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Over the past 30 years, carnitine has become a vital component of the treatment plan for many inborn errors of amino acid, organic acid and fat metabolism. Despite the increased use by metabolic specialists and the approval of L-carnitine by the FDA for the treatment of inborn errors of metabolism, the lack of randomised controlled trials comparing carnitine supplementation with different doses, frequency and duration versus placebo in any of the inborn errors has continued to raise concerns regarding its efficacy.In order to make an informed decision regarding the use of carnitine therapy, for you or your child, it is important you understand more about this molecule.

Carnitine’s main role in the body is transport.It is the vehicle that carries fat into the cellular furnace, the the mitochondria, and the vehicle that removes accumulat- ing”ashes”of poorly burnt fats and amino acids from the mitochondria and carries them out of the body via the urine.These”ashes” attached to carnitine are known as carnitine esters, bound carnitine or acylcarnitines. Without carnitine,fat cannot be transported into the mitochondria to generate energy. Patients with a genetic metabolic disorder often develop carnitine deficiency due to the massive accumulation of unme- tabolized chemicals(ashes) which are only removed attached to carnitine molecule. If they are not given carnitine supplementation, these “ashes” deplete the store of body carnitine and can cause life threatening complete mitochondrial failure with the inability to produce energy from all fuels. In these disorders, supplemental carnitine can directly remove the accumulating unburnt metabolic”ashes” and restore mitochondrial function.

L carnitine is a natural occurring substance similar to vitamins and minerals. The Levo or L form is the only biologically active form of carnitine and the D or Dextro form is not biologically active. Carnitine is synthesized from the amino acid, Lysine, and released during muscle protein breakdown with the final synthetic step occurring in the liver. Carnitine is also obtained from the diet, with the red meat having the highest concentration. In adults, about 50% of the body’s carnitine comes from the diet. Milk, including human milk, contains carnitine and is the main source of carnitine during infancy when synthesis from muscle breakdown is minimal. Carnitine is a small amino acid molecule and when carried in the blood in the kidney both the free carnitine and the carnitine with its metabolic ash will pass through the kidney’s sieve and into the urine. As the urine goes through the kidney’s tubules on its way to the bladder, the kidney actively picks up over 95% of the free carnitine and puts it back into the blood while it allows the carnitine vehicle along with its ash to go out in the urine. Therefore, more ash produced from an inborn error of metabolism will result in more carnitine going out in the urine.

The normal concentration of carnitine in tissues such as blood and muscle in humans is well established. Deficiency of L carnitine occurs and is defined by values 2 standard deviations lower than normal values. (This is the accepted way we define deficiencies of all natural substances such as iron, vitamin C, sodium, etc) As with all natural substances, deficiency can and does occur. Deficiency of carnitine can occur due to decreased synthesis, decreased dietary intake or increased loss or a combination of these factors.

The majority of body carnitine is found in muscle with only 5 percent in the blood. Carnitine deficiency is, therefore, best diagnosed by the content in muscle tissue. This requires an invasive muscle biopsy. A blood, although less accurate, is easy to obtain and in several studies, a low blood free carnitine level correlated well with a muscle level. However, a blood level can miss the deficiency in the muscle if there has been a recent intake of dietary carnitine.

Carnitine deficiency results in decreased energy production in the mitochondrion. Since most of the body’s carnitine is in muscle, it is not surprising that carnitine deficiency causes muscle symptoms of weakness, low tone, delayed motor milestones, poor muscle growth with failure to thrive. cardiac muscle relies heavily on fat metabolism for energy and carnitine deficiency causes weakening of the heart muscle known as cardiomyopathy. These muscle symptoms due to carnitine deficiency generally reverse when carnitine deficiency is corrected. The liver uses carnitine, as well, for the generation of energy. Hepatic (liver) carnitine deficiency will result in altered liver function with elevation of liver enzymes in the blood. The brain is highly dependent on energy supplies and symptoms of carnitine deficiency include convulsions, lethargy, and even coma.

Carnitine deficiency due to an inborn error in the carnitine synthesis pathway is exceedingly rare and likely not compatible with life most cases. A genetic deficiency of the carnitine transporter in the kidney will result in loss of the filtered carnitine being reabsorbed and severe deficiency. These genetic deficiencies of transport and synthesis are referred to as “primary carnitine deficiencies”

