I have been researching the literature on AMN and XALD for some time, and have decided to write this blog, as I have read all of your comments and blogs, and I am deeply concerned about what you are all going through, and I hope that some of my ideas might help to alleviate your symptoms.
Apart from stem cell therapy, the medical profession does not seem to have progressed very far in curing these diseases, and Lorenzo's oil even today appears to be the main means of controlling the diseases. (Please refer to my Sept 12th comment in RELAY's blog "AMN Mystery disease" for my own interpretation of the reasons why Lorenzo's oil is so successful at reducing the rate of VLCFA accumulation).
As you may know, the disease is caused by a mutation in the ABCD1 gene located on the X chromosome. This gene makes a protein that transports harmful very long chain fatty acids (VLCFA) into microscopic organelles called peroxisomes, which then destroy these VLCFA. Without this gene, those with AMN and XALD cannot remove the VLCFA from their bodies, and so the VLCFA gradually accumulate in their blood and tissues, resulting in gradually progressing symptoms.
Luckily there is a similar gene called ABCD2, which is not located on the X chromosome. Therefore every male child has one ABCD1 gene and a pair of ABCD2 genes for every cell in his body, and every female child has two ABCD1 genes and a pair of ABCD2 genes in each of her cells; this is responsible for the genetic implications of the disease described elsewhere.
A male AMN patient will therefore lack any functional ABCD1 genes, while his mother will have only one of her ABCD1 genes functioning, often resulting in her also experiencing AMN symptoms later in life.
The ABCD2 gene does the same job as the ABCD1 gene, although possibly not as efficiently. Therefore in theory, ABCD2 could be recruited as an alternative gene to reduce and abolish VLCFA accumulation in the AMN patient's body.The trouble is, the doctors have found it difficult if not impossible to reliably activate this second gene. Despite the use of statins, phytosterols to reduce cholesterol assimilation, and zero cholesterol ingestion therapies, the ABCD2 gene cannot be coerced into becoming activated.
I have thoroughly investigated this area, and I have found that the ABCD2 gene is only switched on when the nuclear receptor molecule called "peroxisome proliferator activated receptor A" (PPARa) is active. What happens is that the PPARa molecule must first be "flagged" by a molecular ligand. This flagged molecule now combines with another called the "Retinoid X receptor" (RXR), to form a complex (i.e: a molecular sandwich).
This activated complex now migrates into the nucleus and activates the ABCD2 gene, which can only then begin to produce ABCD2 transporters, which will in turn carry the VLCFA into the peroxisomes. Without this series of events, the ABCD2 gene will refuse to work, and remains switched off.
Therefore in order to get the ball rolling, I had to find the right flag. As I mentioned, the doctors tried statins, and reduced cholesterol to switch on another molecule called SREBP2, which is instrumental in cholesterol metabolism and showed promise in activating PPARa. But nothing really worked.
I found that although PPARa is sensitive to fatty acids, it is not sensitive enough. But it is highly sensitive to a molecule called Phytanic acid, which is present in vegetables as phytol, which is a part of the chlorophyll molecule itself. The bond between phytol and its parent chlorophyll molecule is very strong, and normal boiling does not release phytol from the vegetables. Also, our digestive systems cannot break down chlorophyll, so most of the phytanic acid passes through our systems as waste, and the little that we do absorb passes into the peroxisomes and is broken down.
I did some experimenting, and I found that spinach will release phytol if it is strongly boiled; and this phytol will ligand to PPARa and activate the ABCD2 gene.
Unfortunately I found out the hard way, by spilling highly concentrated phytol on my hand, which promptly developed dermatitis due to the simultaneous activation of ABCD2 as well as ABCD1, resulting in rapid depletion of VLCFA from the epidermal tissues, and destruction of the permeability barrier. (Fortunately I was able to devise a means of replacing the lost molecules and reversing the process, although this took months of trial and error).
If you want to try out these ideas, take a spoonful of mustard oil a day to reduce your fatty acid elongation process. Then back this up with a serving of strongly boiled spinach per day, using the boiled vegetable water as a broth. This should contain enough phytol released as available phytanic acid, and it will do no harm as it is not highly concentrated.
