Maple Syrup Urine Disease

Disease Overview

Summary

Maple syrup urine disease (MSUD) is a rare genetic disorder characterized by deficiency of an enzyme complex (branched-chain alpha-keto acid dehydrogenase) that is 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 a number of their toxic byproducts, (specifically their respective organic acids), all accumulate abnormally. In the classic, severe form of MSUD, 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.

The presentation starts with non-specific symptoms of increasing neurological dysfunction and include lethargy, irritability and poor feeding, soon followed by focal neurological signs such as abnormal movements, increasing spasticity and shortly thereafter, by seizures and deepening coma. If untreated, progressive brain damage is inevitable and death occurs usually within weeks or months. The only specific finding that is unique to MSUD is the development 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. The toxicity is the result of damaging effects of leucine on the brain accompanied by severe ketoacidosis caused by accumulation of the three branched chain ketoacids (BCKAs).

The disorder can be successfully managed through a specialized diet in which the three BCAAs are rigorously controlled. However, even with treatment, patients of any age with MSUD remain at high risk for developing acute metabolic decompensation (metabolic crises) often triggered by infection, injury, failure to eat (fasting) or even by psychological stress. During these episodes there is a rapid, sudden rise in amino acid levels necessitating immediate medical intervention.

There are three or possibly four types of MSUD: the classic type; intermediate type, intermittent type and possibly a thiamine-responsive type. Each of the various subtypes of MSUD have different levels of residual enzyme activity which account for the variable severity and age of onset. All forms are inherited in an autosomal recessive pattern.

Introduction

Newborn screening for MSUD is performed throughout the US and in many other countries so that most affected infants are detected through these programs. Where such screening is not available, infants with MSUD usually present with advancing neurological signs. Early diagnosis and treatment stabilize the infants and, if well and consistently performed, can largely mitigate against serious long-term complications.

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Synonyms

• BCKD Deficiency
• branched-chain ketoacid dehydrogenase deficiency
• branched-chain ketoaciduria
• MSUD

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Subdivisions

• classic MSUD
• intermediate MSUD
• intermittent MSUD
• thiamine-responsive MSUD

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Signs & Symptoms

The symptoms and severity of MSUD can vary greatly from person to person and are largely determined by the amount of residual enzyme activity in the body. MSUD can be classified into classic, intermediate, intermittent and thiamine-responsive forms, with each type showing a range of severity. 

Classic MSUD

Classic MSUD is the most common and severe form, characterized by little to no enzyme activity. Symptoms usually appear within the first 2-3 days of life and begin subtly, including:

• Poor feeding at the bottle or breast
• Increased lethargy and irritability

As the disorder progresses infants may exhibit more severe signs, including:

• Abnormal movements
• Increased muscle tone (hypertonia)
• Spasticity
• Seizures
• Episodes of extreme decreased muscle tone (hypotonia)
• Coma and eventual serious neurologic complications leading to respiratory failure and death if untreated

In addition to neurological issues, individuals with classic MSUD may show intellectual limitations and can develop behavioral problems such as:

• Attention deficit hyperactivity disorder (ADHD)
• Impulsivity
• Anxiety and/or depression
• Seizures

Complications of classic MSUD include:

• Osteoporosis (generalized loss of bone mass) which increases the risk of fractures
• Pancreatitis (inflammation of the pancreas)
• Intracranial hypertension (increased pressure in the skull) causing headaches, sometimes accompanied by nausea and vomiting

A distinctive maple syrup odor can be detected in the earwax (cerumen), sweat and urine of affected individuals due to the accumulation of branched-chain keto acids (BCKAs). However, this odor is usually noticeable only during periods of metabolic instability.

Once the disorder is stabilized, there remains a lifelong threat of sudden or gradual metabolic crises, often triggered by an imbalance between residual enzyme activity and increased protein breakdown (catabolism) during periods of stress (e.g., infections, trauma or fasting). These crises can lead to the recurrence of symptoms seen in untreated MSUD and must be managed urgently. 

Intermediate MSUD

Intermediate MSUD is characterized by greater residual enzyme activity than in classic MSUD. While symptoms may appear in the neonatal period, most affected children are diagnosed between 5 months and 7 years of age.

Symptoms of intermediate MSUD include:

• Lethargy
• Feeding difficulties
• Poor growth
• Impaired coordination (ataxia)
• Acute metabolic crises leading to:
  • Seizures
  • Coma
  • Brain damage
  • Life-threatening neurological complications (in rare cases)

As in classic MSUD, the maple syrup odor can be detected in bodily fluids. Intermediate MSUD patients are susceptible to the same degree of neurological complications and acidosis as those with the classic form, though the onset is typically later. Management of intermediate MSUD follows the same principles as the classic form. 

