Dr. Susan Winter spoke on the topic "Use of Carnitine in MSUD" at the MSUD Symposium 2002. Dr. Winter is the Medical Director for the Department of Medical Genetics/Metabolism at the Valley Children's Hospital in Madera, California. She is also one of the medical advisors for the MSUD Family Support Group. Some families have found a benefit in supplementing the MSUD diet of their child with carnitine. On request, Dr. Winter kindly submitted the following article for this issue of the Newsletter.

Carnitine is a natural substance important to the transport of fat into the mitochondria where it is "burnt" to form chemical energy. Carnitine is also important in removing the chemical "ashes" remaining after fat or protein is burnt in the mitochondria. It does this by binding to the chemical ashes and carrying them out of the mitochondria and then out of the body as carnitine bound "ashes" (acylcarnitine derivatives) dissolved in the urine. Carnitine is obtained from red meats and dairy products in the diet and from breast milk. It is also made in the body by breaking down muscle protein and dietary protein and converting them to carnitine.

As with all natural substances, deficiency can occur. Carnitine deficiency is nearly always secondary to other problems and may often be due to more than one factor. In infants and small children with small muscle masses, carnitine deficiency can develop easily due to a poor supply of protein in the muscles or a decrease in the dietary protein needed for synthesis. These small structured children are very dependent on a supply of carnitine from the diet. A chronic metabolic disorder, such as maple syrup urine disease (MSUD) which requires a special low protein diet, makes these infants and children even more vulnerable.

The majority of body carnitine is found in muscle with only 5 percent in the blood. Carnitine deficiency is best diagnosed with a muscle biopsy to test the levels in muscle tissue, but it is a very invasive test. If the blood level is low, the muscle level is always low. However, if the blood level is normal, it may simply reflect a recent dietary intake of carnitine and be falsely reassuring. A rapid response with an increase in energy level, muscle strength and stamina with carnitine treatment, even with normal blood levels, suggests that the muscle needs for carnitine were not being met, and the person was probably muscle carnitine deficient.

Sick children with metabolic disorders often rely on total parenteral nutrition (TPN) that is not routinely supplemented with carnitine, and a deficiency can develop within days or weeks. Children and adults with metabolic disorders are very susceptible to infections such as gastroenteritis [an inflamation of the stomach and intestinal tract]. With this condition, malabsorption of carnitine adds to the problems of supply. Increased loss of carnitine from the blood or urine can occur with hemo- or peritoneal dialysis because carnitine is removed by the dialysis fluids. Carnitine deficiency occurs in patients with kidney disorders and affects the reabsorption of needed chemicals from the filtered urine (renal Fanconi syndrome). This syndrome can be a temporary problem resulting in urinary tract infections - frequently a problem in patients with metabolic disorders. In genetic metabolic disorders affecting fat oxidation and organic acid metabolism, carnitine deficiency occurs due to a massive excretion of carnitine in the urine bound to the un-burnt chemical "ashes." High levels of these un-burnt chemicals attached to carnitine can be detected in the blood and urine. This is the basis of the acylcarnitine derivative testing used in the MS/MS method of newborn screening.

In MSUD, the accumulating amino acids, isoleucine, leucine and valine do not form carnitine bound esters, and therefore their removal is not dependent 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. The inability to generate energy from fat due to carnitine deficiency can prove life threatening.

Carnitine deficiency is nearly always secondary to another disease process, so the symptoms are often those of the primary disease plus additional problems caused by the deficiency. Carnitine replacement therapy can resolve these problems. A deficiency of carnitine results in decreased energy available to muscle, causing muscle weakness and low muscle tone. Energy is required for the growth of muscle and for weight gain, so the child with carnitine deficiency often fails to thrive. A deficiency can affect cardiac muscle and result in poor cardiac contractions (cardiomyopathy). This leads to heart failure which may respond dramatically to carnitine therapy.

Energy is important for brain function and carnitine deficiency can cause convulsions, lethargy, irritability, and even coma. MSUD patients are very susceptible to infection which requires additional energy to resolve. In a genetic defect, which inhibits the ability to generate energy from protein sources, the problem is made worse by a carnitine deficiency. This results in a decrease of the energy generated from fat.

Carnitine is available as a medication approved by the Food and Drug Administration for treating secondary deficiency due to metabolic diseases. In the U.S.A., only one company, Sigma-tau Pharmaceuticals, Inc., supplies pharmaceutical grade oral L-carnitine (Carnitor). It is available with a prescription as a liquid with 100 milligrams of carnitine in each milliliter (500 per teaspoon) and as a tablet with 330 milligrams of carnitine per tablet. Intravenous L-carnitine is also available in vials containing 1 gram in 5 milliliters of solution.

The amount of oral carnitine used depends on the reason for treatment and the clinical state of the patient. Higher doses are generally reserved for individuals with serious metabolic disorders during times of metabolic stress and decompensation. Doses range from 25 to 600 milligrams/ kg/day for oral carnitine and 25 to 300 milligrams/kg/day with IV carnitine. Oral carnitine is poorly absorbed with only 25% 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 bowel bacteria converting carnitine to a very smelly, but non-toxic, trimethylamine. This body odor can be treated by taking a low dose of an antibotic, such as metronidazole, 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 the ketone bodies that are formed. Carnitine is essential for the generation of chemical energy and a deficiency will result in symptoms of decreased 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 safe and also life saving during the times of metabolic stress.