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Maple Syrup Urine Disease

Definition

Maple syrup urine disease (MSUD), which is also known as branched-chain ketoaciduria, branched-chain alpha-keto acid dehydrogenase deficiency, or BCKD deficiency, is a rare but potentially fatal inherited metabolic disorder (IMD) passed down in an autosomal recessive pattern. The special diet associated with MSUD is a low-protein diet characterized by restriction of a specific amino acid known as leu-cine; the use of high-calorie liquid or gel formulas that are free of branched-chain amino acids (BCAAs); and frequent monitoring of the BCAA levels in the patient’s blood plasma. Strict adherence to this diet is necessary to prevent developmental delays, mental retardation, and recurrent metabolic crises leading to respiratory failure and death.

Origins

MSUD was first reported in 1954 by J. H. Menkes, a pediatrician, and his colleagues. The family in Menkes’s case study had lost four infants within the first 3 months of life to a previously undescribed degenerative disorder of the nervous system. The urine of these infants smelled like maple syrup or burned sugar, whence the disease got its name of maple syrup urine disease or MSUD. An effective treatment, however, had to await further biochemical analysis of the metabolic dysfunction underlying the disease. In 1960, a researcher named Dancis established that the metabolic block in MSUD is caused by an insufficient supply of an enzyme that helps to

Symptoms of Maple Syrup Urine Disease

  • Urine that smells like maple syrup
  • Avoiding food
  • Coma
  • Feeding difficulties
  • High-pitched crying
  • Lethargy
  • Poor weight gain
  • Seizures
  • Vomiting

(Illustration by GGS Information Services/Thomson Gale.)

break down three branched-chain amino acids—leucine, isoleucine, and valine—during the process of digestion. The deficient enzyme, now known as branched-chain alpha-keto acid dehydrogenase complex, or BCKD, was purified and defined in 1978.

Following Dancis’s work, S. E. Snyderman and his colleagues reported on the first successful dietary therapy for MSUD in 1964, which they accomplished by restricting the patients’ intake of foods containing high levels of branched-chain amino acids. Most protein-rich foods, such as meat, dairy products, and eggs, however, contain high levels of BCAAs. Dietary therapy of MSUD thus consists of a combination of protein substitutes containing amino acids without any BCAAs, and enough low-protein or protein-free foods to meet the patient’s daily caloric requirements. The MSUD diet of the early 2000s as modified for different age groups is described in further detail below.

Maple syrup urine disease (MSUD)

GENERAL FEATURES. MSUD is an inborn metabolic disorder (IMD), which means that it is a heritable disease characterized by the body’s inability to process one or more specific substances essential to health. A person diagnosed with MSUD lacks the enzyme complex that is needed to break down the three BCAAs. The patient may lack the enzyme complex entirely, it may be inactivated, or it may be only partially active. In all three cases, the three BCAAs and their byproducts, which are called ketoacids, build up in the urine, blood, and other body tissues. In the classical (most severe) form of the disease, a baby born with MSUD develops a severe acidosis (abnormally high levels of acid in the blood) during the first week of life, followed by seizures and coma caused by swelling of the brain tissue, and finally death.

KEY TERMS

Amino acid—One of 20 organic acids used as the building blocks of proteins in humans and other animals. The three amino acids involved in MSUD are called branched-chain amino acids or BCAAs because their chemical structures have side chains of carbon atoms that form a branch rather than a straight line.

Autosomal recessive—A term used to describe a pattern of genetic inheritance in which a child receives two copies of a defective gene, one from each parent, on an autosome (a nonsex chromosome). MSUD is an autosomal recessive disorder.

Branched-chain alpha-keto acid dehydrogenase (BCKD)—The chemical name of the enzyme that is missing or partially inactivated in patients with MSUD.

Carrier—A person who harbors an infectious agent or a defective gene without showing clinical signs of disease themselves and who can transmit the infection to others or the defective gene to their children.

Cerumen—The waxy substance secreted by glands in the external ear canal. It can be tested to screen newborns for MSUD.

Dialysis—A method of artificial kidney function used to remove waste products or other substances from the patient’s body fluids. In the case of patients with MSUD, dialysis may be used to remove BCAAs from the patient’s body during an acute episode requiring hospitalization.

Leucine—An essential amino acid and one of the three branched-chain amino acids implicated in MSUD. Leucine is the most toxic of the three and the one whose level is most closely monitored in dietary therapy for MSUD.

