Carnitine fumarate

I have started giving my son 2 1/2, carnitine fumarate from Whole Foods and his condition had dramatically improved. I mean miraculously and dramatically in 1 day and especially in 1 week. His therapists are astounded. We are working to identify biochemists who can help us figure it out. The closest thing we have to go on is a 1960 paper published in Nature (no abstract available) in which fumarate was successfully given to cows to treat ketotic hypoglycemia. These dairy cows were shunting so much energy into the production of fat for milk that they did not have enough energy for themselves and became listless.

There does not appear to be a downside of giving carnitine fumarate.

Other parents are also noticing extraordinary things including decreased hunger in older children. We are trying to sort out why it is working, but I want to get the word out to as many parents as possible in case it alters their lives like it has altered ours.

Go here for a detailed analysis of acylcarnitine profile in a PWS infant: http://www.pwsdots.org/ResearchNotes/AcylcarnitineProfiles

Introduction to Carnitine Fumarate

Anyway, I talked with Zoe yesterday and it turns out she inadvertently ordered a newer form of carnitine, L-carnitine _fumarate_, from Pure Encapsulations and has completely switched Sulli over to that from the mix of acetyl-l-carnitine and L-carnitine [tartrate] she was using before. She reports that Sulli is noticeably stronger, more energetic yet calmer, smiling and talking/babbling more, showing more curiosity, and reacting to things quicker than she was on the acetyl and L-carnitine [tartrate] combo. Just before Christmas Sulli was already able to stand for several minutes while holding onto someone's fingers, but now she's starting to take steps. Several days ago she spent 1-1/2 hours straight practicing standing while balancing herself with her hands on a wall and then bending her legs to plop down into sitting, and the day before yesterday was working on pulling herself up to standing with a chair. In other words, she's getting ready to start cruising. :-) And the day before yesterday they had an appt with an orthopedist that has a lot of PWS patients and at first he refused to believe Sulli has PWS, saying she didn't present anything like his other PWS patients and questioning how she had been diagnosed. Meanwhile, Sulli sat there merrily grabbing at everything within reach. :-) All of that is dramatic improvement for a 9-1/2-month-old baby that, 3-1/2 months ago, couldn't sit by herself and that the PT estimated probably wouldn't start walking until she was 2-1/2 to 3 years old, and it seems like the fumarate form of L-carnitine has spurred the latest leap towards getting ready to start cruising, along with the previously noted increases in strength, energy, smiling, babbling, curiosity, etc.

So, what is L-carnitine _fumarate_? Most L-carnitine sold by supplement manufacturers is either L-carnitine hydrochloride or L-carnitine _tartrate_ (L-carnitine bound to tartrate). With L-carnitine _fumarate_ (which was developed and patented by Sigma Tau, the maker of Carnitor), the carnitine is bound to fumarate, which is a key substrate in what is called the Kreb's cycle in mitochondria for the production of energy. It is the Kreb's cycle that produces the electrons that are then passed along respiratory transport chain complexes 1-IV for the production of ATP (the basic cellular form of energy). Citrate synthase (which only had 60% of normal activity in Karson's muscle biopsy) is the key enzyme involved in the first step of the Kreb's cycle and as such can be rate-limiting for the whole cycle. Fumarate, though, is the substrate for the next to last step in the Krebs cycle and its related enzyme is fumarase.

About 58% of L-carnitine fumarate is L-carnitine, with the rest being fumarate. After it is ingested, the body separates the L-carnitine from the fumarate. Although I can't say for sure at this point, given Sulli's response it looks like what might be happening is that the L-carnitine part is going off and doing all of the good things it is known for in terms of transporting fatty acids into the mitochondria for burning for energy and whatnot, while the fumarate is entering the Kreb's cycle and boosting its output of electrons that are then transferred to the electron transport chain, resulting in an increase in the production of cellular energy in the form of ATP. If that's what is happening, it could be the extra fumarate is providing a pathway around a metabolic block, possibly in succinate dehydrogenase (SDH), given that SDH is the enzyme that catalyzes the succinate-to-fumarate reaction (in Karson's muscle biopsy SDH was the most reduced enzyme in the electron transport chain at 31% of normal). If so, it could be that the impairment in respiratory chain transport seen in Karson's muscle biopsy (except possibly for some part of the more reduced SDH/complex II activity) is not a primary event but is instead a downstream result of reduced substrate availability in the Kreb's cycle. (Interestingly, fumarase deficiency is a very rare autosomal recessive disorder in which the metabolizing of fumarate in the Kreb's cycle is sharply reduced or completely absent and is characterized by massive secretion of fumarate in the urine, encephalopathy, hypotonia and severe developmental delays, all of which (aside from excessive fumarate secretion) are rather reminiscent of another syndrome that we are all too familiar with.)