Once the phytanic acid has been absorbed by your digetive system, most will pass to the liver cells' peroxisomes for disposal, but there may be enough left over to ligand to PPARa molecules in some of your liver cells, pass to the nucleus, and activate some of your ABCD2 genes. This will allow your body to gradually reduce the accumulated VLCFA by creating ABCD2 transporters, which will carry VLCFA into the peroxisomes so they can be disposed of.
Alternatively you might prefer to try one "green smoothie" a day (This is uncooked vegetables and fruit mixed with ice cream and blended strongly). Many people enjoy green smoothies anyway, and they cannot harm you. I think that the mechanical stimulation from mixing in a high powered blender can break off the phytol tails from chlorophyll molecules in the vegetables, releasing valuable phytanic acid that can be used to activate ABCD2 genes.
I can make no guarantees of success, and you may have to keep up this "diet" for some months before you see any improvements. However, my friend who has AMN has been taking mustard oil and green smoothies for over a year now. He gets his blood tested regularly and I have tracked his fatty acids on a spreadsheet. It is quite amazing how quickly his VLCFA have declined, and they show no signs of levelling off, just a continuous decline. If this is matched by a decline of VLCFA from his tissues, it could be the turning point for his disease progression. Lets hope so.
If anyone out there feels that they want to try out these ideas, or if you want more information, copies of relevant papers etc, please contact me through ALDLIFE.
Also, if you do try this and your symptoms do start to improve, please let me know, so I can make up a progress report, and maybe we can gather some evidence that will convince the doctors to try new ideas such as these, once they have been proven to work. That way everyone will eventually benefit.
All the best,
ROB.
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I loved the article and would appreciate it if you could send me more information. I am a female AMN patient with progressive AMN. I have high VLCFA's and high cholesterol. I would also like to know if you know if the VLCFA's are built up in the liver does the LDL show high and the HDL can be fine??
I found the article to be very informative. I currently take mustard seed oil but never heard about the spinach thing. Can you let me know what's in the green drinks? Is there any way to make them without ice cream (is that just to thicken it?)?
Did you find that your friend has improved or does it just help to stop progression.
Thanks Rob for the informative article. My wife has AMN and is interested in trying the green smoothie. She had two questions: What kind of vegetables do you use for the smoothie? How long do you have to blend it for?
Thanks Britt and JDM for your replies and questions.
It's great that you both want to learn more, because in the absence of a clear way through, it's up to us to learn as much as we can, so that we will know enough to self-medicate, and trust that we are doing it right.
Britt, you can't go wrong with mustard seed oil, as the oleic and erucic acids seem to fully occupy ELOVL3, and prevent it from elongating saturated VLCFA. This greatly slows down the disease progression.
Unfortunately I don't yet know a way of diverting the activities of ELOVL1, so we also need something to counterbalance ELOVL1's continuing elongation activity, by activating ABCD2 which will offset this progression and actually reduce the accumulation of VLCFA.
Using phytanic acid to achieve this ABCD2 activation does work, but it is a two-edged sword, and I highly advise caution here. (Read the part about the dermatitis in my hand, caused by exposure to highly concentrated phytol, if you want proof of phytanic acid's ability to ligand PPARa, and activate the ALDR i.e: ABCD2 gene !)
Raw and normally cooked vegetables release only 1-2% of their phytol as phytanic acid. This goes to the liver, and is easily disposed of. (However I did read that spinach may be an exception, and might release more phytol on cooking). Therefore as cooked spinach is supposed to be a healthy vegetable, there is no harm in eating spinach with most meals, and it could release enough phytanic acid to bind some PPARa molecules, allowing a trickle of ABCD2 activation in the liver and other tissues.
Bear in mind that once phytanic acid is liganded to PPARa this is a permanent or semi-permanent bond. Therefore any activated ALDR genes will not stop manufacturing ABCD2 transporters until the ligand breaks. Therefore it is extremely important that you go slowly with this step, as you do not want all your liver cells to be producing ABCD2 transporters.
