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The goal of diet therapy is to maintain branched chain amino acids (BCAA), particularly leucine, within normal limits as studies have shown a correlation between cognitive decline and elevated blood leucine levels. An aggressive treatment protocol during illnesses is also required for a positive outcome.

To briefly review of the metabolic pathways involved in MSUD, protein from food is digested and broken down into its amino acid components. The primary job of these amino acids is to make necessary tissues for the body such as muscle and heart. Amino acids may also be converted into blood sugars and ketone bodies. The BCAA are essential, meaning they cannot be made by the body and must be consumed from food. Normally, if more protein is eaten than is needed to serve the body’s needs, they will be broken down to make energy. In MSUD, however, the enzyme required is either present in inadequate amounts or is not functioning properly. As a result, leucine and its ketoacid accumulate to toxic levels.

The enzymes involved in the metabolism of the BCAA are large complexes containing 6 different components, coded by 6 different genes. The Carboxylase E1 unit needs the vitamin Thiamin as a co-factor with an alpha and beta subunit to make it function properly. Other components include Transacylase E2, Dehydrogenase E3, and kinase which is the activator of the complex. Phosphorylase inactivates the complex. A genetic disorder can involve a dysfunction in any or multiple parts of this enzyme.

The types of MSUD are related to the portion of the enzyme complex affected and to the degree of enzyme activity. The classical form of MSUD typically only has about 2% activity. Individuals with this form usually present in the newborn period with symptoms. These individuals require the most intensive form of treatment including special medical foods and formula with a very strict protein intake. Intermediate and intermittent forms of MSUD will have more enzyme activity and present later in life, usually from 5 months to 2 years. These disorders are not as common as the classical form. Because these conditions are milder, protein restriction does not have to be as severe, and frequently these individuals will not need a special metabolic formula. They may have to supplement their intake with special low protein foods to ensure adequate calorie intakes. Those with the thiamin responsive form only need to receive large doses of this B vitamin for management of their disease. A rare form of the disorder affects the E3 dehydrogenase complex and may present in the newborn period with lactic acidosis. Because of the many forms of MSUD, there is a great degree in variability in diet management. It is important to keep this in mind when reading the newsletter and other materials regarding diet and treatment of individuals with MSUD.

The effectiveness of treatment is monitored by nutritional status, metabolic control, and compliance. Metabolic control can be monitored at home by checking the urine for ketones with DNPH and tracking dietary protein intake. Nutritional status is monitored by monitoring growth, laboratory data, and by physical exam. It is quite important to closely follow the child’s nutritional status as there have been reports of malnutrition in patients with inborn errors of metabolism (Acosta P. SIMD / Molec Genet and Metab 81, 2004).

The goal of dietary treatment is to maintain blood levels of BCAA within the recommended limits while ensuring adequate calories and protein and avoiding nutritional deficiencies. This will promote optimal growth and development which will ensure quality of life. To accomplish this the diet must be restricted in the BCAA, specifically leucine, while delivering enough protein and calories. This requires the use of special medical formulas with supplementation from isoleucine and valine. Metabolic formulas include all of the essential amino acids needed by the body without the BCAA. These formulas will provide up to 90% of the MSUD child/adult’s protein intake. The variety of metabolic formulas available has significantly increased over the years. Several companies now make formulas for MSUD, including Ross, Mead Johnson, Applied Nutrition, Vitaflow, Milupa, and Nutricia. Infant formulas include Analog, Ketonex1, BCAD1 and are nutritionally complete. Formulas for older children, teens and adults include Acerflex, Maxamaid MSUD, BCAD2, Ketonex2. These formulas are more concentrated in protein and not as dense in calories. Applied Nutrition makes Complex MSUD and Complex MSUD bars which are higher in protein. Even more concentrated formulas such as Maxamum MSUD, Milupa MSUD2, and Vitaflo’s products, MSUD Express and Gel are now available for use. The very first formula used to treat this condition, MSUD Diet Powder from Mead Johnson, has been taken off the market.

The protein in the formula is best used by the body when taken multiple times a day. A study looking at frequency of administration of metabolic formula showed that for the most optimal protein synthesis, the body requires the presence of amino acids at intervals throughout the day in combination with fats and carbohydrates. Amino acids cannot be stored and any surplus will be broken down to form energy. To become a source of energy, the nitrogen that is in amino acids is removed and excreted in the urine. A study of 10 young people, 12 to 26 years of age, with phenyketonuria, a more common metabolic disease involving similar dietary management, found that more nitrogen was wasted in their urine when formula was only ingested once a day versus multiple times a day. Consuming formula less frequently results in poorer use of amino acids for protein synthesis.

In addition to metabolic formulas, the use of protein-free formulas may be necessary to ensure an adequate caloric intake. There are several products to select from including Profree, PFD1, and PFD2 which are all vitamin/mineral fortified, and Dietary Specialties Calorie Supplement, Polycose, and Duocal which provide calories without other nutrients. Special low protein foods provide another source of caloric supplementation. There has been a significant increase in the number of companies that make these foods, and there are so many great recipes and cookbooks available to help improve the variety and quality of the diet.

