Maple Syrup Urine Disease

What is Maple Syrup Urine Disease?

Maple syrup urine disease (MSUD) is an inherited metabolic disorder in which a person's body cannot process protein building blocks (amino acids) properly.

MSUD affects the way the body metabolizes certain components of protein. The three branched-chain amino acids (BCAAs)--leucine, isoleucine, and valine--accumulate in the blood and become toxic to the brain.

First diagnosed in 1954, MSUD is estimated to affect about 1 in 185,000 infants worldwide.

It has a much higher frequency of incidence in the Old Order Mennonite population, where it is estimated to affect about 1 in 380 newborns ¹.

MSUD gets its name from a distinctive sweet burnt sugar or maple syrup odor that emanates from an affected patients’ urine.

The disorder is also characterized by poor feeding, vomiting, lethargy, abnormal movements, and delayed development. If untreated, MSUD can cause mental retardation, physical disabilities, seizures, coma, and death.

Maple Syrup Urine Disease is also known by many other names:

• MSUD
• BCKD deficiency
• branched-chain alpha-keto acid dehydrogenase deficiency
• branched-chain ketoaciduria
• ketoacidemia

Clinical Types of MSUD

The subtypes of MSUD are determined by the amount and type of enzyme activity in an affected child. These amounts can vary widely within each classification.

Classic Neonatal Severe MSUD. This is the most common form of MSUD and characterized by little or no enzyme activity (usually less than 2% of a normal range). 

Infants with this type will show symptoms within the first few days of life ².

Intermediate MSUD. This is a variation of the classic form of MSUD. With this form, there is a higher level of enzyme activity that generally ranges from 3-8% of normal ³.

When a child is ill or fasting, those with intermediate MSUD react just like a child with classic MSUD.

Intermittent MSUD. This is a milder form of MSUD because there is a higher degree of enzyme activity that ranges from 8-15% of normal ⁴.

Most times, children do not have any MSUD symptoms until 12 to 24 months of age and usually due to an illness or a surge in protein intake.

When ill or fasting, children with this form see BCAA levels rise, a characteristic maple syrup odor becomes evident, and the child can go into a metabolic crisis.

Thiamine-responsive MSUD. This is a rarer type of MSUD and results when a child who is thiamine responsive receives large doses of thiamine.

That causes an increase in the enzyme activity, which breaks down leucine, isoleucine, and valine. For most people, only moderate protein restriction is needed for this type of MSUD ⁵.

E3-deficient with lactic acidosis MSUD. Also known as MSUD type III or E3 deficient MSUD, this type presents symptoms that are common to Intermediate MSUD but also includes severe lactic acidosis.

That can be potentially life-threatening. Persistent lactic acidosis takes place between eight weeks and six months of life.

All of these types of MSUD can be caused by mutations in the BCKDHA, BCKDHB, and DBT genes ⁶

These genes provide instructions that make proteins work together as part of a complex. 

The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine. These are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs.

The mutated genes can reduce or eliminate the function of the protein complex. As a consequence, the normal breakdown of these amino acids is compromised.

When these amino acids and their byproducts build up in the body, they become toxic to the brain and other organs.

Signs & Symptoms of Maple Syrup Urine Disease

Several signs and symptoms characterize MSUD. People with the same type may not have all of the following symptoms:

• Abnormal growth 
• Abnormality of the pharynx
• Abnormality of the voice
• Ataxia 
• Coma
• Decreased muscle tone (generalized hypotonia)
• Elevated plasma branched-chain amino acids
• Feeding difficulties in infancy 
• Global developmental delay
• Hallucinations
• Hypoglycemia
• Intellectual disability
• Irritability
• Ketosis
• Limp body with episodes of rigidity
• Lactic acidosis
• Maple syrup odor in urine
• Muscular hypotonia (low or weak muscle tone)
• Pancreatitis
• Paralysis or weakness of one side of the body (hemiplegia/hemiparesis)
• Reduced tendon reflexes
• Respiratory impairment 
• Seizures
• Slurred speech
• Swelling of brain 
• Recurrent vomiting

Can Other Members of the Family Have MSUD or be Carriers?

MSUD is inherited in an autosomal recessive pattern ⁷. That means both parents of a child with MSUD must carry a mutation in the same gene. These mutated genes do not function normally, and that causes MSUD.

Parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene. Typically, they do not show signs and symptoms of the condition.

