U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Maple syrup urine disease(MSUD)

MedGen UID:
6217
Concept ID:
C0024776
Disease or Syndrome
Synonym: MSUD
SNOMED CT: Branched chain ketoacid dehydrogenase deficiency (27718001); Oxo-acid decarboxylase deficiency (27718001); Ketoacidemia (27718001); Branched chain ketoaciduria (27718001); Maple syrup urine disease (27718001); Branched-chain alpha-keto acid dehydrogenase deficiency (27718001); Ketoacid decarboxylase deficiency (27718001); BCKD - branched-chain 2-ketoacid dehydrogenase deficiency (27718001); MSUD - maple syrup urine disease (27718001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Genes (locations): BCKDHA (19q13.2); BCKDHB (6q14.1)
Related gene: DBT
 
Monarch Initiative: MONDO:0009563
OMIM® Phenotypic series: PS248600
Orphanet: ORPHA511

Disease characteristics

Excerpted from the GeneReview: Maple Syrup Urine Disease
Maple syrup urine disease (MSUD) is categorized as classic (severe), intermediate, or intermittent. Neonates with classic MSUD are born asymptomatic but without treatment follow a predictable course: 12–24 hours. Elevated concentrations of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and alloisoleucine, as well as a generalized disturbance of amino acid concentration ratios, are present in blood and the maple syrup odor can be detected in cerumen; Two to three days. Early and nonspecific signs of metabolic intoxication (i.e., irritability, hypersomnolence, anorexia) are accompanied by the presence of branched-chain alpha-ketoacids, acetoacetate, and beta-hydroxybutyrate in urine; Four to six days. Worsening encephalopathy manifests as lethargy, apnea, opisthotonos, and reflexive "fencing" or "bicycling" movements as the sweet maple syrup odor becomes apparent in urine; Seven to ten days. Severe intoxication culminates in critical cerebral edema, coma, and central respiratory failure. Individuals with intermediate MSUD have partial branched-chain alpha-ketoacid dehydrogenase deficiency that manifests only intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy in the face of sufficient catabolic stress. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed neonatal manifestations of MSUD remain asymptomatic with continued treatment adherence. [from GeneReviews]
Authors:
Kevin A Strauss  |  Erik G Puffenberger  |  Vincent J Carson   view full author information

Additional descriptions

From OMIM
The major clinical features of maple syrup urine disease (MSUD) are mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids (BCAA) are present in the urine, resulting from a block in oxidative decarboxylation. There are 5 clinical subtypes of MSUD based on clinical presentation and biochemical response to thiamine administration: the classic neonatal severe form, an intermediate form, an intermittent form, a thiamine-responsive form, and an E3-deficient with lactic acidosis form (DLDD; 246900). All of these subtypes can be caused by mutation in the BCKDHA, BCKDHB, or DBT gene, except for the E3-deficient form, which is caused only by mutation in the DLD gene (Chuang and Shih, 2001). The classic form, which comprises 75% of MSUD patients, is manifested within the first 2 weeks of life with poor feeding, lethargy, seizures, coma, and death if untreated. Intermediate MSUD is associated with elevated BCAAs and BCKA, with progressive mental retardation and developmental delay without a history of catastrophic illness. The diagnosis is usually delayed for many months. An intermittent form of MSUD may have normal levels of BCAAs, normal intelligence and development until a stress, e.g., infection, precipitates decompensation with ketoacidosis and neurologic symptoms, which are usually reversed with dietary treatment. Thiamine-responsive MSUD is similar to the intermediate phenotype but responds to pharmacologic doses of thiamine with normalization of BCAAs. The E3-deficient MSUD is caused by defects in the dehydrogenase (E3) component of the BCKAD complex that is common to the pyruvate and alpha-ketoglutarate dehydrogenase complexes. Patients with E3 deficiency have dysfunction of all 3 enzyme complexes, and patients usually die in infancy with severe lactic acidosis (summary by Chuang et al., 1995). Genetic Heterogeneity of Maple Syrup Urine Disease MSUD1B (620698) is caused by mutation in the BCKDHB gene (248611) on chromosome 6q14, and MSUD2 (620699) is caused by mutation in the DBT gene (248610) on chromosome 1p21. Mutation in the E3 component of the BCKDC complex, DLD (238331), on chromosome 7q31, causes an overlapping but more severe phenotype known as dihydrolipoamide dehydrogenase deficiency (DLDD; 246900). DLDD is sometimes referred to as MSUD3. See also a mild variant of MSUD (MSUDMV; 615135), caused by mutation in the regulatory gene PPM1K (611065).  http://www.omim.org/entry/248600
From MedlinePlus Genetics
Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine. It is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development. If untreated, maple syrup urine disease can lead to seizures, coma, and death.

