What is maple syrup urine disease?

Maple syrup urine disease is a rare inherited disorder caused by the body’s inability to properly process amino acids, leading to a characteristic odor of maple syrup in the baby's urine. If not diagnosed and treated soon after birth, maple syrup urine disease (MSUD) can be life threatening – as early as the first two weeks of life.

Therefore, early detection and treatment essential. In most cases, MSUD can be successfully managed with a specialized diet that breaks down the three specific amino acids – leucine, isoleucine and valine – preventing them and their toxic by-products from accumulating abnormally in the blood. However, even with treatment, some children with this disease can suffer severe disability and paralysis.

In most cases, MSUD is diagnosed at birth as part of routine newborn screening tests, which are required in many states. Pennsylvania, New Jersey and Delaware all require newborn screening for maple syrup urine disease. A heel-prick is used to obtain a sample of the baby’s blood and tested for abnormally high levels of amino acids. Babies who receive abnormal results from early metabolic screening tests may be referred to the Newborn Metabolic Screening Program at Children’s Hospital of Philadelphia.

MSUD is believed to affect 1 in 185,000 births worldwide. MSUD is more common in the Mennonite population in comparison to the general population. MSUD is believed to affect 1 in 380 people in the Old Order Mennonite population and 1 in 26,000 in the Ashkenazi Jewish population. About 2,000 people in the U.S. have been diagnosed with MSUD.

Causes of maple syrup urine disease

Maple syrup urine disease is caused by mutations in one of three genes – BCKDHA, BCKDHB or DBT. These genes provide instruction for the human body to make enzymes (BCKDH complex enzymes) which are essential for breaking down amino acids including leucine, isoleucine, and valine. These amino acids are present in protein-rich foods such as milk, meat, and eggs. Mutations to the three genes result in decreased or no activity of the enzymes. When the amino acids and their toxic byproducts accumulate, serious health issues related to MSUD can occur.

MSUD is inherited as an autosomal recessive pattern, meaning that both parents must carry the mutated gene to have a child with MSUD. Each individual has two copies of each gene. A carrier for MSUD is healthy but carries a mutation in one of the two copies of the gene. When two carrier parents have a child together, they have a 25% chance of having a child with the disorder for each pregnancy. The risk of MSUD occurrence is the same for males and females.

Signs, symptoms, and types of MSUD

The signs, symptoms, and severity of maple syrup urine disease varies greatly among affected patients and depends on the type of MSUD and amount of residual enzyme activity.

Classic MSUD is both the most severe and most common form of the disease, characterized by little or no enzyme activity. Infants with this form of MSUD generally show vague symptoms within a few days of birth, such as poor feeding, increased irritability, and lethargy. Within a few days and as the disease quickly progresses, infants with MSUD will display abnormal or spastic movements, hypertonia, neurological symptoms, and a distinctive odor of maple syrup in their urine, sweat and/or earwax.

Children with classic MSUD may also have:

• Intellectual disabilities or limitations
• Behavioral issues such as attention-deficit/hyperactivity disorder (ADHD), depression, anxiety and impulsiveness
• Loss of bone mass, increased fractures, and pancreatic inflammation
• Headaches, nausea and vomiting

Intermediate MSUD differs from the classic form in that these individuals typically have a higher level of residual enzyme activity and a later onset of symptoms. Most children with intermediate MSUD are diagnosed between 5 months and 7 years old. Like its classic form, intermediate MSUD initially produces nonspecific symptoms including feeding problems, lethargy, and poor growth, which may worsen to include seizures, brain damage, coma, and life-threatening complications. Children with intermediate MSUD also display the characteristic odor of maple syrup in their sweat, urine, and earwax.

Children with Intermittent MSUD typically have normal growth and intellectual development, and most can eat normal levels of protein in their diet. However, these children may experience symptoms of MSUD during periods of increased energy demands on the body, i.e. during illness.

The fourth type, thiamine-responsive MSUD, responds to treatment with vitamin B1 (thiamine), which plays a role in enzyme processing. Symptoms of thiamine-responsive MSUD are similar to intermediate MSUD and rarely occur in the first year of life.

Testing and diagnosis of maple syrup urine disease

Most infants with MSUD are initially identified through newborn screening programs, then diagnosed with additional testing that may include:

• Blood and urine tests
• ESI-Time of Flight mass spectrometry, to identify the levels of three specific amino acids – leucine, isoleucine and valine – in the blood
• Genetic studies of the patient to identify any mutations of the BCKDHA, BCKDHB or DBT genes

If a family has a history of maple syrup urine disease, prenatal testing through chorionic villus biopsy or amniocentesis may be done to identify the disorder before birth, allowing clinicians to plan for early interventions as needed.

MSUD can cause irreversible metabolic damage and be life-limiting. For these reasons, it’s important to diagnose the disease as soon as possible and begin treatment.

Treatment for maple syrup urine disease

Treatment for MSUD includes:

• A life-long protein-restricted diet to promote proper growth and development, and prevent amino acid buildup
• Lifelong monitoring of leucine, isoleucine, and valine amino acid levels in the blood
• Immediate medical intervention if needed to respond to metabolic crises

Babies diagnosed with MSUD should be switched to a synthetic baby formula that will provide them with all the nutrients they need but lack the specific amino acids that cause an abnormal buildup in their blood. Regular monitoring will be needed to ensure that amino acid levels remain within normal ranges. Individuals with thiamine-responsive MSUD can be treated with thiamine (B1) in coordination with other therapies, but thiamine is not recommended to be used as the only treatment.

Long-term outlook

Patients with MSUD will require monitoring including routine physical examinations, follow-up blood and urine tests, as well as periodic assessment of liver functions.

The risk of metabolic crisis remains – even for those patients strictly following a specialized diet and prescribed therapies. In some cases, patients may require hemodialysis or hemofiltration to remove waste, certain fluids, and specific amino acids from the blood. Aggressive therapies for metabolic crises are meant to reduce – then reverse – increased protein levels in the blood. In certain situations, intravenous glucose, intravenous fat, or total parenteral nutrition may be prescribed.

In rare cases, liver transplantation has been used to treat individuals with classic MSUD. A healthy transplanted liver can supply enough enzymes to break down the three affected branched-chain amino acids, allowing individuals to live symptom-free and eat normal foods. The high costs of liver transplantation and the availability of liver donors limit the number of transplants available.