Paradigm shift??
I have spent quite a bit of time looking into alpha-lipoic acid (ALA), not just regarding the appetite issue but also for its neurocognitive and mitochondrial function benefits. (You can see the abstracts I've collected about ALA at http://www.tcmnotes.org/ala-abstracts/.) I do think it might have benefits for PWS, perhaps in concert with acetyl-l-carnitine. However, there are some concerns I need to resolve, for example, its marked hypoglycemic effect during fasting states[1] and its inhibition of insulin[2] and gluconeogenesis[3] (the making of new glucose in the liver), as well as the question of ALA-induced reductions in pyruvate carboxylase and pyruvate dehydrogenase complex activity[4] (and perhaps phosphoenolpyruvate carboxykinase, which is the rate-limiting enzyme of gluconeogenesis), all of which are vital parts of glucose metabolism. So far I have not been able to resolve those questions to my satisfaction, so I really can't say at this point whether or not it is appropriate for PWS. If anyone has used it for PWS, I would very much like to hear about the results.
The reason why I'm concerned about ALA's possible impacts on such things as blood sugar and pyruvate dehydrogenase levels is important, so I'm going to seize the opportunity to discuss that a bit.
I agree with Lara that there is likely to be an impairment of fat metabolism in PWS, but I think there also might be a significant impairment in glucose metabolism, especially gluconeogenesis (the making of new glucose by the liver from fats and amino acids). That suspicion initially arose because of the neonatal presentation of profound hypotonia and mental and physical lethargy which, in the absence of any of the known inborn errors of metabolism, suggests either severe hypoglycemia or hyperammonemia. I haven't been able to find any suggestion of neonatal hyperammonemia in the PWS literature, but have found a few scattered hints at hypoglycemia[5]. What really strengthened my suspicion about impaired glucose metabolism in PWS, though, was an Oct. 2005 article in the journal Endocrinology by Stefan et al, _Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive_.[6] If folks haven't read it yet, I really recommend doing so, as my sense is that it may represent the most important research into PWS to date. Basically what they did was develop transgenic mice in which the PWS region was deleted and then monitored the energy metabolism of fetal and newborn pups. This is what they found:
1. Both the fetal and postnatal PWS mice pups had insulin and glucagon levels below the level of detection, as well as lower overall body fat, all of which strongly suggests a primary pancreatic defect. (Like insulin, glucagon is an important hormone in carbohydrate metabolism that is synthesized and secreted from special cells in the pancreas. Normally, when glucose levels start to drop, glucagon signals the liver to create new glucose (gluconeogenesis) and release it into the bloodstream in order to prevent hypoglycemia (low blood sugar).)
2. As is usual, at birth there was an abrupt loss of the maternal supply of the glucose the pups needed for energy.
3. The newborn pups rapidly used up their serum glucose supply (as is normal) and so had to turn to the breakdown of glycogen (stored in the liver) into the glucose needed for energy.
4. However, liver glycogen supplies were also soon depleted (as is normal) and the pups had to turn to gluconeogenesis. This is where the PWS pups (and probably babies with PWS) started running into serious trouble. Even though a severe metabolic crisis was developing and insulin levels were below the limits of detection, the pups' glucagon levels also remained below the level of detection, which means the liver never got the signal to start up the production of new glucose, with the result that the brain, muscles, etc. didn't have the energy they needed to function properly, resulting in severely hypotonic, lethargic pups with poor suck.
5. As would be expected, when confronted with increasingly severe hypoglycemia and energy deficiency, the pups switched to fatty acid oxidation (burning) for energy production. But it is glucagon that causes the release of lipids (fats) from peripheral tissues so they can be burned for energy and since glucagon was basically nonexistent, that release of lipids didn't occur. As a result, the only source of energy the pups had available was the fats they got directly from nursing. But since the pups were severely hypoglycemic and weak, they were unable to nurse well and so lipid levels remained low (a situation that could be exacerbated by impaired lipid uptake due to down-regulated CD36/FAT expression). The result was the development of a vicious cycle with the pups remaining in a state of severe energy deficiency with resulting hypotonia, lethargy, poor suckling and failure to thrive.
6. Finally, the study authors found that "[a]n increase in plasma ghrelin levels occurs in postnatal TgPWS mice and appears to begin at the onset of severe hypoglycemia but is not directly coincident with hypoinsulinemia [low insulin levels]. These findings are consistent with known regulators of ghrelin expression and secretion because both glucose and insulin have been shown to suppress ghrelin levels. By [day 5], ghrelin levels in TgPWS mice are approximately 3-fold higher than in [wild type] littermates, suggesting that high ghrelin levels in TgPWS might be a physiological adaptive mechanism in an attempt to increase feeding via its actions on the [hypothalamus] to ameliorate the rapidly worsening failure to thrive. However, either this signal is unrecognized due to an unknown mechanism, or it may be too late to elicit a physiological response."
