Note: This article is a work-in-progress and still incomplete. Feedback would be very welcome, so please feel free to e-mail me with any comments you might have. I am particularly interested in the results that others have had with the use of carnitine in those with PWS, so if you have experience with that, please consider writing me or posting about it in the guestbook.
Please note that the information and suggestions in this article have been compiled by someone who is not a licensed health care professional and that the use of carnitine for Prader-Willi syndrome (PWS) is in its infancy. It is therefore essential that you use your own good sense and intimate knowledge of your child, together with the advice of your health care provider(s), before proceeding with a trial of carnitine for your child.
Carnitine is a generic term for various forms of a vitamin-like, naturally occurring metabolic derivative of the amino acid lysine (e.g., L-carnitine (levocarnitine) and acetyl-l-carnitine). As one study put it, carnitine has "multiple physiological functions in major metabolic pathways which are essential for development and growth." (Giovannini 1991) An adult typically has about 20 grams of carnitine stored in their body, primarily in the liver, heart and skeletal muscle. The human body can make some of the carnitine it uses (it is synthesized primarily in the kidneys and liver) and some is also obtained from food (primarily from red meat and dairy products). L-carnitine and acetyl-l-carnitine are available as over-the-counter food supplements in the U.S. In addition, Sigma Tau Pharmaceuticals manufactures Carnitor, a prescription-only form of L-carnitine.
Anecdotal reports about the use of carnitine in PWS
Sullivan
Following the development of late-term polyhydromnios (excessive amniotic fluid) in her mother, Sullivan was born full-term on March 21, 2006, with a weight of 5lb 11oz (2.58 kg) and a length of 19-1/4 inches (49 cm). Initially she was not able to maintain her body temperature and was in the neonatal intensive care unit (NICU) for 11 days. Attempts at both breastfeeding and bottle-feeding were unsuccessful due to poor suck due to severe hypotonia and lack of interest in feeding and so she was fed by a nasogastric (NG) tube for the first four weeks. At age 2 months, genetic testing revealed Prader-Willi syndrome due to maternal uniparental disomy (UPD).
At age four months, there was very little apparent difference between Sullivan's awake and sleeping states. Instead, she seemed to have periods of shallow sleep during which she was more easily aroused, as well as periods of deeper sleep in which she was not as easily aroused. As a result, the overall impression was that she was asleep most of the time. In retrospect, though, her mother thinks Sullivan might have been awake much more than she thought and thus was more easily aroused during her "awake" periods even though she appeared to be asleep due to severe hypotonia.
CoenzymeQ10 (Dr. Judy's formula, which also contains 60 IU of vitamin E) was started on or about July 23 at 60 mg per day. Increased sleeping was observed for the first day or so, after which improvement was observed. There were now clear differences between Sullivan's awake and sleep states. She became more alert when awake and sleep periods were longer and deeper (that is, she was not as easily aroused during them). She became able to push up and lift her head and chest somewhat when laying on her stomach. Head control somewhat improved but was still incomplete and inconsistent. She seemed more cognitively "present" when awake and began reaching for things and made motions as if she was attempting to bring them to her mouth.
Growth hormone treatment (Nutropin AQ at .2 mg per day) was started on or about August 5. Within a week there was improvement in her hypotonia. Her body felt significantly denser and she held her body together more when being held. She did not feel as much like a rag doll, but more like a normal newborn. She also began to move her body a little more and could hold her head up when on her stomach for a little longer. At about this time she also became able to put things in her mouth.
Blood tests taken on August 30 showed serum iron of 43 (normal 40-150), IGF-1 at 40 (normal 55-327), total carnitine at 32 (normal 24-100), and free carnitine at 24 (normal 20-88).
By the time she was almost six months old, Sullivan continued to have little interest in feeding and ensuring that she had sufficient intake was a daily struggle. She slept about 17-18 hours per day (12 hours at night and 5-6 in daytime naps). Head control continued to be highly variable, with periods of consistent head control never lasting more than two hours. She sometimes turned her head to follow things of interest, but the periods in which she did so were not sustained. She could not sit unassisted and did not move very much; for example, she rarely lifted her legs up or held them up when they were lifted during diapering. She also had noticeable weakness on her left side and her left eye "wandered." Her occupational and physical therapists, who saw her weekly, predicted that she would probably begin to walk at about age 2-1/2 to three years.
Acetyl-l-carnitine (100 mg total per day in two divided doses) was started on or about Sullivan's six month birthday, with significant improvement apparent within several days, including sustained periods of consistent, full head control, active looking about with typical infant curiosity, and waving her arms and kicking her feet. Over the course of the next week her physical and mental lethargy resolved almost completely. She became able to roll over a few times in the space of a few minutes. For the first time she demonstrated rooting behavior when hungry and eagerly reached for her bottle when she saw it, although expressions of hunger were still inconsistent. She consistently turned her head to look for the source of sounds and to follow things of interest. The daily total of time spent sleeping decreased to about 13 to 15 hours per day (10 at night and 3-5 in daytime naps). She also added new behaviors to her repertoire, including vigorously rubbing her nose if it had a tickle and consistently reaching out and turning the page of the book as she was being read to.
After one week, the acetyl-l-carnitine was increased to 200 mg/day and Sullivan continued to rapidly improve. Three weeks after starting the carnitine, head control was complete and she was able to sit unassisted for about 15 seconds until reaching for something caused her to lose her balance. She learned to click her tongue against the roof of her mouth by imitating others and then spent the day practicing it. She became very interested in interactions with others and developed a full body laugh. Her left sided weakness was significantly improved and her left eye no longer wandered. Indeed, Sullivan's improvement was so significant that her occupational and physical therapists cut back her sessions from weekly to monthly, saying that she was now essentially developmentally on track - and even advanced in her social development!
