Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine. It is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development. If untreated, maple syrup urine disease can lead to seizures, coma, and death.

Maple syrup urine disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still lead to delayed development and other health problems if not treated.

Mutations in the BCKDHA, BCKDHB, and DBT genes can cause maple syrup urine disease. These three genes provide instructions for making proteins that work together as part of a complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs.

Mutations in any of these three genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious health problems associated with maple syrup urine disease.

Researchers are studying other genes related to the same protein complex that may also be associated with maple syrup urine disease.

Normal Function

The BCKDHA gene provides instructions for making one part, the alpha subunit, of a group of enzymes called the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex. Two alpha subunits connect with two beta subunits, which are produced from the BCKDHB gene, to form a critical piece of the enzyme complex called the E1 component.

The BCKD enzyme complex is responsible for one step in the normal breakdown of three protein building blocks (amino acids). These amino acids—leucine, isoleucine, and valine—are obtained from the diet. They are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. The BCKD enzyme complex is active in mitochondria, which are specialized structures inside cells that serve as energy-producing centers. The breakdown of leucine, isoleucine, and valine produces molecules that can be used for energy.

Health Conditions Related to Genetic Changes

Maple syrup urine disease

More than 80 mutations in the BCKDHA gene have been identified in people with maple syrup urine disease. These mutations most often cause the severe, classic form of the disorder, which becomes apparent soon after birth. Maple syrup urine disease gets its name from the distinctive sweet odor of affected infants' urine. It is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development.

Most BCKDHA mutations change single amino acids in the alpha subunit of the BCKD enzyme complex. In the Old Order Mennonite population, where maple syrup urine disease occurs frequently, the most common mutation replaces the amino acid tyrosine with the amino acid asparagine at position 438 (written as Tyr438Asn or Y438N).

Mutations in the BCKDHA gene disrupt the normal function of the BCKD enzyme complex, preventing it from effectively breaking down leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. This accumulation is toxic to cells and tissues, particularly in the nervous system. The buildup of these substances can lead to seizures, developmental delay, and the other health problems associated with maple syrup urine disease.

Other Names for This Gene

• BCKDE1A
• BCKDH E1-alpha
• branched chain keto acid dehydrogenase E1, alpha polypeptide (maple syrup urine disease)
• MSUD1
• ODBA_HUMAN

Genomic Location

Normal Function

The BCKDHB gene provides instructions for making one part, the beta subunit, of a group of enzymes called the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex. Two beta subunits connect with two alpha subunits, which are produced from the BCKDHA gene, to form a critical piece of the enzyme complex called the E1 component.

The BCKD enzyme complex is responsible for one step in the normal breakdown of three protein building blocks (amino acids). These amino acids—leucine, isoleucine, and valine—are obtained from the diet. They are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. The BCKD enzyme complex is active in mitochondria, which are specialized structures inside cells that serve as energy-producing centers. The breakdown of leucine, isoleucine, and valine produces molecules that can be used for energy.

Health Conditions Related to Genetic Changes

Maple syrup urine disease

More than 90 mutations in the BCKDHB gene have been identified in people with maple syrup urine disease. These mutations most often cause the severe, classic form of the disorder, which becomes apparent soon after birth. Maple syrup urine disease gets its name from the distinctive sweet odor of affected infants' urine. It is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development.

Most BCKDHB gene mutations change single amino acids in the beta subunit of the BCKD enzyme complex. Other mutations insert or delete small amounts of DNA in the gene. A particular mutation is most common in people of Ashkenazi (eastern and central European) Jewish descent; this mutation replaces the amino acid arginine with the amino acid proline at position 183 in the beta subunit (written as Arg183Pro or R183P).

Mutations in the BCKDHB gene disrupt the normal function of the BCKD enzyme complex, preventing it from effectively breaking down leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. This accumulation is toxic to cells and tissues, particularly in the nervous system. The buildup of these substances can lead to seizures, developmental delay, and the other health problems associated with maple syrup urine disease.

Other Names for This Gene

• 2-oxoisovalerate dehydrogenase beta subunit
• BCKDH E1-beta
• branched chain keto acid dehydrogenase E1, beta polypeptide
• branched chain keto acid dehydrogenase E1, beta polypeptide (maple syrup urine disease)
• ODBB_HUMAN

Genomic Location

Normal Function

The DBT gene provides instructions for making part of a group of enzymes called the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex. Specifically, the protein produced from the DBT gene forms a critical piece of the enzyme complex called the E2 component.

