Maple Syrup Urine Disease

What is Maple Syrup Urine Disease?

Maple syrup urine disease (MSUD) is a medical condition that interferes with the body’s ability to break down certain protein components known as amino acids. This happens because of a malfunction in an enzyme complex, known as branched-chain alpha-ketoacid dehydrogenase (BCKAD), which is usually responsible for processing three specific amino acids: isoleucine, leucine, and valine. Normally, these amino acids are used by the body for energy production and muscle building. In the brain, these amino acids help produce proteins, neurotransmitters (chemical messengers in the brain), and energy.

If someone has MSUD, also known as branched-chain α-ketoacid dehydrogenase deficiency, there is a problem with the BCKAD enzyme, located within the energy-producing parts of the cell called mitochondria. This problem interferes with the normal breakdown of these three specific amino acids, causing them to build up in the blood, brain, and other tissues. Their derivatives also build up in the urine, giving it a sweet smell much like maple syrup.

MSUD usually shows up in newborns with symptoms like failure to grow, delayed development, feeding difficulties, fatigue, irritability, and a particular maple syrup smell in the earwax and urine. If not treated early, severe MSUD can lead to permanent brain damage, seizures, or a coma within a week to 10 days of birth, with life-threatening breathing difficulties. Mostly, untreated severe MSUD can result in death within two months.

However, with early and consistent treatment, most people with MSUD can thrive. The long-term treatment generally includes a strict diet limiting intake of the branched-chain amino acids and regular metabolic check-ups. However, even with treatment, there can be sudden worsening of symptoms requiring immediate medical attention.

What Causes Maple Syrup Urine Disease?

Maple Syrup Urine Disease (MSUD) happens because of a change, known as a mutation, in one of three genes named BCKDHA, BCKDHB, or DBT. Genes are what control the traits we inherit from our parents. This disease is caused by a particular type of mutation that you need to inherit from both parents, known as an autosomal recessive mutation.

Branched-chain ketoacid dehydrogenase (BCKAD) is found inside the powerhouses of the cell (mitochondria) in body parts like the muscles, liver, kidney, and brain. It’s made up of 3 parts (E1, E2, and E3). An enzyme called BCAA transaminase helps to break down branched-chain amino acids (BCAA), which are types of proteins.

Most of this breaking down activity happens in the same place where BCKAD is found, inside the mitochondria. One of the results of this process, particularly from breaking down a specific amino acid called leucine, is a substance known as alpha-ketoisocaproic acid. This substance can act like a poison to the nerves and contributes to a condition called encephalopathic syndrome, a severe brain disorder.

Risk Factors and Frequency for Maple Syrup Urine Disease

Maple Syrup Urine Disease (MSUD) is a rare condition, affecting roughly one in every 185,000 births globally. In the United States, about 30 new cases are diagnosed each year in newborns. It’s found more commonly in communities where close-relative marriages are more frequent. MSUD impacts both boys and girls equally.

• In the Ashkenazi Jewish community, MSUD occurs in roughly one in every 26,000 births.
• In the Mennonite community, the rate of occurrence is even higher at one in every 380 newborns. This is often attributed to a “founder effect” in the BCKDHA (E1a) gene.
• Among Portuguese Romani people, it’s estimated that MSUD appears in one out of every 71 births.

Signs and Symptoms of Maple Syrup Urine Disease

Maple Syrup Urine Disease (MSUD) can be divided into different types based on how it shows up in individuals, when it first happens, and how much of a certain enzyme (BCKAD) is left active in the body. The symptoms, responses to stress, and tolerance to leucine – an amino acid – help determine how the disease is identified and classified.

