Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disorder affecting the way in which the body processes certain amino acids that are found in proteins.
The condition gets its distinctive name from the characteristic sweet, maple syrup-like smell of afflicted individuals’ urine. MSUD affects approximately 1 in 185,000 newborns worldwide1.
Genetically, MSUD follows an autosomal recessive inheritance pattern, meaning a child must inherit two copies of the mutated gene, one from each parent, to develop the condition. Parents that carry a copy of the mutated gene typically show no symptoms but have a 25% chance of having a child with MSUD if both parents are carriers 2.
The genetic basis of MSUD
The condition is caused by mutations in one of three genes, BCKDHA, BCKDHB or DBT3. Each of these genes provide instructions for the human body to make enzymes that are essential for breaking down amino acids such as leucine, isoleucine, and valine. These are branched-chain amino acids that are a part of protein rich foods such as meats, dairy, and eggs. Mutations in any of these genes can cause a reduced or complete cessation of enzyme activity. A buildup of amino acids and their toxic byproducts can result in serious health issues related to MSUD.
Symptoms
The severity of MSUD and its symptoms can vary greatly based on the amount of residual enzyme activity present in the body, as such it can be classified into four forms: classic, intermediate, intermittent, and thiamine responsive. Each type can show a range of severity4.
Classic MSUD
This is the most common and severe form of MSUD. It is characterized by very little to no enzyme activity. The symptoms are usually observed in newborns within 2-3 days of birth and begin subtly with poor ability to feed from the breast or from a bottle, increased lethargy, and irritability.
As the disorder progresses, more signs may be exhibited such as abnormal or spastic movement, hypertonia, seizures, and a distinctive maple syrup smell in their urine, sweat and earwax.
Children with classic MSUD may also develop:
- Intellectual disabilities or limitations
- Behavioral difficulties such as attention deficit hyperactivity disorder (ADHD), depression, anxiety, and impulsiveness
- Osteoporosis
- Pancreatitis
- Headaches, nausea, and vomiting
Intermediate MSUD
In intermediate MSUD there is a greater level of residual enzyme activity than in classic MSUD, while some symptoms may develop in the neonatal period, most are usually diagnosed between 5 months and 7 years old using metabolic blood tests and genetic testing.
Symptoms include:
- Slow growth
- Feeding problems
- Lethargy
- Ataxia
Symptoms can worsen to include:
- Seizures
- Brain damage
- Coma
- Life threatening neurological complications
Additionally, children will also display the characteristic maple syrup odor in their sweat, urine and earwax. The risks of intermediate MSUD are the same as in the classic form however, the onset is later. Management of both forms is the same.
Intermittent MSUD
Intermittent MSUD is generally milder with later onset symptoms where children tend to experience regular growth, intellectual development and are able to tolerate regular levels of protein in their diet. MSUD symptoms can be triggered during times of metabolic stress including infections, physical or psychological stress, and fasting.
Thiamine-responsive MSUD
This rare form responds to high doses of thiamine (vitamin B1) in treatment, which enhances the residual enzyme activity within the body. Clinically it presents very similarly to intermediate MSUD though it’s rarely observed during the neonatal period.
Diagnosis
MSUD is tested for through newborn screening programs, it is then diagnosed through additional blood and urine tests, ESI-Time of Flight mass spectrometry, and genetic studies of the patient.
In families that have a history of MSUD prenatal testing may be done through either amniocentesis or chorionic villus biopsy to identify the disorder before birth, allowing clinicians to prepare early interventions as required. Due to the life altering impact if untreated, it is important to diagnose MSUD as early as possible.
Treating maple syrup urine disease
Managing MSUD requires a lifelong commitment to dietary control and careful monitoring. The primary goal of treatment is to maintain safe levels of branched-chain amino acids while ensuring adequate nutrition for normal growth and development.
Treatment includes:
- A protein-restricted diet to prevent amino acid accumulation
- Lifelong monitoring of leucine, isoleucine, and valine levels in the blood
- Immediate therapy as required in response to metabolic crises. This can include glucose and insulin via IV, nutrient delivery via IV or nasogastric feeding tube, hemodialysis, and brain monitoring for signs of swelling or infection.
Diagnosis in babies will often result in a switch to a synthetic baby formula specially tailored to provide them with the nutrients they need without the specifi c amino acids that cause a build up in their blood. Regular monitoring is required.
Individuals with thiamine-responsive MSUD can be treated with thiamine (vitamin B1) along with other therapies however, it is not recommended that thiamine is used as the only treatment in these situations.
MSUD in the long term
Even with strict dietary control, MSUD patients face the risk of metabolic crises. In some cases, patients may require hemodialysis or hemofiltration to remove waste and specific amino acids from the blood.
In some cases, liver transplantation has been used to treat individuals with classic MSUD. This can supply enough enzymes to break down the branched chain amino acids in the blood, allowing individuals to maintain a regular diet and live symptom free. Due to the high costs of transplantation and the limited availability of liver donors, this is usually a rare option.
How can Pentec help MSUD patients?
Supporting the rare disease community is at the core of Pentec’s mission. Through ZOIA, a Pentec company, we're able to provide medical foods and specialized nutritional products exclusively dedicated to the rare disease.
Through our online marketplace patients can directly access a wide variety of items from trusted manufacturers. Furthermore, our 11,000 square-foot U.S. FDA-registered medical food warehouse and storage facility ensures that we can supply patients across the country, offering a diverse selection of products and providing peace of mind during market supply shortages.
In addition to delivery services, our dedicated team at ZOIA help patients and HCPs navigate the complexity of insurance coverage while providing clinical support.
By collaborating with patient advocacy groups such as the Maple Syrup Urine Disease Family Support Group, we demonstrate our commitment to enhancing the quality of life of these individuals requiring specialized nutritional products. With access to a vast selection of formula, low protein and medical food options, ZOIA Pharma strives to empower patients and their families to manage inherited metabolic disorders more effectively.
Managing MSUD requires dedication and support, but with the right resources and care team, it doesn't have to defi ne your life. ZOIA is proud to be part of the solution, helping to make the management of MSUD more straightforward and allowing patients to focus on what matters most - living their lives to the fullest.
To learn more about our product offerings visit the ZOIA website.
For more information on other inherited metabolic disorders, read our spotlights on PKU and HCU.
