NAC.

***Here's the absract of a Russian paper that I just found on PubMed (note that vitamin B12b is hydroxocobalamin):

Tsitologiia. 2007;49(1):70-8.
[Prooxidant and cytotoxic action of N-acetylcysteine and glutathione combined with vitamin Bl2b].
[Article in Russian]
Solov'eva ME, Solov'ev VV, Faskhutdinova AA, Kudriavtsev AA, Akatov VS.
Abstract

We studied the prooxidant and cytotoxic action of thiols N-acetylcystein (NAC) and glutathione (GSH) combined with vitamin Bl2b. The synergism of action of the thiols and Bl2b resulted in human carcinoma cell damage was found. It was shown that GSH and NAC in physiological doses combined with Bl2b caused the initiation of apoptosis. It was established that prooxidant action of the thiols combined with vitamin Bl2b, i. e. generation and accumulation of hydrogen peroxide in culture medium, led to intracellular oxidative stress and injury of cell redox system. These effects were completely abolished by nonthiol antioxidants catalase and pyruvate. The chelators of iron phenanthroline and deferoxamine did not suppress the H2O2 accumulation in culture medium but significantly inhibited the cell death induced by the thiols combined with Bl2b. Therefore, the thiols GSH and NAC widely used as antioxidants, in combination with vitamin Bl2b show prooxidant characteristics and induce, with the participation of intracellular iron, apoptotic HEp-2 cell death.

PMID:
17432610
[PubMed - indexed for MEDLINE]

***Maybe this is the mechanism that caused the effects you have reported. The puzzling thing is that CerefolinNAC is used to treat preAlzheimer's patients, apparently beneficially, and it has also been rated fairly highly by PWCs on the CureTogether.com site, so it apparently is helpful to quite a few people. Perhaps it depends on the redox status of the people. If they are in severe oxidative stress, perhaps it causes problems, while if other antioxidants are present, as discussed in the Russian abstract, it does not cause problems, and is even helpful.

For the inability to utilize cyanocbl or hydroxcbl, they don't supply the methyl groups needed for the alternate pathway with the paradoxical folate deficiency.

***Oh, right! Thanks! I missed that! Yes, that now makes sense to me, too. As I've suggested, you are using methyl B12 to supply the 1-carbon groups that are needed in the folate metabolism to make DNA. The other forms of B12 would not supply these methyl groups. So that's another thing that would be consistent with MTHFS enzyme deficiency.

CblC is much more complete than my results which did not result in MCV> 100. It is rare to discover CblC in adults since the kids usually die if not treated as children. Hydroxcbl works for some and the rest die even if treated. I never had "failure to thrive" or anything like that. My body's failure with cyanocbl was partial.

***As I understand it from the recent literature, there are a large number of possible SNPs that can produce the CblC problem, and there is a range in severity, depending on which SNP is involved.

Of the group of other diseases that have low CSF cobalamin, MS is the one with the pattern of frequent remission and then worsening as those with paradoxical folate deficiency. It also is the one that has elevated CSF Hcy and normal CSF MMA

I do agree that there are some genetic factors present. There is the folate problem. There is some problem with dealing with inactive cobalamins but not the same problems as the Cbl X diseases. And finally I appear to have the same low CSF cobalamin as others with CFS/FMS. Each of my 3 children inherited various degrees of these 3 problems.

***I still haven't figured out the low CSF cobalamin problem. There must be a genomic variaton in a cobalamin transporter in the blood-brain barrier. I haven't studied that yet.

***It would be surprising to me if there were three separate unusual genomic variations in the same person that caused these three separate problems. This seems very unlikely (Ockham's razor). It would seem that they must be connected somehow, such as by having the genes for them all next to each other on the same chromosome, and one factor that causes all three of these variations, or maybe having the same promoter for the expression of their genes, or something like that. The fact that your 3 children have related issues does seem to confirm that there is a genomic basis for this. What about your parents? You may have mentioned this already, but do (or did) they seem to have B12 or folate related health issues?

Best regards,

Rich

 

[drex13]

Hi Rich and Freddd,
Just wondering, what is CblC ?

 

[richvank]

Hi Rich and Freddd,
Just wondering, what is CblC ?

Hi, drex.

CblC is a protein that is found in all cells. It is part of the pathway for tailoring and chaperoning forms of vitamin B12 within the cells. It normally participates in removing the beta ligand from the incoming form of B12 (aquo-, hydroxo- methyl- or adenosyl-) so that the appropriate amounts of methyl- and adenosyl-B12 for the cell's needs can then be formed.
The most common genetic variations in the intracellular B12 processing pathway are found in this protein. If they are very severe ones, the person's cells are not able to make either of these coenzyme forms of B12. The milder ones just inhibit the production of these coenzyme forms.

