Maple Syrup Urine Disease (MSUD)

Maple syrup urine disease (MSUD)

Table of Contents

Other Names for This Condition

  • BCKD deficiency
  • Branched-chain alpha-keto acid dehydrogenase deficiency
  • Branched-chain ketoaciduria
  • Ketoacidemia
  • MSUD


Maple syrup urine disease (MSUD) represents a rare yet severe genetic disorder characterized by the body’s inability to metabolize specific amino acids, which are the fundamental constituents of proteins. This metabolic impairment results in the accumulation of harmful substances in both the blood and urine. In typical circumstances, our bodies effectively break down proteins found in foods like meat and fish into amino acids. Any surplus amino acids that are not required are typically metabolized and excreted from the body. However, infants afflicted with MSUD face difficulties in breaking down certain amino acids, namely leucine, isoleucine, and valine, leading to dangerously elevated levels of these amino acids, which can have detrimental effects.

In vitro fertilization (IVF) and preimplantation genetic testing (PGT) are significant advancements in the realm of reproductive medicine and genetics, particularly for individuals at risk of transmitting genetic disorders like Maple syrup urine disease (MSUD). For couples with a known risk of passing on Maple syrup urine disease (MSUD) to their offspring, IVF coupled with PGT offers a proactive approach. In this process, eggs are fertilized in a lab setting, and the resulting embryos are screened for the specific genetic mutations associated with Maple syrup urine disease (MSUD). This enables the selection of embryos without the disorder for implantation, significantly reducing the likelihood of the child inheriting Maple syrup urine disease (MSUD). Thus, IVF and PGT provide a powerful combination for family planning, particularly for those with a genetic predisposition to this condition, allowing them to minimize the risk of genetic transmission while achieving pregnancy.

Types of maple syrup urine disease (MSUD)

The four main types of MSUD are:

  • Classic
  • Intermediate
  • Intermittent
  • Thiamine-responsive

Classic MSUD is the most prevalent and severe form of the condition, characterized by minimal enzyme activity, typically around 2 percent or less of normal levels. Symptoms manifest shortly after birth, often triggered when the infant’s body begins processing protein from feedings.

Intermediate MSUD, on the other hand, is a rare variant of MSUD with varying symptoms and onset ages. Individuals with this type exhibit higher enzyme activity compared to classic MSUD, approximately ranging from 3 to 8 percent of normal activity. It tends to be less severe, with symptoms usually appearing in children between 5 months and 7 years old.

Intermittent MSUD doesn’t hinder regular physical and intellectual growth and development. Symptoms typically arise between 1 and 2 years of age. It is a milder form of classic MSUD, where affected individuals possess significant enzyme activity, approximately 8 to 15 percent of the normal level. The initial onset often occurs when a child experiences stress, illness, or an unusual increase in protein. Children with intermittent MSUD develop normally until an infection or period of stress triggers symptoms. People with this form typically tolerate higher levels of the three amino acids compared to classic MSUD.

Thiamine-responsive MSUD represents a rare subtype that tends to improve with substantial doses of thiamine (vitamin B-1). Symptoms usually emerge after infancy, and while thiamine can be beneficial, dietary restrictions remain necessary. Treatment allows individuals with thiamine-responsive MSUD to have a higher tolerance for the three amino acids.


Maple syrup urine disease (MSUD) is a rare genetic disorder that impacts approximately 1 in every 185,000 infants across the globe. Its prevalence tends to be higher in populations characterized by a limited gene pool or when close relatives procreate. For instance, MSUD is notably more frequent among the Old Order Mennonites in the United States, affecting 1 in every 380 births within their community due to the practice of intermarriage. Furthermore, it exhibits a higher incidence among the Ashkenazi Jewish population, where approximately 1 in every 26,000 births is affected. In the United States alone, around 2,000 individuals have received a diagnosis of MSUD.


MSUD symptoms vary by type:

1. **Classic MSUD**:

   – Severe and common.

   – Infants show symptoms like poor feeding, irritability, and a maple syrup odor in urine.

   – Can lead to intellectual disabilities, behavioral issues, and more.

2. **Intermediate MSUD**:

   – Less severe with later onset.

   – Symptoms include feeding problems and growth issues.

   – Can progress to seizures and brain damage.

3. **Intermittent MSUD**:

   – Normal growth and intellect.

   – Symptoms occur during energy-demanding periods like illness.

4. **Thiamine-Responsive MSUD**:

   – Rare and responds to vitamin B1 treatment.

   – Similar to intermediate MSUD.

Early diagnosis and intervention are crucial for each type.


Symptoms of MSUD may resemble those of several other disorders, including:

  1. **Urea Cycle Disorders**:

   – Urea cycle disorders are a group of rare conditions that impact the urea cycle, a series of biochemical processes responsible for converting nitrogen into urea and eliminating it from the body through urine.

   – These disorders can lead to symptoms such as ammonia buildup, vomiting, lethargy, and neurological problems.

  1. **Propionic Acidemia**:

   – Propionic acidemia is an uncommon autosomal recessive metabolic disorder resulting from a deficiency of the enzyme propionyl CoA carboxylase.

