OVERVIEW

What is Maple Syrup Urine Disease?

Maple Syrup Urine Disease (MSUD) is caused by a deficiency in metabolic enzymes, leading to impaired degradation of branched-chain amino acids (primarily leucine, isoleucine, and valine—essential amino acids obtained from food). This results in the accumulation of these amino acids and their metabolic intermediates (three keto acids) in the body.

These three keto acids are excreted in the patient's urine, giving it a sweet, caramel-like odor resembling maple syrup, hence the name "Maple Syrup Urine Disease," also known as "Branched-Chain Ketoaciduria."

These keto acids can damage the nervous system, causing central nervous system impairment (e.g., increased muscle tone, seizures, lethargy, and coma), feeding difficulties in infancy, and metabolic acidosis. Without prompt and effective treatment, affected infants often die during infancy.

MSUD is a genetic disorder, and consanguineous marriages increase the risk of offspring developing the disease.

Is Maple Syrup Urine Disease Common?

Overall, it is rare.

Globally, MSUD occurs in about 1 in 185,000 live births. Portugal has one of the highest incidence rates, with 1 in 86,800 live births affected.

The disease is more prevalent in regions or countries with high rates of consanguineous marriages. For example, among the Mennonite population in Pennsylvania, the incidence is as high as 1 in 200 live births.

What Are the Types of Maple Syrup Urine Disease?

Based on enzyme deficiency and clinical manifestations, MSUD is classified into five types: classic, E3-deficient, thiamine-responsive, intermittent, and mild.

The first two types typically manifest in the neonatal period, while the latter three may appear at any time during infancy or childhood. The classic type is the most common, accounting for 75% of cases.

SYMPTOMS

What are the common manifestations of maple syrup urine disease?

• Classic maple syrup urine disease: This is the most common and severe type of maple syrup urine disease. Even with treatment, survivors may suffer from intellectual disability and neurological damage. Newborns may exhibit irritability, feeding difficulties, vomiting, limb stiffness, and lethargy within 48 hours after birth. By the fourth day, symptoms can progress to alternating lethargy and irritability, limb stiffness, apnea, seizures, and signs of cerebral edema. Breastfed newborns may show symptoms later, possibly delayed until two weeks after birth. Without proper diagnosis and treatment, affected infants often die within weeks or months.

• Intermittent maple syrup urine disease: In this type, the metabolic enzyme deficiency is less severe, leading to intermittent episodes, often triggered by surgery, infection, high-protein diets, or frequent vomiting. Symptoms during episodes resemble the classic type but are milder. However, some patients may still die during an episode.

• Mild maple syrup urine disease: Newborns may have a maple syrup odor in their urine and mild symptoms. Later, other illnesses may trigger maple syrup urine disease, with symptoms similar to the classic type but milder. Vitamin B1 therapy is effective.

• Thiamine-responsive maple syrup urine disease: Thiamine (vitamin B1) acts as a coenzyme in branched-chain amino acid metabolism. This type also presents with mild symptoms and responds well to vitamin B1 treatment.

• E3-deficient maple syrup urine disease: This type involves defects in multiple metabolic enzymes, leading to severe manifestations.

What serious consequences can maple syrup urine disease cause?

Severe cases of maple syrup urine disease, if not treated promptly and effectively, may result in death during the acute phase due to metabolic acidosis. Without long-term treatment, intellectual disability and neurological damage may occur as sequelae.

CAUSES

What causes maple syrup urine disease?

Maple syrup urine disease is a genetic disorder caused by gene mutations, inherited in an autosomal recessive pattern. Consanguineous marriage significantly increases the risk of offspring developing the disease.

Who is more likely to develop maple syrup urine disease?

Mennonites and Amish populations are prone to this disease. Regions and countries with high rates of consanguineous marriage have a higher incidence.

Is maple syrup urine disease contagious?

Maple syrup urine disease is an inherited congenital disorder and is not contagious.

Is maple syrup urine disease hereditary?

Yes, it follows an autosomal recessive inheritance pattern. Simply put, if both parents are asymptomatic carriers of the disease-causing gene, their offspring have a 25% chance of developing the disease.

In consanguineous marriages, the high genetic similarity between spouses increases the likelihood of both carrying the disease-causing gene, raising the risk of affected offspring.

DIAGNOSIS

How is maple syrup urine disease diagnosed?