Four weeks after the supplementation with acetyl-l-carnitine was started, Sullivan presented as an essentially developmentally normal, very alert and observant, and exceptionally engaging seven-month-old baby. She could sit unassisted for well over two minutes and wave her hands without losing her balance and falling. She could also bend over while sitting to mouth her toes and then rise back up. She watched closely when the raspberry sound was demonstrated to her and quickly started to try to imitate it by pursing her lips around her tongue. When tickled about her chest and tummy, she responded with laughter and full body movement. In sum, a month of acetyl-l-carnitine supplementation has transformed a very hypotonic, hypersomnolent, and severely developmentally delayed baby into -- Sullivan unleashed! Yeah!!!!
11/14/06 Update: On or about October 27, Sullivan's vitamin supplement (Poly-Vi-Sol), CoQ10 and acetyl-l-carnitine were briefly discontinued following a cold and runny stools. The Poly-Vi-Sol was restarted on the second day. For the first two days, Sullivan maintained her gains, but by the third morning she began to display some lethargy. Acetyl-l-carnitine was re-instituted at a dose of about 25 mg and the lethargy resolved. Since then, Sullivan has continued to do well with a total daily dose of about 25-50 mg of acetyl-l-carnitine. Her latest enthusiasm is bouncing and "jumping" while being held and she is now able to stand for about 15 seconds while holding onto something.
In addition to acetyl-l-carnitine's effectiveness in resolving Sullivan's hypotonia and lethargy, it also seems to have resolved her cataplexy. Cataplexic episodes were first noticed in Sullivan prior to starting acetyl-l-carnitine supplementation and were marked by a sudden brief loss of all muscle tone when she seemed particularly happy or was intently concentrating on something. They did not occur after acetyl-l-carnitine was started, re-occurred on the third morning after the acetyl-l-carnitine was stopped, and have not occurred since the acetyl-l-carnitine was re instituted.
Comment: Based on Google and PubMed searches, the above anecdotal report may be the first to suggest that acetyl-l-carnitine might be effective for cataplexy-like episodes in PWS. Cataplexy has a known association with PWS (Smit 2006), with various studies reporting it in eight of 35, four of 25, and three of 173 subjects with PWS (Tobias 2002), and the narcolepsy-cataplexy complex has been associated with low levels of hypocretin (orexin), which is also significantly reduced with PWS. (Nevsimalova 2005) Interestingly, both low hypocretin levels and reduced locomotor activity under fasting conditions have been found in systemic carnitine-deficient juvenile mice (Yoshida 2006), which suggests that the low levels of hypocretin in PWS (and perhaps in narcolepsy-cataplexy) might be at least in part due to an actual or functional carnitine deficiency.
Differences between L-carnitine and acetyl-l-carnitine
Both L-carnitine and acetyl-l-carnitine play a critical role in the transport of long-chain fatty acids into the mitochondria for "burning" (oxidation) in order to produce the energy needed to fuel the thousands of various processes that take place within the body, including cognition and muscle contraction. Both forms are also involved in the transport of acetyl groups into the mitochondria and acetyl-l-carnitine is also an intracellular energy reservoir of acetyl groups, which are used to form adenosine triphosphate (ATP), the main energy source for the majority of cellular functions, as well as the neurotransmitter acetylcholine. Both forms of carnitine also play important roles as anti-oxidants by removing and recycling oxidation residues (acyl-coenzyme A - acyl-CoA) from the mitochondria, thereby helping to promote optimal mitochondrial functioning.
A number of web sites (mostly those selling carnitine products) include claims that acetyl-l-carnitine crosses the blood-brain barrier more easily than L-carnitine. I have not been able to find any research supporting that claim; instead, the studies I have found indicate that both forms readily cross the blood-brain barrier. (Friedrich 2003, Inano 2003, Kido 2001) However, there is evidence that acetyl-l-carnitine competes with L-carnitine for preferential uptake in heart mitochondria (Idell-Wenger 1981) and that may be true in the brain as well - Burlina 1989 found that L-carnitine strongly suppresses the uptake of acetyl-l-carnitine in mouse brains, while Huth 1981 found that L-Carnitine uptake by rat brains was competitively inhibited by acetyl-l-carnitine.
In practice, it does seem that acetyl-l-carnitine has more of an effect on neurological functioning than does L-carnitine, perhaps due to its role as a donor of acetyl groups for the synthesis of ATP and acetylcholine. In that regard, it is interesting to note that glucose infusion inhibits the uptake of radio-labeled [2-11C]acetyl-l-carnitine by the brain, which suggests that acetyl-l-carnitine may have a role in transporting acetyl groups into the brain during an energy (metabolic) crisis, that is, during hypoglycemic states. (Kuratsune 1997)
Carnitine deficiency
Carnitine is a conditionally essential nutrient for newborns because their reserves are rapidly depleted following birth but their ability to synthesize it is not fully developed. As a result, newborns and infants are dependent on external sources of carnitine. Breast milk contains carnitine and infant formulas based on soy and cow's milk are now routinely fortified with L-carnitine.
As far as I can determine, neither primary carnitine deficiency nor any of the identified forms of secondary carnitine deficiency have been found in PWS. However, for those considering carnitine supplementation for their child with PWS, it may useful to know a bit about primary and secondary carnitine deficiencies.