CAUSES. MSUD is caused by a mutation in any of four genes, known as BCKDHA, BCKDHB, DBT, and DLD respectively. These four genes code the proteins that form the BCKD complex, which is needed to break down BCAAs into smaller molecules. Mutations in any of the four genes will eliminate or reduce the function of the BCKD complex, thus allowing the levels of BCAAs and their byproducts in the patient’s body to rise.

SYMPTOMS AND DIAGNOSIS. The symptoms of MSUD vary in severity and time of onset, depending on the subtype of MSUD. As of 2007, researchers distinguish 5 subtypes, defined by the amount and type of enzyme activity present in the body:

  • Classic MSUD: This is the most common subtype of the disease, with less than 2% of BCKD enzyme activity present. Newborns show symptoms within the first 4 to 7 days of life, including poor feeding, poor weight gain, recurrent vomiting, high-pitched crying, seizures caused by swelling of the brain, and alternating rigidity and softness of the muscles. The baby may make repetitious gestures resembling the movements of fencing or bicycling. The baby’s urine develops a characteristic odor of maple syrup as soon as the other symptoms develop. If untreated, a child with classic MSUD will eventually stop breathing and die.
  • Intermediate MSUD: A rare form of the disease that differs from the classic form chiefly in a slightly higher amount of BCKD enzyme activity in the patient’s body, about 3 to 8 percent. Treatment and management is similar to that of classic MSUD. Only 20 patients have been reported with this subtype.
  • Intermittent MSUD: The second most common form of MSUD, with enzyme activity between 8 and 15% of normal. Children with intermittent MSUD may not show any signs of the disorder until they are 12 to 24 months of age, usually in response to an illness or a rapid increase in protein intake. During episodes of illness or other metabolic stress, the child may develop seizures or other signs of metabolic stress. Children or adolescents with this form of MSUD are at risk of developmental delays, including mental retardation, as well as metabolic crises.
  • Thiamine-responsive MSUD: A rare form of the disease, in which the level of enzyme activity in the child’s body is increased by giving doses of thiamine hydrochloride.
  • E3-deficient MSUD: A very rare variant of the disease, reported in only 10 patients as of 2007. These patients suffer from deficiencies in two other enzyme complexes as well as a lack of BCKD.

Early diagnosis of MSUD is essential to prevent neurological damage and death in infancy. Some states, but not all, have mandatory screening programs for MSUD. Classic MSUD can be diagnosed in many cases before the physical symptoms appear by swabbing the baby’s ear canal within 12 to 24 hours of birth and testing the cerumen (ear wax) for the odor of maple syrup. A child suspected of having MSUD should be given a blood test without delay. The blood test used to confirm the diagnosis is the BCAA analysis, which examines the levels of the 20 amino acids in the baby’s blood and their relationship to one another. The doctor can also order molecular genetic testing or tests that measure the levels of organic acids in the baby’s urine. Prenatal diagnosis of MSUD can be performed by mutation analysis or by measuring the concentrations of BCAAs in the amniotic fluid that surrounds the baby inside the mother’s womb.

TREATMENT. The first step in treatment of classic MSUD is prompt reduction of the levels of BCAAs in the body tissues of the affected child, particularly the level of leucine, which is the most toxic of the three BCAAs. In the 1960s and 1970s, dialysis was the method most commonly used to lower the BCAA levels rapidly. As of 2007, however, the preferred method involves administration of special intravenous solutions of amino acids that do not contain BCAAs, with glucose (sugar) added to meet the body’s energy needs. In some cases insulin is added to the solution. These infusions lower the BCAA levels by enabling the child’s body to use the excess BCAAs to synthesize proteins.

In extreme cases, MSUD can be treated by liver transplantation, but dietary therapy is a lower-risk form of treatment and has equally favorable results.