Best regards,

Rich

 

[Freddd]

***I still haven't figured out the low CSF cobalamin problem. There must be a genomic variaton in a cobalamin transporter in the blood-brain barrier. I haven't studied that yet.

***It would be surprising to me if there were three separate unusual genomic variations in the same person that caused these three separate problems. This seems very unlikely (Ockham's razor). It would seem that they must be connected somehow, such as by having the genes for them all next to each other on the same chromosome, and one factor that causes all three of these variations, or maybe having the same promoter for the expression of their genes, or something like that. The fact that your 3 children have related issues does seem to confirm that there is a genomic basis for this. What about your parents? You may have mentioned this already, but do (or did) they seem to have B12 or folate related health issues?

Best regards,

Rich

There was only one common factor tying all 10 who tried it together and all had a similar response, they were all successful on the active b12/Metafolin protocol. If they had not had success, they would be more likely to still have the deficiency symptoms glutathione causes in the first place and hence no change, no detrimental response. The side effects of cerefolin with NAC reflect the "NAC DETOX reaction" which are also folate deficiency symptoms which are reversed by Metafolin but they didn't recognize it since how could it be that when taking cerefolin. Metanx and Deplin don't have those side effects since they don't have NAC. These glutathione and NAC "detox" reactions are way too common to be some rare mutation.

***This is puzzling to me. As I understand what you are saying, these ten people had been on methylfolate and methyl B12 and had improved, and then they switched to CerefolinNAC and they went downhill with symptoms indicative of folate deficiency. Is that right? If so, then yes, it looks as though the added NAC is what caused these problems. Do you know what dosage of CerefolinNAC they used? Each caplet contains 600 mg of NAC.

My mistake, there should have been a paragraph separating the Cerefolin remarks from the 10 persons trying GLUTATHION, glutathione precursors (mostly NAC+l-glutamine) or un-denatured whey. These 10 people all were sucessful on mb12 + Metafolin and folic acid. Most also had some success with hycbl and folic acid. The only common factors were mb12 and usually folic acid and Metafolin. One was a vegan. Hydroxycbl at several mgs injected daily had gotten him up out of a wheelchair but hit a wall then. Mb12 injected at 30mg a day in 2 doses allowed him to get rid of orthosis' and a Zimmer (walker in American English) and be able to get back to work as an EMT. He was also having episodes of fecal incontinence as was I when I began to fall a lot because I had no idea where my feet and lower legs were and was headed for a wheel chair. Most had these deficiencies for unknown reasons. About half had been diagnosed with CFS/FMS and all had similar symptoms plus additional ones. All had substantial improvement. The glutathione rapidly caused folate deficiency symptoms followed by increasing b12 deficiency symptoms including mood and personality changes, and substantial setbacks with revival of many previous symptoms.

Cerefolin-NAC is mentioned as the side effects listed match "NAC Detox", "Glutathione detox" and acute folate dficiency in general. It indicates that a substantial number of people have these responses to NAC and glutathione. Metanx and Deplin don't have any of these side effects. Deplin insert states "Metafolin is well tolerated and has no side effects different from placebo". For some reason Cerefolin and Cerefolin-NAC have a combined side effects list, possibly to dilute the incidence of side effects by 50%. Thats why I had to compare to Deplin and Metanx. These glutathione and NAC "detox" reactions are way too common to be some rare mutation.

So, since the only real difference between people who have an induced NAC/Glutathione folagte deficiency and those who don't is that the people that do have that response have gotten rid of the folate deficiency symptoms in the first place, or never had them, and therefore have a basis of comparison.


***It would be surprising to me if there were three separate unusual genomic variations in the same person that caused these three separate problems. This seems very unlikely (Ockham's razor). It would seem that they must be connected somehow, such as by having the genes for them all next to each other on the same chromosome, and one factor that causes all three of these variations, or maybe having the same promoter for the expression of their genes, or something like that. The fact that your 3 children have related issues does seem to confirm that there is a genomic basis for this. What about your parents? You may have mentioned this already, but do (or did) they seem to have B12 or folate related health issues?

My three children have different degrees of the problems. My recently deceased daughter was the most afflicted, my other daughter the least and my son in the middle. My biological mother and her father are the only ones I know about. She had and survived colon cancer but is alive and well at 86. Her father had to be injected with b12 starting as soon as it was available and had MS. He died at 89. I know a little of her 3 or 4 daughters and from the health problems described one probably had high Hcy at the very least and almost died of a heart attack in her 40s. The only reason she survived was that she was in the doctors office at the time. She wasn't forthcoming about the others. Both of my daughters have her and her daughters physique and look like me and don't match my wife and her mother at all.