The five main types of MSUD hinge almost entirely on the residual BCKAD enzymatic activity. The different types are:

• Classic Maple Syrup Urine Disease: This is not only the most common subtype of the disease, but also the most severe. Points to note include:
  • There is little to no BCKAD enzyme activity.
  • This type of MSUD usually starts showing up during the first 10 days of life.
  • Characteristic odor of maple syrup is noticeable in a newborn’s ear wax around 12 hours after birth and in the urine within the first week after birth.
  • If left untreated, the disease’s progression is rapid and often fatal.
  • After 2 to 3 days, a child could develop encephalopathy – a brain disease – with worsening lethargy and occasional issues with breathing.
  • Without treatment, death may occur within 2 months or less.
  • Trace amounts of a protein called leucine are typically 2 to 4 times higher than normal, though they can go even higher.
• Intermediate Maple Syrup Urine Disease: This is a less severe form, usually presenting between 5 months to 7 years of age. Characteristics include:
  • Patients generally have some BCKAD activity remaining.
  • Symptoms may include poor growth, delays in development, intellectual struggles, decreased appetite, and anorexia.
  • There could be noticeable maple syrup odor in the urine.
• Intermittent Maple Syrup Urine Disease: It’s an infrequent form of MSUD that could come up at any age but often emerges in the first 1 to 2 years of life. Main features include:
  • Patients have 5% to 20% of normal BCKAD activity left.
  • There could be rapid progression, and symptoms can include seizures, encephalopathy, and difficulty maintaining balance.
• Thiamine-Responsive Maple Syrup Urine Disease: Patients with this type respond well to large therapeutic doses of thiamine, a type of vitamin. This form of MSUD shares similarities with other forms, but the treatments and responses are what distinguishes it.
• E3-Deficient Subtypes of Maple Syrup Urine Disease: These subtypes are defined by a mutation in the gene encoding the E3 subunit. Clinical features include:
  • Newborns present with lactic acidosis, encephalopathy, feeding difficulties, liver failure, and sometimes early death.
  • This subtype is associated with elevated levels of lactate, alanine, and alpha-ketoglutarate – a product of deamination of glutamate.

Please remember, although these symptoms can help identify the different forms of MSUD, they are not exact and can sometimes show up in other conditions as well.

Testing for Maple Syrup Urine Disease

Maple Syrup Urine Disease (MSUD) is a serious condition that can cause permanent damage in the first few weeks of life. So, it’s important to diagnose it quickly. That’s why a test for MSUD is done on all newborn babies within 48 hours of birth. If this testing hasn’t been done, or the results are late, the doctor will need to spot the early signs of the disease.

A doctor will take into account the baby’s signs and symptoms, and also carry out a biochemical analysis and molecular testing. This helps to confirm the diagnosis and assess how severe the disease is.

Initial blood testing for MSUD is routinely done on all newborns in the United States and other countries. However, this test might miss some forms of the disease. Further tests will be needed if the baby shows signs and symptoms of MSUD, even if the initial test is negative. These signs and symptoms can include certain brain disorders and ketoacidosis, a serious condition caused by a lack of insulin.

Prenatal tests, before the baby is born, can confirm the presence of MSUD. To make this diagnosis, they look at the activity of a certain enzyme in cells from the placenta or from fluid surrounding the baby in the womb. They can also measure the levels of certain amino acids in this fluid. If these tests identify a mutation in the family, this can help make a diagnosis before a baby is born.

Standard newborn screening for MSUD is done 24 to 48 hours after birth. This uses a device called a tandem mass spectrometer, which can measure the levels of certain amino acids. However, this test can give a false-positive result in people with another condition. Further lab tests will be done if there are high levels of certain amino acids.

Since 1964, newborns in the United States have routinely been screened for MSUD. This is best done within 24 to 48 hours after birth using a method called tandem mass spectrometry amino acid profiling. However, this method may misdiagnose certain forms of the disease, especially those that show normal leucine levels. If this happens, another test, such as plasma amino acid testing or liquid chromatography, may be conducted to determine serum alloisoleucine levels.

A plasma amino acid test is the most reliable test for diagnosing MSUD. It checks for high levels of certain types of amino acids. If alloisoleucine levels are above a certain threshold, this strongly suggests MSUD.

Molecular tests are available to identify specific genetic abnormalities that cause MSUD. Genes encode proteins that make up the enzymes necessary for breaking down certain amino acids. A mutation in these genes can lead to MSUD.

