Imagine a world where the sweet scent of maple syrup takes on a whole new meaning, a world where it’s not just a delightful addition to pancakes but a telltale sign of a rare genetic disorder. Maple Syrup Urine Disease (MSUD), where a seemingly innocuous odor can signify a complex and challenging condition. Parents should consider their child’s well-being and be vigilant for any unusual odors or symptoms.

What is Maple Syrup Urine Disease (MSUD)?

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder resulting from genetic mutations affecting the breakdown of branched-chain amino acids (BCAAs), such as:

• Leucine
• Isoleucine
• Valine

When enzyme function is compromised, these amino acids accumulate in the body, leading to toxicity. The condition earns its name from the distinctive sweet odor of affected individuals’ urine, resembling that of maple syrup. 

Without medical intervention, MSUD can result in a variety of cognitive and physical impairments. Proper management is essential as the condition can be life-threatening if left untreated.

Leucine, isoleucine, and valine are essential branched-chain amino acids vital for protein synthesis, muscle repair, and energy production. 

• Leucine regulates blood sugar levels, promotes insulin secretion, and aids neurotransmitter synthesis. 
• Isoleucine contributes to energy production, hemoglobin synthesis, and glucose regulation. 
• Valine supports muscle growth, energy production, and nervous system function, ensuring overall health and vitality.

Other names of MSUD

• BCKD deficiency
• Branched-chain alpha-keto acid dehydrogenase deficiency
• Branched-chain ketoaciduria
• Ketoacidemia
• MSUD
• BCKDC deficiency
• branched-chain ketoaciduria
• branched-chain ketonuria I

Inheritance Pattern of MSUD: Worldwide vs. in India

Maple Syrup Urine Disease (MSUD) follows an autosomal recessive inheritance pattern, indicating that the disorder arises from mutations in both copies of the gene associated with it. Individuals with MSUD inherit one mutated gene from each parent, who are typically unaffected carriers of the condition. In India, as in other parts of the world, MSUD follows the same inheritance pattern.

MSD exhibits an autosomal recessive inheritance pattern. The likelihoods per birth are as follows:

If both parents are carriers:

• 25% (1 in 4) of offspring will develop the disorder.
• 50% (2 in 4) of offspring will carry the gene but remain unaffected.
• 25% (1 in 4) of offspring will be unaffected and not carriers.

Each child has a 25% chance of inheriting the disorder, a 50% chance of being a carrier without experiencing symptoms, and a 25% chance of being free of MSUD and unaffected. 

If one parent has the disorder and the other does not:

• 0% (0) of offspring will inherit the disorder, as only one parent is affected and the other always transmits a normal gene.
• 100% (4 in 4) of offspring will carry the gene but remain unaffected.

In this scenario, each child of the couple has a 100% chance of being a carrier of the mutated gene, but they will not develop the disorder. This is because the child will inherit one copy of the mutated gene from the affected parent and one normal copy from the unaffected parent. As a result, the child will not have the disease but will be a carrier of the MSUD gene.

If one parent is a carrier and the other is unaffected:                            

• 50% (2 in 4) of offspring will carry the gene but remain unaffected.
• 50% (2 in 4) of offspring will be unaffected and not carriers.

Each child of parents where one is a carrier of MSUD has a 50% chance of being an unaffected carrier and a 50% chance of being free of MSUD. This is because the unaffected parent passes on a normal gene, while the carrier parent may pass on either a normal or mutated gene. Thus, children can inherit one normal gene from the unaffected parent and one normal or mutated gene from the carrier parent, making them unaffected carriers, or they can inherit two normal genes, making them free of MSUD and unaffected.

Prevalence Of MSUD

In India, Maple Syrup Urine Disease (MSUD) has a prevalence of approximately 1 in 100,000 births, which is attributed to the high number of annual births and consanguinity rates. This condition is characterized by an estimated worldwide incidence of 1 in 185,000 infants, with certain populations, such as the Old Order Mennonite community, experiencing a higher frequency, with an incidence of up to 1 in 380 births. 