Since protein and specifically the amino acid, leucine, must be limited, it is important to keep track of the exact amount provided from foods by using a food list. A number of sources are available, including an MSUD Food list developed by Emory University, Bowes and Church, and the USDA nutrient data base available at www.nal.usda.gov/fnic/foodcomp. A computer listing called MyDiet.com developed by Nutricia is also available. The Ross Metabolic Protocols provide guidelines for amount of protein, calories, BCAA, and fluids required per age group, but these guidelines must be tailored to meet the individual patient’s needs.

Estimates of the leucine content of foods can be made by using food labels to determine the amount of protein per serving and calculating the percent of leucine in a gram of protein. This varies with the type of food, with 4.5% of the protein in vegetables, 3.5% of the protein in fruits, and 10% of the protein in breads and starches consisting of leucine. Alternatively, 7% of the total protein from any food source can be assumed to be from leucine. For example, a slice of bread with 2 grams of protein will have an estimated 140 (7%) to 200 (10%) mg of leucine. Some clinics like to assume a larger percent, using a figure of 10%, while other clinics may assume less. It is important to check with your clinic for the appropriate calculations to estimate the leucine content of foods not on your list.

When illness or infection occurs, body proteins may be broken down. This can result in elevated levels of BCAA despite dietary compliance. It is a good idea to have a sick day protocol for treatment during illnesses. Frequently there will be a change in the medical formula recipe, and a reduction in the amount of leucine consumed from foods and in the formula. Increasing the amount of isoleucine and valine prescribed is typically indicated. It is always good to push fluids and calories to help flush out the toxins in the body. Additional medications, such as Zofran for vomiting, or Tylenol for fever, can help the individual, and it is always advisable to seek medical attention for other illnesses, i.e. antibiotics for ear infection. Parents are asked to monitor their child’s metabolic control during illness by checking the urine for ketones. It is important to keep the clinic informed of your child’s progress and to seek medical attention if there is no improvement. Use of an Emergency Care Protocol helps to ensure that the appropriate care is given promptly when acutely ill. The ER protocol should include information on the patient’s condition and the acute management needed along with contact information for the Metabolic team for further assistance.

Unfortunately, complications may occur. Feeding disorders may result from the anorexia and vomiting associated with compromised metabolic control. Difficulties with enteral tolerance including reflux and other GI disorders, oral-motor difficulties, or organ dysfunction such as pancreatitis may also occur. Because of the restrictive nature of this diet, nutritional deficiency is a possibility. Deficiencies in trace metals, such as selenium and molybdenum have been reported as several of the formulas did not include them. Marginal calcium intake, along with the chronic acidosis related to elevated branched chain ketone levels, can lead to decreased bone mineralization and increasing the risk of developing osteoporosis. Many individuals following protein restricted diets for various inborn errors of metabolism have been found to be deficient in the essential fats, eicosapentanoic and docosahexanoic acids. Primary dietary sources for these essential fats are typically high in protein and excluded from diet. Ask your clinic about supplementation of these oils.

While we have focused on the need to restrict protein, problems can develop from over-restriction of protein as well. These include poor growth, fat deposits in muscle, decreased resting energy expenditure, skin rashes, decreased immunity, decreased appetite, hair loss, and osteopenia. Specific amino acid deficiencies can also occur such as acrodermatitis enteropathica associated with isoleucine deficiency. Valine deficiency can lead to poor growth, drowsiness, irritability, crying, and decreased blood protein levels. Thus it is important to ensure that individuals with MSUD are receiving sufficient amounts of all essential amino acids including isoleucine and valine while restricting leucine to the proper amount. Carnitine deficiency can cause fatty myopathy, cardiomyopathy, depressed liver function, and neurologic dysfunction, hence some individuals need to supplement this nutrient.

Dietary treatment changes with age. It is important to have regular follow ups with your Metabolic Clinic to make sure that the treatment is adjusted appropriately to account for growth and metabolic stability. It is important to comply with dietary treatment as the clinic will continually try to change the plan if it is not working, but the plan will not work appropriately if not followed correctly and communicated with the clinic.

There are many other factors that may have a large impact on dietary management for MSUD. Physical activity is very important as when individuals are more active, they develop more muscle. When they have more muscle, they can tolerate more leucine in their diet. I encourage all of our patients in our clinic to try to be as active as possible. Maintaining good dental hygiene and regularly seeing a dentist is important as infections in the gums and mouth can lead to compromised metabolic control. Traveling with MSUD can go well if planned in advance.

Treatments beyond diet are now being evaluated for MSUD, but these still need to be evaluated over the long term. In the future there may be medications that can help with management. Earlier detection and more successful treatment will improve outcomes. There will be more reports of successful pregnancies for women with MSUD, an increased experience with organ transplantation, and eventually gene therapy may be an option. But for the time being, dietary management remains the main treatment for MSUD.

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