The vast majority of patients with carnitine deficiency become deficient due to complications of other disorders. Deficiency due to causes other than genetic diseases of synthesis or transport of carnitine are called”secondary carnitine deficiencies”. There are often multiple factors contributing to these secondary deficiencies. Deceased dietary intake, especially in children under 2 years of age, will result in carnitine deficiency. When infant soya formulas were first introduced , years ago, they were very deficient in carnitine and normal infants developed symptomatic deficiency states which went unrecognized for years. These children, once started on solid foods with meat, quickly improved. Dietary protein restriction, as required by children with MSUD and other inborn errors, will result in decreased dietary carnitine and require supplementation. Children and adults receiving total parenteral nutrition(TPN) can develop carnitine deficiency with days or weeks unless the TPN is supplemented with carnitine. Diarrhea with decreased absorption of food, including carnitine, will result in many deficiency states including symptomatic carnitine deficiency. Increased loss of carnitine occurs during hemo-or peritoneal dialysis and can be prevented with post dialysis intravenous carnitine therapy. Kidney disease resulting in poor reabsorption of carnitine in the tubule will result in carnitine deficiency.This can be due to a long standing kidney tubular dysfunction either genetic or acquired. This can also be a temporary problem occurring with urinary tract infections. As mentioned above, the increased loss of carnitine carrying the ashes that result from inborn errors of metabolism will also result in severe carnitine deficiency. The quantity of carnitine ashes also known as acylcarnitines, in diseases such as propionic acidemia and methylmalonic acidemia, can result in a thousand fold loss of carnitine and life threatening deficiency.

In MSUD, the accumulating amino acids, isoleucine, leucine and valine do not form acylcarnitines, and therefore their removal is not dependant on carnitine nor improved with carnitine supplementation. Even though the child with MSUD cannot use carnitine to detoxify the accumulating metabolites, additional carnitine is needed to generate energy from fat. Individuals with MSUD rely heavily on fat metabolism as the energy source during episodes of decompensation. The presence of ketones in the urine signals this emergency state. In addition to transporting the fat into the mitochondria for energy production, carnitine is needed to remove the ketone bodies which accumulate during times of decompensation.

L-carnitine is available as a pharmaceutical grade drug and is approved by the Food and Drug Administration to treat both primary carnitine deficiency and secondary carnitine deficiency due to inborn errors of metabolism and dialysis. Several companies have pharmaceutical grade L-carnitine is available by prescription in several forms:

1.Oral liquid L carnitine contains 100 milligrams of carnitine in each milliliter. 2. Oral L carnitine tablet with 330 milligrams of carnitine per tablet. 3. Intravenous L-carnitine in vials containing 1 gram in 5 milliliters of solution.

L-carnitine is also available as a health food product but these products do not require the use of pharmaceutical grade carnitine and are not tightly regulated and may contain doses of L-carnitine different from what their label indicates. Therefore , it is recommended that treatment with pharmaceutical grade carnitine by prescription be used to treat deficient or potentially deficient and symptomatic patients.

The dose and form of L-carnitine prescribed will depend on the underlying cause of the deficiency state. Simple dietary deficiency with no underlying disorder will respond nicely to low doses of oral carnitine for a short course. Higher doses and lifelong treatment may be needed for individuals with organic acidurias with increased loss of acylcarnitines. Intravenous L carnitine is often used during times of metabolic stress and decompensation. L-carnitine doses range from 25 to 600 milligrams per kilogram body weight per day for oral carnitine and 25 to 300 milligrams per kilogram body weight per day with IV carnitine. Safety studies were done on these doses during the drug trials for FDA approval. Oral carnitine is poorly absorbed with only 20% actually absorbed. The rest is excreted in the stool.

About 10% of patients taking oral carnitine experience side effects of diarrhea and/or stomach upset and in about 7% of individuals, a very fishy body odor develops. This odor is generated in the bowel by normal anaerobic bowel bacteria converting carnitine to a very smelly but non-toxic, trimethylamine. This body odor can be treated by taking a low dose of antibiotic, such as 125 mg. metronidazol, for a course of 10 days to destroy the offending bacteria that makes the trimethylamine. The gastrointestinal upset and diarrhea associated with oral carnitine administration usually improves if the dose is lowered or given with food. intravenous carnitine is fully available for body use because it bypasses the bowel absorption problems and for this reason is the preferred route of administration during a life threatening crisis. Intravenous carnitine will burn if infused too quickly and cause pain and irritation if it gets under the skin (interstitial).

In summary, the child with MSUD has decreased intake and synthesis of carnitine and an increased need for carnitine to use in fat oxidation and for the removal of ketone bodies that are formed during decompensation. Carnitine is essential for the generation of chemical energy availability; muscle weakness, poor growth, decreased resistance to infections, cardiac dysfunction and neurologic problems.Treating fatty acid oxidation defects, organic acidurias and amino acid disorders, including MSUD, with L-carnitine has been shown to be sage and also lifesaving during the times of metabolic stress.

All patients with MSUD are at risk of developing carnitine deficiency. During times of crisis, IV or oral carnitine will aide with the removal of ketone bodies. Monitoring of plasma carnitine levels should be done periodically and if low supplementation be started. Alternatively, supplementation with oral L-carnitine at a dose of 50-100 milligrams per kilogram weight per day will provide adequate levels of carnitine to deal with potential stresses in patients with MSUD. You need to discuss, with your metabolic team, the role carnitine will play in your overall treatment plan.



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