What Is Maple Syrup Urine Disease?

Overview

Maple syrup urine disease is a rare disorder among a class of conditions known as inborn errors of metabolism. Inborn errors of metabolism are typically inherited and cause problems in metabolic pathways. Metabolic pathways are a series of reactions required for cells to function properly so that organs and tissues remain healthy. Inborn errors of metabolism cause problems in metabolic pathways by changing the function of certain substances in these pathways, therefore preventing the natural order of the pathway and stopping other substances from being broken down, causing a deficiency or an accumulation of a particular product. Depending on the substance which is being altered, this change can have significant effects on the body, leading to symptoms and disease complications.¹^,²^,³^,⁴

In the case of maple syrup urine disease, there is decreased function of the branched-chain ketoacid dehydrogenase complex (BCKAD), a substance necessary for breaking down branched-chain amino acids from which our cells derive energy and other substances. As a result of this decreased function, the branched-chain amino acids accumulate, reaching excessive levels in the body.²

There are different subtypes of maple syrup urine disease, characterised by how much the function of the BCKAD complex is reduced. These subtypes are classic, intermediate, intermittent, thiamine-responsive and E3-deficient. Whilst the classic and E3-deficient forms typically present in newborns, intermediate, intermittent, and thiamine-responsive forms can present at any age.

Furthermore, whilst signs and symptoms can differ within the disease subtypes, they typically include maple-syrup-odoured or sweet-smelling urine (caused by the presence of branched-chain amino acids in the urine), lethargy, irritability, muscle spasms, and disorders of the brain. If the disease is left untreated, serious complications such as seizures, blindness and severe neurological damage can arise. 

Lifelong dietary changes, characterised by limited consumption of branched-chain amino acids, can decrease symptoms and disease progression, and a rapid diagnosis with consistent monitoring of levels of branched-chain amino acids can help patients live free of maple syrup urine disease complications.^2,5,8

Causes of maple syrup urine disease

Maple syrup urine disease is caused by a mutated gene, which both parents are carriers of, being inherited by a newborn. The newborn must possess both copies of the mutated gene from each parent in order to develop the disease. When both parents are carriers of the mutated gene, the newborn has a 25% chance of inheriting maple syrup urine disease and a 50% chance of being a carrier of the mutated gene.²

The inherited mutated gene causes the functional activity of the branched-chain alpha-keto acid dehydrogenase complex to be decreased. In normal metabolism, the function of the BCKAD complex is to break down branched-chain amino acids so that the cells can produce glucose, proteins, fatty acids, and cholesterol and can signal to other cells. Decreased functional activity of the BCKAD complex causes branched-chain amino acids to accumulate without being broken down, reaching excessive levels in the body and leading to the signs, symptoms, and complications of maple syrup urine disease.²^,8

Signs and symptoms of maple syrup urine disease

Signs and symptoms emerge at different times depending on the subtype of maple syrup urine disease, whether that be the classic, intermediate, intermittent, thiamine responsive or E3-deficient subtype. Classic and E3-deficient maple syrup urine disease present with signs and symptoms shortly after birth, whereas intermediate, intermittent, and thiamine-responsive subtypes can emerge at any age.² ⁵ ⁸

Maple syrup urine disease presents with a range of signs and symptoms. The subtype of disease possessed by an individual is determined by the specific symptoms being experienced, age of disease onset and by how much residual activity the BCKAD complex still exhibits. The range of possible symptoms include:² ⁵ ⁸

• Maple-syrup-odoured or sweet-smelling urine
• Lethargy
• Irritability
• Muscle spasms
• Disorders of the brain (encephalopathy)Poor growth, poor feeding, and developmental delays

Sometimes, maple syrup urine disease can cause acute metabolic decompensation, where levels of branched-chain amino acids can elevate, typically due to physical or psychological stress or infections, despite a patient being managed and treated. This is a medical emergency characterised by several signs and symptoms:⁶

• Decreased appetite
• Nausea and vomiting
• Irritability
• Muscle spasms
• Poor balance and coordination
• Loss of consciousness

Diagnosis of maple syrup urine disease

Ruling out other disorders

Confirming a diagnosis of maple syrup urine disease involves ruling out other disorders that may present similarly:⁵

• Hyperketosis syndromes
• Urea cycle defects
• Glycine encephalopathy
• Propionic acidemia

Specific tests

Blood tests, as a part of newborn screening, which typically takes place five days following birth and involves pricking the newborn’s heel to collect blood, can detect elevated levels of branched-chain amino acids in the blood, suggesting a diagnosis of maple syrup urine disease. Furthermore, the detection of alloisoleucine in a plasma amino acid analysis can confirm a diagnosis of the disorder.⁵

Elevated ketones in urine are suggestive of maple syrup urine disease but can also be indicative of other disorders.⁵