Primary carnitine deficiency is caused by a defect in a gene on chromosome 5 that encodes for a protein, OCTN2, that facilitates the uptake of carnitine into certain tissues in the body. Presenting signs and symptoms usually occur during infancy or early childhood and are often triggered by periods of fasting or illnesses such as colds or flu, particularly when food intake is reduced. Symptoms typically include encephalopathy, confusion, an enlarged, poorly pumping heart (cardiomyopathy), vomiting, muscle weakness, and low blood sugar (hypoglycemia). Serious complications such as heart failure, liver problems, coma, and sudden unexpected death are possible, with the result that primary carnitine deficiency is sometimes mistaken for Reye's syndrome and sudden infant death (SIDS).
Secondary carnitine deficiency is often caused by inborn respiratory chain defects or mitochondrial disorders that impair the oxidation of fatty acids in the mitochondria (beta-oxidation), such as occurs in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Secondary carnitine deficiency can also be caused by some anticonvulsants such as valproic acid (Depakote) and the antibiotic pivampicillin. Secondary carnitine deficiencies can present with a broad range of signs and symptoms, but physical and mental lethargy, muscle weakness and hypotonia, and altered mental status are very common threads. For more detailed information, see the eMedicine article on carnitine deficiency.
As noted above, none of the known primary or secondary deficiencies of carnitine has been found to be co-morbid with PWS; indeed, a search at PubMed for "prader carnitine" results in "no items found." However, the fact that carnitine supplementation has markedly improved the mental and physical lethargy, muscle weakness and hypotonia in the early presentation of PWS suggests that an as yet unrecognized secondary or functional carnitine deficiency might be a factor in PWS. In that regard, it is interesting to note that carnitine levels in muscle can be depleted even when serum carnitine levels are within normal ranges. (eMedicine)
Carnitine deficiency (both primary and secondary) has been associated with the following symptoms and conditions:
hypoglycemia (low blood sugar) and impaired ketogenesis, including nonketotic (hypoketotic) hypoglycemia and fasting hypoglycemia in infants (Longo 2006, Stanley 2004, Kelly 1998, Winter 1987)
accumulation of lipids within skeletal muscle, heart tissue and liver (Kelly 1998)
glutaric acidaemia type II due to deficient ETF-dehydrogenase activity (Mandel 1988)
Research overview
Research journal abstracts that I've collected about carnitine are here.
As far as I can determine, no research has ever been conducted into the efficacy of carnitine supplementation in PWS; indeed, as noted above, a search at PubMed for "prader carnitine" turns up empty.
Clinically and in research, carnitine has been used for or shown to:
(L-carnitine) Increase mitochondrial ATP production. (Marriage 2004)
(L-carnitine) Markedly improve hypotonia, ataxia and recurrent infections in an infant with organic acidaemia (glutaric acidaemia type II due to deficient ETF-dehydrogenase activity). (Mandel 1988)
(L-carnitine) Improve physical activity, muscle hypotonia, communication and sleep time in Rett syndrome (a severe neurodevelopmental disorder). (Plochl 1996)
(L-carnitine) Significantly improved alertness, eye contact, interest in surroundings, physical activity levels, and verbal communication in Rett syndrome. (Plioplys 1993)
(L-carnitine) Improve motor function including apraxia and overall well-being in some girls with Rett syndrome. (Ellaway 1999)
(L-carnitine) Improve liver function and neurological symptoms in infants with cystic fibrosis. (Kelly 1998)
(L-carnitine) Prevention and treatment of apnea in premature infants. (Kumar 2004)
(L-carnitine) Improve nerve conduction velocity and sympathetic skin responses in children with neuropathy due to Type I diabetes. (Uzun 2006)
(acetyl-l-carnitine) Improve the symptoms of chemotherapy-induced peripheral neuropathy. (Maestri 2005)
(acetyl-l-carnitine) Cause peripheral nerve regeneration and improve the symptoms of antiretroviral toxic neuropathy caused by the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in those who are HIV+. (NRTIs disrupt neuronal mitochondrial DNA synthesis and impair energy metabolism.) (Hart 2004)
In animal studies:
(L-carnitine) Reduce brain injury after hypoxia-ischemia injury in newborn rats by preventing the increases in the ratio of acyl-CoA:CoA, glutamate, glycine, and superoxide, and reduction of the mitochondrial phospholipid cardiolipin caused by hypoxia. (Wainwright 2006)
(acetyl-l-carnitine) Increase the release of dopamine in the brains of live rats. (Harsing 1992)
(acetyl-l-carnitine) Increase the synthesis and release of acetylcholine in synaptosomes of old rats. (Ando 2001)
(acetyl-l-carnitine) Increase the release of acetylcholine in the striatum and hippocampus of freely moving rats. (Imperato 1989)
(acetyl-L-carnitine) Reduce impulsive behavior in adolescent rats. (Adriani 2004)
(acetyl-l-carnitine) Increase the learning capability of old rats. (Ando 2001)
(acetyl-l-carnitine) Improve short-term memory deficits and cognitive function in old rats. (Hagen 2002)
(acetyl-l-carnitine + alpha lipoic acid) Reverse age-related cellular metabolic decline in old rats. (Hagen 2002)
(acetyl-l-carnitine + alpha lipoic acid) Reverse the age-related increase in oxidants in old rats. (Hagen 2002)
(acetyl-l-carnitine) Increase ambulatory activity in both young and old rats. (Liu 2004, Hagen 2002)
(acetyl-l-carnitine) Reverse age-related alterations in fatty acid profiles and loss in cardiolipin levels. (Hagen 2002)
(L-carnitine and alpha lipoic acid) Decrease oxidant generation, lipid peroxidation, protein carbonylation and DNA strand breaks in aged rats. (Sundaram 2006)
(L-carnitine + alpha lipoic acid) Improve the age-related decline in mitochondrial respiratory activity in rats. (Sethumadhavan 2006, Iossa 2002)
(acetyl-l-carnitine) Improve ATP production in skeletal muscle mitochondria in rats through an increase in mitochondrial protein content. (Iossa 2002)
(acetyl-l-carnitine) Partly reduce the leptin resistance that occurs in old rats. (Iossa 2002)
(acetyl-l-carnitine) Significantly decrease serum leptin levels in old rats. (Iossa 2002)
(acetyl-l-carnitine) Significantly decrease fat gain and body fat content in young rats, salmon and broiler chickens and significantly increase protein gain and body protein content in old rats. (Iossa 2002)
Safety and side effects
L-carnitine
No reports of L-carnitine toxicity from overdosage exist. (Kelly 1998)
According to the prescribing information for Carnitor, the intravenous LD50 of L-carnitine in rats is 5.4 g/kg.