Similarly, the Ashkenazi Jewish population has an elevated incidence, with approximately 1 in every 26,000 births affected. Overall, MSUD predominantly affects populations with a limited gene pool or where close relatives have children together, leading to potential developmental delays and mortality if left untreated.

Symptoms and Signs of MSUD

Symptoms of classic MSUD typically emerge in newborns within the first 48 hours after birth, while signs of intermediate, intermittent, and thiamine-responsive MSUD often manifest before age 7 in older children. Without intervention, these symptoms can escalate from mild to potentially life-threatening. Seeking immediate medical attention at the first indication of MSUD is crucial.

Neurological symptoms of MSUD can manifest due to the buildup of toxic substances in the blood and brain. These symptoms may include irritability, lethargy, poor feeding, developmental delay, seizures, tremors, and coma.

Common signs of MSUD include:

• A distinctive sweet odor in urine, sweat, or earwax.
• Lethargy or weakness.
• Irritability or fussiness.
• Loss of appetite.

Without treatment, symptoms can progress to a metabolic crisis, where the body’s ability to process food becomes impaired. This leads to an accumulation of amino acids and toxic byproducts in the body.

Signs of a metabolic crisis may include:

• Abnormal muscle movements, such as arching of the head, neck, and spine.
• Seizures or convulsions.
• Vomiting.
• Coma.

Untreated metabolic crises can result in death. Even individuals with diagnosed MSUD who are managing the condition can experience trigger events, such as infections, injuries, or stress, which can precipitate a metabolic crisis. Prompt medical assistance is essential in such situations.

Different Types of MSUD

There are several types of MSUD, including classic MSUD, intermediate MSUD, intermittent MSUD, and thiamine-responsive MSUD. These variations differ in severity and age of onset.

Classic MSUD, the most severe and common type, typically manifests within the first three days after birth. Symptoms emerge swiftly, necessitating prompt medical intervention to manage the condition effectively.

Intermediate MSUD, less severe than the classic form, usually presents in children aged between 5 months and 7 years. While the symptoms may be less intense, proper management is still crucial to prevent complications and maintain optimal health.

Intermittent MSUD occurs when symptoms arise due to infection or stress, though affected individuals often exhibit higher tolerance levels for the amino acids involved compared to classic MSUD. Careful monitoring and timely intervention are essential to address symptoms promptly.

Thiamine-responsive MSUD can be managed with high doses of vitamin B1 (thiamine) and a controlled diet. With proper treatment, individuals with this type of MSUD may experience improved tolerance for the amino acids, highlighting the importance of tailored therapeutic approaches.

Role of MSUD Enzyme

• Maple Syrup Urine Disease (MSUD) is caused by a deficiency of the enzyme branched-chain alpha-keto acid dehydrogenase complex (BCKDC). 
• This enzyme is essential for breaking down certain amino acids, including leucine, isoleucine, and valine, found in protein-rich foods. 
• In individuals with MSUD, the lack of this enzyme leads to the harmful buildup of these amino acids and their byproducts, which can result in serious health complications if left untreated. 
• The toxicity observed in Maple Syrup Urine Disease (MSUD) primarily arises from the accumulation of branched-chain amino acids (BCAAs), particularly leucine, resulting from an enzyme complex deficiency responsible for their breakdown. 
• This buildup of toxic metabolites can trigger severe neurological symptoms, including central respiratory failure, impaired skeletal muscle function, and potentially fatal brain swelling, particularly in infants.

The metabolic pathway of MSUD is as follows:

• BCAAs (leucine, isoleucine, and valine) are taken up by cells and converted into their respective alpha-ketoacids by branched-chain aminotransferase.
• The alpha-ketoacids are then broken down by the BCKAD enzyme complex, which consists of three subunits: E1α, E1β, and E2.
• If the BCKAD enzyme complex is deficient due to mutations in the genes encoding the subunits, the BCAAs and their alpha-ketoacids accumulate, leading to toxicity and neurological symptoms.

