Sunday, July 8, 2012

Interesting Lab Results - Learning more about GAMT

This is a conversation that took place on our facebook support group.

And the Results are in...

Gave John his last supplements around 6pm.
Went to Duke and had 1st Blood Draw at 9am (15 hrs later) - no supplements that morning, no food.
Feed John a 4 oz yogurt with 3 grams protein along with his milk & all medicines apx. 9:45am
Repeated Blood Draw 4 hours later

1st Blood Draw....
7.1 GAA
40 Ornithine
124 Creatine
40 Arginine
201 Glycine

2nd Blood Draw... (4 hours after 1st)
5.2 GAA
241 Ornithine
352 Creatine
50 Arginine
195 Glycine

A few comments. I was surprised at how much the GAA level moved. I was not expecting this. I had thought up until now that the GAA level moved more gradually over time.

Another surprise... I would have thought the Arginine level would have increased more than it did. I gave him a 3 gram protein yogurt and it didn't make that much of a difference in the arginine level. I had wanted to feed him one of the highest foods with protein in it to see what would happen. My guess is that it didn't increase much because of the ornithine counterbalancing it, but makes me wonder, what if it would have been a bigger thing of yogurt with 5 grams of protein? Would the GAA level and arginine level have been the same? I gave John a 3 gram yogurt, yet his GAA still went down and the arginine only went up slightly. Makes me wonder, can John be eating more protein than I'm giving him?

Also, makes me realize that I should try to give him his nighttime dose of medicine as close to bedtime as possible to keep everything from dropping off overnight and therefore preventing the GAA level from going up.

Let me know your thoughts. Dr. Clark - What do you think about these results?

Joseph Clark Missy, thanks for this. I’m going to need to assume the GAA concentration is in micromolar and normal should be about 1.2. Is this what your lab is saying? GAA is found in very few foods and none of the foods I saw listed. So the body (Kidney and Liver mostly) is making GAA and ornithine via AGAT most all of the time and a lot of that is done at night. When you gave John the creatine and ornithine at 9:45 AM, the signal to make GAA was inhibited by the ornithine and creatine. Yes, that is kind of a quick fall, but also the body prioritizes what it spends time doing. When we eat the body gets flooded with stuff to do as far as managing toxins in the food, hanging on to good things in the food etc. Hence, a large percentage change in GAA for a short period of time could occur. I’m not sure of the sensitivity in the kidney for excreting GAA. One paper I found said it was about 5 micromolar. Which means that once the kidney stopped making it the kidneys were excreting it. So I think the GAA fell so much because of the excretion into the urine and the decreased synthesis. Were urine levels done?

Arginine and glycine are amino acids used in many other processes and in many foods. I have to admit I am not convinced that very strict protein restriction is necessary in GAMT patients especially in growing children. I know it is hard for parents to know what to do because the experts do not agree. We don’t agree because we really do not know. So I for one very much agree with you suggestion that John could be eating more protein. What the right level is or the best proteins, we still do not know. Ornithine would not be a reason for the arginine not increasing as much. Ornithine decreases the amount of arginine consumed by AGAT.

I very much agree that giving night time meds/supplements as close to bedtime for the reasons you suggested. The body’s chemistry goes into overdrive at night, so this strategy might very well help control things.

My general impression of the results is they have a lot of good news. I think it is great that the GAA does change and that John’s body is responding in a positive and controlled way. Positive that GAA goes down, controlled that arginine and glycine do not change much. I also think that it indicates that at this time John’s body is ready to handle the proteins and amino acids in his diet. I say “at this time,” because as we get older and as John stops growing the ability to handle the arginine and glycine may change.

What none of us really knows is what the right level of GAA is; referencing the 5.2. Labs report different numbers as normal and use different units. We think we know what average is in people with normal GAMT and AGAT activity. But we do not know what GAA should be in GAMT patients. We know that GAA can inhibit creatine kinase in the brain and eventually lead to seizures and other bad things in the brain. So it is something we must pay attention to, but with relatively little hard data to go on.

Best wishes.