Many people also drink a green smoothies per day, and this has not harmed them. So I emphasise here that one plate with spinach or one smoothie a day should be the limit until we all know better what we are dealing with. This should over a period of months gradually activate more and more ALDR genes to produce ABCD2 transporters, so we should see a drop in blood VLCFA levels, together with a gradual decline of VLCFA in tissues. We can't expect miracles in a day or a week, we have to be patient so we don't overactivate the process.
To answer your question JDM about the green smoothies:
It can be any vegetable(s), mixed with any fruits to give it a nice taste, together with milk, ice cream, juice, to make it drinkable. Spinach has soft leaves which are easily broken up in the blender, spilling out their cellular contents. If you blend on a high level for half a minute until the mixture goes homogenous green, you know that all of the cells and fibres have burst open. Once this has happened, you can be sure that some of the chlorophyll molecules have been bashed about enough to release their phytol tails.
Britt, once the mixture hits the digestive system and is absorbed, the intestinal epithelium packages up little bags called CHYLOMICRONS, which pass around the bloodstream and release free fatty acids (including phytanic acid) to the tissues. What is left behind (including cholesterol) goes to the liver. The hepatic cells then produce VLDL, containing triglycerides (actually three fatty acids attached to a gycerol backbone) and cholesterol. This mixture is transported to muscle and adipose (fatty) tissues. As they lose fats, VLDL convert to IDL, then LDL (low density lipoprotein) vesicles. LDL's are the endocytosed (swallowed) by liver, adrenal, and adipose tissue cells, releasing fats and cholesterol.
HDL are released from the liver cells as discs, and they swell up as they absorb cholesterol from the blood and tissues, and return to the liver, where hepatocytes turn the cholesterol into bile acids.
The liver cells do a lot of things Britt, and I don't think the high VLCFA alter LDL or HDL, that is a separate issue. If you want to know more about HDL and LDL, and you have a spare couple of hours:
1. Go to GOOGLE.
2. Type any of these: CHYLOMICRON, VLDL, IDL, LDL, HDL, REVERSE CHOLESTEROL TRANSPORT (RCT).
3. Go straight to the WIKIPEDIA article on that topic, and ignore the rest until you have read and understood the whole Wikipedia article.
4. Once you have the basic info in your head, you can start on the heavier stuff, so that it begins to make sense to you.
My friend with AMN says that his coordination seems to have improved, and he is stronger than he was. His VLCFA have dropped exponentially since he started the mustard oil and smoothies. Once he gets a tissue biopsy done, we can see if his tissue VLCFA have also declined. If so, this might improve the renal insufficiency and adrenal problems as well. If his neurological symptoms start showing improvement, that would mean that VLCFA are also declining in his CNS, allowing repair to begin. We must wait and see.
If you have regular blood tests, please ask your doc for copies going back over the years. I must establish a baseline, so we know what we are measuring against. I can copy my existing spreadsheets and charts for each new set of patient data, so we can see over the coming months whether these new therapeutic approaches are making any difference, and if so, is it reducing VLCFA and / or symptoms?
Please let me know if you can get these results for me.
This comment is for you Britt, as you are already taking mustard seed oil:-
I just re-checked the charts on my friend who has AMN.
He used to take Lorenzo's oil, then stopped for a couple of years. Now he is taking mustard oil.
While he was on Lorenzo's oil, his blood erucic acid levels were high, but when he stopped taking it, they dropped back to almost zero. Now he is on mustard oil, his erucic acid (22:1) levels have risen again.
In tandem to this, his nervonic acid (24:1) and his hexacosenoic (26:1) show exactly the same pattern.
All this shows that his ELOVL3 elongation system is indeed processing the erucic acid, and elongating it by two carbons to nervonic acid, then elongating it again to hexacosenoic acid.
It also shows that all these monounsaturated very long chain fatty acids are making their way into peroxisomes for disposal, but this process is slower than the rate of increase posed by daily ingestion of a spoonful of oleic and erucic acids. Once he stopped taking Lorenzo's oil, all of these acids declined back to normal, showing that their excess in the blood is only caused by the supplementation, is temporary, and is not a problem as it can be rectified.
