The Dec. 1992 issue of the Organic Acidemia Association Newsletter printed an article on protein malnutrition written by Dr. Hillman of the University of Missouri, Columbia. I asked Dr. Hillman to adapt the article for our Newsletter. He kindly answered my request.

It is important for parents and older children with MSUD to understand the basics of protein nutrition. This knowledge helps in understanding the importance of the diets and formulas (medical foods) for persons with MSUD. If you have questions on this subject, please discuss it with your nutritionist or doctor.

Malnutrition (or under-nutrition) can involve any of the groups of nutrients that are necessary to sustain life and to maintain growth in infants and children. It may involve protein, calories, minerals, or the co-factors for enzymes that we usually ingest as vitamins. Children can have a generalized lack of all nutrients, or a deficiency of a specific nutrient or group of nutrients.

In most children with MSUD, because of the nature of the disorder and its dietary therapy, nutritional problems usually involve proteins and their component parts, the amino acids. For that reason, this discussion will be limited to protein and amino acid malnutrition.

Proteins are associated with all forms of life and have many different functions in the body. Proteins act as catalysts for most chemical reactions, as the structural support system which holds everything together; as hormones, as antibodies, and as carriers of other vital substances in the blood stream.

Proteins are formed by joining component parts, called amino acids, into chains. The human body does not have the ability to produce some of these amino acids and they must be ingested from vegetable or animal sources. These eleven amino acids are called essential amino acids. They include the three branched-chain amino acids, leucine, isoleucine and valine. An additional nine amino acids are necessary to make proteins. Because the human body can make these, they are considered non-essential amino acids. Some of these amino acids are made from essential amino acids, others from carbohydrates or fats. Although some essential amino acids are stored in the body, the amount that is stored is only adequate for a few days of fasting in an adult, and is totally inadequate to sustain growth in an infant or child.

When proteins are ingested from any source, they are broken down into individual amino acids. With very little exception, only the amino acids can be absorbed. Since the amino acids are the same in animals or vegetables, the source of protein is usually not important. It is important, however, that an adequate amount of all the essential amino acids be present. A normal adult consumes about 100 gm of protein each day and recycles about 70 gm of body protein. Each day about 10 gm of protein is lost in the stool, so about 160 gm of amino acids are utilized daily.

To understand the treatment of MSUD, it is necessary to know the varying fates of amino acids once they are absorbed into the body. Amino acids can be used: 1) to make new proteins and cells; 2) to make other important compounds needed by the body; 3) as a source of energy.

Firstly, amino acids are incorporated into new proteins. Body proteins and body cells are constantly replaced. However, different proteins and cells turn over at very different rates. Some have to be replaced in very short periods of time (hours) and some need only be replaced after very long periods (months or even years). Also the need for amino acids to make proteins varies with the body's growth and activity. Thus, if a person ingests a relatively constant amount of protein, some of time the amino acids will not be needed and will be burned for energy.

Secondly, some amino acids are used to make other important compounds within the body. These include genetic material, compounds that serve to excrete wastes, and many of the chemicals that make the nervous system work.

When amino acids are present in excess, or when they cannot be utilized because of imbalances (discussed later), they undergo a third fate. This is the breakdown of amino acids into organic acids to be used as energy. Most children with organic acidemias have blocks in their ability to "burn" organic acids and these accumulate. In MSUD these are the compounds which produce the acidosis and give the distinctive odor.

How much protein is necessary? Many different techniques have been used to estimate the protein requirement in a healthy human. Despite the variation that comes from different methodology, it is estimated that the so-called average man, weighing 70 kgs. (154 lbs) needs about 0.5 gms of protein per kg per day to maintain his/her body. To be safe, a minimum of 56 gm of protein or roughly 0.75 gms per kg per day is recommended. In comparison, the needs of the growing child are much higher. At birth, the child needs over 2.0 gms per kg per day to maintain growth. This amount gradually decreases with age but is always higher than the adult figure until growth ceases after puberty. The present recommendation of the World Health Organization is to maintain 1.8 gms per kg per day in the growing child after the newborn period. Other groups have recommend more.

All of these listed protein requirements in man are based on the assumption that the ingested protein is ãbalancedä and contains adequate amounts of all the essential amino acids. The standard for an ideal protein is the casein in human milk. It is assumed that the ratio of amino acids in human milk is ideal and all computations of the ãqualityä of protein are made by comparison of the amino acids with those in casein. Thus, it is recommended that vegetarians eat beans with grains because the mixture of the two sources of protein provides amino acids in roughly the balance found in milk. Remember that only the amount of amino acids is important, not their source or sources.

Balance of amino acids is important because of the way that proteins are made. Proteins are manufactured like a long set of beads. Each bead is an amino acid in a particular pattern. The amino acids are added one at a time so that if the next amino acid is missing the process stops. If a particular amino acid is in short supply, even if all other amino acids are present in excess, the body cannot replace its proteins. The amino acids that can not be used to make protein are then used for energy. Under-nutrition with a single amino acid is functionally equivalent to total protein malnutrition.

How does this relate to protein malnutrition in children with MSUD? All people must ingest enough amino acids to maintain their body proteins, and, in children, to allow for growth. Because the newborn grows so rapidly, the diet of an infant with MSUD may not be very different from other infants (all amino acids are used for growth). Indeed, some infants with MSUD will not become ill until their growth rate slows at several months of age.

Most people can eat protein in excess because any extra can be burned to provide energy. The child with MSUD cannot burn a particular group of amino acids without producing a toxin (the organic acids) that can made them quite ill. However, they still need enough of the amino acid for maintainence and growth.

Thus, those caring for these children are faced with a difficult balancing act of providing just enough of the branched chain amino acids, but not too much. The requirements for these amino acids can be quite low in children with MSUD. In many cases, complete protein must be limited or a deficiency of the other essential amino acids would occur if they are not given by some other means. The special formulas provide the other amino acids as well as the vitamins and minerals that may be deficient on such a very limited diet. The balancing act is particularly difficult in infants and children because they do not grow at a constant rate, or if they have been sick, may have a period of rapid "catch-up" growth. It can be very difficult in older individuals because they may refuse to take the special formulas. Particularly during the early years the diet can only be regulated by constantly monitoring growth and blood levels of amino acids.

Because proteins and cells turn over at different rates, different parts of the body and different proteins are affected at different times in children with under-nutrition. The single most sensitive index of protein nutrition is growth (length, not weight). Usually growth rate will fall before many other problems are seen. Often skin problems (rashes or breakdown) will occur as an early sign particularly in areas that are irritated for other reasons. Gastro-intestinal (GI) problems are common because the surface of the intestine is one of the most rapidly replaced cell surfaces in the body. GI problems can then make the condition worse by leading to poor absorption of nutrients. If the condition continues long enough, the bodyâs ability to fight infection may decrease.

It is impossible to maintain these children without constantly monitoring them in some fashion. Their amino acid needs are not constant. A flexible dietary prescription to meet the needs of the individual child is crucial. Overall, the increasing success in maintaining children with MSUD on these strange and difficult diets without malnutrition is a tribute to the art and science of the parents, nutritionists, and physicians who care for them.


The MSUD Family Support Group is currently funding several research projects and we are proactively looking for researchers interested in developing new treatments or finding a cure for MSUD. Significant funding is necessary if we are to accomplish this goal.
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