Post from another GAMT mother: This makes me feel like spreading creatine and ornithine into more than three doses would be helpful. Maybe first thing in the morning, lunch, afternoon, and evening? At one point my nutritionist said that food and supplements should be in proportion, meaning give half of her day's supplements if there's a meal where she eats half of her day's allotment of protein. Dr. Clark- are you feeling like that is completely inaccurate and that the body is making GAA anytime, food intake or not, based on John's results? I had heard "the supplements work with her food" as if a dose late in the evening on a near empty stomach would be a waste? What do you think?

Joseph Clark  I think there are a couple of things to consider. 1) most of these supplements do work on an empty stomach. BUT and importantly 2) they are somewhat like salts. So if taken on an empty stomach they can, in some people, cause an upset stomach. I’ve done this to myself with creatine (with and without food) and taken with food feels better. With regard to in proportion for creatine and ornithine; that is not necessary. The most important thing is to make sure Sam gets what she is prescribed each day. I do believe that the body is making GAA nearly all the time (outside of starvation or disease). It will increase and decrease though based on modulators such as ornithine and creatine. I do not think a dose on an empty stomach would be a waste metabolically. But do make sure she does not get an upset stomach.
To explain my concern regarding the upset stomach. Creatine in the stomach acts a lot like a salt. If you eat a bunch of salt it can cause water to enter the stomach and make a person feel nauseas and even vomit. We want to avoid that with Sam and the other GAMT kids because it would make giving them the creatine and treatments harder.
Regarding your nutritionists, he/she is correct with regard to pure “dietary supplements” as a dietary supplement is often something that helps the body absorb or metabolize something else. But for Sam and children with GAMT creatine and ornithine are much more than dietary supplements and more like drugs that the body needs to have a fairly constant supply of as part of the treatment. Creatine is supplying the body with creatine for energy metabolism AND inhibiting AGAT. Ornithine is inhibiting AGAT so less GAA is made.

Finally, when we get back to the protein restriction. That is theoretically done to decrease Arginine and glycine, which are the molecules used by AGAT to make GAA and ornithing. My personal opinion is that it would be very hard to restrict arginine and glycine to low enough levels where AGAT would be unable to use them to work. Remember the body needs them for other things. When I did the rough math calculation, excuse the science and math here, I estimated that the arginine would need to be 2 (John’s was 40 after fasting) and glycine 3 (John’s was 201 after fasting). Again, no hard scientific evidence but I am still not convinced that protein restriction is absolutely necessary because it is impracticable to get low enough to be effective. However, don’t change what your physician recommends without consulting him/her.

Missy- thank you so much for sharing. I think this is a step in the right direction- and knowing how the levels adjust in such a relativley short amount of time. wow! I wonder what would happen if we gave the largest dose of creatine/ornithine in the evening? I'm intersted to see how the sodium benzoyte might change these #'s too?

Dr. Clark, Thank you so much for your input. Your contribution is so appreciated!

§        Dr. Clark's response - Sodium benzoate works by pulling ammonia out of the body. Ammonia is converted to urea for excretion in the urine by going through the urea cycle. The urea cycle starts when ammonia is converted to carbamyl phosphate. Carbamyl phosphate commits the body to making urea. The VERY next reaction consumes ornithine. So when sodium benzoate is given to the GAMT patients the thinking is it is sparing the loss of ornithine by the urea cycle. If ornithine is not consumed by the urea cycle maybe it can stay around to inhibit AGAT. That is the theory. Sodium Benzoate has a long history for treating patients with urea cycle deficits and is generally considered to be safe. It is actually found in some foods as a preservative. Based on its safety and the importance of sparing ornithine I do think the sodium benzoate is a good option for GAMT patients. I think some physicians may be hesitant to use it in GAMT patients because usually sodium benzoate is indicated to decrease ammonia, and may feel uncomfortable prescribing it when someone has normal ammonia. Hopefully if there is a concern it can be addressed. One caveat for anyone talking to their physician about management of GAMT. I am not comfortable with a treatment that would have strict protein restriction and sodium benzoate simultaneously. The reason is this will change the body’s nitrogen metabolism in ways we do not understand. In a growing child their body needs ammonia and nitrogen to grow. So combining very low protein and sodium benzoate should be avoided. I’m sorry this is getting so complicated, but I think it is important. We want the children with GAMT to continue to grow and develop normally and changing protein and ammonia metabolism too much will impact on normal development.