When diagnosing maple syrup urine disease, doctors primarily rely on amino acid and organic acid analysis.

• The detection of L-alloisoleucine in the patient's blood is a unique characteristic of this disease;

• Patients may show elevated levels of branched-chain amino acids and branched-chain organic acids in the blood;

• During acute episodes, the concentration of α-ketoisovaleric acid in the blood increases, and α-hydroxyisovaleric acid rises in the urine.

The above tests can confirm the diagnosis.

What tests can determine whether someone has maple syrup urine disease?

• Newborn screening: If a newborn's urine or sweat has a maple syrup odor or unexplained metabolic acidosis occurs, this disease should be highly suspected. Tandem mass spectrometry can be used for screening, but it may not detect patients with milder conditions.
  For newborns with a family history of maple syrup urine disease, DNA analysis can be performed, or blood samples can be taken 18–24 hours after birth for amino acid analysis.

• Blood glucose and blood gas analysis: These tests help diagnose the disease by detecting hypoglycemia and metabolic acidosis.

• Measurement of branched-chain amino acids and their metabolites: This can confirm the diagnosis. Samples may include blood or urine.

• DNA analysis: Used to confirm the diagnosis and predict treatment responsiveness.

Which diseases can maple syrup urine disease be easily confused with? How to differentiate them?

Due to shared neurological damage symptoms, maple syrup urine disease may be confused with other brain disorders. Doctors need to perform laboratory tests to distinguish them, primarily through the detection of branched-chain amino acids and their metabolites.

TREATMENT

Which department should I visit for maple syrup urine disease?

Pediatrics, Endocrinology.

Can maple syrup urine disease heal on its own?

Maple syrup urine disease does not resolve on its own. Without timely and effective treatment, it can lead to intellectual disability, neurological damage, or even death.

How is maple syrup urine disease treated?

Treatment for maple syrup urine disease mainly includes dietary therapy, acute metabolic crisis management, medication, and surgery.

• Dietary therapy: Should begin as early as possible and be maintained for life. If started within the first week after birth or before severe neurological damage occurs, normal development is possible. It is essential to restrict branched-chain amino acids in the diet, aiming to maintain blood levels within the normal range. Special formula foods or medical nutrition products can be used. In the initial phase, weekly blood amino acid analysis is required for dietary adjustments.

• Acute metabolic crisis treatment: Acute metabolic imbalance leads to the accumulation of branched-chain amino acids and their byproducts, causing severe acidosis and rapid neurological decline, requiring urgent intervention. Treatments include dialysis, standard intravenous nutrition without branched-chain amino acids, glucose with low-dose insulin, and recombinant growth hormone therapy.

• Medication: For patients responsive to thiamine, vitamin B1 (10–1000 mg daily) may be administered.

• Surgery: For classic maple syrup urine disease, liver transplantation can be considered upon diagnosis. It shows rapid effects post-surgery, restoring normal biochemical metabolism.

Can maple syrup urine disease be completely cured?

There is no cure, but timely and proper treatment can ensure survival and symptom improvement.

DIET & LIFESTYLE

What should maple syrup urine disease patients pay attention to in their diet?

The diet must restrict the intake of branched-chain amino acids in food, but excessive restriction should be avoided. Dietary adjustments should be made based on blood amino acid analysis results.

If branched-chain amino acids (such as leucine and isoleucine) are excessively restricted, skin damage may occur, such as perioral papular rash and diaper dermatitis.

Do maple syrup urine disease patients need follow-up examinations? How?

Patients with maple syrup urine disease require regular follow-up examinations.

• For patients diagnosed in infancy, it is recommended that those under 3 months of age be monitored weekly, those aged 3–12 months every two weeks to one month, and thereafter monthly. The monitoring involves measuring plasma amino acid concentrations to adjust branched-chain amino acid intake based on the results.

• For patients diagnosed after infancy, monthly monitoring of plasma amino acid concentrations is advised until levels stabilize, followed by monitoring every 3–6 months.

PREVENTION

How to prevent maple syrup urine disease?

Avoid consanguineous marriage.

If there is a family history or risk factors for maple syrup urine disease, prenatal diagnosis can be performed by measuring enzyme activity in amniotic fluid or chorionic villus cells, with selective termination of pregnancy to prevent the birth of an affected fetus.