What Is Maple Syrup Urine Disease?
Maple Syrup Urine Disease (MSUD) is a very rare genetic metabolic disorder that is usually diagnosed in newborn infants characterized by the deficiency of certain enzymes (branched-chain alpha-keto acid dehydrogenase complex) required to break down (metabolize) the three branched-chain amino acids (BCAAs) [Leucine, Isoleucine, and Valine] in the body. The result of this metabolic failure is that all three BCAAs, along with their various byproducts, accumulate abnormally throughout the body. In the classic, severe form of MSUD, the plasma concentrations of the BCAAs begin to rise within a few hours of birth. If untreated, symptoms begin to emerge, often within the first 24-48 hours of life. Those with MSUD are unable to correctly process certain types of amino acids and proteins, which results in a sweet, maple syrup smell to show up in urine as amino acids build up to unhealthy levels in the body.
The “non-specific” symptoms include lethargy, irritability, and poor feeding, followed soon by focal neurological signs such as abnormal movements and increasing spasticity, and shortly thereafter, by convulsions and deepening coma. If untreated, progressive brain damage is inevitable and death ensues usually within weeks or months. The finding that is unique to MSUD is the emergence of a characteristic odor, reminiscent of maple syrup that can most readily be detected in the urine and earwax and may be smelled within a day or two of birth. If untreated, maple syrup urine disease can lead to seizures, coma, and death.
MSUD is thought to affect 1 in 185,000 newborns globally, although there is a higher occurrence of MSUD in Mennonite populations where it occurs in approximately 1 of every 380 infants.
MSUD is an inherited genetic disorder acquired when both parents carry the recessive gene. If one parent carries the disorder, the child may become a carrier without displaying any symptoms of MSUD.
Maple syrup urine disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still lead to delayed development and other health problems if not treated.
The disorder can be successfully managed through a specialized diet. However, even with treatment, both affected children and adults patients with MSUD remain at high risk for developing episodes of acute illness (metabolic crises) often triggered by infection, injury, failure to eat (fasting), or even by psychological stress. During these episodes, there is a rapid, sudden spike in amino acid levels necessitating immediate medical intervention.
There are three or four types of MSUD: the classic type; intermediate type, intermittent type, and possibly a thiamine-responsive type. The various subtypes of MSUD have different levels of residual enzyme activity, severity, and age of onset. MSUD is commonly tested in newborns so that it may be caught early.
What Are The Sub-types Of Maple Syrup Urine Disease And Their Symptoms?
The symptoms and severity of MSUD vary greatly from person to person and are generally related to the amount of enzyme activity.
Classic Maple Syrup Urine Disease is by far the most common and severe form of MSUD and has little to no enzyme activity. Most infants with Classic MSUD have subtle symptoms at first, such as:
- Poor feeding
- Increasing lethargy
- Increasing irritability
As the baby gets sicker, the symptoms begin to increase:
- Fencing and cycling movements
- Further disengagement with the outside world
- Increasing hypertonia, muscle spasticity
- Maple syrup smelling urine in the sweat and urine
- Brain damage
- Death due to respiratory failure
Complications of Classic Maple Syrup Urine Disease:
Even after MSUD has been treated and stabilized, there can be additional complications, including:
- Recurrent metabolic decompensation related to an increased breakdown of proteins, due possibly to infection, stress, fasting, trauma, or any major changes in diet
- Intellectual limitation
- Impulse control disorders
- Generalized loss of bone mass
- Intracranial hypertension
- increased headaches, often associated with nausea and vomiting
Intermediate Maple Syrup Urine Disease occurs when a person – generally in children between five months and seven years – develops levels of residual enzyme activity that is seen with classic MSUD. Symptoms of Intermediate MSUD can include:
- Neurological impairments
- Developmental delays
- Feeding problems
- Poor growth
- Maple syrup odor in urine, earwax, and sweat
- Metabolic crises
- Brain damage
- Life-threatening neurological complications
Children who have Intermediate MSUD are susceptible to the same neurological conditions and extreme symptoms as those with classic MSUD and as such, follow the same treatment program.
Thiamine-response MSUD is a form of the disorder that responds to treatment with thiamine (Vitamin B1) which helps the body convert carbohydrates into energy. However, no child should be treated only with thiamine and must also follow a partially-restrictive diet. Symptoms are rarely present at birth.
While the majority of patients fall into the categories above, several families with multiple affected members have been identified who do not fit the criteria for any of the above subtypes. These unique patients are deemed unclassified MSUD.
Diagnosis and Risks Associated With Maple Syrup Urine Disease:
Most infants with MSUD are identified through newborn screening programs. Tandem mass spectrometry, an advanced newborn screening test that screens for more than 30 different disorders through one blood sample, has aided in the diagnosis of MSUD. However, some infants who have mild or intermittent forms of MSUD may have totally normal amino acids after birth and can be missed by newborn screening. In areas in which the screening test is not available, a diagnosis of MSUD may be based upon the classic symptoms of the disorder.
Early diagnosis in suspected children, allows for management of asymptomatic infants before the onset of the symptoms, and diagnosis through DNA testing is readily available.
Genetic testing for mutations in the BCKDHA, BCKDHB and DBT genes is also available to confirm the diagnosis and is necessary for carrier testing at-risk relatives and prenatal diagnosis for at-risk pregnancies.
Treatment for Maple Syrup Urine Disease:
The treatment of classic, intermediate, intermittent, and thiamine-responsive MSUD has two chief components:
- Lifelong therapy to maintain amino acids in the body
- Immediate medical intervention for metabolic crises.
People who have MSUD have to follow a special protein-restrictive diet to eliminate the number of amino acids in the body and should be started as soon as possible after birth to ensure proper growth and development. There synthetic formula available that provide the proper nutrients but lack certain amino acids (leucine, valine, and isoleucine). Children with MSUD must be regularly monitored to ensure that their amino acid levels remain within acceptable ranges.
Some doctors recommend a trial of thiamine therapy to determine whether an affected child is thiamine-responsive, however, no child with MSUD can rely solely on thiamine therapy and must follow a restrictive diet as well.
It’s important for caregivers to know that even with the therapies and diets, a risk of metabolic crisis still exists. These metabolic crises must be treated immediately, The aim for emergent treatment for metabolic crises is to attempt to reduce and reverse the increase in protein catabolism (the destructive metabolism) and may include a high glucose intake, glucose-insulin IV, and parenteral insulin.
Other treatments are symptomatic and supportive. Early intervention is important in ensuring that children with MSUD reach their highest potential.
Genetic counseling is recommended for affected individuals and their families.
Additional Maple Syrup Urine Disease Resources:
MSUD Family Support Group is a nonprofit organization that offers support and resources for those with MSUD and their families.
CLIMB (Children Living with Inherited Metabolic Disorders) is the National Information Center website in the UK and has incredible resources for those in the UK