Detection of uric acid levels in the body can be done rapidly, making it an important tool alongside establishing a patient’s signs and symptoms to determine whether a patient is undergoing acute metabolic decompensation, which is a medical emergency.⁶

Medical history

Sometimes, people with maple syrup urine disease present with signs and symptoms later in life or go undiagnosed or untreated at birth. A consultation with a doctor wherein an individual’s medical history is analysed and signs and symptoms are disclosed will aid in confirming a diagnosis of maple syrup urine disease.⁵

Management and treatment of maple syrup urine disease

Medical nutritional therapy

Lifelong dietary changes can stop the signs, symptoms, and complications of maple syrup urine disease. These dietary changes involve a lack of consumption of branched-chain amino acids, with this being achieved through low protein intake. This typically involves limiting intake of certain foods, including meat, fish, cheese, eggs, legumes, and nuts. Before such a therapy can be prescribed, it is essential that the patient has been confirmed as possessing maple syrup urine disease.¹^,²^,⁷

A paediatric nutritionist or metabolic disease specialist can help in establishing a diet plan suitable for a patient with maple syrup urine disease. As the disease tends to present in newborns, parents play a big role in ensuring that their child follows the correct diet and avoids specific foods. However, as a child transitions into adulthood, counselling from a dietitian can help prepare them to self-administer their nutritional plan as they adopt a more independent lifestyle.²

Medical emergency

For metabolic decompensations, hospital care is urgently required to prevent serious consequences, such as permanent brain damage and death. This urgent therapy typically involves administering a rehydration/caloric formula to the patient. This formula contains high levels of proteins (free of branched-chain amino acids) to induce protein synthesis in the patient so that excess branched-chain amino acids in the blood are removed and changed into proteins.⁷

Surgery

Sometimes, liver transplantation is considered a management and treatment option for those with maple syrup urine disease. By having a liver transplant, a patient is no longer prone to metabolic decompensation since the implanted liver will be able to break down branched-chain amino acids.

Furthermore, a patient no longer needs to continue implementing lifelong dietary changes. However, in order to prevent the body from rejecting the transplanted liver, the patient will have to take immunosuppressive medication for the rest of their life.¹

Complications of maple syrup urine disease

Maple syrup urine disease can cause several complications, particularly when it fails to be diagnosed or treated early:¹^,²

• Seizures
• Brain damage
• Developmental delays
• Coma
• Respiratory failure
• Death

FAQ

How common is maple syrup urine disease?

Globally, maple syrup urine disease is rare, with it occurring in approximately one in 185,000 to 491,000 births.²^,⁷

Can maple syrup urine disease be detected before birth?

Prenatal testing, which can be conducted through several techniques, such as chorionic villus sampling and amniocentesis, can typically detect whether an offspring has maple syrup urine disease before birth. However, most cases of maple syrup urine disease are detected after birth through routine newborn screening.²

Is maple syrup urine disease preventable?

Couples who both carry the mutated gene of maple syrup urine disease have a one-in-four chance of having a child with maple syrup urine disease and a two-in-four chance of having a child who carries the mutated gene of maple syrup urine disease. Couples cannot prevent maple syrup urine disease from occurring in their offspring when naturally conceiving. However, couples can consult with a doctor to explore alternative options to natural conception, circumventing the associated risks of their child having maple syrup urine disease, such as adoption or donation of eggs or sperm.²

Can maple syrup urine disease be cured?

Maple syrup urine disease cannot be cured, but symptoms and complications of the disorder can be avoided through lifelong dietary changes, wherein consumption of branched-chain amino acids is prevented by limiting the intake of foods such as meat, fish, cheese, eggs, legumes, and nuts. 

In certain cases, liver transplantation can be considered to treat and manage a patient with maple syrup urine disease, which removes symptoms and allows the body to normally process branched-chain amino acids, although the patient will need to take immunosuppressants for the rest of their life to prevent rejection of the transplant.¹

Summary

Maple syrup urine disease is a rare disorder caused by the inheritance of a mutated gene. As this mutated gene prevents branched-chain amino acids from being broken down, these branched-chain amino acids accumulate, reaching excessive levels in the body and leading to the symptoms of maple syrup urine disease. 

These include sweet-smelling urine, lethargy and disorders of the brain. If not diagnosed and treated early, maple syrup urine disease can cause various complications such as seizures, brain damage and developmental delays. Maple syrup urine disease can be detected as part of newborn screening but sometimes is diagnosed later in life. 

Treatment typically involves dietary changes wherein the patient avoids consumption of foods containing branched-chain amino acids, with this being achieved through low protein intake. In more severe cases, a liver transplant may be required. Emergency medical care can be necessary if branched-chain amino acid blood levels spike, such as during acute metabolic decompensation.