Diagnosis of MSUD

Maple Syrup Urine Disease (MSUD) is diagnosed through newborn blood spot screening, which collects blood from the baby’s heel to test for inherited conditions like MSUD. If the screening shows a positive result, further tests are conducted to confirm the diagnosis. These include specific blood and urine examinations to measure amino acid levels and genetic testing to identify the responsible gene mutation.

Newborn screening is typically done around 5 days after birth. If MSUD is confirmed, immediate treatment is essential to prevent complications. Treatment must continue throughout life.

Classic MSUD is diagnosed shortly after birth through newborn screening or prenatal testing. For other forms of MSUD, symptoms may appear later, and diagnosis is made through metabolic blood tests and genetic testing. Distinctive signs like the sweet maple smell in bodily fluids can also aid in diagnosis.

Prenatal detection of MSUD: It can be done through chorionic villus biopsy or by amniocentesis, and molecular genetic testing for mutations in the BCKDHA, BCKDHB, DBT, and DLD genes is rarely available to confirm the diagnosis. 

Diagnosis Cost in India 

Maple Syrup Urine Disorder (MSUD) Neonatal Screen Blood Test in Mumbai costs ₹530. The Neoxpert Expanded Screening Panel, which includes Newborn Screening for 48+ Analysts, is priced at ₹6,360 in Mumbai. 

Additionally, the Amino Acid test specifically for MSUD costs ₹2,100. In Bangalore, the Neonatal Screening for MSUD is priced at ₹450. The DBT Gene Maple Syrup Urine Disease Type 2 NGS Genetic DNA Test costs ₹20,000.

Treatment of MSUD

Treatment for MSUD involves strict dietary management to limit the intake of BCAAs. This may include a specialized formula low in BCAAs and supplementation with specific amino acids. In severe cases, liver transplantation may be necessary.

Maple Syrup Urine Disease (MSUD) necessitates a comprehensive treatment approach, and dietary restrictions to manage its metabolic complications. The primary treatment involves adhering to a lifelong low-protein diet, specifically limiting the intake of three crucial amino acids. Babies born with MSUD require immediate administration of specialized formula, often supplemented with additional nutrients.

Thiamine is essential for the functioning of the branched-chain amino acid (BCAA) enzyme complex and can enhance leucine tolerance in individuals with thiamine-responsive MSUD. High doses of thiamine have been found to increase residual enzyme activity, improving leucine tolerance in this subtype of MSUD. 

However, it’s important to maintain some dietary restrictions on branched-chain amino acids (BCAAs) despite thiamine therapy. Thiamine-responsive MSUD is rare, and thiamine treatment has shown positive outcomes in reported cases, making it a vital component of management alongside dietary control and medical oversight.

Ongoing research explores novel therapies such as norleucine and antioxidants. Thiamine-responsive MSUD can be managed with high doses of vitamin B1 (thiamine) alongside dietary restrictions.

Why Liver Transplant Treatment? 

In severe cases of MSUD, liver transplantation can stabilize metabolism and prevent crises by providing the necessary enzyme activity to metabolize accumulated BCAAs. This intervention mitigates neurological complications and enables patients to maintain a regular diet, improving their quality of life. However, it does not reverse existing impairments. Liver transplantation is considered when dietary restrictions and medical therapy are inadequate for managing MSUD.

Success Rate Of Liver Transplant

Liver transplantation for MSUD shows high success rates: 98% patient and 96% graft survival in a study of 54 procedures, mainly using deceased donor livers. Another study with 37 patients confirms its efficacy in achieving metabolic control and improving quality of life.

Liver transplantation for MSUD is life-saving but requires careful consideration with a specialized healthcare team familiar with metabolic disorders and transplantation. Evidence supports its effectiveness in achieving metabolic stability and improving outcomes.

Post-Care Management Of Liver Transplant

Post-care management following a transplant for MSUD (Maple Syrup Urine Disease), patients need thorough post-care management to ensure the procedure’s success and their continued well-being. This involves closely monitoring blood amino acid levels through regular tests to prevent metabolic imbalances. 