There are different treatment strategies for different patient presentations.

Symptomatic adults:

Diagnostic tests such as DNPH urine test, direct chemical analysis of urine, or testing for elevated serum alloisoleucine levels using plasma amino acid analysis.

Symptomatic newborns:

In newborns showing unexplained ketonuria or positive screening test results, diagnostic evaluation should include plasma amino acid analysis to check for elevated BCAA and alloisoleucine and urine analysis. It’s important to remember not to feed newborns and infants higher than average protein intake.

Newborns with an affected sibling:

When a newborn has a sibling with diagnosed MSUD, further testing should be done, including blood tests to check for pathogenic variations, early dietary therapy as well as molecular testing and urine organic acid analysis. DnPH tests can be carried out 48-72 hours after birth.

Treatment Options for Maple Syrup Urine Disease

Treatment for Maple Syrup Urine Disease (MSUD), a genetic metabolic disorder, usually involves addressing the patient’s nutritional needs and managing any severe metabolic disruptions. It’s crucial for a pediatric nutritionist and a metabolic disease specialist to be involved in treating MSUD patients.

Keeping MSUD under control involves dietary therapy that restricts the intake of branched-chain amino acids (BCAAs), which the body struggles to break down in this disease. This dietary adjustment is lifelong. In newborns who screen positive for MSUD, they should be put on a special MSUD dietary formula that doesn’t contain BCAAs. Alongside this, high rate glucose infusion and 20% intravenous lipids are beneficial and can help prevent further brain damage. An insulin infusion can also be useful in some cases.

The idea of nutritional therapy is to help the body build up (anabolism) and prevent the breakdown of cells (prevent catabolism). Other goals involve promoting average growth and weight gain, preserving intellectual function, and maintaining acceptable levels of plasma BCAAs. Different life stages will require adjustments to the amount of dietary BCAA allowed, based on lab results and growth measurements.

Acute episodes of metabolic decompensation, where BCAA levels increase significantly, could occur due to poor diet adherence or infection. Other factors such as trauma can also trigger a metabolic crisis. In such situations, treatments can include treating the infection or underlying stressor causing the metabolic crisis, limiting protein intake for a short period, and providing ample caloric support and hydration. In severe cases, dialysis or other treatments might be necessary.

Patients can monitor their own condition at home through regular blood spot evaluations and the use of a special reagent that helps detect high levels of branched-chain ketoacids in urine. If an exacerbation is suspected, the findings can help guide dietary restrictions and monitoring measures.

For women with MSUD who are pregnant, it’s essential to maintain tight metabolic control before and throughout the pregnancy. As the fetus grows, the mother’s need for protein and BCAAs will increase. Regular checks on plasma amino acid concentrations and fetal growth measurements can help avoid nutritional deficiencies. The postpartum period may also present significant risk for the mother, requiring special measures to prevent metabolic decompensation.

Complications from MSUD can also occur, including cerebral edema and cerebral herniation, which can be fatal if not treated promptly. Infections, acute pancreatitis, and neuropsychiatric illnesses are also potential complications. Standard treatment protocols can be effective in managing these issues.

Finally, liver transplantation could be an option for severe MSUD patients who can’t be managed through diet. The liver transplantation helps control the branched-chain amino acid metabolism and reduces the need for severe dietary restrictions. However, it does not reverse previous brain damage, cognitive dysfunction, or psychiatric illnesses. Still, if done promptly after initial diagnosis, it can prevent further symptoms.

What else can Maple Syrup Urine Disease be?

