Maple syrup urine disease

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Maple syrup urine Syndrome
Isoleucine (pictured above), leucine, and valine are the branched-chain amino acids that build up in MSUD.
Classification and external resources
ICD-10 E71.0
ICD-9 270.3
OMIM 248600
DiseasesDB 7820
MedlinePlus 000373
eMedicine ped/1368
Patient UK Maple syrup urine disease
MeSH D008375

Maple syrup urine Syndrome (MSUD), also called branched-chain ketoaciduria, is an autosomal recessive[1] metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia.[2] The condition gets its name from the distinctive sweet odor of affected infants' urine.[3]


MSUD is a metabolic disorder caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products (ketoacids) in the blood and urine. The enzyme complex consists of four subunits designated E1α, E1β, E2, and E3. The E3 subunit is also a component of pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex.[4] MSUD can result from mutations in any of the genes that code for the enzyme subunits.

Diagnosis and symptoms[edit]

The disease is named for the presence of sweet-smelling urine, with an odor similar to that of maple syrup. The smell is also present and sometimes stronger in the ear wax of an affected individual. Prior to the easy availability of plasma amino acid measurement, diagnosis was commonly made based on suggestive symptoms and odor. Affected individuals are now often identified with characteristic elevations on plasma amino acids which do not have the characteristic odor.[5] The compound responsible for the odor is sotolon (sometimes spelled sotolone).[6] Infants with this disease seem healthy at birth but if left untreated suffer severe brain damage and eventually die.

From early infancy, symptoms of the condition include poor feeding, vomiting, dehydration, lethargy, hypotonia, seizures, hypoglycaemia, ketoacidosis, opisthotonus, pancreatitis, coma and neurological decline.


Maple syrup urine disease can be classified by its pattern of signs and symptoms, or by its genetic cause. The most common and severe form of the disease is the classic type, which appears soon after birth. Variant forms of the disorder may appear later in infancy or childhood and are typically less severe, but still involve mental and physical problems if left untreated.

There are several variations of the disease:

  • Classic Severe MSUD
  • Intermediate MSUD
  • Intermittent MSUD
  • Thiamine-responsive MSUD
  • E3-Deficient MSUD with Lactic Acidosis


Keeping MSUD under control requires careful monitoring of blood chemistry and involves both a special diet and frequent testing.

A diet with minimal levels of the amino acids leucine, isoleucine, and valine must be maintained in order to prevent neurological damage. As these three amino acids are required for proper metabolic function in all humans, specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized and tested, allowing MSUD patients to meet normal nutritional requirements without causing harm.[7] Some patients with MSUD may also improve with administration of high doses of thiamine, a cofactor of the enzyme that causes the condition.

Usually, patients are also monitored by a dietitian. Their diet must be adhered to strictly and permanently. However, with proper management, those afflicted are able to live healthy, normal lives and not suffer the severe neurological damage associated with the disease.

Genetic prevalence[edit]

Maple syrup urine disease has an autosomal recessive pattern of inheritance.

Maple syrup urine disease affects approximately 1 out of 185,000 infants.[8] Due in part to the founder effect,[9] however, MSUD has a much higher prevalence in children of Amish, Mennonite, and Jewish descent.[10][8][11]

Mutations in the following genes cause maple syrup urine disease:

These four genes produce proteins that work together as the branched-chain alpha-keto acid dehydrogenase complex. The complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food (in particular, protein-rich foods such as milk, meat, and eggs). Mutations in any of these genes reduce or eliminate the function of the enzyme complex, preventing the normal breakdown of isoleucine, leucine, and valine. As a result, these amino acids and their by-products build up in the body. Because high levels of these substances are toxic to the brain and other organs, this accumulation leads to the serious medical problems associated with maple syrup urine disease.

This condition has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene – one from each parent – must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.


On 9 May 2014, the UK National Screening Committee (UK NSC) announced its recommendation to screen every newborn baby in the UK for four further genetic disorders as part of its NHS Newborn Blood Spot Screening programme, including Maple syrup urine disease.[12]

See also[edit]


  1. ^ Podebrad F, Heil M, Reichert S, Mosandl A, Sewell AC, Böhles H (April 1999). "4,5-dimethyl-3-hydroxy-25H-furanone (sotolone)--the odour of maple syrup urine disease". Journal of Inherited Metabolic Disease 22 (2): 107–114. doi:10.1023/A:1005433516026. PMID 10234605. 
  2. ^ Ogier de Baulny H, Saudubray JM (2002). "Branched-chain organic acidurias". Semin Neonatol. 7 (1): 65–74. doi:10.1053/siny.2001.0087. PMID 12069539. 
  3. ^ [1]
    Genetics Home Reference (GRH) - Genetic Conditions - Maple Syrup Urine Disease. GHR is a service of the U.S. National Library of Medicine. Reviewed February 2006; Published June 12, 2009
  4. ^ Pasquali, Marzia; Longo, Nicola (December 13, 2011). "58. Newborn screening and inborn errors of metabolism". In Burtis, Carl A.; Ashwood, Edward R.; Bruns, David E. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics (5th ed.). Elsevier Health Sciences. p. 2062. ISBN 978-1-4160-6164-9. 
  5. ^ "#248600 Maple Syrup Urine Disease; MSUD". Johns Hopkins University. Retrieved 2012-11-04. 
  6. ^ Strauss, Kevin A; Puffenberger, Erik G; Morton, D Holmes (January 30, 2006). "Maple Syrup Urine Disease". In Pagon, Roberta A; Bird, Thomas D; Dolan, Cynthia R; Stephens, Karen; Adam, Margaret P. GeneReviews™ [Internet]. University of Washington, Seattle (published December 15, 2009). PMID 20301495. Retrieved May 15, 2012{{inconsistent citations}} 
  7. ^ Hallam P, Lilburn M, Lee PJ (2005). "A new protein substitute for adolescents and adults with maple syrup urine disease (MSUD)". J. Inherit. Metab. Dis. 28 (5): 665–672. doi:10.1007/s10545-005-0061-6. PMID 16151896. 
  8. ^ a b Rare diseases - June 2004. Maple syrup urine disease by Mary Kugler, R.N.
    Article describes MSUD prevalence among Amish and Mennonite children.
  9. ^ Jaworski MA, Severini A, Mansour G, Konrad HM, Slater J, Henning K, Schlaut J, Yoon JW, Pak CY, Maclaren N et al. (1989). "Genetic conditions among Canadian Mennonites: evidence for a founder effect among the old country (Chortitza) Mennonites". Clin Invest Med 12 (2): 127–141. PMID 2706837. 
  10. ^ Puffenberger EG (2003). "Genetic heritage of Old Order Mennonites in southeastern Pennsylvania". Am J Med Genet C Semin Med Genet 121 (1): 18–31. doi:10.1002/ajmg.c.20003. PMID 12888983. 
  11. ^
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