That is because each person has two genes that code for the enzyme activity involved in the breakdown of the branch-chained amino acids.

One gene comes from the father and one from the mother. A person is only considered a carrier if one of their genes functions normally, but the other does not. A carrier is not affected by one abnormal gene.

If both genes don’t function normally, that person is afflicted by MSUD. 

It's 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 ⁸:

• 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 
• a 1 in 4 chance that the baby will not be a carrier or have MSUD.

The average incidence of MSUD is about 1 in 185,000 babies, but in some populations, the rate is much higher.

For example, a variant of MSUD (BCKDHA, E1a), appears in some Mennonite populations of Pennsylvania, Kentucky, New York, Indiana, Wisconsin, Michigan, Iowa, and Missouri approximately 1 in 380 live births.

The corresponding carrier rate in these areas is as high as 1 in 10 for classic MSUD. 

Diagnosis of Maple Syrup Urine Disease 

Many infants are diagnosed with MSUD through newborn screening tests. All states in the U.S. now screen all newborns with blood testing for MSUD.

Ideally, every infant should be tested for MSUD on the day after birth. Results should be reported within 24 hours. 

In recent years, an advanced newborn screening test called tandem mass spectrometry screens for more than 30 different disorders through a single blood sample.

Also, a plasma amino acid test or a urine organic acid test may be performed to assist in diagnosis. 

While newborn tests are essential, infants with intermittent or mild forms of MSUD may have normal blood amino acids at birth. That means testing for MSUD can be missed by newborn screening.

When a newborn screening does not take place or the condition is undiagnosed for any reason, a diagnosis may be suspected by noting symptoms.

These can include several possible findings ranging from maple syrup scented urine, lethargy, neurologic signs, a metabolic crisis, or other telltale signs.

Testing for MSUD may also include a urinalysis to detect high levels of keto acids.

Another possible test is an enzymatic diagnosis that is confirmed through white blood cells or cells sampled from a patient’s skin.

Confirmation of the presence of MSUD is also stablished through prenatal DNA testing. Testing for mutations in the BCKDHA, BCKDHB, and DBT genes can also confirm a diagnosis.

Molecular genetic testing is also necessary when carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies. 

Complications of MSUD

Both short-term and long-term complications can stem from MSUD.

At any time, a sufferer is at risk of entering a metabolic crisis. This can lead to a potentially life-threatening medical emergency that requires an immediate reduction in concentrations of leucine and other branched-chain amino acids in plasma.

A metabolic crisis may take place due to a lack of proper dietary discipline, or as a result of major trauma or surgery. In infants and young children, it is usually the result of some kind of infection.

Viral infections can be challenging to spot, and with the presence of MSUD, the first sign of a new infection may be a maple syrup odor in the urine, a bout of vomiting, or a positive test for ketones in the urine.

Because trauma care or surgical procedures can trigger a metabolic crisis, these situations should include a consultation with a metabolic specialist.

A metabolic crisis often takes place even before any diagnosis of MSUD has occurred. Because the onset can be rapid, young infants admitted to a hospital are often admitted in a coma.

Severe complications can also include seizures, lack of blood flow to the brain, and metabolic acidosis.

Episodes of imbalance can take place at any age, even in adult life, after years of strict control. It is crucial to employ optimal and rapid treatment methods to turn the crisis around as quickly as possible.

Using intravenous solutions of amino acids remains an effective way to treat metabolic imbalance in MSUD.

Complications can also include other long-term issues ranging from ADHD, developmental delays, brain damage, blindness, spasticity, and other neurological conditions. Eventually, these conditions can lead to death if left untreated.

That is why prenatal and newborn testing is essential. With an early diagnosis, MSUD can be more effectively managed over time.

If no prenatal testing is done, it is recommended to have a newborn undergo plasma amino acid analysis during the first 24 hours of life.

It should be noted that samples obtained any earlier than this can sometimes yield false-negative results. Also, if pathogenic variants have been identified in a family, a cord blood sample can be used for genetic testing.

To avoid complications that can lead to acute situations, people with MSUD should have a full amino acid profile measured at least once a week.

This proactive approach can reduce the possibility of hospitalization and allow MSUD to be managed in the home.

Specialized dipsticks test the patient's urine for ketones as a way of looking for signs of metabolic decompensation.

Drawing blood for full nutritional analysis as part of a regular metabolic consultation is also recommended. This is especially important during puberty and periods of rapid growth. 