Studies indicate that L-carnitine has no mutagenicity. Experiments to determine the long-term carcinogenicity of L-carnitine have not been conducted, but it is unlikely to be carcinogenic, given its key role in major physiological processes.
According to Kelly 1998 and Kopelevich 2005, only the L-carnitine form is biologically active and the D,L-carnitine form (racemic mixture) should not be used, as D-carnitine is not biologically active and has been shown to compete with L-carnitine for absorption and transport, increasing the risk of carnitine deficiency. In uremic patients, use of the racemic mixture has been correlated with myasthenia-like symptoms in some individuals.
"The safety and efficacy of oral levocarnitine [L-carnitine] has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine." (Carnitor)
"Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to Carnitor. There are, however, no adequate and well controlled studies in pregnant women." (Carnitor)
There is a medical debate about the use of L-carnitine in long-chain fatty acid oxidation defects (eg, LCHAD deficiency, trifunctional protein deficiency, MTP deficiency, VLCAD deficiency), particularly during metabolic crises, because it may enhance formation of long-chain acylcarnitines, which may cause ventricular arrhythmogenesis. (eMedicine)
Acetyl-l-carnitine
Several studies and anecdotal reports indicate that higher doses of acetyl-l-carnitine can be over-stimulating and/or cause insomnia and headache in some people. (Maestri 2005, Vermeulen 2004) The use of acetyl-l-carnitine in infants and young children with PWS, especially in the beginning, should therefore be accompanied by close monitoring for irritability (fussiness, crankiness, etc.), hyperactivity, difficulty falling asleep, easy and/or frequent awakening, and a reduction in overall sleeping time below age-appropriate levels, and if any of those signs should occur, the dose should be reduced or stopped.
Kidd 1999 states that acetyl-l-carnitine can intensify dream activity.
Kidd 1999 states that acetyl-l-carnitine may be contraindicated for those who are bipolar (manic-depressive), presumably because of its activating effect.
Increased agitation has been reported in some with Alzheimer's disease when taking oral acetyl-L-carnitine. (PDRHealth)
In those with seizure disorders, an increase in seizure frequency and/or severity has been reported in a small number of those taking acetyl-l-carnitine. (PDRHealth)
Large single doses of carnitine may cause transient nausea, vomiting, abdominal cramping and/or diarrhea in some people; reducing the dose typically resolves such symptoms. In general, daily dosages should be divided into smaller amounts spaced evenly throughout the day to maximize both bowel tolerance and uptake. (Kelly 1998)
Dosage
L-carnitine
Kelly 1998 states, "As a general guideline, the average therapeutic dose [of L-carnitine for adults] is 1000 mg given two to three times daily for a total of 2000-3000 mg. No advantage appears to exist in giving an oral dose greater than 2000 mg at one time, since absorption studies indicate saturation at this dose."
The recommended oral dosage of the tablet form of Carnitor [L-carnitine] for adults is 990 mg two or three times a day.
The recommended oral dosage of the tablet form of Carnitor [L-carnitine] for infants and children is between 50 and 100 mg per kg per day in divided doses, with a maximum of 3 g/day. The dosage should begin at 50 mg/kg/day and the exact dosage should depend on clinical response.
Clinical trials
Five children with severe neurologic handicaps and "excessive lethargy" were treated with 35-50 mg/kg/day of L-carnitine. (Plioplys 1994)
Uzun 2005 used 2 grams of L-carnitine per meter2 per day in children with diabetic neuropathy.
Campos 1993 used 50-200 mg/kg of L-carnitine four times daily in patients with mitochondrial myopathy and "carnitine insufficiency" who presented with muscle weakness, failure to thrive, encephalopathy, and cardiomyopathy. (Kelly 1998)
50 mg/kg/day of L-carnitine was used to treat a 17-year-old female with Rett syndrome. (Plioplys 1993, Kelly 1998)
L-carnitine, starting at 75 mg/kg/day and later increased to 150 mg/kg/day, was used to treat a 3-1/2-year-old girl with Rett syndrome. (Plochl 1996, Kelly 1998)
50 mg/kg/day of L-carnitine was used in 13 children with idiopathic dilated cardiomyopathy. (Kelly 1998)
1 g of L-carnitine twice daily orally for one week followed by 1 g daily for the second week was used in a small trial of women with diagnosed placental insufficiency. (Kelly 1998)
Acetyl-l-carnitine
Maestri 2005 used acetyl-l-carnitine at 1 g/die i.v. infusion over 1-2 hours in adults with with chemotherapy-induced peripheral neuropathy.
Hart 2004 used 1,500 mg twice daily (total of 3 grams/day) for the treatment of antiretroviral toxic neuropathy in HIV+ adults.
