Maple Syrup Urine Disease

Definition

Symptoms of maple syrup urine disease

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 three 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 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.

Description

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 by-products, 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.

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 by-products in the patient's body to rise.

MSUD is an autosomal recessive disease, which means that a child with MSUD has inherited a defective gene from both parents. The parents are said to be carriers of the disease because they can transmit it to their children without being affected by it themselves. With each pregnancy, the two carrier parents have a 1:4 chance that the baby will have MSUD. The chances are 2:4 that the child will be a carrier, and 1:4 that the child will neither have MSUD nor be a carrier. MSUD is a rare disorder in most ethnic groups, affecting one child in 180,000 in the general North American population and about one in 185,000 children worldwide. Among the Old Order Amish and the Mennonites in Pennsylvania, however, the rate is much higher, affecting one child in every 176 live births. As a result, Pennsylvania was the first state to mandate screening of newborns for MSUD.

The symptoms of MSUD vary in severity and time of onset, depending on the subtype of MSUD. Known subtypes, defined by the amount and type of enzyme activity present in the body, include:

Early diagnosis of ‘SUD is essential to prevent neurological damage and death in infancy. Some states, but not all, have mandatory screening programs for ‘SUD. Classic ‘SUD can be diagnosed in many cases before the physical symptoms appear by swabbing the baby's ear canal within 12–24 hours of birth and testing the cerumen (ear wax) for the odor of maple syrup. A child suspected of having ‘SUD 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 ‘SUD 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 ‘SUD 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. In the twenty-first century, 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.

Lifelong therapy of ‘SUD has two mainstays: strict adherence to a diet based on restriction of the patient's leucine intake; and aggressive treatment of acute episodes, which can be triggered by surgery, infectious diseases, or emotional stress. These episodes are characterized by vomiting, diarrhea, sleepiness, irritability, staggering, slurred speech, hallucinations, and unusual breathing patterns. In many cases, putting the child on a “sick day” dietary regimen and immediate notification of the child's doctor will prevent the need for hospitalization. If the child cannot keep food down, hospitalization with intravenous feeding or dialysis may be necessary. Preventing cerebral edema (swelling of the tissues of the brain) is the central concern in managing acute episodes of ‘SUD. Excess fluid accumulates in the brain as a result of the rise in the levels of amino acids and a loss of electrolyte balance. If untreated, cerebral edema puts pressure on the parts of the brain that control breathing and can lead to respiratory failure and death. It can, however, be treated by doctors familiar with the management of ‘SUD.

In extreme cases, ‘SUD 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 ‘SUD diet has the following characteristics:

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 three 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 Krispies treats.

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.

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

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

SICK DAY CARE. In order to help prevent a child from requiring hospitalization during an acute attack of MSUD, he or she is placed on a diet with an even lower level than usual of leucine and a higher intake of special formula. The sick day diet is intended to provide enough calories and amino acids to meet the body's needs and to promote protein synthesis in order to use up the excess BCAAs in the blood. The child may also be given more frequent blood tests during this period.

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 had been followed for over 40 years.

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.

QUESTIONS TO ASK YOUR DOCTOR

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 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.

See also Low-protein diet .

Resources

BOOKS

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

PERIODICALS

Carecchio, M., et al. “Movement Disorders in Adult Surviving Patients with Maple Syrup Urine Disease.” Movement Disorders 26, no. 7 (2011): 1324–28.

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, no. 5 (2005): 665–72.

le Roux, C., et al. “The Longest-Surviving Patient with Classical Maple Syrup Urine Disease.” Journal of Inherited Metabolic Disease 29, no. 1 (February 2006): 190–94.

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, no. 5 (November 1954): 462–67.

Morton, D. H., et al. “Diagnosis and Treatment of Maple Syrup Disease: A Study of 36 Patients.” Pediatrics 109, no. 6 (June 2002): 999–1008.

Snyderman, S. E. “The Therapy of Maple Syrup Urine Disease.” American Journal of Diseases of Children 113, no. 1 (January 1967): 68–73.

Snyderman, S. E., et al. “Maple Syrup Urine Disease, with Particular Reference to Dietotherapy.” Pediatrics 34 (October 1964): 454–72.

WEBSITES

“Maple Syrup Urine Disease (MSUD) Family Support Group.” http://www.msud-support.org (accessed April 10, 2018).

Defendi, Germaine L. “Maple Syrup Urine Disease (MSUD).” Medscape. Updated May 2, 2018. http://emedicine.medscape.com/article/946234-overview (accessed April 10, 2018).

MedlinePlus. “Maple Syrup Urine Disease.” U.S. National Library of Medicine, National Institutes of Health. https://medlineplus.gov/ency/article/000373.htm (accessed April 10, 2018).

Ramachandran, Tarakad S. “Inherited Metabolic Disorders.” Medscape. Updated December 28, 2017. http://emedicine.medscape.com/article/1183253-overview (accessed April 10, 2018).

Strauss, Kevin A., Erik G. Puffenberger, and D. Holmes Morton. “Maple Syrup Urine Disease.” GeneReviews. http://www.ncbi.nlm.nih.gov/books/NBK1319 (accessed April 10, 2018).

ORGANIZATIONS

National Digestive Diseases Information Clearinghouse, 2 Information Way, Bethesda, MD, 20892–3570, (800) 891–5389, TTY: (866) 569–1162, Fax: (703) 738–4929, nddic@info.niddk.nih.gov, http://www.digestive.niddk.nih.gov .

National Organization for Rare Disorders, 55 Kenosia Ave, Danbury, CT, 06810, (203) 744-0100, (800) 999-6673, Fax: (203) 798-2291, http://www.rarediseases.org .

Rebecca J. Frey, PhD

  This information is not a tool for self-diagnosis or a substitute for professional care.