One thing I found in general questioning is that in parents of autistic children, the parents with CFS/FMS are very over-represented. That affects both gestation in the mother and genetics. Those with autism also have low CSF cobalamin levels compared to body level. My most severely affected daughter had very delayed speech as I did, did stimming and other such autistic related behaviors, it came on with a cold and she stopped talking for several years, the day after she spoke her first sentence. Fortunately development normalized by age 6, as it did with me. My exwife has some folate problems not further diagnosed. They all had night terrors and other sleep disorders, they all had lot's of streps, lots of toncillitis, depression, abnormal fatigue, "growing pains" and so on.

Next time I talk to my bio-mother I'll ask about some of the specific folate deficiency symptoms.


Another possible clue to incidence is that research on Metafolin idicates that some people had unexpected and unexpectedly large neurological effects when given Metafolin.

 

[Freddd]

Hi Rich and Freddd,
Just wondering, what is CblC ?

Cobalamin C disease (CblC, Cbl C) is one of a series of lettered diseases caused by lacking enzymes etc. Cobalamin D disease is concerned with adenosylb12 and mb12.

"...5 previously described groups (mut, cbl A, cbl B, cbl C and cbl D). The designation cbl E is used for the disorder ..."
http://books.google.com/books?id=7afvNWFhpZAC&pg=PA2743&lpg=PA2743&dq=Cbl+D+disease&source=bl&ots=swmHMdIqQ4&sig=DpHEUaAiwwEszlPwxqQMU5XEKUQ&hl=en&ei=iTQyTuOPFpPXiALVpp3ECA&sa=X&oi=book_result&ct=result&resnum=7&ved=0CDsQ6AEwBg#v=onepage&q=Cbl%20D%20disease&f=false

 

[richvank]

Hi, Freddd.

I've been thinking about what the effects of taking TMG would be in your case, if you do indeed have a deficiency in the MTHFS enzyme, which I think you must have, based on what you have reported.

As is obvious from its name (trimethylglycine), TMG contains three methyl groups.

TMG is a reactant for the BHMT (betaine homocysteine methyltransferase) reaction that occurs in the liver and the kidneys. This is an alternative to the methionine synthase reaction for converting homocysteine to methionine, and it therefore also contributes to the production of SAMe. In the BHMT reaction, when homocysteine is converted to methionine, TMG is converted to DMG. That is, it loses one methyl group. The DMG can then give methyl groups to THF (tetrahydrofolate), producing 5,10-methylene tetrahydrofolate. It does this by means of the DMG dehydrogenase reaction,which then forms sarcosine, and the sarcosine can likewise then contribute another methyl group by means of the sarcosine dehydrogenase reaction. This is the same reaction that I suggest you are using when you overdrive your methylation cycle by taking high dosages of both methyl B12 and methylfolate. Finally, this reaction converts sarcosine to glycine, and then glycine can also contribute the last methyl group to THF as well.

The result of all this would seem to be that you would get a lot of benefit from TMG, again assuming that you have an MTHFS enzyme deficiency. I think you have mentioned that you do take TMG, and that you have experienced some benefit from it. It's not totally clear to me how it would complement the methyl B12 and methylfolate supplementation, since that is also supporting SAMe and sarcosine production in your case. I guess it would further increase the rate of production of SAMe in the liver and kidneys, and since that is already overdriven, it would call upon the glycine N-methyl transferase reaction to speed up the shunting of methyl groups from SAMe to glycine, producing sarcosine. I would think that at some point the capacity of this reaction would be exceeded, and then the ratio of SAMe to SAH would rise higher than its normally regulated range, speeding up the various methyltransferase reactions in the body. I'm not sure what the effects of that would be.

As I mentioned before, I think it would be really interesting to see what your results would be on the methylation pathways panel. Since I'm raising that again, I'll add that I think that combining it with the 40-plasma amino acids panel from Metametrix would give an even better picture of what's going on.

I really think that your case is unique, Freddd. As I mentioned before, I haven't found a case of MTHFS enzyme deficiency reported in the literature, and I think the evidence is pointing to that in your case. And the treatment that you have found on your own, namely high-dose methyl B12 and methylfolate, is also something that is unique. I don't think the B12 research or clinical communities are aware that one can raise the methyl B12 action in the cells by diffusion, without help from the transcobalamin receptors, which you appear to be doing. I think this could help a lot of people. I would really like to see your B12, folate, and glutathione metabolism characterized by lab testing.

Best regards,

Rich

 

[npeden]

My strength totally returned when i got off folinic and hydroxy; felt totally fragile before.. and i have sod2 snp which means i cannot tolerate folate. but 14 drops, 3 mgs., of manganese, yasko, and i can eat it fine. the rest of this is over my head but i would simply suggest looking to see if you have sod2 snp and if i missed something more complex, please forgive me. good, deep consult. wishing you the best, Rich.