Okay, you have to explain to me why that would be beneficial to take phos ethanolamine as opposed to phos chol. The transporter will not pick up phosphatidylcholine to take it into the mitochondria so I'm not following you. Are you suggesting a way to bypass the transporter to get phos chol into the mitochondria? (side note: the transporter in question is in regard to SLC44A1. The paper on it came out last summer, entitled, "The solute carrier 44A1 is a mitochondrial protein and mediates choline transport" by Bakovic and Michel) Where does phos ethanolamine turn into phos chol?
The SAM-e sky high can be quite dangerous. It easily results in liver damage which Dr Mudd has seen in another patient with a totally different anamolie that caused high SAM-e. And with me at the levels it was at (we're talking the difference between 35 versus 1900) my liver enzymes were bad. Whether that was because of the SAM-e too high or a virus we'll never be sure, but because they had documented liver damage with the other patient with sky high SAM-e, it's a safe assumption to presume at least some of the liver enzymes going out of whack was in regard to the SAM-e. Dr Mudd and Dr Finkelstein together decided the SAM-e level was too dangerous.
And side note, it took a ridiculous amount of SAM-e to start to elevate the SAH. It was as if the SAM-e would keep escalating and stop right there. Little of it would be passed further on down the cycle. It just kept building up.
Hi, Gen.
You have probably the world's most knowlegeable people about this part of the biochemistry working on your case. I, on the other hand, am an amateur. So you probably shouldn't pay too much attention to my comments!
-)
You have got me interested, though, so I have today done some homework, reading papers mostly authored by the people you are working with or have mentioned.
As I understand what you have reported, you have two known polymorphisms (or mutations) in this part of the biochemistry: one in the choline transporter SLC44A1, and one in the mitochondrial enzyme choline dehydrogenase (CHDH). Both interfere with the activity of these proteins, so that the transport of choline into the mitochondria is inhibited, as is the conversion of choline to betaine. The result was that your betaine level was low, thus lowering the activity of the BHMT enzyme in your liver and kidney cells and causing the homocysteine level in your blood to rise to 45 micromoles per liter, well above the normal range.
As I understand it, because your cells were not able to transport choline well, your doctors decided to try supplementing with phosphatidylcholine, hoping that it would be transported into the mitochondria, break down to form choline, and supply that to the choline dehydrogenase enzyme. Is that right? You wrote that choline is not well absorbed, so that phosphatidylcholine is the supplement form. As far as I know, this is not generally true. Choline supplements include choline chloride, choline citrate, choline bitartrate, and phosphatidylcholine. Lecithin contains phosphatidylcholine, and has been used as a choline supplement. As far as I am aware, these forms are all readily absorbed by most people, so I'm guessing that it is your transporter polymorphism that led to the choice of phosphatidylcholine as the choline form in your case.
As I understand it, some choline is normally oxidized to form betaine by the enzyme choline dehydrogenase, located in the mitochondria, and then the betaine is exported to the cytosol of the cells, where the BHMT (betaine homocysteine methyltransferase) reaction takes place to convert homocysteine to methionine. This is not happening very much in your case, for two reasons: the choline can't get into the mitochondria very well, and it can't get converted to betaine very well, either.
If I have this right, so far, then I can understand why supplementing with choline would not be effective in your case. However, it does seem as though supplementing with betaine (TMG) would be helpful. You reported that dosages higher than 1,000 mg of TMG did decrease your homocysteine level, but this caused your SAMe level to rise to tens to hundreds of times normal, which may have been responsible for increasing your liver enzyme levels. Meanwhile your SAH level rose only slightly.
This causes me to wonder if there is a problem with your glycine N-methyl transferase (GNMT) enzyme. Normally, this enzyme prevents the ratio of SAMe to SAH from going too high, by transferring methyl groups to glycine, forming sarcosine. The sarcosine reacts to form 5, 10-methylene tetrahydrofolate in the folate metabolism. I'm also wondering why some of the other methyltransferase reactions, such as the one that makes creatine, or others of the 50 to 100 known methyltransferase reactions, didn't accept methyl groups, limiting SAMe and bringing SAH up. This is very puzzling. I'm glad you have some smart people looking at it!
-)
I now understand that the suggestion I made earlier, to supplement with phosphatidylethanolamine, will not help to raise betaine. Most of the reactions of phosphatidylethanolamine to form phosphatidylcholine, catalyzed by PEMT (phosphatidylethanolamine N-methyl transferase) occur in the endoplasmic reticulum and in a membrane associated with the mitochondria, but not inside the mitochondria themselves. So this would not deliver phos. choline to the mitochondria, let alone raise betaine. So that's a non-starter. Sorry about that.
I hope they get this figured out, as I'm sure you really do, too! I'll be interested to hear how your MRS scan came out.
Best regards.
Rich