The Pure Caps capsules contain 586 mg of L-carnitine fumarate, with 340 mg of that being L-carnitine and 246 mg being fumarate. Sulli is only getting 1/4 capsule a day, which works out to about 85 mg of L-carnitine and 60 mg of fumarate for a 16 lb (7.25 kg) baby, which is about 12 mg/kg/day of L-carnitine and 8 mg/kg/day of fumarate. That's a surprisingly small amount of L-carnitine to be providing such dramatic benefit, given that the recommended dosage range for Carnitor is 35-50 mg/kg/day, and provides further support for the hypothesis that the fumarate part could be providing a significant amount of the benefit.

I've spent some time looking into the safety of L-carnitine fumarate and fumarate. L-carnitine fumarate is a relatively new form of carnitine and there aren't many clinical studies involving its use. The studies I found all have to do with Sigma Tau's patented formula for male infertility, ProXeed (yes, among other things, carnitine helps sperm swim better :-). The daily dose of that formula contains 2 g/day of L-carnitine fumarate, 1 g/day of acetyl-l-carnitine, 4 g/day of fructose and an unspecified amount of citric acid (which is also a metabolite in the Kreb's cycle), and in clinical trials seems to have been very well tolerated aside from the usual occasional side effects of large doses of carnitine (i.e., transient nausea and digestive upset, loose stools, etc.).

I have not been able to find any reports of fumarate being used as a supplement. However, fumarate is a component of ferrous fumarate (used globally for iron deficiency anemia in children and adults), as well as a number of drugs, including quetiapine and retroviral inhibitors such as tenofovir. In general it seems to be a safe substance (although it probably shouldn't be used by those with fumarase deficiency).

So what's the bottom line here? Assuming Sullivan continues to respond well to the L-carnitine fumarate (which I think is likely) _and_ no problems with its use crop up (which I don't expect), _and_ it is similarly beneficial for others with PWS, it could be that the L-carnitine vs. acetyl-l-carnitine question will become moot and the L-carnitine fumarate form could become the carnitine of choice for those with PWS. I am very excited about Sulli's response to it, as well as by the possibility that it could help pinpoint more clearly exactly where the disturbance of mitochondrial functioning in PWS is occurring.

For those who are interested in trying L-carnitine fumarate, the Pure Caps page for it is at http://www.purecaps.com/itemdy00.asp?T1=LCF1, with supplementary information at http://www.purecaps.com/PDF/pi/l_Carnitine_Fumarate.pdf. Jarrow also has (http://www.jarrow.com/product.php?prodid=191), as does Doctor's Best (http://www.drbvitamins.com/nutritionalproducts_details.asp?id=16). Make sure the label specifies that the L-carnitine is the fumarate form and not the more commonly available L-carnitine tartrate. All of the L-carnitine fumarate on the market is made by Sigma Tau and is pharmaceutical grade.

Please note that I am in the process of revising the carnitine and Coenzyme Q10 articles to suggest that, especially for older children, carnitine and/or CoQ10 supplementation be started with very low doses and then very slowly increased in order to give the child (and their parents) plenty of time to adapt to more normal levels of mental and physical energy. That suggestion comes from Rachel T. mentioning to me that they have tried CoQ10 with Erin several times and always stopped because of the development of irritability. At first I was puzzled by why that would happen, as nothing like that has been reported in the medical literature, but as I thought about it more, it started to make a lot of sense. After all, older children with PWS have lived with a significant mental and physical energy deficit for years and to them that is "normal." Then CoQ10 or carnitine is started, and all of a sudden the world is a brighter, busier place, they're experiencing all kinds of new perceptions and sensations, and their thinking is zipping along at a significantly faster pace. It's probably much like going from a dim room out into bright sunlight, except way more intense because the increase in energy they're experiencing is a full body and mind experience. So it's not surprising that it could be a somewhat disorienting experience that could lead to emotional, mental and physical reactions that others interpret as irritability. I therefore consider it important that the increase in mental and physical energy provided by CoQ10 and/or carnitine be increased very slowly so as to give the child and their parents plenty of time to adapt, physically, mentally and emotionally, to each step up to a higher level of energy as the dose is slowly increased. It will also probably be helpful if the parents talk with the child ahead of time about what kinds of things they might experience when the CoQ10 or carnitine.