Intermittent MSUD 

Intermittent MSUD is generally milder and often characterized by normal growth and intellectual development. Affected individuals can often tolerate normal levels of protein in their diet, and symptoms typically only occur during periods of metabolic stress, similar to classic MSUD.

Triggers for symptoms include:

• Infections
• Physical or psychological stress
• Fasting

During stress, patients may develop symptoms typical of metabolic crises, such as elevated leucine levels leading to neurological symptoms. 

Thiamine-responsive MSUD

Thiamine-responsive MSUD is a rarer form that responds to high doses of thiamine (vitamin B1), which enhances residual enzyme activity in the body. The clinical presentation is similar to intermediate MSUD, but it rarely presents in the neonatal period.

• Affected individuals respond to large doses of thiamine, which boosts enzyme function.
• Thiamine treatment is combined with a partially restricted protein diet, as no individual with this form of MSUD has been treated solely with thiamine.

 Unclassified MSUD

In addition to the above subtypes, several families have been identified with multiple affected members who do not fit neatly into any of the defined categories. These patients are referred to as unclassified MSUD and they do not follow the typical progression or symptomatology seen in other forms of the disease.

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Causes

MSUD is caused by changes (variants) in one of three different genes: BCKDHA, BCKDHB and DBT. Variants in these genes result in absent or decreased activity of human branched-chain alpha-ketoacid dehydrogenase complex (BCKAD) enzymes. These enzymes are responsible for breaking down the branched chain amino acids leucine, isoleucine and valine that are in all proteins. Accumulation of these amino acids and their toxic byproducts (ketoacids) results in the serious health problems associated with MSUD. The toxicity of these amino acids is restricted to leucine; indeed, extra valine and isoleucine are often given during treatment. Accumulation of their respective ketoacids results in the metabolic acidosis.

MSUD follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

The estimated incidence in a general population is 1 in 185,000 live births. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Due to this “founder effect”, the disorder occurs with greater frequency among individuals in the Mennonite populations in the United States, where the incidence is estimated to be as high as in 1 in 380. MSUD occurs in the Ashkenazi Jewish population with an incidence estimated at 1:26,000 live births.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of MSUD. Comparisons may be useful for a differential diagnosis.

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures and/or coma. The liver may be abnormally enlarged (hepatomegaly), life-threatening complications may result. The urea cycle disorders include ornithine transcarbamylase (OTC) deficiency: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinate synthetase deficiency (citrullinemia); argininosuccinate lyase (ASL) deficiency; arginase deficiency (argininemia) and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)

Propionic acidemia is a rare autosomal recessively inherited metabolic disorder caused by a deficiency of the enzyme propionyl CoA carboxylase, one of the enzymes necessary for breaking down certain amino acids. Symptoms usually become apparent during the first weeks of life and may include hypotonia, poor feeding, vomiting, dehydration and seizures accompanied by worsening metabolic acidosis and often with hyperammonemia. Without appropriate treatment, coma and life-threatening complications are usual. In milder cases, the condition may only present later during infancy and may then be associated with less severe symptoms and findings.

Methylmalonic acidemia (MMA) is a rare inborn error of metabolism in which people have trouble metabolizing certain proteins and fats in food. The symptoms usually arise during early infancy but may even remain occult until adulthood. The presentation is similar to that of propionic acidemia. Over the course of the disease, patients can develop intellectual disability, chronic kidney disease, pancreatitis and feeding problems. Mutations in several different genes can cause MMA and thus different treatments are required for each type. The mainstay of treatment is a carefully balanced dietary restriction of certain amino acids; namely, methionine, threonine, isoleucine and valine. Some require specific forms of cobalamin (vitamin B 12). All MMAs are autosomal recessive genetic disorders and can be caused by variants in five different genes: MMAA, MMAB, MMADHC, MCEE and MUT.

Glycine encephalopathy is an inborn error of metabolism characterized by the accumulation of large amounts of the amino acid glycine in blood and, particularly, in the cerebrospinal fluid (CSF). The metabolic block occurs in the conversion of glycine into smaller molecules. There are four forms of this disorder: a relatively common neonatal form, an infantile form, a mild-episodic form and a late-onset form. Common presenting symptoms of the disease include hypotonia, seizures, unexplained coma and developmental delay in neonates and infants. Metabolic acidosis is not a feature.