Food intake must also be monitored closely, and day-to-day protein intake must be calculated to ensure specially tailored formulas are kept within acceptable limits.

If adequate calories cannot be obtained from natural food without exceeding protein tolerance, a patient may be directed to eat low protein products such as starch-based baking mixtures, imitation rice, and pasta.

Treatment and Care Options for Maple Syrup Urine Disease

Patients diagnosed with acute metabolic crises related to MSUD should begin treatment as soon as possible.

The immediate goal is to lower the levels of branched-chain amino acids, especially leucine, in the blood. Various techniques have been used to reduce leucine levels.

These include dialysis or a process that removes plasma from the body and passes through a filter before being returned to the body. This is called hemofiltration.

Aggressive therapy for metabolic crises focuses on reducing and reversing increased protein catabolism. That means that any method to increase calories to reduce protein catabolism may be helpful.

One course of treatment includes a high glucose intake with intravenous glucose, if necessary.

A glucose-insulin drip might supplement this since insulin enhances protein synthesis. Intravenous fat is another important source of calories and sometimes introduced as well. 

Overall, the goal is to maintain a complex approach to metabolic control. This means a carefully constructed daily diet is the primary focus on treatment over the long term.

Because a patient can't break down leucine, isoleucine, and valine, a synthetic diet that provides needed nutrients and all amino acids except for those three are administered.

Under strict supervision, these three amino acids are added with limited amounts of food to provide the necessary protein for normal growth and development.

Special care is given not to exceed the level of tolerance. Close monitoring of protein intake is required for life.

Treatment can also include tests to monitor amino acid levels and keto acid derivatives in a patient's blood and urine. Medical professionals monitor illnesses, stress, and the consumption of too much protein, all of which can raise levels to harmful ranges.

When metabolic imbalances take place, they require a change in diet and may lead to hospitalization. Keeping a close watch is critical because even mild illnesses can be life-threatening.

In some cases, a liver transplant is a treatment option. A liver from a donor who does not have MSUD can have enough enzyme activity that will allow the person with MSUD to live free from the effects of the condition.

Even after a transplant, the recipient will still carry the gene for the disorder. Still, they are no longer in danger from metabolic medical conditions and can eat a regular diet.

Many people choose to undergo genetic counseling if there is an identified risk of MSUD. Counseling provides much-needed information on the nature, inheritance pattern, and genetic implications of MSUD so to make informed medical and family decisions.

Genetic counseling may include a genetic risk assessment by using genetic test results and family history to understand the genetic status of family members fully.

Prognosis of Maple Syrup Urine Disease

If left untreated, MSUD can be fatal.

However, with immediate intervention and strict long-term monitoring and care, the prognosis for patients is excellent.

Children with MSUD can lead active and healthy lives, but the emphasis should always be on the lookout for MSUD symptoms, which can flare and produce a metabolic crisis.

Following strict dietary guidelines, children can grow into adulthood and can remain healthy.

What to do Next: Living with Maple Syrup Urine Disease 

Several support and advocacy groups can assist you with services and connect you with additional resources. Many of these are leading the way in research and treatment advancements for MSUD.

Maple Syrup Urine Disease Family Support Group
Powell, OH
Telephone: +1-740-972-5619
E-mail: [email protected]
Website: http://www.msud-support.org/ 

MSUD Family Support Group

24806 SR 119 

Goshen, IN 46526 

Phone: 219.862.2992 

Fax: 219.862.2012 

E-mail: [email protected] 

Web site: http://www.msud-support.org/

Genetic Metabolic Dietitians International
P.O. Box 1462
Hillsborough, NC 27278
E-mail: [email protected]
Website: http://www.gmdi.org/ 

Metabolic Support UK
5 Hilliards Court
Sandpiper Way
Chester Business Park
Chester, CH4 9QP United Kingdom
Toll-free: 0800 652 3181
Telephone: 0845 241 2173
E-mail: https://www.metabolicsupportuk.org/contact-us
Website: https://www.metabolicsupportuk.org 

Save Babies Through Screening Foundation, Inc
P.O. Box 2313
Palm Harbor, FL 34682-2313
Toll-free: 888-454-3383
E-mail: [email protected]
Website: http://www.savebabies.org 

 Genetic and Rare Diseases Information Center (GARD), USA 

 National Organization for Rare Disorders, USA

Children’s Hospital of Pittsburgh – Center for Rare Disease Therapy