   – Symptoms may include poor feeding, vomiting, lethargy, and metabolic acidosis. In severe cases, it can lead to neurological issues and organ damage.

  1. **Methylmalonic Acidemia (MMA)**:

   – MMA is another rare metabolic disorder where individuals have difficulty metabolizing specific proteins and fats from food.

   – Symptoms can include vomiting, lethargy, poor growth, and metabolic acidosis. Neurological complications may also arise.

  1. **Glycine Encephalopathy**:

   – Glycine encephalopathy is an inborn error of metabolism characterized by the accumulation of excessive glycine in the blood and cerebrospinal fluid.

   – Symptoms may involve seizures, developmental delays, intellectual disabilities, and other neurological problems.

These disorders share similarities in terms of metabolic disruptions and can manifest with symptoms overlapping those of MSUD. Accurate diagnosis through specialized testing and medical evaluation is crucial to differentiate between these conditions and ensure appropriate treatment and management.


Children born with Maple Syrup Urine Disease (MSUD) inherit a genetic mutation that disrupts their ability to metabolize the amino acids leucine, isoleucine, and valine. Amino acids play a crucial role in the growth and development of children, as they are essential components used by the body to synthesize proteins. In individuals with normal, non-mutated genes, these genes provide instructions for producing enzymes, which are specialized chemicals responsible for breaking down these specific amino acids. However, when genetic mutations are present, there is a significant reduction or absence of the necessary enzyme activity required to effectively metabolize these amino acids.

Maple syrup urine disease (MSUD) can be attributed to mutations in the BCKDHA, BCKDHB, and DBT genes. These specific genes are responsible for providing instructions to produce proteins that work together as part of a complex essential for the breakdown of the amino acids leucine, isoleucine, and valine. These amino acids are commonly found in various foods, especially protein-rich sources like milk, meat, and eggs.

When mutations occur in any of these three genes, the functioning of the protein complex is compromised, leading to a reduction or complete loss of its normal activity. Consequently, the normal breakdown of leucine, isoleucine, and valine is hindered. This disruption results in the accumulation of these amino acids and their metabolic byproducts within the body.

Elevated levels of these substances can be detrimental to the brain and other organs, causing serious health complications associated with maple syrup urine disease. Therefore, the genetic mutations in these genes contribute to the underlying biochemical imbalances and health issues observed in individuals with MSUD.


Maple syrup urine disease (MSUD) follows an autosomal recessive inheritance pattern:

  1. Both parents are carriers (have one normal and one mutated gene) but do not have MSUD.
  2. If both parents are carriers:

   – Child has a 25% chance of inheriting two mutated genes, causing MSUD.

   – Child has a 50% chance of being a carrier.

   – Child has a 25% chance of inheriting two normal genes, avoiding MSUD.

  1. If an individual has two normal genes, they cannot pass on MSUD.

Carrier status means having one normal and one mutated gene. Carriers don’t develop MSUD but can pass the mutated gene to their children. The risk is the same for both genders. MSUD prevalence is higher in communities with shared genetic mutations.


MSUD can lead to various complications, including:

  1. Brain Damage, Neurological Issues, and Developmental Delays: Elevated amino acid levels can harm the brain, causing damage, neurological problems, and developmental delays if not managed properly.
  2. Risk of ADHD, Anxiety, and Depression: Individuals with MSUD have a higher risk of developing ADHD, anxiety, and depression.
  3. Bone Loss (Osteoporosis): MSUD can lead to osteoporosis, making bones more prone to fractures.
  4. Pancreatitis: Inflammation of the pancreas (pancreatitis) can occur, especially during metabolic crises.
  5. Chronic Headaches: Elevated skull pressure may result in chronic headaches.
  6. Movement Disorders: Some experience tremors and muscle contractions.
  7. Coma and Death: Untreated metabolic crises can lead to coma and, in severe cases, death.
  8. Intellectual Disability: Severe, prolonged MSUD can cause intellectual disability.

Early diagnosis, meticulous management, and dietary adherence can reduce these risks. Regular medical oversight and a controlled diet are crucial for improving the lives of those with MSUD.

Diagnosis and Tests

Diagnosing Maple Syrup Urine Disease (MSUD) involves a multi-step process:

  1. Newborn Screening: Initial screening through a heel prick identifies most cases. High amino acid levels trigger further testing.
  2. Additional Testing:

   – Blood and Urine Tests: Confirm the diagnosis and assess amino acid levels.

   – Mass Spectrometry: Measures specific amino acids (leucine, isoleucine, valine) in the blood.

   – Genetic Studies: Identify gene mutations associated with MSUD.

  1. Prenatal Testing: For at-risk families, prenatal testing (chorionic villus biopsy or amniocentesis) detects MSUD before birth, enabling early intervention.
  2. Diagnosis for Later-Onset Cases: Diagnosis in older children relies on metabolic blood tests, genetic analysis, and symptom evaluation, including the distinctive maple syrup odor in sweat, urine, or earwax.

