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Some little hearts need more carnitine to live.

Being big-hearted is one thing; having a big heart is quite another. And little Kelly's heart was not only big, it was enormous. How Kelly survived, thrived, and today, at age nine, has arrived at the very top of her class in school can be summed up in one word: carnitine.

It was seven years ago in the Post that Kelly's grandfather, Dr. Lowell Clemmons, Sr., told the story of her rare heart disease called endocardial fibroelastosis, an inherited disorder in which synthesis of carnitine is disturbed. At that time, essentially no one knew about a proper therapy. Two of the country's outstanding pediatricians offered the same dismal prognosis: "A fatal disease with no known treatment. Maybe three months to live, maybe six months, maybe ...... Kelly was about a year old at the time.

Judy, Kelly's mother, was not one to give up without a struggle. Her diligent research led her to a children's heart-disease specialist, Dr. Marjorie Tripp, in Madison, Wisconsin, who had successfully treated two patients suffering from Kelly's problem. Promising the parents nothing, Dr. Tripp placed their daughter in the hospital for diagnostic procedures and for several days administered carnitine. A derivative of lysine, as she explained, it is necessary to prevent

the heart muscle from getting flabby. And that, in layman's terms, is what threatened Kelly's life: a big, flabby heart that would not contract normally.

After starting on the drug, Kelly was allowed to go home. Soon she began to look better, she began to eat, to gain weight. Her family began to have hopes that she might live a little longer than had been predicted. That, as we reported, was a long time ago, and at this writing, we telephoned Kelly's mother for an update. It couldn't have been more encouraging:

"Oh, she's a really healthy nine-year-old," Judy told us. "She's still taking carnitine and has no problem at all. We tried taking her off, but her carnitine level dropped so low the doctors felt that she couldn't do without it. She's on the school softball team, she swims, she loves everybody and everything. Today she's off fishing with one of her uncles."

Kelly is taking three grams of carnitine a day and will probably have to take it for the rest of her life.

"But that's not so bad," her now-deceased grandfather had said. "After all, as a diabetic I'm going to be taking insulin the rest of my life; it's the only way I m going to have a 'rest of my life.' "

Judy told us she still talks with Dr. Tripp occasionally, adding, "We know there aren't many who have exactly the same kind of genetic problem Kelly had. But one mother who had five babies lost three to carnitine deficiency before she found Dr. Tripp. Dr. Tripp treated and saved one of her two surviving children. Their other child was not affected. That was the case that brought me to Dr. Tripp originally."

As for carnitine itself, what a difference a few years make. Although discovered as a component of the human body approximately 80 years ago, it remained virtually unknown as a medicine until the past seven years. Today we know that carnitine is vital to normal body functions, because it transports lipids (fats) into the mitochondria of cells to be converted into energy. Without carnitine, one of the body's most important sources of energy is cut off.

Carnitine deficiencies occur most often in young children like Kelly and particularly in newborns whose bodies may not produce enough carnitine to provide proper muscle development. Children with carnitine deficiencies may have muscle weakness, poor weight gain, recurrent infections, and altered levels of consciousness.

If carnitine is the problem, treatment with carnitine supplements can produce dramatic results. Dr. Susan Winter, an assistant clinical professor of pediatrics at the University of California, San Francisco, Fresno, remembers her first carnitine case in 1982. Rafael, an infant, was suffering from a mysterious illness. His continual infections and progressive weight loss made it clear, Dr. Winter said, "despite all our efforts, Rafael was dying from his disease." But as a mother of young children herself, Dr. Winter could not accept this prognosis. She consulted all her colleagues for a clue. She relates her story: "Austin Shug, Ph.D., from Madison, Wisconsin, provided the first piece in the puzzle suggesting that carnitine might play a role in Rafael's metabolic disorder. He has spent more than 30 years researching carnitine and its role in cellular metabolism. Dr. Shug was convinced that carnitine deficiency was an underlying cause of some serious health problems, such as muscle disease, liver dysfunction, and growth and heart problems. He measured Rafael's blood carnitine level and found his hypothesis correct.

"An Italian-based company, Sigma-Tau Pharmaceuticals, provided our clinic with what was then the experimental drug treatment necessary for Rafael's survival. Within weeks, his condition improved dramatically. Where Rafael was once so weak that he was unable to sit up or lift his head at the age of nine months, he was suddenly growing, thriving, and gaining weight.

"After witnessing such a rapid response in Rafael, I began measuring carnitine levels on all my metabolic patients," Dr. Winters continues. "To my surprise, many of the children with defects similar to Rafael's were found to be carnitine deficient. I began more patients on carnitine therapy and saw similar improvement in their muscle strength, growth, and general health.

