Introduction

Maple Syrup Urine Disease (MSUD) is a disorder in the body's ability to use three of the essential amino acids in protein. These three essential amino acids (Leucine, isoleucine and valine) are often called the branched-chain amino acids (BCAAs).

Protein in the body is made up of 20 amino acids, eleven of these are essential and nine are nonessential. The essential amino acids must be supplied in the daily diet. The nonessential amino acids can be obtained from the diet or produced in the body from other amino acids.

In MSUD, the enzymes necessary to break down leucine, isoleucine and valine are either absent, inactive, or only partially active. Because of the enzyme deficiency in MSUD, the BCAAs and their byproducts, called ketoacids, become elevated. It is these elevations that cause an infant or child with MSUD to become symptomatic.

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Genetics

MSUD is a recessive genetic disease. This means both parents of a child with MSUD must carry a mutation in the same gene (the same genetic code). These mutated genes do not function normally, thus causing disease. A person with a gene mutation is called a carrier. Carriers are not affected by their one abnormal gene. (Just as everyone carries genetic codes, such as those for the color of hair and eyes, everyone also carries several abnormal genes which can cause disease.)

Each individual person has two genes that code for the enzyme activity involved in the breakdown of the BCAAs; one gene coming from the father and one from the mother. If one gene functions normally, but the other does not, then the person is a carrier of MSUD. If neither gene functions normally, then that person has MSUD. It is also possible to receive the normal gene from each parent and not have any mutated genes for the disease.

When parents are both carriers of the gene for MSUD, with each pregnancy, there is a 1 in 4 chance of having a baby with MSUD, a 2 in 4 chance that the baby will have only one gene for MSUD and be a carrier like the parents, and a 1 in 4 chance that the baby will neither be a carrier nor have MSUD.

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MSUD Classifications

Four general classifications are used to identify the types of MSUD: classic, intermediate, intermittent and thiamine-responsive. These terms refer to the amount and type of enzyme activity present in the affected child, which can vary considerably within each classification.

Classic is the most common type of MSUD. In classic MSUD, little or no enzyme activity (usually less than 2% of normal) is present. Infants with classic MSUD will show symptoms within the first several days of life. They generally have poor tolerance for the BCAAs, so protein must be severely restricted in their diet.

Intermediate MSUD is a variant of the classic type of the disease. Those with intermediate MSUD have a higher level of enzyme activity (approximately 3 to 8% of normal). They can usually tolerate a greater amount of leucine. However, when ill or fasting, the child with intermediate MSUD reacts just like a child with classic MSUD. Management is similar for the intermediate and classic types of MSUD.

Intermittent MSUD is a milder form of the disease because of the greater enzyme activity present (approximately 8 to 15% of normal). Often the child does not have symptoms until 12 to 24 months of age, usually in response to an illness or surge in protein intake. During episodes of illness or fasting, the BCAA levels elevate, the characteristic maple syrup (or burnt sugar) odor becomes evident, and the child can go into a metabolic crisis.

Thiamine-responsive MSUD is basically just what the name implies. Giving large doses of thiamine to the thiamine-responsive child will increase the enzyme activity which breaks down leucine, isoleucine and valine. In most cases only moderate protein restriction is needed for this more rare type of MSUD.

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Diagnosis/Screening

Infants can be screened for MSUD through mandatory state screening programs. Unfortunately, many states do not include MSUD in their newborn screening programs. Furthermore, the methods used by some states are outdated and can be inaccurate. Thus, many neonates are diagnosed only after they start showing symptoms of MSUD.

Infants with classic MSUD appear normal at birth with symptoms appearing within 3 to 7 days. In infants with intermediate MSUD, symptoms are milder and may not be apparent as soon. Symptoms include fussiness, lethargy, decreased nursing/feeding, poor weight gain, hypotonia (poor muscle tone) or hypertonia (excessive muscle tension), vomiting, a high-pitched cry, seizures and the characteristic maple syrup smell of the urine more noticeable in a diaper after it is dried. (This odor can sometimes be detected as early as the first day by swabbing the ear canal of a newborn with classic MSUD.)

If a maple syrup odor is present, or if there is any question regarding the diagnosis of a newborn, the baby should be seen by a physician and tested for MSUD without delay. The diagnosis can be confirmed by BCAA analysis, a blood test that looks at the levels of the 20 amino acids and their relationships to each other. A correct diagnosis requires the experience of someone trained in metabolic diseases.