Doctors should rule out other medical conditions that can present themselves similarly to neonatal encephalopathy. These might include:

• β-ketothiolase deficiency (a rare genetic disorder affecting the body’s ability to process protein)
• Birth asphyxia (a condition caused by a lack of oxygen during birth)
• Encephalitis (an inflammation of the brain)
• Beta-hydroxy beta-methylglutaryl-CoA lyase deficiency (a disorder of leucine catabolism)
• Hypoglycemia (also known as low blood sugar)
• Kernicterus (a severe form of jaundice)
• Meningitis (an infection causing inflammation around the brain and spinal cord)
• Nonketotic hyperglycinemia (a rare genetic disorder affecting glycine metabolism)
• Organic acidopathies such as propionic acidemia and methylmalonic acidemia
• Status epilepticus (a seizure that lasts longer than five minutes)
• Urea cycle defects (disorders that inhibit the body’s ability to remove ammonia from the bloodstream)

Sotolone, a substance found in foods and plants like fenugreek, certain rums, molasses, candy cap mushrooms, caramel, sherry, and lovage, can cause a maple syrup-like smell from the body. Eating too much of these during pregnancy may lead to a mistaken diagnosis of Maple Syrup Urine Disease (MSUD). In neonatal intensive care units, a similar sweet smell can also come from the use of topical benzoin, a resin applied to the skin.

What to expect with Maple Syrup Urine Disease

Patients who start treatment before or as soon as they notice symptoms usually have a good chance of recovery. Things like the level of leucine (an amino acid which triggers brain inflammation) in the blood, severity, and duration of brain swelling (called cerebral edema) and brain disorders (encephalopathy), influence how well a person’s brain functions after the disease.

People suffering from a classic form of MSUD (a genetic disorder that elevates the level of certain amino acids in the blood) can do well academically, even more than what their neurological tests might suggest. According to one study, 61% of adults with MSUD can live independently and adapt well into society. But, more than half, that is, 56% of patients still need emotional (psychological) and mental (psychiatric) support.

On the other hand, patients with a late-onset form of MSUD could have slight developmental delays based upon the remaining activity of a specific enzyme (BCKAD).

In cases of classic MSUD, if there’s a delay in diagnosis beyond 7 to 14 days, this could result in irreversible learning disabilities, falling into a deep unconscious state (coma), severe lung issues (respiratory failure), brain damage, seizures, and a condition that affects muscle control (cerebral palsy).

Also, if acid levels in the blood increase (metabolic acidosis) during an acute episode, it could imply a worse outcome. The rate of mortality from MSUD during a sudden severe health crisis is as high as 25%. The most common cause of death from MSUD is malignant cerebral edema, which refers to a harmful swelling in the brain.

Possible Complications When Diagnosed with Maple Syrup Urine Disease

If Maple Syrup Urine Disease (MSUD) is not detected and treated promptly, it can lead to severe outcomes. Patients receiving treatment may suddenly fall sick due to a spike in the level of certain amino acids in their blood. Symptoms of such crises include intense exhaustion, irritability, vomiting, and a decrease in alertness. If these signs are overlooked or if the person is not given treatment, different complications may occur:

• Pancreatitis, which is inflammation of the pancreas.
• Blindness
• Swelling in the brain, also known as cerebral edema.
• Lack of blood supply to the brain or cerebrovascular ischemia.
• Shortage of essential amino acids, showing itself through anemia, hair loss, stunted growth, and skin inflammation.
• Intellectual disabilities
• Permanent damage to the nerves
• Metabolic acidosis, a condition where there’s too much acid in the body.
• Muscle stiffness
• Osteoporosis, a disease where bones become weak and brittle.
• Repeated infections of the food pipe due to suppression of T-cells caused by elevated plasma leucin.
• Seizures

Preventing Maple Syrup Urine Disease

Understanding their illness well helps patients stick to care practices that are best for them. This understanding also allows doctors and other healthcare team members to provide the best medical results according to proven scientific research. To learn more about the disease, patients can use resources such as:

• Online educational handouts from the New England Consortium of Metabolic Programs
• The American College of Pediatrics website
• Maple Syrup Urine Disease (MSUD) family support groups
• The National Library of Medicine Genetics Home Reference
• The National Center for Biotechnology Information (NCBI), which has information about genes and diseases
• Metabolic Support UK
• The European Registry and Network for Intoxication Type Metabolic Diseases
• The Organic Acidemia Association