Adjustments to dietary restrictions and supplements may be necessary based on these assessments. Following a strict low-protein diet is crucial to avoid the buildup of harmful amino acids. Patients also require ongoing medical supervision to watch for signs of rejection or other transplant-related complications. This often involves regular visits to specialized metabolic clinics or transplant centers.

Additionally, patients must adhere to prescribed medications, including immunosuppressants, to prevent rejection in the long term. Comprehensive support from healthcare professionals, including metabolic dietitians, transplant specialists, and mental health professionals, is essential to address patients’ physical, emotional, and psychological needs during the post-transplant period.

Dietary Restrictions for MSUD

Foods To Avoid  In MSUD Diet: Managing MSUD requires avoiding high-BCAA foods like meat, fish, poultry, eggs, dairy, legumes, nuts, seeds, soy, wheat, chocolate, and high-protein vegetables. This prevents BCAA buildup.

Foods To Include In MSUD Diet: Recommended low-BCAA foods for individuals with MSUD include cereal, puffed rice, banana, unsweetened rice milk, hash browns, catsup, Honey Nut Cheerios, non-dairy creamer, granola bars, pasta salad (with regular pasta), baby carrots, fresh pear, candy corn, cornstarch, corn syrup, cranberry-apple juice, guava sauce, diced raw guava, and frozen lemonade concentrate. These foods help maintain a low-protein diet, crucial for preventing BCAA buildup. Close collaboration with a metabolic dietitian and healthcare team ensures proper nutritional management.

The Role of Nutrition in MSUD

Nutritional Management is paramount in addressing Maple Syrup Urine Disease (MSUD) to ensure proper growth and development while averting metabolic crises. It involves closely monitoring protein intake and supplementing with essential nutrients to maintain metabolic stability and support healthy development.

Individuals with Maple Syrup Urine Disease (MSUD) require lifelong management through a specialized diet aimed at regulating branched-chain amino acids (BCAAs) intake while ensuring sufficient macronutrients. 

The main objective of this diet is to prevent neurological damage and metabolic crises by carefully monitoring BCAAs present in all-natural proteins. Since most foods contain some level of protein, close monitoring of daily intake is crucial to avoid exceeding individual tolerance levels. A low-protein diet is essential to mitigate neurological damage and metabolic crises, with synthetic nutrient formulas available for MSUD infants to support proper growth and development without BCAAs. This dietary regimen is prescribed and adjusted by a dietitian based on regular assessments.

Food for Special Medical Purpose (FSMP) For MSUD:

Special medical formulas are available for individuals with MSUD to ensure proper nutrition while avoiding excessive intake of BCAAs. These formulas are carefully formulated to meet nutritional needs while minimizing the risk of metabolic complications.

Special Formula For Infants 

In managing MSUD in infants, the diet regulates breast milk or infant formula intake to restrict leucine, often limited to as little as 5oz or 1.5g of protein daily. However, this may not meet the infant’s total nutritional needs. To supplement, a BCAA-free infant protein substitute is used. As the infant grows, the amount of substitute increases. Specialized infant formulas tailored for MSUD dietary management are low in BCAAs while providing essential nutrients. Typically powdered, they are recommended under medical supervision.

These formulas are fortified with prebiotic oligosaccharides, promoting immune system strength and digestive well-being in infants. Featuring DHA, they offer levels akin to those naturally present in breast milk, supporting cognitive development. Additionally, they contain essential vitamins and minerals, including calcium and vitamin D, crucial for the formation and maintenance of healthy bones and teeth.

The formulas are amino acid-modified, enriched with iron, and designed for infants and toddlers with MSUD. They are lactose-free, non-GMO, and gluten-free, providing approximately 40% energy from fat and including DHA/ARA for brain and eye development.

Special low-protein foods like biscuits, pasta, pizza bases, and burgers, many with minimal protein content, are available for individuals managing Maple Syrup Urine Disease (MSUD). Additionally, specific products such as MSUD EASY Tablets, MSUD gel, and MSUD amino5 are designated as food for special medical purposes and should be used under medical guidance. 