Diet and Nutritional Interactions
Carnitine biosynthesis in the body requires two essential amino acids, lysine and methionine, as well as vitamin C, iron, vitamin B6, and niacin, and involves a series of enzymatically catalyzed reactions. A well balanced diet can supply an additional 100-300 mg of carnitine each day. (Kelly 1998)
Because iron is an essential co-factor for the endogenous synthesis of carnitine, those who are iron-deficient may also have a secondary carnitine deficiency. (Cemeroglu 2001, Citak 2006)
Because L-carnitine is found primarily in animal proteins, especially red meat, it is theoretically possible to consume a high protein diet consisting of beans, legumes, and/or egg whites and still develop carnitine deficiency. (Kelly 1998)
Vegetarian diets are typically low in carnitine and could produce carnitine deficiency in some people. (Kelly 1998)
One study suggests that a high-fat, low-carbohydrate diet might increase endogenous carnitine synthesis. (Kelly 1998)
Although it is generally thought that medium-chain triglycerides (MCTs) do not use the carnitine transporter system, at least one study has found that administration of MCTs does impact plasma concentrations of free carnitine and acylcarnitines, which suggests that those on a ketogenic diet high in MCTs should be monitored for signs or symptoms suggestive of carnitine deficiency. (Kelly 1998)
Very low calorie diets (between 420-600 kcal/day) can result in reduced plasma and urinary carnitine levels, but those on restricted calorie diets who consumed most calories as meat, fish and/or poultry maintained significantly higher levels of plasma total carnitine. (Kelly 1998)
In rats, administration of the methylcobalamin, cyanocobalamin, and hydroxycobalamin forms of vitamin B12 have been shown to stimulate carnitine synthesis. (Kelly 1998)
Because the choline-betaine pathway shares an enzyme with the lysine to carnitine pathway, supplementation with high amounts of choline, phosphatidylcholine, lecithin or CDP-choline (citicoline) might decrease carnitine synthesis. (Kelly 1998)
Drug interactions
Anticonvulsants, including phenobarbital, valproic acid (Depakote), phenytoin, and carbamazepine, can significantly decrease carnitine levels. (Kelly 1998)
Treatment with the antibiotic pivampicillin (used in Europe) is well known to significantly interfere with carnitine metabolism in some people. (Kelly 1998)
L-carnitine should be used cautiously if at all with pentylenetetrazol (a respiratory stimulant drug), since evidence suggests the combination might enhance the side-effects of the drug. (Kelly 1998)
Possible explanatory mechanisms for carnitine's benefit in PWS
At this point there is no certain explanation for why carnitine seems to benefit at least some of those with PWS. Unfortunately, many important aspects of Prader-Willi syndrome are still very poor understood, including, for example, the status of mitochondrial functioning and fatty acid metabolism in PWS. Investigation of the mechanisms by which L-carnitine, acetyl-l-carnitine and other nutritional supplements such as Coenzyme Q10 that play an essential role in energy metabolism and improve PWS symptomology, such as the severe hypotonia that characterizes infancy in PWS, could provide significant clues to the disturbances in energy metabolism, neurological development and functioning, and other important physiological processes caused by the actual or functional deletion of the paternally expressed genetic information in the q11-q13 region on chromosome 15. That, in turn, could point the way to other possible beneficial treatments for PWS. At this point, though, it is only possible to list some of the possible explanatory mechanisms for the role of carnitine supplementation in the improvement of significant aspects of PWS symptomology.
A number of aspects of PWS, including hypotonia and lethargy, strongly suggest that there is impaired energy metabolism in PWS, including possibly impaired uptake and transport of long-chain fatty acids. Carnitine plays an essential role in the transport of long-chain fatty acids into the mitochondria for energy production.
Acetyl groups are used by the body to form adenosine triphosphate (ATP), the main energy source for the majority of cellular functions, as well as the neurotransmitter acetylcholine (ACh). Both L-carnitine and acetyl-l-carnitine are involved in the transport of acetyl groups into the mitochondria and acetyl-l-carnitine is also an intracellular energy reservoir (donor) of acetyl groups that has been shown to increase the synthesis and release of acetylcholine in the brains of rats. (Ando 2001, Imperato 1989) Acetyl-l-carnitine has also been shown to increase plasma ATP. (Capecchi 1997)
Respiratory insufficiency such as hypoventilation, apnea and hypopnea are very common in PWS and can result in chronic intermittent hypoxia (low blood oxygen levels), which in turn causes a significant increase in the production of free radical as well as many other damaging effects. Both L-carnitine and acetyl-l-carnitine are potent anti-oxidants that have been shown to have strong protective effects against the damage caused by hypoxia. (Wainwright 2006, Wainwright 2003, Dell'Anna 1997)
Silencing of the FMR1 gene due to hypermethylation is frequent in fragile X syndrome and research indicates that L-carnitine and acetyl-l-carnitine can partially reverse the hypermethylation-induced silencing of that gene. (Pascale 2003, Tabolacci 2005) In PWS, expression of the genes in the PWS region on the maternal chromosome 15 is similarly silenced by methylation, so it may be that carnitine can partially de-methylate the maternally imprinted (methylated) genes in the PWS region, thereby allowing partial expression of those genes.
There is some evidence of an impairment of the dopaminergic system in PWS. (Horsthemke 2003, Akefeldt 1998a, Akefeldt 1998b) Acetyl-l-carnitine has been shown to increase the synthesis and release of dopamine in the brains of live rats. (Harsing 1992)
There is evidence that the outgrowth and development of cerebral neurons is impaired in PWS. (Lee 2005) Acetyl-l-carnitine has been shown to increase the production of nerve growth factor (NGF) by cultured nerve cells and to help them respond better to NGF. (Kidd 1999, Taglialatela 1994) Acetyl-l-carnitine has also been shown to promote the growth and secretory activity of neuropeptide-producing cells in the hypothalamus, including gonadotropin-releasing hormone (GnRH) neurons. (Krsmanovic 1994, Krsmanovic 1992)
Studies have found low levels of hypocretin (Hcrt-1) in the cerebral spinal fluid in PWS, with the severity of the deficiency correlating with the severity of excessive daytime sleepiness. (Nevsimalova 2005) Both low hypocretin levels and reduced locomotor activity under fasting conditions have been found in systemic carnitine-deficient juvenile mice (Yoshida 2006), which suggests that the low levels of hypocretin in PWS (and perhaps in narcolepsy-cataplexy, which are associated with PWS) might be due to an actual or functional carnitine deficiency instead of a central hypothalamic disturbance as is commonly assumed.