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Diagnosis

Many infants with MSUD are identified through newborn screening programs. Tandem mass spectrometry, an advanced newborn screening test that screens for more than 40 different disorders through one blood sample, has aided in the diagnosis of MSUD. As with all inborn errors, Infants with mild or intermittent forms of the disorder may have totally normal blood metabolites after birth and thus can be missed by newborn screening.

For patients who present later, the diagnosis usually comes at a time of metabolic decompensation when plasma amino acids and urine organic acids are normally tested at which time they are wildly abnormal. The presence of the maple syrup odor is so characteristic that this, together with appropriate symptoms, can be diagnostic enough to initiate therapy until the patient is transferred to an ICU. Initial confirmation is done by examination of plasma BCAAs and urine organic acids. The activity of the BCAA complex activity can be performed in white blood cells or cultured skin fibroblasts.

Prenatal detection cannot, at present, be done on maternal blood (looking for the fetal DNA). It is done either through chorionic villus biopsy or by amniocentesis. These analyses must be performed in a laboratory that is experienced in the relevant techniques. Molecular genetic testing for variants in the BCKDHA, BCKDHB and DBT genes is also available to confirm the diagnosis and is necessary for purposes of carrier testing for at-risk relatives and prenatal diagnosis for at-risk pregnancies.

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Standard Therapies

Treatment

The treatment of maple syrup urine disease (MSUD), including the classic, intermediate, intermittent and thiamine-responsive forms, has two main approaches, long term dietary management and treatment of episodes of acute metabolic decompensation. This treatment includes:

• Lifelong dietary management to maintain an appropriate intake of branched-chain amino acids (BCAAs)
• Maintenance of normal metabolic conditions, ensuring that levels of BCAAs in the body are kept within the therapeutic range
• Immediate medical intervention during metabolic crises to prevent or correct elevated levels of BCAAs, especially leucine

Long-term dietary management

The foundation of treatment for MSUD is the dietary restriction of branched-chain amino acids (BCAAs), including leucine, isoleucine and valine which are essential nutrients that the body cannot synthesize on its own. Lifelong adherence to a protein-restricted diet is necessary to limit the intake of BCAAs, starting as early as possible after birth to promote normal growth and development. Specialized, synthetic formulas provide all necessary nutrients but lack BCAAs to ensure proper growth while avoiding the buildup of toxic metabolites.

Diet management involves a careful balance between providing sufficient nutrition for normal development while keeping BCAAs within acceptable levels. Leucine must be carefully monitored and restricted in the diet. The exact amount of BCAAs that can be tolerated by a child depends on their residual enzyme activity and the amounts of leucine, isoleucine and valine are adjusted according to the blood (plasma) levels. Regular monitoring of amino acid levels is essential to ensure the diet remains appropriate and effective.

In some patients, a trial of thiamine therapy may be recommended, particularly for people who retain some residual enzyme activity. If thiamine responsiveness is observed, thiamine supplements can be administered. However, no one with MSUD has been treated solely with thiamine.

Even with strict dietary control, people affected with MSUD remain at risk for metabolic crises, especially when levels of leucine become too high. Immediate medical intervention is required to prevent severe complications. The goals of treating metabolic crises are to:

• Reduce the levels of toxic metabolites by temporarily stopping BCAA intake until plasma levels normalize
• Reduce protein catabolism and promote anabolism, the process of building complex molecules from simple ones, such as proteins from amino acids. During catabolism the complex molecules such as proteins are broken down into simple molecules such as amino acids.
• Stabilize the patient’s condition through intravenous or enteral nutritional support

Aggressive therapy during crises includes administering intravenous glucose (5-8 mg/kg/min for infants) to rapidly lower leucine levels and provide sufficient calories to meet energy demands. In some people, insulin infusions are added to promote protein synthesis and reduce the body’s reliance on protein breakdown for energy. The use of intravenous fat is also crucial as an additional calorie source.

If dietary management alone is insufficient to lower leucine levels, hemodialysis or hemofiltration procedures may be indicated to remove BCAAs and keto acids from the blood. These techniques involve filtering the blood to eliminate excess leucine and other metabolites.

After the crisis is controlled, the intake of BCAAs is resumed gradually, but only once plasma levels normalize. Parenteral nutrition or total parenteral nutrition (TPN) solutions, free of BCAAs, are often used to support the person’s nutritional needs during this time. Parenteral nutrition is a method of providing nutrients to a patient directly into their bloodstream through a vein.

Liver transplantation has been used to treat individuals with classic MSUD. This procedure has resulted in individuals being symptom-free and able to eat normal foods. The new liver supplies enough enzyme activity to break down the three BCAAs.