I think the need to proceed very slowly is somewhat less of an issue for infants and toddlers, especially those who are badly delayed in such things as babbling and talking, head control, sitting, and walking, as they have not spent nearly as much time entrained by a significant energy deficit and I think it is important to get them developmentally on track as soon as possible. But as always, it is critical that parents use their intimate knowledge of their child and intuition in determining the approach that will be best for their child.

I also need to note that there is the possibility that the irritability reported in some of those with PWS when CoQ10 supplementation is started could be due to the increased energy unmasking an intrinsic behavioral disturbance that was previously "sedated" by a serious impairment in cellular energy availability. At this point I have no way of determining how much of that irritability could be the result of a some level of understandable disorientation due to a sudden increase in mental and physical energy (as described above) or is due to an unmasking effect. If it does turn out that CoQ10, carnitine, or anything else that improves energy metabolism and mitochondrial function in PWS to more normal levels can unmask a previously sedated behavioral disturbance, I think there are ways that could be dealt with, but that is beyond the scope of this post. I will note once again, though, that my hunch is that at least some of the severe behavioral problems associated with PWS are due to (1) chronic intermittent hypoxia and sleep fragmentation caused by under- or untreated breathing disorders, and/or (2) untreated energy metabolism problems that lead to repeated episodes of hypoglycemia, which is well-known to cause severe irritability and anxiety as well as psychotic-like symptoms and out-of-control rages. I therefore consider it essential that any breathing disorder be aggressively treated and every effort made to ensure stable blood sugar levels throughout the day.

Anyway, many thanks to Rachel for raising the question of Erin's response to CoQ10 with me. I think there is a huge amount of important "details" like that, that never make it into the scientific literature and textbooks about PWS, so I'd like to reiterate once again that I'm really dependent on folk's sharing their experiences as I try to help systematize the experience with the use of nutritional and other approaches to PWS into a more defined protocol. In particular, if anyone decides to try the fumarate form of L-carnitine with their child, I would _really_ like to hear about it. :-)

One Story

Day 1

I read this and put my 2 1/2 year old on creatine fumurate that night. He seemed to sleep fine. Jumping is challenging for him. He can only just now reliable leave the ground and land a couple of times in a row (and get air). This morning when I woke up, I told him to jump. He put his hands behind his back and jumped 6 inches off of the ground. He spent the entire day jumping until he collapsed exhausted at noon. We had to make him stop to eat.

I am a believer.

Day 4

We have the lower dose capsules. We gave Kian (30 pounds) 1 1/2 capsules spread throughout the day in three doses. He was using all of Superman strength to run to the bathroom. We backed down to one capsule spread throughout the day and that seems to work.

I don't know if this is possible or how it would work, but we have all noticed that within 4 days his hands went from pudgy to normal looking and his manual dexterity now seems normal for his age. Is he burning fat?

Day 8

We had a lot of adults at our house this weekend and I experimented on all of them.

My father took 1-2 of the 250 mg capsules each day. He said he cannot remember ever sleeping better. And, he was sleeping on the bathroom floor in the basement. (Don't even ask! :-)). Otherwise, no real energy difference, but he was running around trying to keep up with Superman all week and so perhaps he should have taken 10 capsules.

My husband is thin and fast metabolism. He took 4 on the first day and was irritable and snappish. He stopped taking them.

I have taken 1-4 a day. I am sleeping well. Otherwise, I am not sure. I am on such adrenaline because of the effects on Kian that I cannot say.

My aunt took 1-2 a day. She felt that she was more alert and less sleepy.

Nanny Julie took 1 and felt much more focused and mentally alert.