There are anecdotal reports that daily injections of the methylcobalamin form of vitamin B-12 significantly improve some aspects of PWS. In rats, administration of the methylcobalamin form of vitamin B12 has been shown to stimulate carnitine synthesis (Kelly 1998) so it may be that carnitine supplementation is a way to circumvent the effects of a functional vitamin B-12 deficiency in PWS.
Suggestions for the use of carnitine in those with PWS
January 8, 2007 - Important note: I am in the process of making a substantial revision to the following section, so please check back in a few days for the most current suggestions for use of carnitine for PWS. For a preview of the changes, see this entry in the PWS Dots Journal. Thanks.
Please note that there have been no clinical trials of either L-carnitine or acetyl-l-carnitine in those with PWS and that the following suggestions are based primarily on a review of the scientific literature, anecdotal reports by healthy adults, my experience (both personally and as a traditional Chinese herbalist who had clients that used carnitine), and several anecdotal reports of its use in PWS. It is recommended that carnitine supplementation in those with PWS be carried out in consultation with your health care providers (e.g., pediatrician, nutritionist, etc.).
If you decide you want to try carnitine with your child with PWS, the first step is to decide whether to use acetyl-l-carnitine or L-carnitine, or possibly a combination. The following are some things to consider in deciding which form of carnitine to use:
As discussed above, both forms of carnitine improve the ability of the body's cells to generate the energy they need to function properly. L-carnitine's ability to improve cellular energy metabolism seem to be most evident in muscle, such as in reducing muscle fatigue, although it can also provide meaningful improvement in cellular energy metabolism in the brain. On the other hand, acetyl-l-carnitine seems to have a noticeably stronger effect than L-carnitine in terms of improving cellular energy metabolism and activity in the brain, while also improving muscle function, although perhaps to a lesser extent than L-carnitine.
What this means on a practical level is that if your child with PWS is mentally energetic, alert and curious, generally has sufficient mental stamina to get through the day, and has age-appropriate sleep patterns, but also has some muscle weakness and hypotonia, becomes physically fatigued easily, and/or has low physical energy levels in general, then L-carnitine is probably the more appropriate form of carnitine to try. On the other hand, if your child has significant signs of mental and physical lethargy, lack of alertness and responsiveness to others and their environment, and hypersomnolence (oversleeping), then acetyl-l-carnitine may be the more beneficial form of carnitine to try. If your child falls somewhere in between those two patterns, I would probably try L-carnitine first.
There are a few small clinical trials of acetyl-l-carnitine in those with Downs (De Falco 1994) and fragile X (Calvani 2001) syndromes that found an improvement in attention (Downs) and hyperactivity (fragile X). Another study found that acetyl-l-carnitine reduced impulsivity in adolescent rats. (Adriani 2004) There is therefore a possibility that acetyl-l-carnitine may have a beneficial effect for those with PWS who also have some signs of ADD/ADHD; however, that possibility needs to be carefully weighed against the risk that acetyl-l-carnitine's stimulatory effect might instead worsen ADD/ADHD symptoms in those with PWS. (Note that the biochemical basis for acetyl-l-carnitine's stimulatory effect is very different from that for such drugs as Ritalin and Adderall, which are basically forms of amphetamine.) As a result, I would only use acetyl-l-carnitine with considerable caution in any child with PWS who displays signs of ADD or ADHD. By considerable caution, I mean starting out with very small doses of acetyl-l-carnitine, increasing the dose in very small increments, and vigilant monitoring for any signs of an exacerbation of ADD/ADHD symptoms as well as other indications of an over-stimulatory effect (crankiness, reduction of sleep below age-appropriate levels, etc.).
Van Oudheusden 2002 found that L-carnitine reduced ADHD symptoms in 13 of 24 boys. However, given that L-carnitine can be converted by the body to the more stimulating acetyl-l-carnitine, extra caution in terms of diligent monitoring for behavioral and cognitive effects seems to me to be advisable when using L-carnitine in those with PWS who also have symptoms of ADD and ADHD.
As far as I can determine, there have been no studies of the use of either form of carnitine in those with obsessive-compulsive symptoms and therefore the effect of carnitine supplementation on OCD symptoms is unknown. As a result, increased caution in using carnitine in a child with PWS who also has OCD symptoms seems warranted to me, especially when using the more stimulatory acetyl-l-carnitine.
Some suggestions relevant to both L-carnitine and acetyl-l-carnitine
In general, get the best quality supplement that you can afford. Sigma Tau and Lonza are the two primary global manufacturers of bulk pharmaceutical grade carnitine and their Biosint(TM) and Carnipure carnitine products are used by reputable supplement companies such as Pure Encapsulations, Doctors Best, Now Foods, and Jarrow. However, good results have been reported with many other reputable brands (I take Rexall brand acetyl-l-carnitine from WalMart).
Buy a supplement with the least amount of other ingredients such as fillers, preservatives and colorants. In general, supplements that contain natural preservatives such as small amounts of vitamin E (5-10 IU) or vitamin C (5-10 mg) are preferable to those that use synthetic preservatives such as methylparaben, sodium benzoate, and the like.