While liver transplantation cannot reverse the neurological damage that has already occurred, it can prevent additional episodes of decompensation and preserve the remaining neurological function. Liver transplantation may guarantee normal or near-normal neurological outcomes if performed early following diagnosis. Certainly, the objective is to prevent the need for liver transplantation in newborns diagnosed with maple syrup urine disease by immediately fostering early dietary intervention of BCAAs restriction.

People affected with MSUD must be closely monitored during critical periods, such as pregnancy. Several successful pregnancies in patients with MSUD have been reported, but the immediate postpartum period requires particular care to prevent catabolism and maintain metabolic stability. Catabolism is the process of breaking down large, complex molecules into smaller ones, releasing energy in the process, as per example, when protein breaks down large protein molecules into smaller polypeptides and amino acids.

Genetic counseling is recommended for patients and their families to provide information about the inheritance pattern of the disorder and to discuss family planning options.

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Clinical Trials and Studies

Research into potential gene therapy for MSUD is ongoing, though no human trials have yet been conducted. Early studies using retroviral vectors to correct the enzyme deficiency in MSUD have shown promising results in laboratory settings.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS

Danner DJ. Maple Syrup Urine Disease. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:468-9.

Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:1971-96.

JOURNAL ARTICLES

Mengler K, Garbade SF, Gleich F, Thimm E, May P, Lindner M, Lüsebrink N, Marquardt T, Hübner V, Krämer J, Neugebauer J, Beblo S, Gillitzer C, Grünert SC, Hennermann JB, Kamrath C, Marquardt I, Näke A, Murko S, Schmidt S, Schnabel E, Lommer-Steinhoff S, Hoffmann GF, Beime J, Santer R, Kölker S, Mütze U. Treatment outcomes for maple syrup urine disease detected by newborn screening. Pediatrics. 2024 Aug 1;154(2):e2023064370. doi: 10.1542/peds.2023-064370.

Simon E, Flaschker N, Schadewaldt P, Langenbeck U, Wendel U. Variant maple syrup urine disease (MSUD) – the entire spectrum. J Inherit Metab Dis. 2006;29:716-24.

Chuang DT, Chuang JL, Wynn RM. Lessons from genetic disorders of branched-chain amino acid metabolism. J Nutr. 2006;136:243S-9S.

Strauss KA, Mazariegos GV, Sindhi R, et al., Elective liver transplantation for the treatment of classical maple syrup urine disease. Am J Transplant. 2006;6:557-64.

Ogier de Baulny H, Saudubray JM. Branched-chain organic acidurias. Semin Neonatal. 2002;7:65-74.

Saudubray JM, Nassogne MC, de Lonlay P, et al. Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatal. 2002;7:3-15.

Morton DH, Strauss KA, Robinson DL, et al. Diagnosis and treatment of maple syrup urine disease: a study of 36 patients. Pediatrics. 2002;109:999-1008.

Wendel U, Saudubray JM, Bodner A, et al. Liver transplantation in maple syrup urine disease. Eur J Pediatr. 1999;158 Suppl 2:S60-64.

Rashed MS, Rahbeeni Z, Ozand PT. Application of electrospray tandem mass spectrometry to neonatal screening. Semin Perinatol. 1999;23:183-93.

Chuang DT. Maple syrup urine disease: it has come a long way. J Pediatr. 1998;132:S17-23.

INTERNET

Strauss KA, Puffenberger EG, Carson VJ. Maple Syrup Urine Disease. 2006 Jan 30 [Updated 2020 Apr 23]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1319/  Accessed October 10, 2024.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:248600; Last Update: 03/01/2024. Available at: https://omim.org/entry/248600 October 10, 2024.

Maple syrup urine disease. Genetics Home Reference. Reviewed July 2017. Available at: https://ghr.nlm.nih.gov/condition/maple-syrup-urine-disease. Accessed October 10, 2024.

Defendi GL. Maple Syrup Urine Disease (MSUD) Treatment & Management. Medscape Reference. February 28, 2023. https://emedicine.medscape.com/article/946234-treatment#d7 Accessed October 10, 2024.

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Patient Organizations

MSUD Family Support Group

NORD Member

Phone: 740-972-5619 Email: [email protected]

Related Rare Diseases: Maple Syrup Urine Disease

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Organic Acidemia Association

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Related Rare Diseases: Medium Chain Acyl CoA Dehydrogenase Deficiency, Maple Syrup Urine Disease, Isovaleric Acidemia, ...

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Metabolic Support UK

Email: [email protected]

Related Rare Diseases: Glucose-Galactose Malabsorption, Sandhoff Disease, Aromatic L-Amino Acid Decarboxylase Deficiency, ...

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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