The BCKD enzyme complex is responsible for one step in the normal breakdown of three protein building blocks (amino acids). These amino acids—leucine, isoleucine, and valine—are obtained from the diet. They are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. The BCKD enzyme complex is active in mitochondria, which are specialized structures inside cells that serve as energy-producing centers. The breakdown of leucine, isoleucine, and valine produces molecules that can be used for energy.

Health Conditions Related to Genetic Changes

Maple syrup urine disease

More than 70 mutations in the DBT gene have been identified in people with maple syrup urine disease, most often in individuals with mild variants of the disorder. These variant forms become apparent later in infancy or childhood, and they lead to delayed development and other health problems if not treated.

Mutations in the DBT gene include changes in single DNA building blocks (base pairs) and insertions or deletions of a small amount of DNA in the DBT gene. These changes disrupt the normal function of the E2 component, preventing the BCKD enzyme complex from effectively breaking down leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. This accumulation is toxic to cells and tissues, particularly in the nervous system. The buildup of these substances can lead to developmental delay and the other health problems associated with maple syrup urine disease.

Other Names for This Gene

• BCATE2
• dihydrolipoamide branched chain transacylase (E2 component of branched chain keto acid dehydrogenase complex; maple syrup urine disease)
• E2 component of branched chain keto acid dehydrogenase complex
• MSUD2
• ODB2_HUMAN

Genomic Location

Maple syrup urine disease is a genetic condition. Babies inherit it from their biological (birth) parents.

• Maple syrup urine disease is an autosomal recessive condition. Babies inherit the condition when each parent passes down the same nonworking gene that causes maple syrup urine disease (BCKDHA, BCKDHB, or DBT) to their baby. Only babies with two matching nonworking genes—for example, one nonworking BCKDHA from the mom and one nonworking BCKDHA from the dad—have this condition. Babies with two nonworking genes that do not match—for example, one nonworking BCKDHA from the mom and one nonworking BCKDHB from the dad—will not have this condition.
  • People with one working copy and one nonworking copy of the BCKDHA, BCKDHB, or DBT gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the BCKDHA, BCKDHB, or DBT gene, they have a 1 in 4 chance of having a child with maple syrup urine disease.
  • Carriers for maple syrup urine disease often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with maple syrup urine disease.
  • Parents who already have a child with maple syrup urine disease still have a 1 in 4 chance of having another child with maple syrup urine disease. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of maple syrup urine disease can vary widely and usually start shortly after birth (1 to 10 days). Symptoms can result from eating foods or milk the body cannot break down or by going long periods without eating. Illness or infection can also bring on symptoms. Milder forms of maple syrup urine disease may not appear until later in childhood or adulthood.

Signs of the condition may include the following:

• Poor feeding
• Sleepiness or lack of energy (lethargy)
• Poor weight gain or weight loss
• Fast and shallow breathing
• A maple sugar smell in the earwax, sweat, or urine
• High-pitched cry
• Vomiting
• Seizures
• Delayed development
• Unusual body movements and spasms (bicycling or fencing movements)

Newborn screening for maple syrup urine disease is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much branched-chain amino acids are in your baby’s blood. Babies with high levels of the amino acids leucine, isoleucine, and/or valine might have maple syrup urine disease.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for maple syrup urine disease is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition can happen. Babies who receive supplemental nutrition, also known as total parenteral nutrition (TPN) or hyperalimentation, may have false-positive screening results for maple syrup urine disease.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

Treatment for maple syrup urine disease (MSUD) involves a protein-restricted diet and supplements. With early treatment, people with MSUD avoid many of the more severe symptoms. Guidelines exist for medical and diet management of people with MSUD.

Liver transplant is an option in some cases. Liver transplant is considered a cure, although it cannot reverse any neurological damage caused before the transplant was performed.

Specialists involved in the care of someone with MSUD may include:

• Medical geneticist
• Metabolic dieticians
• Gastroenterologist
• Neurologist
• Developmental pediatrician
• Psychologist/psychiatrist

Maple syrup urine disease affects an estimated 1 in 185,000 infants worldwide. The disorder occurs much more frequently in the Old Order Mennonite population, with an estimated incidence of about 1 in 380 newborns.