Care must of course be used when attempting to translate the findings from mouse studies to humans, but I think Stefan et al have potentially moved PWS research light years beyond the usual "central hypothalamic dysfunction" mantra of current PWS "experts," which has never been able to provide a comprehensive explanatory mechanism of any depth for what is going on with PWS and instead seems to just feed into an attitude of, "Well, what can you do, it's a central hypothalamic dysfunction. <shrug>" Indeed, the essential weakness of the "central hypothalamic dysfunction" (CHD) dogma becomes readily apparent when it is realized that the _only_ clinical guidance it has been able to provide for the last 20+ years is the recommendation of growth hormone treatment. Even that recommendation, though, is purely empirical, as the CHD theory has never been able to demonstrate exactly how the presumed CHD leads to growth hormone deficiency. The Stefan energy metabolism model, however, easily explains why there is growth hormone deficiency in PWS - growth takes energy, which is exactly what the PWS infant has a severe shortage of, so the physiological processes of a newborn frantically trying to cope with a severe energy deficit become focused almost entirely on survival, not growth.
In addition to growth hormone deficiency, the Stefan energy metabolism model also helps to explain other notable aspects of PWS, including the biphasic presentation, severe neonatal hypotonia and lethargy (and their resolution at about four to six months of age), hyperphagia, hypogonadism, low muscle mass, low resting energy expenditure, cognitive deficits, and certain behavioral aspects (e.g., temper tantrums). (Note that I am not saying there is no central hypothalamic dysfunction in PWS, as there may very well be. It remains to seen, though, how much of that presumed CHD is truly central in nature and how much is actually the effects of real (in the neonatal phase) and, later on, perceived energy starvation.)
PWS mice typically die within a week of birth, but that doesn't happen with PWS babies because NG tube feeding is implemented when it's finally realized after a day or two that there's a serious feeding problem. Later, when they're finally strong enough to suck, we're always sticking a bottle in their mouth in order to maintain adequate nutrient intake. Eventually solids are introduced, which usually means such first foods as rice cereal, banana, applesauce, etc., all of which just happen to be wonderful sources of glucose. It has been a puzzle to me why PWS babies typically emerge from the severe hypotonia and lethargy of early infancy around the age of four to six months, but now I suspect it may be at least in part due to the start of feeding glucose-rich foods (it (also) may be that is when the pancreas is finally able to synthesize enough glucagon to prompt the liver into making glucose or some related metabolic process has matured enough to the point that the infant finally has enough energy available for such things as movement and alertness). However, by that time their whole metabolic regulatory system is seriously out of whack due to their body's desperate attempts to compensate for the severe energy starvation during the neonatal period and early infancy, including chronically elevated ghrelin levels, and so the body is primed for hyperphagia to develop when an as yet undefined trigger occurs. That trigger could be something like a spurt in the maturation of the pancreas' endocrine activity or some other metabolic process.
If the Stefan energy metabolism model of PWS is correct, what does that mean in practical terms? Unfortunately, there is more research that needs to be done in order to say for sure. (For example, the Stefan authors note that "[i]t will be important in future studies to examine the expression levels of genes encoding critical gluconeogenic enzymes or the levels and/or activity of phosphoenolpyruvate carboxykinase[7] or pyruvate carboxylase, for example, that could be altered in the TgPWS mouse.") However, the Stefan findings as well as what is known about energy metabolism in general and experience from the clinical treatment of inborn errors of glucose metabolism (such as pyruvate carboxylase deficiency[8] and pyruvate dehydrogenase complex deficiency[9]) do suggest that complete avoidance of fasting states (which require gluconeogenesis to avoid the development of hypoglycemia) is critical at least during the neonatal period and early infancy.
Central to the Stefan energy metabolism model is the hypothesis that hyperphagia in PWS "results from a failure in compensatory mechanisms" that were resorted to in order to cope with the severe energy deficit characteristic of the neonatal stage and early infancy. Another way to conceptualize that is that the body continues to think it is still facing a survival-threatening state of energy starvation and so is determined to grab every bit of food in sight to alleviate that while continuing to minimize energy-consuming processes such as growth. If the Stefan hypothesis is correct, the question then is how to convince the body that the threat of energy starvation is past. Answering that could be complicated by the fact that fat absorption might be impaired (due to CD36/FAT down-regulation and perhaps other factors) and that gluconeogenesis and/or other aspects of carbohydrate metabolism may also be impaired. What I'd really like to see is something like a day-long conference of 10 or so clinical nutritionists who have experience working with inborn errors of fatty acid and carbohydrate metabolism during which they review the Stefan article and other pertinent materials with a goal of providing recommendations as to how to persuade the PWS body that it doesn't have to worry about energy starvation any longer. Short of that, though, the following might be helpful:
1. Avoidance of fasting states, that is, any period over about 3 hours without food.
2. As Lara and Peter have found, the judicious addition of healthy fats to the diet via flax seed meal and oil, fish and fish oil, avocados, omega-3 eggs, nuts like walnuts, pecans, macadamia, etc. is likely to be helpful. Indeed, I suspect the benefits of flax and fish oil supplements for PWS stem at least in part from the increase in the amount of dietary fat suitable for burning for energy. Peter's point about scrupulous avoidance of trans fats (hydrogenated oils, margarine, etc.) is very well-taken, and I would also avoid poor quality generic oils such as vegetable or cooking oils.