The MSUD special diet

At all stages of the life cycle, the MSUD diet has the following characteristics:

  • Careful evaluation of leucine intake on an individual basis. Leucine is an essential amino acid and cannot be excluded completely from the diet, even though it is the most toxic of the BCAAs and is present in foods in higher concentrations than either valine or isoleucine. The patient’s tolerance of leucine must be calculated following measurement of BCAA levels and remeasured at appropriate intervals during the first 6 to 12 months of life.
  • Intake of a protein substitute that provides BCAA-free amino acids.
  • Inclusion of a supplement that provides necessary vitamins, minerals, and trace elements.
  • Isoleucine and valine supplements, taken as needed. In some cases the patient’s levels of these two BCAAs fall below desirable levels, or are too low in reference to the leucine level. The proportion of amino acids is important because isoleucine and valine levels drop more rapidly than leucine. When Levels of ioleucine and valine are too low, severe rashes may result. Also leucine may be restricted from further depletion. Supplementation is necessary at such times to lower the risk of an acute episode of MSUD.
  • An adequate intake of calories from one of three sources: foods naturally low in or free from protein; specially formulated low-protein foods; and protein-free energy supplements containing glucose polymers and fats.

INFANCY. Infants diagnosed with MSUD are given a special MSUD formula supplemented with controlled amounts of infant formula. Breastfeeding is beneficial to some children with MSUD but does not remove the need for the special formula.

CHILDHOOD TO AGE 10. As children grow older, they must continue to take a protein substitute along with other foods that are weighed and measured at home to supply the correct amount of leucine. In 2003, Vitaflo, a company based in the United Kingdom, introduced a line of protein substitute products and isoleucine-valine supplements for children and adults with MSUD. These products can be purchased only with a doctor’s prescription. The protein substitute formulation for children from 12 months to 10 years of age is an unflavored powder containing 8.4 g of protein equivalent, designed to be mixed with cold water to form either a gel or a drink. The formula includes all necessary vitamins, minerals, and trace elements as well as amino acids except for the 3 offending amino acids, and can be flavored with special packets in black currant, orange, lemon, raspberry, or tropical flavors. The product takes less than a minute to prepare and should be drunk at once; however, it can be stored in the refrigerator and used within 24 hours. The child must drink water or a permitted drink along with the MSUD Gel.

If needed, a packet of valine or isoleucine supplement, which also comes in powder form, is to be mixed in with the MSUD Gel and flavoring.

Vitaflo also makes a chocolate-flavored low-protein high-calorie supplement called VitaBite, which can be eaten like a candy bar, or used in permitted recipes as a filling for cakes or mixed into Rice Kris-pies treats.

The child should have leucine levels reevaluated every 6 to 12 months.

ADOLESCENT AND ADULT. The MSUD protein substitute for children over the age of 8, teenagers, and adults contains 15 g of protein equivalent and is intended to be taken as a low-volume drink. The powder, which contains the daily requirements of amino acids, vitamins, minerals, and trace elements, is mixed in a special shaker with 80 mL (about 1/3 cup) of cold water, shaken well, and drunk immediately along with water or a permitted beverage. Like the MSUD Gel, Express can be flavored and mixed with isoleucine or valine supplements. It can also be stored for no longer than 24 hours in a refrigerator if necessary.

As with children, adolescent and adult patients should have their leucine levels measured periodically.

Function

The function of the special dietary regimen and products for maple syrup urine disease is to prevent recurrent metabolic crises in the patient and associated damage to the central nervous system so that the patient can survive infancy, develop normally, and have a normal life expectancy.

Benefits

The benefits of strict adherence to the MSUD diet are normal physical and intellectual development and a normal life span with no limitations on activity. Several patients diagnosed with MSUD as children have been able to complete their education, marry, and have children without complications. The longest-lived patient with MSUD as of 2007 has been followed for over 40 years and is still in good health.

Precautions

Children with MSUD must be taught from an early age that strict adherence to their dietary regimen is critical to their health and growth, and that they must take responsibility for avoiding high-protein foods and otherwise controlling their diets.

Special care must be taken with even minor illnesses or infections, as the risk of an acute episode of MSUD is increased at these times.

Children and adolescents with MSUD may occasionally need psychotherapy or medications to cope with the anxiety and depression that often accompany diseases requiring careful attention to diet.

Risks

Failure to comply with the MSUD diet puts the patient at risk of elevated blood levels of BCAAs, subsequent swelling of brain tissue, seizures, and death from respiratory failure.

Research and general acceptance

Studies published since the late 1960s indicate that dietary restriction of branched-chain amino acids is an effective and low-risk approach to managing MSUD. A 2005 study of the new line of Vitaflo products found that the four patients in the study not only liked the taste, texture, and appearance of Vitaflo Express, but found it “very easy to prepare.” In addition, the researchers found that leucine concentrations improved in all subjects; three of the four patients improved to the point that they could add more natural protein to their diets.