These products are formulated to meet the nutritional needs while adhering to the stringent dietary restrictions of MSUD. This dietary management prevents metabolic complications and promotes healthy growth and development. 

• A powdered amino acid supplement designed for individuals with Maple Syrup Urine Disease (MSUD) is available, suitable for use as part of a customized modular feed or in acute emergencies. This supplement can be utilized from infancy to adulthood. 
• Additionally, there is a powdered protein substitute suitable for individuals with MSUD, which can be easily prepared into a smooth semi-solid consistency. It is intended for weaning onto a second-stage protein substitute and should be used under medical supervision.

Importance of Specialized Infant Formula

Infant formula for MSUD differs from regular infant formula as it is specialized low-protein formula devoid of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine. This unique formula undergoes a process where the protein is broken down into individual amino acids to eliminate the BCAAs, resulting in a slightly altered smell and taste. 

Synthetic nutrient formulas are available for MSUD-affected infants to ensure proper growth and development without BCAAs. Prescribed by a dietitian and adjusted based on regular blood tests, the formula ensures the baby’s amino acid levels remain within a safe range. 

While breastfeeding is possible, a measured volume of protein substitute is prescribed to limit leucine/protein intake. For bottle-fed infants, the dietitian prescribes a volume of infant formula providing the necessary leucine/protein spread over several feeds per day, with protein substitutes used to ‘top up’ feeds as needed. 

Infant formula feeds should be offered first to track daily leucine/protein intake. An emergency regimen is also provided for illness, comprising primarily protein substitute and glucose, to be started at the first sign of illness, with immediate contact with the specialist team for further instructions. 

Explosive Growth Forecast for MSUD Treatment Market

The Maple Syrup Urine Disease (MSUD) treatment market is poised for significant growth, with a projected Compound Annual Growth Rate (CAGR) of 11.20% from 2021 to 2030. Anticipated to surge from USD 8,935 million in 2022 to USD 19,652 million in 2030, this expansion is driven by escalating demand for innovative, disease-specific treatments and heightened awareness among healthcare providers and the public alike. 

The market landscape is predominantly influenced by “Intermittent MSUD” in the type segment, with the introduction of new drugs and increased regulatory designations expected to further fuel market expansion. Key players are reshaping the market through strategic initiatives such as product launches, collaborations, mergers, and acquisitions. The competitive landscape encompasses company profiles, financials, revenue metrics, R&D investments, global reach, and product innovations. 

Notably, the substantial prevalence of MSUD in India underscores the pivotal role of market growth and development within the region. With a forecasted growth rate of 11.20% during the forecast period, the Maple Syrup Urine Disease Treatment Market presents promising opportunities for stakeholders.

Indian Government’s Initiative: Financial Support for Rare Disease Treatment

The Union Ministry of Health & Family Welfare Rare Diseases Cell, New Delhi, has increased the grant for rare disease treatment from Rs 20 lakh to Rs 50 lakh. The previous policy restricted the grant to rare diseases listed under Group 1, providing Rs 20 lakh for one-time treatment. 

However, the new rule allows any rare disease patient, irrespective of category, to claim the enhanced Rs 50 lakh grant. This amendment aims to provide financial relief to a significant number of rare disease patients in the country. 

The enhanced financial assistance will cover treatment in government tertiary hospitals and applies to about 40% of the population eligible under the Pradhan Mantri Jan Arogya Yojana norms. The guidelines for the revised policy are yet to be finalized.

Additionally, State Governments have the option to provide support for patients managing rare diseases with special diets, hormonal supplements, or other cost-effective interventions.

Conclusion

Maple Syrup Urine Disease (MSUD) presents a complex challenge, but with proper management, individuals affected by this rare metabolic disorder can lead fulfilling lives. Through a combination of dietary restrictions, medical interventions, and ongoing support from healthcare professionals, it is possible to mitigate the risks associated with MSUD and promote optimal health outcomes. Continued research, advocacy, and awareness are crucial for MSUD. Collaboration among healthcare professionals, policymakers, and support networks is essential for better outcomes.

Last Updated
03 Mar 2024 | 11:00 AM (IST)