Superman is still going strong. Today the speech therapist could not believe his progress. Note that Kian has always been a bit ahead of normal for speech. Now he is a chatterbox. I found myself telling him to be quiet last week because he was interrupting! She was most impressed by his change in trunk strength and production. For the nontechnical audience, that means that he is now quite loud. He now needs a fair amount of coaching about indoor and outdoor voice.

He is getting 1 250 mg capsule spread out in 3 dosages throughout the day. His diarrhea seems to be gone. He doesn't seem to be irritable, just irritating. ;-)

Last week was the best week of my life!

Stream of Consciousness

So, we know that glucose is first converted to pyruvate by glycolysis. The 2 molecules of pyruvate is then converted to acetyl CoA, which is the starting material for the citric acid cycle. However, acetyl coA is also the starting point for the synthesis of fatty acids which occurs in the liver. The fatty acids are then converted into triglycerides and transported from the liver to the adipose tissue for storage in the fat cells. If there is a preferential utilization of pyruvate for fatty acid synthesis, then we can see how fumarate would help increase energy by supplementing the citric acid cycle. Now, if you couple that with your point that insulin levels are uniquely lower in PWS children (how true is that, help!?) then you can see how carbs get preferentially converted into fats, which are harder to derive energy back out of. The question I then have to ask is, how is glucose being distributed in the bloodstream? If it goes to the muscles, then it will be utilized in the citric acid cycle to generate energy, or converted into glycogen for reserve. If it stays in the liver after digestion, then it gets converted into glycogen and triglycerides (and the argument again is that in PWS, there is preferential synthesis of triglycerides). So this brings us all back to the hormonal control of liver function...

Carnitine and seizures

The question of a possible link between seizures and carnitine supplementation is something I've spent a fair amount of time investigating as part of my effort to make sure that carnitine is safe for use with those PWS. The possible link between seizures and carnitine is mentioned in the prescribing information for Carnitor and at the PDRHealth link in the carnitine article, and is something listed under the safety section in the article. I've conducted quite a few searches at Google, PubMed, etc., trying to get a good fix on what the actual risk, if any, is with regard to carnitine supplementation for PWS at the dosage ranges I've suggested, as well as searches at the U.S. FDA and its Adverse Events Reporting Database (http://www.fda.gov/cder/aers/). In general I've concluded that carnitine is probably more likely to reduce the incidence of seizures in PWS than increase them.

Some points regarding this question:

1. I've never been able to locate any of the reports regarding a possible link between carnitine supplementation and seizures, only passing references to the existence of such reports. That suggests that the reports are very limited in number and that the linkage was possibly questionable in at least some of those reports (that is, there may have been other confounding factors).

2. Intractable seizures (that is, seizures that can't be controlled by conventional anti-convulsants drugs) are a primary symptom in a number of metabolic and mitochondrial disorders and carnitine is commonly prescribed for those disorders responsive to it with a resulting significant improvement in seizure control.

3. Carnitine is used concurrently with certain anti-convulsant drugs such as Depakote (valproic acid, valproate) to both treat and prophylactically prevent the severe carnitine deficiency and resulting hyperammonemia that can result with the use of those drugs.

4. Elevated blood ammonia (hyperammonemia) is common in inborn errors of metabolism that present with seizures. In animal studies, carnitine has been shown to be effective in preventing brain damage and seizures due to toxic insults such as ammonia.

5. There is a 1984 study (see below) in which acetyl-l-carnitine caused transient seizure activity when it was injected into mice brains. I have not been able to find anything that followed up on that study and its implications, if any, for oral doses in humans are unclear.

6. Various forms of carnitine are available over-the-counter in the U.S. (and elsewhere) and are widely used by athletes, those wanting to lose weight, and others, and it does not seem probable to me that the FDA would allow continued OTC sales if there was a demonstrated link between carnitine supplementation and seizures, given the FDA's demonstrated eagerness to ban other supplements when questions about their safety arose.

