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. :-)