"Within two years I had accumulated information on 51 pediatric patients and began preparing my first manuscript describing this deficiency state. Through research I discovered that carnitine deficiencies result not only from hereditary or genetic disorders but acquired metabolic illness as well. I also found there is a much greater incidence of carnitine deficiency among children than adults. Many children, particularly newborns, have a lower capacity for biosynthesis and require additional dietary monitoring. Carnitine is present in a healthful, well-balanced diet consisting of red meats, dairy products, human milk, and carnitine-enriched infant formulas.

"Certainly, carnitine is not the panacea or miracle cure' we seek for every illness that causes parents and doctors sleepless nights. And not every patient I've treated for carnitine deficiency has shown a dramatic response.

"Angelo, at the age of three months, was hospitalized with severe heart failure due to a weak, poorly contracting heart muscle. The attending cardiologist had started many cardiac medications with only mild success. His carnitine measurement indicated a severe deficiency, and treatment was initiated. Angelo responded to the therapy, and to this day, six years later, he is still able to run and play. He has nearly complete resolution of his cardiomyopathy, a rare event in this disease before treatment with carnitine.

"Aaron was born with a cleft palate

and was referred to our clinic for genetic counseling at the age of six weeks. Because he was not gaining weight, I turned my attention to that problem. Feeding an infant with a cleft palate can be a very difficult task, so I naturally attributed Aaron's inability to gain weight to his mother's lack of success in feeding. I too was unsuccessful in feeding him and realized the problem was more complex. Like many other infants with carnitine deficiency, at feeding time Aaron would stiffen his body and scream. His level of carnitine, upon testing, did indicate a deficiency, most likely due to his poor dietary intake with the cleft palate. Three days following treatment, Aaron was calm, no longer stiff, eating, and gaining weight.

"Allison, age nine, exhibited a severe exercise intolerance. As a toddler, she was uncharacteristically inactive, and as the years went by it became increasingly apparent that she had health problems-she would become quickly exhausted while exercising and begin vomiting, sometimes developing a fever. Allison was examined by several cardiologists and neurologists who were unable to explain the phenomenon. One neurologist, however, suspected. a metabolic problem and referred her to me. I immediately noticed a fatty feel to her muscle, suggesting a possible fat [lipid] storage disorder. I prescribed carnitine treatment. Within 24 hours of the first dose of carnitine, Allison's tolerance to exercise began to improve. That weekend, she and her family traveled to the mountains, and she was able to join them on a walk without any problems. One year later, Allison is taking ballet lessons and participating in school sports.

"Nathan had experienced continuous ear and upper respiratory tract infections from age six months. Lethargic and frail, he had been hospitalized for failure to thrive and diarrhea. Although Nathan's plasma carnitine level was not abnormal, I began carnitine treatment based on the symptoms. Two weeks later, Nathan was growing and gaining weight and was free of infection.

"Monica had a brain tumor at a young age. She underwent surgery and irradiation treatments, and she suffered some neurologic problems as a consequence, including seizures. Treated successfully for several years with valproic acid, a seizure medication that alters the body's level of carnitine, Monica suddenly regressed and ended up hospitalized and nearly comatose. We measured her carnitine level and began treatment. She showed a rapid improvement in her neurologic performance and seizure control and was clearly better within days.

"A diet lacking in carnitine, bowel problems with poor absorptions of foods, chronic diarrhea, kidney problems, metabolic disease, or treatment with valproic acid are just some of the ways this deficiency can develop. Symptoms include muscle weakness, poor weight gain, recurrent infections, and altered levels of consciousness."

Dr. Winter suggests that if a child has one of the predisposing conditions or one or more of the symptoms, carnitine deficiency might be the cause. However, carnitine deficiency is a relatively unknown disorder. The best way to investigate this possibility further would be to consult with the child's physician, who may refer to existing literature on the topic. Car-. nitine deficiency can best be determined by muscle biopsy, but the process is invasive. Examination of plasma is a noninvasive, but less effective, alternative to biopsy.

For those diagnosed with carnitine deficiency, treatment with L-carnitine, cleared by the Food and Drug Administration in July 1986, is now available by prescription.

Parents whose child has been diagnosed as having a metabolic or genetic disorder should consider establishing contact with a local support group through such organizations as the Alliance of Genetic Support Groups, March of Dimes National Registry For MPS/ML Disorders, and the Society for Inherited Metabolic Disorders. "Handling special medical problems and finding proper care doesn't have to be a dark mystery. Use the avenues of a good detective," Dr. Winter advises.

She urges parents to look for unusual developmental signs or poor growth in a child-the easy-to-spot clues-and seek prompt medical care.