Especially in the beginning and for small children, buy the smallest capsules you can find (typically 250 mg).
Even the smallest capsules will usually have too much L-carnitine or acetyl-l-carnitine in them for use with young children, which means you will have to open the capsules and divide out an appropriate dose. Using a small mirror or piece of glass and a single-edge razor blade can help in dividing the capsule contents.
Always start with low doses and slowly increase the dose every 3-4 days so that you can monitor for any adverse effects.
The daily dose should be administered in two or more divided doses to avoid the transient gastrointestinal disturbances (nausea and diarrhea) that can occur with large single doses and to maximize bowel uptake and provide stable levels throughout the day.
Always use the minimum effective dose. Although L-carnitine and acetyl-l-carnitine are both "natural" substances created within the body, it is important to remember that they have a broad range of effects, including possible changes in gene regulation and expression, metabolism, neurotransmitter synthesis, etc., much of which is still poorly understood. It is therefore important to use only the amount needed to achieve a more normal level of cellular energy production and no more.
Carnitine is water-soluble, so it can be mixed into expressed breast milk, formula or other liquid. Some forms (such as L-carnitine tartrate) are rather tart tasting and so may need to be disguised a bit to make them acceptable to a finicky child.
L-carnitine supplementation in PWS
As noted above in the Dosage section, the prescribing information for Sigma Tau's Carnitor for infants and children recommends 50 to 100 mg per kilogram per day in divided doses, with a maximum of 3 grams/day. Since Carnitor is nothing more than L-carnitine, its dosage range provides a good starting point for L-carnitine supplementation, regardless of the brand.
Sigma Tau states that the starting dose of its prescription form of L-carnitine for infants and children should be 50 mg/kg/day, but I personally would prefer a somewhat more cautious approach starting with, for example, 20 mg/kg/day, and then slowly increasing the amount every 3-4 days by 10 mg/kg/day until the dose that provides maximum benefit is reached.
Since there are 2.2 pounds to a kilogram, to determine your child's weight in kilograms just divide their weight in pounds by 2.2. For example, if your child weighs 22 pounds, their weight in kilograms would be 10 kg (22 pounds/2.2 = 10 kg). If you decide to start out with the suggestion of 20 mg/kg/day of L-carnitine, the starting daily dose for a child that weighs 10 kg would therefore be 200 mg (10 x 20), which you should then divide into two doses, that is, 100 mg in the morning with breakfast and another 100 mg with an afternoon snack or dinner.
While slowly increasing the amount of L-carnitine upwards by 10 mg/kg every 3-4 days, you will want to closely monitor your child's energy levels, exercise tolerance, muscle strength and general mental status, that is, their levels of alertness, concentration ability, and mental energy throughout the day, as well as their digestion, mood (relaxed, cranky, etc), and sleep pattern.
During the process of titrating the dose of L-carnitine upwards, you will reach a point at which an increase in dose results in no further improvement in hypotonia, exercise tolerance, alertness, etc. That is an indication that the prior dose was sufficient, so you should drop back to the previous dose.
Knowing the effective dose of L-carnitine per kilogram will make it easier to periodically adjust the dose as your child grows, so once you have determined the minimum fully effective dose, calculate the dose per kilogram by dividing the dose (in milligrams) by your child's weight in kilograms and make a note of it. For example, if your child weighs 10 kg and the minimum fully effective dose of L-carnitine is 350 mg/day, then the dose per kilogram is 35 mg (35 mg/kg/day).
Acetyl-l-carnitine supplementation in PWS
There is no prescription form of acetyl-l-carnitine, so unlike the situation with L-carnitine, there is no U.S. FDA-sanctioned starting dose for acetyl-l-carnitine. Anecdotal reports and my experience suggest that the minimum effective dose of acetyl-l-carnitine will often be considerably smaller than the effective dose of L-carnitine and that there is more variability in the effective dose from one person to another. As a result, the starting dose of acetyl-l-carnitine should be lower than that for L-carnitine and the dose should be titrated upwards in smaller increments.
For infants under the age of one year with PWS who have significant hypotonia, mental and physical lethargy, hypersomnolence, and borderline or frank failure to thrive due to poor nutrient intake from lack of interest in feeding, my suggestion would be to start at a total dose of 25 mg/day (that is, 1/10th of a 250 mg capsule), followed by an observation period of at least four days.
If there is no improvement or some improvement but with periods of lethargy as well as excessive sleeping, I would suggest increasing the dose by another 25 mg/day (for a total of 50 mg/day), then observe for another four to five days.
My sense is that the primary measures of improvement for the use of acetyl-l-carnitine in infants with PWS should be an increase in alertness, physical activity, and age-appropriate sociability and interest in others and their environment, as well as reduction in the amount of time spent sleeping to a more age-appropriate level. Of particular importance is what I think of as the "smile quotient." That is, if the infant's alertness, activity levels, and responsiveness to others and their environment improves to the point where they smile easily, but then the amount of smiling drops down after an increase in dose, that indicates that the minimum fully effective dose of acetyl-l-carnitine has been exceeded with the result that the baby is feeling some uncomfortable mental tension or pressure. In such a situation, the dose should be dropped back down to what it was when the baby had the highest "smile quotient," regardless of their level of residual hypotonia, muscle weakness, and/or hypersomnolence.
In addition to a drop in "smile quotient," other possible signs of over-stimulation in an infant due to a too large dose of acetyl-l-carnitine include increased fussiness, crankiness and irritability, difficulty falling asleep, and a reduction in overall sleep time below age appropriate levels. (Babycenter.com and Utah University Health Care have charts showing average sleep amounts for infants and young children.) If any of those signs occur, that is an indication that the minimum effective dose has been exceeded and that the dose should be reduced to what it was before the appearance of those signs.
