Maple Syrup Urine Disease

  • Author: Olaf A Bodamer, MD, PhD, FAAP, FACMG; Chief Editor: Luis O Rohena, MD  more...
Updated: Nov 04, 2014


Maple syrup urine disease (MSUD) is an aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding keto acids leads to encephalopathy and progressive neurodegeneration in untreated infants. Early diagnosis and dietary intervention prevent complications and may allow for normal intellectual development. Consequently, MSUD has been added to many newborn screening programs, and preliminary results indicate that asymptomatic newborns with MSUD have a better outcome compared with infants who are diagnosed after they become symptomatic.

In 1954, Menkes et al reported a family in which 4 infants died within the first 3 months of their lives because of a neurodegenerative disorder. The urine of these infants had an odor resembling maple syrup (burned sugar).[1] Therefore, this disorder was called maple sugar urine disease and, later, maple syrup urine disease. In the following years, Dancis et al identified the pathogenetic compounds as branched-chain amino acids and their corresponding alpha-keto acids.[2] In 1960, Dancis et al demonstrated that the enzymatic defect in MSUD was at the level of the decarboxylation of the branched-chain amino acids.[3] Snyderman et al initiated the first successful dietary treatment of MSUD by restricting intake of branched-chain amino acids.[4] In 1971, Scriver et al reported the first case of thiamine-responsive MSUD.[5] The branched-chain alpha-keto acid dehydrogenase (BCKD) complex was purified and characterized in 1978.[2]



MSUD is caused by a deficiency of the BCKD complex, which catalyses the decarboxylation of the alpha-keto acids of leucine, isoleucine, and valine to their respective branched-chain acyl-CoAs. These are further metabolized to yield acetyl-CoA, acetoacetate, and succinyl-CoA.[6, 7]

The BCKD complex, which is associated with the inner mitochondrial membrane, has 3 different catalytic components (ie, E1, E2, E3) and 2 associated regulatory enzymes (ie, BCKD phosphatase, BCKD kinase). In addition, the E1 component consists of 2 distinct subunits (ie, E1 alpha, E1 beta) that form an alpha-2 beta-2 heterotetramer. The E3 component is associated with 2 additional alpha-ketoacid dehydrogenase complexes, namely pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Mutations in E1, E2, or E3 cause MSUD. No good genotype-phenotype correlation between molecular and clinical phenotypes is known, with the exemption of mutations in E2, which cause thiamine-responsive MSUD. Mutations in E3 cause additional deficiencies of pyruvate and alpha-ketoglutarate dehydrogenases.[8] Mutations in the regulatory enzymes have not been reported.[9]

Accumulation of leucine in particular causes neurological symptoms, whereas elevation of plasma isoleucine is associated with the maple syrup odor. Leucine is rapidly transported across the blood-brain barrier and is metabolized to presumably yield glutamate and glutamine.[10, 11]




United States

MSUD occurs in about 1 case per 180,000 newborns in the United States but may be as common as 1 case per 176 newborns in selected inbred populations (ie, the Mennonites in Pennsylvania). As an autosomal recessive disorder, MSUD is more prevalent in populations with a high frequency of consanguinity.[6]


Quental et al identified a homozygous 1-bp deletion (117delC) in the BCKDHA gene in Portuguese Gypsies and estimated the carrier frequency for this deletion to be as high as 1.4%.[12]


Infants with untreated early onset (ie, classic) MSUD have significant developmental delay and die within the first months of life. Children or juveniles with late-onset (ie, intermediate, intermittent) forms of MSUD may have some form of developmental delay, depending on the residual activity of BCKD. All children are at increased risk for metabolic decompensation during periods of increased protein catabolism (eg, intercurrent illness, trauma, surgery). Morbidity can almost entirely be prevented with early diagnosis (in a neonate younger than 10 d), with appropriate treatment at presentation and during episodes of potential metabolic decompensation.


MSUD has been reported to occur in all ethnic groups, although the incidence and prevalence may widely vary.[6]


No sex predilection is noted.

Contributor Information and Disclosures

Olaf A Bodamer, MD, PhD, FAAP, FACMG Park Gerald Chair in Genetics and Genomics, Associate Chief, Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital, Harvard Medical School

Olaf A Bodamer, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.