3. Since CD36/FAT down-regulation suggests an impairment in the absorption and metabolism of palmitic acid, it might be a good idea to avoid coconut and palm oil, given that both are high in palmitic acid.
4. Because fish oil is also high in palmitic acid, if fish oil supplements are used it might be advisable to use products that have high amounts of EPA and DHA relative to the total amount of fish oil. For example, the Nordic Naturals Ultra Omega mentioned by Lara has 1280 mg of omega-3 oils per 2000 mg of total fish oil and Coromega provides 1230 per 2000 mg, while the supplement that my friend's baby reacted so badly to requires 4,295 mg of total fish oil to provide roughly the same amount of EPA and DHA as the Coromega and Ultra Omega products.
5. Carbs should be low-glycemic so that their glucose slowly trickles into the bloodstream, not hit it all at once. For the same reason, carbs should not be eaten by themselves but always in conjunction with protein and fat. As many PWS parents already do, fruit juices should be minimized, that is, by diluting them or restricting them to small amounts. In general, most carbs should be in the form of veggies, not fruits and grains.
6. Protein and fats should probably constitute the bulk of the diet due to their high satiety effect and ability to support growth (including lean muscle mass) while providing a steady stream of the substrates needed for energy production via fatty acid metabolism.
7. A high-quality, complete and balanced vitamin and mineral supplement, particularly one that provides at least several times the RDA for B vitamins (which are required to make the enzymes necessary for both glucose and fatty acid metabolism), seems advisable. Regular monitoring of iron levels is also advisable with supplementation implemented if they drop below the mid-normal range. (Ferrochel is my preferred iron supplement due to its high uptake efficiency and safety profile.)
8. Because those with PWS may be more dependent than others on fatty acid metabolism to provide the energy needed for proper physiological functioning and carnitine is necessary for the transport of fatty acids into the mitochondria for burning for energy, supplementing with L-carnitine may also help convince the body that it can stop worrying about a shortage of energy.
Taken together, points 1-6 above suggest something like six mini-meals spaced about three hours apart throughout the day, each comprised of roughly 40% protein, 40% high quality fats and 30% low glycemic carbs (primarily veggies). The various Zone Diet books by Barry Sears, PhD, have menu examples, recipes and snack examples that meet the 40-40-30 protein-fat-carbs ratio. My experience (with both myself and clients) is that the 40-40-30 macronutrient ratio typically provides sustained high levels of mental and physical energy and satiety while promoting lean muscle mass and optimal body fat levels, especially when used in conjunction with regular exercise (which for most toddlers and young children means their usual busy activity).
Note that the above suggestions are merely my best guess as to what might help re-program the PWS body from perceived starvation mode to more normal metabolic functioning and could be totally wrong. Also, there are likely to be other things such as other supplements, herbs, etc. that could help with the re-setting of the body's perception of available energy supplies. However, that's a whole other huge topic.
Anyway, Teresa, I'm thrilled that you've joined the HolisticPWS list and thought to ask about lipoic acid. :-)
Take care, Oneida
1. Apr. 1999. Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats. </pws-abstracts/99/4/1/apr-1999-lipoic-acid-acutely-induces-hypoglycemia-in-fasting-nondiabetic-and-diabetic-rats.html> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10206446&query_hl=10&itool=pubmed_DocSum
2. July 2006. Alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells. </pws-abstracts/2006/7/1/july-2006-alpha-lipoic-acid-regulates-amp-activated-protein-kinase-and-inhibits-insulin-secretion-from-beta-cells.html> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16752177&query_hl=1&itool=pubmed_DocSum
3. May 1984. Inhibition of gluconeogenesis in rat liver by lipoic acid. Evidence for more than one site of action. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1153543&blobtype=pdf
4. Oct. 2004. R-lipoic acid inhibits mammalian pyruvate dehydrogenase kinase. </pws-abstracts/2004/10/1/oct-2004-r-lipoic-acid-inhibits-mammalian-pyruvate-dehydrogenase-kinase.html> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15512796&query_hl=10&itool=pubmed_DocSum
5. E.g, Oct. 1996. General anesthesia in Prader-Willi syndrome. http://www.tcmnotes.org/pws-abstracts/96/10/1/oct-1996-general-anesthesia-in-prader-willi-syndrome.html "Our data support the hypothesis that hypoglycemia in the Prader-Willi syndrome originates from inadequate lipolysis during starvation." [Note that by starvation they are referring to a fasting state, as typically occurs before, during and after surgery.]
6. Oct. 2005. Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive. http://www.tcmnotes.org/hormone-metabolic-aspects-pws-mouse-with-ftt/
7. Phosphoenolpyruvate carboxykinase - http://www.nutritionandmetabolism.com/content/2/1/33
8. Pyruvate carboxylase deficiency - http://www.emedicine.com/PED/topic1967.htm
9. Pyruvate dehydrogenase complex deficiency - http://www.emedicine.com/PED/topic1969.htm