I am not aware of any research upon which to base an estimate of the maximum dose of acetyl-l-carnitine for an infant with PWS, but in the absence of a concurrent diagnosed disorder of energy metabolism or carnitine deficiency, I would suspect that an infant who requires 200 mg/day or more of acetyl-l-carnitine to show improvement in their hypotonia, lethargy and hypersomnia is probably not going to respond to higher amounts or may have some other problem that needs investigation by a medical professional.
If there is some residual hypotonia and muscle weakness after you've determined the amount of acetyl-l-carnitine that results in an active, alert baby with a high "smile quotient," you may want to consider adding a small amount of L-carnitine to see if that helps. If so, I would suggest starting with 25 mg of L-carnitine and follow the usual protocol of waiting four days to judge the response before deciding to increase the L-carnitine another 25 mg.
Because the body can normally convert L-carnitine to the more activating acetyl-l-carnitine, I would also continue to monitor the baby's "smile quotient," sleep sufficiency, etc., in case some part of the L-carnitine is getting converted to the acetyl form with the result that the baby becomes overly stimulated, in which case I would reduce the acetyl form to the level that restores a high "smile quotient."
After you have finally found a balance of L-carnitine and acetyl-l-carnitine that seems to be "right" in terms of an alert, smiling, active and responsive baby with good muscle tone, calculate the dose of each per kilogram and make a note of them as a good starting point for review in 3-6 months, since the doses will need to be periodically adjusted to account for the baby's growth.
For children with PWS who are between one and five years of age, I would suggest following the above procedure for infants under one year of age.
For children with PWS over five years of age, I would suggest following the above procedure for infants under one year of age except with a starting dose of acetyl-l-carnitine of 50 mg/day and incremental upward steps of 25 mg/day.
For older teenagers and adults with PWS, I would suggest following the above procedure for infants under one year of age except with a starting dose of acetyl-l-carnitine of 100 mg/day and incremental upward steps of 50 mg/day.
If you try L-carnitine or acetyl-l-carnitine with your child with PWS, please consider writing me or posting in the guestbook to let me know the results.
Selected research in detail
In five children with severe neurologic handicaps whose management was complicated by excessive lethargy, L-carnitine at 35-50 mg/kg/day resulted in a marked improvement in alertness and arousability. In four cases, when L-carnitine was discontinued for a month, they all promptly became lethargic. When L-carnitine was re-started, the lethargy resolved and the improvement has been maintained for up to 14 months. In three children who were tested, serum carnitine levels (total and free) were normal before starting L-carnitine treatment. (Plioplys 1994)
An eight-week randomized, placebo-controlled, double-blind crossover trial of L-carnitine in 35 subjects with Rett syndrome (which includes hypotonia among its symptoms) suggested it was of some benefit for some of the subjects. (Ellaway 1999)
In a five-year-old girl with Rett syndrome with normal milestones that became retarded in the second year with muscle hypotonia of unknown cause and loss of known abilities, carnitine supplementation started at 3-1/2 years (75 mg/kg/day, later increased to 150 mg/kg/day) resulted in normalisation of plasma carnitine and improvement of physical activity, muscle hypotonia, communication and sleep time, with a one month washout and resumption of carnitine confirming the results. (Plochl 1996)
A 17-year-old girl with Rett syndrome, taking no other medications, was treated with L-carnitine (50 mg/kg/day). Within 2 months of initiation of treatment, she became much more alert, developed good eye contact, started reaching for objects with both hands, and answered simple questions with one or two words. L-carnitine was discontinued and within 1 week she lapsed into her pretreatment condition of lethargy with no interest in her environment, not reaching for objects, poor eye contact, and not speaking. One week after L-carnitine was resumed, she again became alert, started reaching for objects, and saying one or two words. Her serum carnitine levels (free and total) were within normal limits before and after L-carnitine treatment, but were higher while she was taking L-carnitine. (Plioplys 1993)
In a randomized, double-blind, placebo-controlled double-crossover trial, home and school behavior, including agressive behavior, of 13 of 24 boys with ADHD improved with carnitine supplementation. (Van Oudheusden 2002)
In rats, acetyl-l-carnitine supplementation at 1g/kg per day:
Improved ATP production in skeletal muscle mitochondria through an increase in mitochondrial protein content (elevated skeletal muscle respiration in old rats due to an increase in mitochondrial protein mass).
Significantly decreased body lipid percentage (decreased the efficiency of lipid deposition) in young rats.
Significantly increased body protein percentage (increased efficiency of protein deposition) in old rats.
Significantly decreased serum leptin levels (partly reduces the leptin resistance that occurs) in old rats.
The percentage of metabolizable energy (ME) intake stored as lipid was lower in acetyl-l-carnitine-treated young rats, whereas the percentage of ME intake stored as protein was greater in acetyl-l-carnitine-treated old rats compared with their age-matched controls. (Iossa 2002)
In another rat study (Hagen 2002), acetyl-l-carnitine (0.75 g/kg per day for old rats and 1.2 g/kg wt per day for young rats) plus alpha lipoic acid (0.12 g/kg per day for young rats and 0.075 g/kg per day for old rats):
Partially reversed the age-related decline in average mitochondrial membrane potential and significantly increased hepatocellular O(2) consumption, indicating that mitochondrial-supported cellular metabolism was markedly improved by this feeding regimen.
Increased ambulatory activity in both young and old rats, with the improvement significantly greater in old versus young animals and also greater when compared with old rats fed acetyl-l-carnitine or alpha lipoic acid alone.
Restored hepatocellular ascorbate levels in old rats to those seen in young rats.
Reduced the levels of malondialdehyde in old rats to levels comparable to those in young rats.