Brendan Lee, MD, PhD Professor, Robert and Janice McNair Endowed Chair in Molecular and Human Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine

Brendan Lee, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, Society for Pediatric Research

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Biomarin; Retrophin;.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

  1. Menkes JH, Hurst PL, Craig JM. A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics. 1954 Nov. 14(5):462-7. [Medline].

  2. Chuang DT. Maple syrup urine disease: it has come a long way. J Pediatr. 1998 Mar. 132(3 Pt 2):S17-23. [Medline].

  3. Dancis J, Levits M, Westall RG. Maple syrup urine disease: branched-chain keto-aciduria. Pediatrics. 1960 Jan. 25:72-9. [Medline].

  4. Snyderman SE, Norton PM, Roitman E, Holt LE Jr. Maple syrup urine disease, with particular reference to dietotherapy. Pediatrics. 1964 Oct. 34:454-72. [Medline].

  5. Scriver CR, Mackenzie S, Clow CL, Delvin E. Thiamine-responsive maple-syrup-urine disease. Lancet. 1971 Feb 13. 1(7694):310-2. [Medline].

  6. Chuang DT, Shih VE. Maple syrup urine disease. Scriver CR, Beaudet AL, Valle DL, Sly WS, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill Co; 2000.

  7. Harris RA, Joshi M, Jeoung NH, Obayashi M. Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J Nutr. 2005 Jun. 135(6 Suppl):1527S-30S. [Medline].

  8. Park HD, Lee DH, Hong YH, Kang DH, Lee YK, Song J, et al. Three Korean patients with maple syrup urine disease: four novel mutations in the BCKDHA gene. Ann Clin Lab Sci. 2011 Spring. 41(2):167-73. [Medline].

  9. Henneke M, Flaschker N, Helbling C, et al. Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease. Hum Mutat. 2003 Nov. 22(5):417. [Medline].

  10. Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005 Jun. 135(6 Suppl):1539S-46S. [Medline].

  11. Yudkoff M, Daikhin Y, Nissim I, et al. Brain amino acid requirements and toxicity: the example of leucine. J Nutr. 2005 Jun. 135(6 Suppl):1531S-8S. [Medline].

  12. Quental S, Macedo-Ribeiro S, Matos R, Vilarinho L, Martins E, Teles EL, et al. Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community. Mol Genet Metab. 2008 Jun. 94(2):148-56. [Medline].

  13. Hoffmann GF, von Kries R, Klose D, et al. Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany. Eur J Pediatr. 2004 Feb. 163(2):76-80. [Medline].

  14. Morton DH, Strauss KA, Robinson DL, et al. Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics. 2002 Jun. 109(6):999-1008. [Medline].

  15. Hallam P, Lilburn M, Lee PJ. A new protein substitute for adolescents and adults with maple syrup urine disease (MSUD). J Inherit Metab Dis. 2005. 28(5):665-72. [Medline].

  16. Wendel U, Saudubray JM, Bodner A, Schadewaldt P. Liver transplantation in maple syrup urine disease. Eur J Pediatr. 1999 Dec. 158 Suppl 2:S60-4. [Medline].

  17. Mazariegos GV, Morton DH, Sindhi R, Soltys K, Nayyar N, Bond G, et al. Liver Transplantation for Classical Maple Syrup Urine Disease: Long-Term Follow-Up in 37 Patients and Comparative United Network for Organ Sharing Experience. J Pediatr. 2012. 160:116-121. [Medline].

  18. Heldt K, Schwahn B, Marquardt I, et al. Diagnosis of MSUD by newborn screening allows early intervention without extraneous detoxification. Mol Genet Metab. 2005 Apr. 84(4):313-6. [Medline].

  19. Hoffmann B, Helbling C, Schadewaldt P, Wendel U. Impact of longitudinal plasma leucine levels on the intellectual outcome in patients with classic MSUD. Pediatr Res. 2006 Jan. 59(1):17-20. [Medline].

  20. Mitsubuchi H, Owada M, Endo F. Markers associated with inborn errors of metabolism of branched-chain amino acids and their relevance to upper levels of intake in healthy people: an implication from clinical and molecular investigations on maple syrup urine disease. J Nutr. 2005 Jun. 135(6 Suppl):1565S-70S. [Medline].

  21. Righini A, Ramenghi LA, Parini R, et al. Water apparent diffusion coefficient and T2 changes in the acute stage of maple syrup urine disease: evidence of intramyelinic and vasogenic-interstitial edema. J Neuroimaging. 2003 Apr. 13(2):162-5. [Medline].

Medscape Consult
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.