BOOKS

Chuang, David T., and Vivian E. Shih. “Maple Syrup Urine Disease (Branched-Chain Ketoaciduria).” Chapter 87 in Charles R. Scriver, ed., et al., The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York: McGraw-Hill, 2001.

PERIODICALS

Bodamer, Olaf A., MD, and Brendan Lee, MD, PhD. “Maple Syrup Urine Disease.” eMedicine, March 29, 2006. Available online at <http://www.emedicine.com/>ped/topic1368.htm.>

Hallam, P., M. Lilburn, and P. J. Lee. “A New Protein Substitute for Adolescents and Adults with Maple Syrup Urine Disease (MSUD).” Journal of Inherited Metabolic Disease 28 (October 2005): 665–672.

Kark, Pieter R., MD, and Tarakad S. Ramachandran, MD. “Inherited Metabolic Disorders.” eMedicine, December 8, 2006. Available online at <http://www.emedicine.com/neuro/topic680.htm.>

le Roux, C., E. Murphy, M. Lilburn, and P. J. Lee. “The Longest-Surviving Patient with Classical Maple Syrup Urine Disease.” Journal of Inherited Metabolic Disease 29 (February 2006): 190–194.

Menkes, J. H., P. L. Hurst, and J. M. Craig. “A New Syndrome: Progressive Familial Infantile Cerebral Dysfunction with an Unusual Urinary Substance.” Pediatrics 14 (November 1954): 462–467.

Morton, D. H., K. A. Strauss, D. L. Robinson, et al. “Diagnosis and Treatment of Maple Syrup Disease: A Study of 36 Patients.” Pediatrics 109 (June 2002): 999– 1008.

Snyderman, S. E. “The Therapy of Maple Syrup Urine Disease.” American Journal of Diseases of Children 113 (January 1967): 68–73.

Snyderman, S. E., P. M. Norton, E. Roitman, and L. E. Holt, Jr. “Maple Syrup Urine Disease, with Particular Reference to Dietotherapy.” Pediatrics 34 (October 1964): 454–472.

OTHER

Online Mendelian Inheritance in Man, OMIM. Baltimore, MD: Johns Hopkins University. MIM Number: ndash248600, Maple Syrup Urine Disease: June 13, 2005. Available online at <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=248600> (accessed March 7, 2007)">

ORGANIZATIONS

Cambrooke Foods, LLC. 2 Central Street, Framingham, MA 01701. Telephone: (866) 456-9776 or (508) 782-2300. Website: <http://www.cambrookefoods.com> <http://www.cambrookefoods.com> Cambrooke Foods is a supplier of low-protein foods for people with phenylketonuria and MSUD; it is also a distributor of Vitaflo products within the United States.

Clinic for Special Children. 535 Bunker Hill Road, Stras-burg, PA 17579. Telephone: (717) 687-9407. Website: <http://www.clinicforspecialchildren.org/index.html>. The clinic is a nonprofit medical and diagnostic service for children with MSUD and other inherited metabolic disorders, founded by one of the leading researchers of MSUD.

Maple Syrup Urine Disease (MSUD) Family Support Group. 82 Ravine Road, Powell, OH 43065. Telephone: (740) 548-4475. Website: <http://www.msud-support.org>.

National Institutes of Health (NIH) National Digestive Diseases Clearinghouse. 2 Information Way, Bethesda, MD 20892-3570. Telephone: (800) 891-5389 or (301) 654-3810. Website: <http://www.niddk.nih.gov>

National Organization for Rare Disorders (NORD). 55 Kenosia Avenue, P.O. Box 1968, Danbury, CT 06813-1968. Telephone: (800) 999-6673 or (203) 744-0100. Website: <http://www.rarediseases.org.

Vitaflo USA, LLC. 123 East Neck Road, Huntington, NY 11743. Telephone: (888) 848-2356. Website: <http://www.vitaflousa.com>. Vitaflo USA is the distributor of the MSUD protein substitutes developed by the parent company in the United Kingdom. The Canadian distributor is ParaMed Specialities, Inc., 995 Wellington Street, Suite 200, Montreal, Quebec H3C IV3. Telephone: (514) 395-2396. Website (French and English): <http://www.paramedinc.com/>

Rebecca J. Frey, PhD


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