Melissa P. Wasserstein, MD
Assistant Professor,
Human Genetics and Pediatrics
Mount Sinai School of Medicine,
New York, NY

Maple syrup urine disease (MSUD) is a rare genetic disease named for the distinctive, sweet odor of the urine and sweat. It is caused by deficient activity of the branched chain a-ketoacid dehydrogenase complex, which is involved in the breakdown of leucine, isoleucine, and valine. Although MSUD is a life-threatening disorder, it can be well-managed with prompt, careful, and thorough treatment for life. Successful medical therapy is highly contingent on accessibility to a medical team that is experienced in the care of infants, children, adolescents, and adults with MSUD.

MSUD is characterized by episodes of metabolic decompensation, usually caused by infection, excessive protein intake, or fasting. Early signs that are usually apparent to parents include poor feeding and excessive sleepiness in infants, and ataxia (“wobbly” gait), slurred speech, and vomiting in older children. During decompensations, the concentrations of the branched chain amino acids in the body are elevated. Leucine in particular is associated with neurotoxicity. High concentrations of isoleucine and valine are not associated with any obvious toxicity, although elevated concentrations of isoleucine and its metabolites cause the characteristic smell.

It is clear that outcome correlates with the age of onset of therapy, the quality of metabolic control over time, and the number and severity of metabolic decompensations. Successful medical treatment of MSUD has three components:
1) early identification and rapid institution of therapy within the first week of life;
2) a daily medical regimen, or “maintenance therapy,”
3) an aggressive treatment protocol that is used during metabolic decompensations.

The first component of therapy, early identification, is achievable in states that include MSUD in their Newborn Screening Panel. MSUD is currently on the Newborn Screening Panel in 36 states and the District of Columbia, and is slated to be included in a few more states in the future. In New York, positive results are typically available by about 5 days of age. Confirmation of diagnosis and institution of therapy are performed within hours of notification.

The second component, maintenance therapy, is mainly dietary. Success requires close collaboration and excellent communication between the family and the medical team, particularly the metabolic nutritionist. The goal of maintenance therapy for patients of all ages is to keep plasma concentrations of leucine, isoleucine, and valine (the branched chain amino acids, or BCAA) within normal limits, while providing adequate protein, carbohydrates, fat, and other nutrients to allow the body to grow and function normally. Maintenance therapy involves restricting the intake of the BCAA using specialized metabolic formulas. In addition to carbohydrates, fats, vitamins, and minerals, these formulas provide the essential amino acids other than the BCAA, and therefore are the main source of protein for MSUD patients. Small amounts of natural protein are also included in the diet. The amount of natural protein is prescribed on an individual basis, depending on how much each patient can tolerate while maintaining satisfactory plasma concentrations of leucine, isoleucine, and valine. Our practice is to measure BCAA concentrations weekly for the first six months of life, bi-weekly from six to 12 months of life, and then at least monthly thereafter. Leucine levels that remain chronically elevated can cause mental retardation. Deficiencies of any of the BCAAs are also dangerous, and if not corrected rapidly can cause failure to gain weight, anemia, hair loss, and skin rashes. Many patients take solutions of pure isoleucine, leucine, or valine. These are prescribed in order to carefully and precisely quantify the intake and plasma concentration of each amino acid. Infants and young children undergoing rapid growth face frequent adjustments in their dietary prescription. Older children, adolescents and adults may face difficulties with compliance with the diet, so regular measurements of BCAA concentrations are essential.

In contrast, the goal of decompensation therapy is to rapidly reduce elevated plasma leucine levels to a non-toxic level. We use a combination of branched-chain amino acid free hyperalimentation, intravenous glucose, insulin, and intralipids. Mannitol may be given if cerebral edema is suspected. Close observation in an intensive care unit to monitor neurological signs and symptoms, fluid status, and vital signs is essential. Occasionally, hemodialysis is needed to rapidly lower the leucine level. Hemodialysis can often normalize the plasma leucine within several hours, and if performed by experienced physicians, is safe and extremely effective.

Liver transplantation is another option for treatment. It works by replacing the defective enzyme with a functioning one. A successful liver transplant can obviate the need for the severe dietary restrictions and minimize the risk of metabolic decompensation. There are many factors that must be weighed for each patient when considering liver transplantation. These factors include, but are not limited to: the risk of surgery, the possibility of organ rejection, the need for anti-rejection medications, accessibility to medical therapy, dietary compliance, and overall metabolic control.

With early detection, excellent dietary control, and rapid reversal of metabolic decompensation, we have seen remarkable outcomes in our patients. Aside from eating different food for lunch, our younger patients are indistinguishable from the other children at school. Our older patients, many of whom are college graduates, are independent, self-sufficient adults. Thus, with early diagnosis, meticulous medical therapy, and close collaboration between the family and the medical team, MSUD is a manageable disease with a favorable outcome.

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A Child's Life

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