(Don't forget, ABCD1 and ABCD2 transporters only transport SATURATES, not monounsaturates, so the loss of ABCD1 only affects disposal of saturated VLCFA).
Diverting ELOVL3's attention into elongating monounsaturates instead of saturates greatly reduces the rate of saturated VLCFA accumulation, and the increase in monounsaturates is temporary and is slowly and constantly being reversed by peroxisomes, so no problem.
Hi Rob. Thank you so much for replying. Now I'm more curious than ever. You said, "we must wait and see". How long before your friend has his muscle tissues tested? How long to wait and see if this works? I'm going to start the process anyway but I just wanted a general idea of how long before we know.
Rob I know you like to keep track of things and you're very good at it. I was thinking that maybe you could put together a plan (almost like a diet plan) that people could follow to be sure they aren't taking too little or too much of the green smoothies. Example: week 1 then tell how much of each thing to use and how many times a day. If people do this and have a way of recording their progress with you in maybe a chart or something that sends the information back to you. This way maybe you could have your own informal study.
My friend has blood drawn every three months. I am curious to find if anybody in the ALDLIFE AMNEASIER network has blood drawn regularly. If so, we could take copies of the results over the past few years. I already have a spreadsheet for my friend, on which I continually update his VLCFA and all fatty acid levels (a lot of work).
It would be easy for me to throw in new figures for other patients, as the charts are already done. Can anyone send me their results???
Also you mention biopsy. I don't know if this is ever done for AMN patients. My friend does not want his body opened up, and I don't blame him! But if the doctors can check VLCFA levels in innocuous parts of the body (like cheek cells), maybe that would not be a bad idea. Depends if NHS would go for that.
The smoothies are whatever you want to put in them: spinach, kale, beans, peas, bananas, blueberries etc for nicer taste, mixed with ice cream milk or juice., and all blended strongly for half a minute until homogenous.
Just one large glass a day should get some ABCD2 transporters made, so that over a period of time there will be more transporters in more liver cells, and VLCFA levels should begin to drop. It's important not to overdo it, as the phytanic / PPARa / ABCD2 bonding once made is either permanent or semi-permanent, so its not a good idea to tamper with nature too much until we have learned exactly what we are dealing with.
We all eat boiled veg and boiled spinach, many of us drink green smoothies, and many also take a spoon of cod-liver oil per day (contains phytanic acid from plankton, which the cod eat), so we can't really get too excited about side effects as long as we tread carefully and don't rush to try and rid the body of all its VLCFA in a week ..... it will take time.
What is most important right now is to establish a baseline if we want to start any record-keeping. Because without a baseline, there's nothing to measure results against, so we get a "null result", i.e: no proof of anything.
Even then, scientists these days require "double-blind placebo controlled experiments" before they will even listen to you. But at least if everyone at ALDLIFE begins to get better, they would at least have to admit something was working...Capiche?
Hi Rob. Thank you for responding! Sorry about all of the questions. I think it's just a curious (wanting to know more) nature.
I think I misinterpreted your post again. You referred to tissue biopsy and I interpreted it as muscle biopsy. I was just wondering if like you said people who have blood drawn routinely could send in data for the spreadsheet just so there would be some evidence for those who want to know. If it seems to help then like you said, "they would at least have to admit something was working".
I myself will be giving it a try. Unfortunately we don't have our blood drawn routinely as it all comes out of pocket but I would be willing just to see if there is any improvement.
If you do have any blood results going back over the years, with details of the different fatty acid levels, including VLCFA, and would like me to work them up into a set of charts for you, please let me know, and we can find a way to communicate directly.
It would certainly help if we could establish a baseline for more than just my friend, because no doctors would be likely to accept his astounding VLCFA decline as being due to these therapies derived from my research findings, unless they were backed up by similar VLCFA drops in other patients using the same therapies. (i.e: they would laugh and put his VLCFA decline down to pure luck, without any additional proof).
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