In addition to synthesis in the liver and kidney, the body's carnitine pool is replenished from the diet. The highest concentrations of L-carnitine are found in red meat and dairy products. The typical nonvegetarian diet in the United States provides about 100 to 300 milligrams of L-carnitine daily. Vegetables, cereals, and fruits contain little or no carnitine. Strict vegetarians, therefore, have negligible sources for this nutrient. The total body pool of carnitine in an adult of normal weight is approximately 1,500 mg. Of this quantity, 98 percent is found in muscle, including the heart muscle, and only 2 percent in liver, kidney, and other tissues. The concentration of carnitine in the blood is less than that in tissues.

The only known route for carnitine removal from the body is excretion in the urine. Renal clearance reflects to some degree the plasma concentration: when the plasma's carnitine falls, the urine excretion of carnitine diminishes.

The carnitine function is closely linked with the cell's membrane function. Humans, like other living organisms, are composed of cells. A typical cell is separated from the surrounding fluids by the all-important cell membrane. Inside of the cell is the cytoplasm and the nucleus. Cytoplasm contains many structures, called organelles, necessary for the cell's function. Among cellular organelles, the ones called mitochondria are especially interesting. Mitochondria have been considered to be the "powerhouse" of the cell, because it is here that the nutrients, including oxygen and the various foodstuffs, are metabolized to supply energy for all the cells. The amount of energy it is possible to achieve upon oxidation of fatty acids is approximately 2.25 times more per gram than from carbohydrate or protein oxidation. (Fatty acids are the products of the digestive process of dietary lipids that reach the body cells as energy.)

There is only one problem-mitochondrial membrane permeability. Only part of the nutrients can pass directly from the cytoplasm into the mitochondria according to their concentration gradient. The rest are able to penetrate the mitochondrial membrane only with a very special type of molecular vehicle. This type of transport is necessary for the movement of molecules of fatty acids from the cytoplasm into the mitochondrial space. This is the role that carnitine plays. Without carnitine, fatty acids can't pass into the mitochondrial space.

Nearly all cells of the human body can use fatty acids directly as a source of energy. The degree of utilization of fatty acids varies considerably from tissue to tissue and depends to a significant degree upon the metabolic status of the body, whether it is fed or fasted, exercised, and so on. For instance, nervous tissue apparently oxidizes fatty acids to a minimal degree, but cardiac and skeletal muscles depend heavily on fatty acids as a major energy source. During prolonged fasting, most tissues are able to use fatty acids for their energy requirement.

When carnitine concentration in the cells is too low, only a limited number of fatty acids can be introduced into the mitochondria, and the amount of energy production will be restricted. There are at least a few different causes for impairment of carnitine function within cells.

The first is the reduced capacity for synthesis. There are several potential causes of such reduced synthetic capacity: deficient intake of lysine and methionine, vitamin C, vitamin B 6, niacin, or iron; advanced disease of the liver or kidney; and prematurity of the synthesis pathways in newborns. It has been found that the efficiency of carnitine synthesis is age dependent. In the liver the activity of carnitine synthesis increases from 12 percent efficiency in infants during the first months of life to 100 percent efficiency by age 15. There is convincing evidence that premature infants have a lower capacity of carnitine synthesis than do full-term newborns.

Synthesis of carnitine in some geriatric patients fed carnitine-free diets may not be adequate to maintain normal body carnitine levels. Another common cause of an insufficient amount or even lack of carnitine is a congenital block in synthesis. The other causes include excess losses of carnitine as a consequence of kidney disease, and hemodialysis. The proper renal excretion of carnitine is also age dependent. Mechanisms that can regulate carnitine excretion are not fully matured in the newborn. Increased tissue requirement for carnitine may also occur as a consequence of rapid growth of the infant.

Lack or prolonged deficiency of carnitine leads to a diminished amount of energy received from fatty acids' oxidation. Skeletal muscles are generally involved with weakness. Cardiac muscle, like skeletal muscle, is dependent on fatty acids for energy during fasting, and cardiomegaly (enlarged heart), cardiac failure, and arrthymias are manifestations of carnitine deficiency.

The carnitine status of vegetarians is very interesting. It has been reported that approximately 4 percent of adults in the United States consume a vegetarian diet, and 90 percent of vegetarians are ovolactovegetarians-they include eggs and dairy products in their diets. Strict vegetarian diets contain less than 10 percent as much carnitine as typical omnivorous diets of the developed nations, and ovolactovegetarian diets contain about 20 percent as much.

Until the issue is resolved, one should be aware of potential carnitine deficiencies of vegetarians.
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Title Annotation:endocardial fibroelastosis therapy
Author:Jaskiewicz, Jerzy
Publication:Saturday Evening Post
Date:May 1, 1990
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