Early diagnosis is vital to prevent metabolic damage, and timely treatment and dietary management can greatly improve the long-term outlook for individuals with MSUD.

Management and Treatment

Managing Maple Syrup Urine Disease (MSUD) involves:

  1. Protein-Restricted Diet:

   – Lifelong diet to limit leucine, isoleucine, and valine intake.

   – Nutritionists create tailored, nutrient-rich diet plans.

  1. Monitoring:

   – Lifelong monitoring of amino acid levels through blood and urine tests.

   – Diet adjustments based on test results.

  1. Immediate Medical Care:

   – During metabolic crises, seek immediate hospital care.

   – Interventions may include IV glucose, nutrient delivery, hemodialysis, and more.

  1. Dietary Management for Infants:

   – Infants switch to special formulas excluding harmful amino acids.

   – Supplements may be needed.

   – Thiamine-responsive MSUD may require high-dose vitamin B1.

Collaboration with healthcare providers and adherence to the treatment plan are essential for better MSUD management, ensuring a healthier life and reduced risks associated with the condition.

Is there a cure for maple syrup urine disease (MSUD)?

Since 2004, liver transplants have proven to be a successful treatment option for individuals with classic MSUD. A new liver can produce the enzymes required to metabolize the three amino acids (leucine, isoleucine, and valine). Following a liver transplant, individuals can typically transition to an unrestricted diet, live without the symptoms of MSUD, and avoid further complications associated with the disorder.

However, it’s crucial to note that individuals who have undergone a liver transplant for MSUD still carry the gene responsible for the condition. This means that they can pass the genetic mutation onto their children. Therefore, it’s highly advisable for individuals who have undergone a liver transplant for MSUD to consult with a genetic counselor before attempting to conceive a child. Genetic counseling can provide valuable insights into the risks and considerations associated with the genetic transmission of MSUD and help individuals make informed family planning decisions.

What are the side effects of a liver transplant for maple syrup urine disease (MSUD)?

Liver transplantation, like any major surgery, carries inherent risks and potential complications. Some of the common complications associated with liver transplantation include:

  1. Bleeding: Surgical procedures can result in bleeding, which may require additional intervention to control.
  2. Infection: Infections can occur post-transplant and may necessitate antibiotic treatment.
  3. Blood Clots: Blood clots are a risk, particularly after surgery. Anticoagulant medications may be administered to prevent this complication.
  4. Organ Rejection: The body’s immune system may recognize the transplanted liver as foreign and attempt to reject it. To prevent rejection, individuals typically need to take immunosuppressant medications to suppress the immune response.
  5. Weakened Immune System: Immunosuppressant medications can weaken the immune system, making individuals more susceptible to infections. Close monitoring and preventive measures are essential.

Despite these potential complications, liver transplantation has been a life-saving and life-changing treatment for many individuals with MSUD. Following a successful liver transplant, individuals can often lead normal lives without the concerns and limitations associated with MSUD. The benefits of the transplant often outweigh the risks, but close medical supervision and adherence to post-transplant care plans are essential to minimize complications and maximize the long-term success of the procedure.

Pregnancy management: 

For women with Maple Syrup Urine Disease (MSUD) considering pregnancy or already pregnant, maintaining strict metabolic control is vital. This involves:

  1. Regular Monitoring: Frequent checks of plasma amino acid levels to ensure safety for both the mother and the fetus.
  2. Dietary Management: Adjusting the diet to prevent harmful elevations in maternal leucine levels, safeguarding the fetus from potential harm.
  3. Fetal Growth Monitoring: Continuous monitoring of fetal growth to ensure the baby receives essential nutrients for healthy development.
  4. Labor and Delivery: Close monitoring during labor and postpartum care is crucial to manage metabolic stress and potential complications.

Meticulous control and healthcare provider collaboration are essential for a safe and healthy pregnancy for women with MSUD.

Genetic counseling.

MSUD is inherited in an autosomal recessive manner. Siblings of an affected individual have a 25% chance of being affected, a 50% chance of being unaffected carriers, and a 25% chance of being unaffected and not carriers. Carrier testing is available for at-risk relatives, and prenatal diagnosis is an option if the pathogenic variants are identified in the family.


You cannot prevent maple syrup urine disease (MSUD), but you can lower the risk of having an affected child by ensuring that you and your partner do not carry the gene mutations responsible for MSUD. Genetic testing and counseling can help assess and manage this risk.

Outlook / Prognosis

The outlook for individuals with maple syrup urine disease (MSUD) depends on early treatment and strict management. Early diagnosis and prompt treatment offer a better chance of a normal life with an average life expectancy. Regular monitoring, a protein-restricted diet, and medical supervision are essential. Despite these measures, there is still a risk of metabolic crises. In severe cases, therapies like hemodialysis or hemofiltration may be necessary. While lifelong management is required, individuals with MSUD can lead relatively normal lives with proper care.

Living With

When should I call my doctor about maple syrup urine disease (MSUD)?

Seek immediate medical care if your child shows MSUD signs. For older children and adults, contact a healthcare provider if you detect a maple syrup odor in urine or sweat, although it’s very rare.

Call now to make an appointment