Maple Syrup Urine Disease (MSUD)

What is Maple Syrup Urine Disease (MSUD)?

Maple syrup urine disease is a genetic disease characterised by incomplete metabolism of the amino acids leucine, isoleucine and valine. It owes its unusual name to the characteristic sweet-smelling urine of those affected.

In individuals with this disease, poor processing of leucine, isoleucine and valine causes a build up of these molecules and their by-products in the blood and urine. Untreated, this can cause seizures, severe brain damage and coma. Few infants survive without intervention. The condition shows similarities to isovaleric acidaemia, in which leucine metabolism is affected.

Amino acids are the building blocks of proteins. After eating proteins, the body ‘metabolises’ or breaks them down into amino acids. Animal proteins include dairy products, meat, eggs and fish. Proteins are also found in plants including soy, legumes, grains and nuts. The body uses the amino acids to make its own proteins essential for life – for example enzymes; structural proteins in muscles, hair, skin, cells and cartilage; proteins that generate movement in muscles; or those involved in cell functioning or immune responses. In periods of fasting or illness, the body often switches to use its own proteins to generate energy.

Leucine, isoleucine and valine are essential amino acids meaning that the body cannot make them. Therefore, these amino acids come from ingested protein or from the breakdown of previously ingested and stored proteins. Leucine, isoleucine and valine are classified as ‘branched amino acids’, which describes their specific chemical composition. 

Another name for maple syrup urine disease is branched-chain ketoaciduria. This describes the presence in the urine of keto acids. These are metabolic by-products created when the body resorts to using its own protein and fat stores for energy.

How common is maple syrup urine disease?

Globally, around 1 in 185,000 people live with maple syrup urine disease. It may be more common in Amish or Mennonite communities in the USA, affecting as many as 1 in 380 newborns.

What causes maple syrup urine disease?

The disease may be linked to a mutation in any of four genes. These genes code for proteins that work together as a complex called the branched-chain alpha-keto acid dehydrogenase complex. The subunits of the enzyme complex are termed E1α, E1β, E2, and E3. When functional, the complex is involved in the metabolism of leucine, isoleucine and valine. Genetic mutation reduces or eliminates the function of complex, thus interfering with the correct processing of these amino acids. In general, the severity of the disease is linked to the degree of enzyme activity that remains.

Maple syrup urine disease is a recessively inherited genetic disorder, meaning that a child would only have the condition if both parents ‘carry’ the genetic mutation. Genes are arranged in structures called chromosomes that contain two strings or ‘alleles’. Offspring inherit one allele from their father and one from their mother. Carrying one copy of the mutated gene does not affect health, but when two mutated copies come together, the linked enzyme is deficient either in quantity or effect and the disease is expressed. For each and every pregnancy, there is a 1 in 4 chance of two carriers of the genetic mutation having a child with maple syrup urine disease. 

What are the symptoms and signs of maple syrup urine disease?

There are five types of maple syrup urine disease: classic, intermittent, intermediate, thiamine-responsive and dihydrolipoyl dehydrogenase deficient forms.

The classic form is the most common and severe, and is associated with the lowest level of remaining enzyme activity. Infants appear healthy at birth then symptoms develop from about the age of 1 to 2 weeks. These include poor feeding, vomiting, dehydration, weight loss and extreme tiredness. Pronounced accumulation of metabolic products causes the blood and tissues to become abnormally acidic (metabolic acidosis). Keto acids also build up in the blood, tissues and urine (ketoacidosis). The urine takes on the characteristic smell of maple syrup. Abnormal neurological signs such as floppiness, seizures and abnormal posturing of the arms may develop and neurological decline continues if treatment is not initiated.

The other types of maple syrup urine disease appear later in childhood and are less severe than the classic variant. Those with intermittent disease may have up to 20% remaining enzyme activity. The disease tends to reveal itself between the ages of 5 months and 2 years, although it can be as late as 5 years before symptoms develop. Metabolic crises (i.e. metabolic acidosis, ketoacidosis and high levels of the amino acids) occur intermittently. Otherwise, growth and development are quite normal. The crises are triggered by infections, fever and periods without food, and are due to the body breaking down stored proteins and releasing the toxic substances into the blood.

Individuals with intermediate-type maple syrup urine disease have up to 30% enzyme activity. They show gradual neurological problems due to slowly increasing levels of amino acids. If untreated, these problems affect the brain and affect intellectual functioning. This form is usually diagnosed before the age of 7 years.

Thiamine-response maple syrup urine disease is similar to the intermediate type except that, as the name suggests, individuals respond well to treatment with thiamine (vitamin B1). Enzyme activity is usually up to 40% of normal levels.

Finally, the E3-deficient variant is similar to intermediate maple syrup urine disease except an additional type of acidosis occurs, known as lactic acidosis. This form is extremely rare, manifests between the ages of 8 weeks and 6 months, and is characterised by progressive brain damage and movement disorder.

How is maple syrup urine disease diagnosed?

The distinctive smell of the urine usually raises the suspicion of maple syrup urine disease. Blood and urine tests showing high levels of the amino acids leucine, isoleucine and valine, and signs of ketacidosis and metabolic acidosis confirm the diagnosis.

In some countries, infants are routinely screened for maple syrup urine disease at birth. 

How is maple syrup urine disease treated?

Maple syrup urine disease is treated through dietary restriction of leucine, isoleucine and valine. The aim of treatment is to reduce levels of these amino acids in the body to prevent them causing brain damage. This diet needs to be continued indefinitely and must be initiated only after consultation with a dietician.

The leucine-, isoleucine- and valine-restricted diet must be managed carefully to ensure optimal nutrition. As such, natural protein intake is limited and a formula free of leucine, isoleucine and valine is given. A range of such formulas is available, designed specifically to meet the nutritional needs of children at different ages. These specially formulated powders contain a balanced mix of essential and non-essential amino acids, vitamins, minerals and carbohydrates to avoid malnutrition of other amino acids and to sustain normal growth in children. Several low-protein food products are also available.

During periods of illness, fasting and infection, aggressive treatment is initiated to prevent the body breaking down its own proteins. This comprises giving additional fluids, carbohydrates and fats plus, in some cases, dialysis to reduce amino acids levels in the blood.

Individuals with intermittent maple syrup urine disease may only require treatment during periods where there is increased risk of metabolic crisis.

A trial of thiamine supplementation lasting for at least 3 weeks is normally recommended for all individuals with maple syrup urine disease, to identify those with thiamine-response disease. 

Although there is no cure, with diet and correct management of crises, most individuals with maple syrup urine disease are able to live normal lives.