Hi, lampkld2.
As you requested, I studied your recent 24-hour urine amino acids test results. I interpreted the results in the light of the earlier urine organic acids test results, dated October 11, 2010. Although this test was run over a year before the amino acids test, I believe it is valid to consider them together, because it appears from your report that you are suffering from a lifelong condition. I have also taken into account information you have supplied to me earlier about your case, as well as what you have posted on the Phoenix Rising forums.
The bottom line is that I strongly suspect that you inherited a genetic mutation in one of the enzymes involved in vitamin B6 metabolism. Im not sure which one yet.
I will give you the reasons why I suspect this below, but I think it will be important to do some additional, more specific testing to determine whether this is in fact the case. I will suggest some tests.
The reasons I believe that there is a problem in your B6 metabolism are as follows:
1. There are markers suggesting low P5P function: high alpha-aminoadipic acid;
high alpha-amino-N-butyric acid; low-normal to low cystathionine; alpha-hydroxybutyrate below the detection limit; scattered levels of other amino acids, suggesting low activity of the transaminases, which require P5P and are needed to convert one amino acid into another as well as to feed them into the Krebs cycle to be burned as fuel.
2. You reported The B6 gave me neuropathy, even in doses of no more than 200, so
I stopped. My serum B6 level remained elevated for a long time after that. I
think this suggests that vitamin B6 is not being properly used in your metabolism.
3. Your health history, symptoms and your other known biochemical abnormalities seem to involve organs or systems in which B6 is normally needed. These include the immune system (note your low white cell count, which suggests a problem with DNA synthesis, which requires B6 support of the SHMT enzyme), gluconeogenesis (note that your pyruvate was below the detection limit, which suggests a problem with maintenance of glucose), heme synthesis (note that you reported pyrroluria), the nervous system (both neurotransmitters and probably myelin are implicated, both of which require B6 for their synthesis. Motor neuropathy is especially significant.), muscles (you reported muscle atrophy, and the muscles depend a lot on B6), fatty acids metabolism (it needs B6 a lot), and zinc-related issues (zinc is needed for at least two of the enzymes involved in B6 metabolism).
The way B6 metabolism is supposed to work is as follows: There are three forms of vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine), and each can have a phosphate group attached. These various forms of B6 come in with the food or supplements. The ones that have phosphate groups attached have them removed by a phosphatase enzyme in the gut, before they are absorbed.
After being absorbed, they are transported to the liver via the portal vein. In the liver, a majority of the ingested B6 is converted to 4-pyridoxic acid by the enzyme aldehyde oxidase (which requires molybdenum). Some of the rest is converted to P5P by the addition of a phosphate group by reactions catalyzed by pyridoxal kinase, and by conversion of the two other forms of B6 to pyridoxal by reactions catalyzed by pyridoxine phosphate oxidase (an enzyme that requires FMN, which is made from riboflavin, vitamin B2), and put out into the circulating blood, bound to albumin. Pyridoxal kinase is the enzyme that adds the phosphate group, which comes from ATP that preferentially has a zinc ion bound to it (Note that this is unusual, because magnesium is usually bound to ATP). Being bound to albumin protects the P5P in the blood.
There are other forms of B6 normally found in the blood as well. P5P constitutes about 57%, pyridoxal represents about 23%, and there is also some pyridoxine, pyridoxamine phosphate and pyridoxamine.
Pyridoxal and pyridoxine readily diffuse into cells. P5P must first have its phosphate group removed to reform pyridoxal, and this is done by a phosphatase attached to the external surface of the cell membrane. It is believed to be alkaline phosphatase, which is also a zinc-dependent enzyme. Inside, pyridoxal kinase again adds a phosphate group to pyridoxal to form P5P again. This prevents the P5P from leaving the cell, and it is then bound to enzymes for which it serves as a coenzyme.
The mechanism of neuropathy caused by excessive B6 is not understood.
In your case, perhaps the level of P5P is not being properly limited because not enough B6 is being converted to 4-pyridoxic acid. Or, perhaps not enough of the B6 is being converted to P5P, but is entering the blood without a phosphate group, and too much of it is able to diffuse into cells, producing neuropathy. Or perhaps the P5P is not able to enter cells at a normal rate because the phosphate group is not being removed at a high enough rate. Perhaps B6 is not able to stay inside the cells properly, because the phosphate group is not being put back on at a high enough rate. Which of these is going on will depend on which enzyme has a mutation.
In order to shed some more light on what is going on in your B6 metabolism, I think it would be helpful to run some more tests. The Health Diagnostics and Research Institute offers two tests that I think would be helpful. They are the plasma B6 (P5P) test and the EGOT enzyme activity test (EGOT stands for Erythrocyte Glutamate Oxaloacetic Transaminase Test). If these are run at the same time, it should be possible to determine both whether the level of P5P in the plasma is normal, and also whether it is getting into the cells and assisting with a transamination reaction at a normal rate.
These tests require an order from a physician or a chiropractor. The best way to order the panel is by fax, on a clinicians letterhead. Here is the contact info:
Health Diagnostics and Research Institute
540 Bordentown Avenue, Suite 2300
South Amboy, NJ 08879
USA
Phone: (732) 721-1234
Fax: (732) 525-3288
Lab Director: Elizabeth Valentine, M.D.
Dr. Tapan Audhya, Ph.D., is willing to help clinicians with interpretation of tests by phone.
If it turns out that not enough P5P is getting into the cells, it might be possible to put more in using a liposomal form of P5P.
One more thing: Using 23andme.com, it might be possible to look for polymorphisms in the enzymes involved in B6 metabolism, though this might be difficult in view of the likelihood that the polymorphisms have not yet been well studied for these enzymes.
Best regards,
Rich
Interestingly, my serum Ammonia was normal..