At times the peculiar maple syrup smell in the urine or sweat can occur in older, healthy children or adults who are non-symptomatic. The reason for this is unknown. However, these persons should be checked for a milder form of MSUD, especially if there are other symptoms of MSUD.

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Treatment

Initial treatment of a neonate with MSUD requires a prompt reduction in the levels of the BCAAs. High levels of leucine are very toxic and can lead to brain injury resulting in mental retardation, neurological difficulties in walking and speech, seizures, or death. Dialysis is no longer the preferred method of reducing high levels of BCAAs. A much more effective treatment is the administration of intravenous (IV) solutions of amino acids that do not contain the BCAAs and which have glucose (a type of sugar) added for additional calories. Using IV solutions, developed specifically for this purpose, allows the excess leucine, valine and isoleucine to be utilized for protein synthesis in the body, thus rapidly decreasing the BCAA levels. Sometimes insulin or a similar agent is also given to speed up the utilization of the excess BCAAs. Adding additional isoleucine and valine helps prevent deficiencies of these two BCAAs since these levels drop more rapidly than leucine. Levels too low in isoleucine and valine can cause severe rashes on the infant and prevent leucine from dropping to an acceptable level.

Long-term treatment of MSUD involves a carefully controlled diet which strictly limits dietary protein in order to prevent the accumulation of BCAAs in the blood. The major component of the diet is a special formula designed for children with MSUD. These MSUD formulas do not contain any leucine, isoleucine or valine but are otherwise nutritionally complete. They contain all the necessary vitamins, minerals, calories and the other amino acids needed for growth.

Initially the infant will be given an MSUD formula supplemented with carefully controlled amounts of a protein-based formula such as Enfamil or Similac. The protein-based formula provides the infant with the limited amount of BCAAs needed to grow and develop normally. Frequent monitoring of blood levels and adjustments in the formula mixture are necessary to ensure the correct balance of leucine, isoleucine, and valine.

As children with MSUD grow, they continue taking the special formula. They are allowed other foods which are weighed or measured in the home to supply the prescribed amount of leucine each day. Typically the MSUD diet does not include any high protein foods such as meat, nuts, eggs, and most dairy products. Children gradually learn to accept the responsibility for controlling their diets. There is no age at which diet treatment can be stopped. Lifelong therapy is essential for an optimal outcome.

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Sick Day Care

Any common illness or infection can cause elevations in the BCAAs which may precipitate an episode of vomiting, diarrhea, irritability, sleepiness, unusual breathing, staggering, hallucinations, and slurred speech. Left untreated, the child can go into a coma and die. Thus, any signs of illness require initiation of a sick day plan and immediate contact with a health care provider to begin treatment for the illness.

The sick day plan is designed to keep a child out of the hospital. The main focus of the sick day regimen is to provide adequate calories and amino acids to meet the body's needs and to use up the excess BCAAs in the blood by promoting protein synthesis. Usually the "sick day diet" decreases leucine intake and increases the amount of formula the child is prescribed. Blood may be taken more frequently at these times to check amino acid levels.

If the child cannot tolerate feedings during illness, hospitalization may be necessary to provide the calories and desired amino acids through a specially prepared IV solution (see under Treatment ). These solutions do not contain any BCAAs. Additional calories may be provided by adding lipid (fat) and/or glucose to the IV mixture. Frequent assessments of the child's clinical status and blood levels are essential.

Cerebral edema is a major concern in managing MSUD. Cerebral edema is the accumulation of excess fluid on the brain caused by an imbalance between electrolytes and the amino acids. This pool of fluid puts pressure on the brain and affects its function, which can interfere with breathing and can cause death. The fluid can be seen on CT and MRI scans of the brain. Cerebral edema can be treated successfully by physicians familiar with the latest in the treatment of MSUD.

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Outcome

With strict dietary compliance and good medical care, children with MSUD can, and do, lead relatively normal lives. Therapy must be started at the earliest possible age to achieve the best possible outcome. Careful control of the diet to insure the correct balance of the amino acid levels is the best strategy for the optimal function of persons with MSUD.

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Summary

MSUD is a serious disorder with life-threatening consequences unless addressed promptly. However, MSUD is manageable, just as diabetes is manageable. Careful monitoring and adherence to dietary restrictions are essential. Even minor illnesses and infections must be taken seriously and require special care. Treatment for MSUD has improved greatly over the past few years. It is of utmost importance that all children who have MSUD receive the benefit of the most up-to-date treatment.

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