7. As noted in the Questions post, there is a 1993 report of trimethylaminuria in a girl with PWS, as well as a 1997 report of seizures in a non-PWS boy with trimethylaminuria. There are also reports of transient trimethylaminuria in those taking large doses of carnitine (e.g., more than 3 or more grams per day, mostly by bodybuilders, who are known to take large doses of various things in their quest to become huge and "ripped"), because carnitine can be a precursor to trimethylamine. However, recent estimates are that 1% of people have some level of impairment in the ability to break down trimethylamine, so it could very well be that the girl with PWS who also had trimethylaminuria was simply unfortunate enough to have inherited both. In addition, the theoretical linkage between trimethylaminuria and seizures suggested by the 1997 report is weak, given that the vast majority of those with trimethylaminuria are otherwise healthy aside from their unfortunate odor. As a result, I think the theoretical possibility of seizures developing in someone in PWS due to the development of trimethylaminuria because of carnitine supplementation is probably pretty remote. However, it is something worth keeping an eye on and was a minor reason why I asked about smells in PWS. (The main reason has to do with a suspicion about a possible impairment in the metabolizing of sulfur-containing compounds such as methionine.)

8. Many clinical trials of carnitine have been performed to determine its efficacy for range of neurological conditions such as Alzheimers, dementia, Parkinsons, etc. In addition, a number of studies have investigated its effects on athletic performance and weight loss. None of those studies have reported seizures as a result of carnitine supplementation.

Given all of the above, I do not believe that carnitine is contraindicated for PWS in the absence of a diagnosed seizure disorder. In addition, given the well-documented linkage between metabolic and mitochondrial disorders and seizures and the benefit that carnitine has had in seizure control in some of those disorders, as well as the presence of metabolic and mitochondrial impairment in PWS, it could be that even if there is a seizure disorder present in someone with PWS, carnitine might be medically helpful - under a doctor's guidance and monitoring - in its control.

CF and Hunger

You may remember, back during the discussion about the Stefan study, the hypothesis that the hyperphagia in PWS is the result of an attempt by the mind-body to compensate for what it perceives as a state of energy starvation. If some part of the reason the body thinks it is starving for energy is because of an impairment in fumarate synthesis in the Kreb's cycle, and we are successfully getting around that impairment by supplying fumarate through carnitine fumarate, that is likely to send a reassuring message to the mind-body that the threat to survival is over and it can now start to relax about food. Your report and Kathryn's hint that might be happening (or maybe they're both coming down with a stomach bug at the same time :-) ). If more experience with carnitine fumarate show that it is having that effect, it might be really interesting at some point to have ghrelin levels tested in those with PWS who are using it.

I know it's really hard to take it a bit slow with the carnitine fumarate, given all of the exciting things being reported. But your report and others suggest that it is prompting some profound changes and re-balancing throughout the body, so especially for someone Hannah's age and older, I think it is important to continue to keep things a little slow so the body and mind have the time to adjust, as we don't want to inadvertently throw things out of balance in a new way while treating the old imbalances.

More to the Story

I've just spent the last several days trying to decipher a serum acylcarnitine profile for a 11-month-old boy that a mom on the list sent to me (I'll be posting more about it in the next day or so). The test is similar to the newborn screening card that the nurse does right after birth, but in this case, I'm not looking at it in terms for screening for other genetic syndromes but because of what it indicates is going on in terms of carbohydrate, fat and protein metabolism in PWS. It's a pretty tangled web to try to unravel and I'm still not finished pursuing all of the clues it provides, but one thing that is clear is that the impairment in mitochondrial function in PWS is part of a larger problem in terms of energy metabolism in general. That is, there are some important feedback signals about food availability that the body's energy metabolism system isn't getting in PWS and as a result certain enzyme systems important for the use of carbohydrates, fats and protein for energy production aren't responding as they should. In other words, the mitochondrial impairment doesn't exist in isolation, it's part of an overall disturbance in general energy metabolism, so if you decide to let the neurologist investigate further (and it's great that he's open to doing that), it's important that he not focus only on mitochondrial function.

There are some good reasons to explore this further. Some of the disturbances in protein metabolism that are suggested by the acylcarnitine pattern are somewhat similar to some other genetic syndromes in which the metabolizing of certain amino acids is impaired and some of those syndromes are very responsive to high dose vitamin B12, biotin and/or riboflavin supplementation, so it may be that similar supplementation in PWS might be helpful. Also, some of those similar syndromes are treated with special diets that minimize the amounts of certain amino acids because their incomplete metabolization can result in a buildup of toxic metabolites that affect neurological and mitochondrial function, so it could be that such a diet may also be helpful for PWS. Interestingly, L-carnitine is almost always a part of the treatment for those other syndromes. :-)