Maple syrup urine disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still lead to delayed development and other health problems if not treated.  https://medlineplus.gov/genetics/condition/maple-syrup-urine-disease

Professional guidelines

PubMed

Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH
Mol Genet Metab 2020 Mar;129(3):193-206. Epub 2020 Jan 16 doi: 10.1016/j.ymgme.2020.01.006. PMID: 31980395
Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226
Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH
Mol Genet Metab 2014 Jul;112(3):210-7. Epub 2014 May 17 doi: 10.1016/j.ymgme.2014.05.006. PMID: 24881969

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Increased Leucine, Maple Syrup Urine Disease, 2021

American College of Medical Genetics and Genomics, Algorithm, Leucine Elevated, 2021

MSUD Nutrition Management Guidelines

American College of Medical Genetics ACT Sheet, Carrier Screening ACT Sheet Ashkenazi Jewish Genetic Disorders

Recent clinical studies

Etiology

Hassan A
Tremor Other Hyperkinet Mov (N Y) 2023;13:9. Epub 2023 Mar 28 doi: 10.5334/tohm.747. PMID: 37008993Free PMC Article
Van Calcar SC, Sowa M, Rohr F, Beazer J, Setlock T, Weihe TU, Pendyal S, Wallace LS, Hansen JG, Stembridge A, Splett P, Singh RH
Mol Genet Metab 2020 Sep-Oct;131(1-2):23-37. Epub 2020 Oct 6 doi: 10.1016/j.ymgme.2020.10.001. PMID: 33093005
Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH
Mol Genet Metab 2020 Mar;129(3):193-206. Epub 2020 Jan 16 doi: 10.1016/j.ymgme.2020.01.006. PMID: 31980395
Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226
Frazier DM, Allgeier C, Homer C, Marriage BJ, Ogata B, Rohr F, Splett PL, Stembridge A, Singh RH
Mol Genet Metab 2014 Jul;112(3):210-7. Epub 2014 May 17 doi: 10.1016/j.ymgme.2014.05.006. PMID: 24881969

Diagnosis

Hassan A
Tremor Other Hyperkinet Mov (N Y) 2023;13:9. Epub 2023 Mar 28 doi: 10.5334/tohm.747. PMID: 37008993Free PMC Article
Ewing CB, Soltys KA, Strauss KA, Sindhi R, Vockley J, McKiernan P, Squires RH, Bond G, Ganoza A, Khanna A, Mazariegos GV, Squires JE
J Pediatr 2021 Oct;237:59-64.e1. Epub 2021 Jun 18 doi: 10.1016/j.jpeds.2021.06.028. PMID: 34153280Free PMC Article
Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226
Hawkes N
BMJ 2016 Mar 24;352:i1680. doi: 10.1136/bmj.i1680. PMID: 27012884
Painter MJ, Bergman I, Crumrine P
Pediatr Clin North Am 1986 Feb;33(1):91-109. doi: 10.1016/s0031-3955(16)34971-9. PMID: 3513103

Therapy

Hassan A
Tremor Other Hyperkinet Mov (N Y) 2023;13:9. Epub 2023 Mar 28 doi: 10.5334/tohm.747. PMID: 37008993Free PMC Article
Brown G
J Inherit Metab Dis 2014 Jul;37(4):577-85. Epub 2014 May 1 doi: 10.1007/s10545-014-9712-9. PMID: 24789339
Chuang DT, Chuang JL, Wynn RM
J Nutr 2006 Jan;136(1 Suppl):243S-9S. doi: 10.1093/jn/136.1.243S. PMID: 16365091
Fernstrom JD
J Nutr 2005 Jun;135(6 Suppl):1539S-46S. doi: 10.1093/jn/135.6.1539S. PMID: 15930466
Painter MJ, Bergman I, Crumrine P
Pediatr Clin North Am 1986 Feb;33(1):91-109. doi: 10.1016/s0031-3955(16)34971-9. PMID: 3513103

Prognosis

Ewing CB, Soltys KA, Strauss KA, Sindhi R, Vockley J, McKiernan P, Squires RH, Bond G, Ganoza A, Khanna A, Mazariegos GV, Squires JE
J Pediatr 2021 Oct;237:59-64.e1. Epub 2021 Jun 18 doi: 10.1016/j.jpeds.2021.06.028. PMID: 34153280Free PMC Article
Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH
Mol Genet Metab 2020 Mar;129(3):193-206. Epub 2020 Jan 16 doi: 10.1016/j.ymgme.2020.01.006. PMID: 31980395
Abiri M, Saei H, Eghbali M, Karamzadeh R, Shirzadeh T, Sharifi Z, Zeinali S
Metab Brain Dis 2019 Aug;34(4):1145-1156. Epub 2019 May 22 doi: 10.1007/s11011-019-00435-y. PMID: 31119508
Winchester S, Singh PK, Mikati MA
Handb Clin Neurol 2013;112:1213-7. doi: 10.1016/B978-0-444-52910-7.00043-X. PMID: 23622331
Painter MJ, Bergman I, Crumrine P
Pediatr Clin North Am 1986 Feb;33(1):91-109. doi: 10.1016/s0031-3955(16)34971-9. PMID: 3513103

Clinical prediction guides

Strauss KA, Carson VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Taylor CM, Haas-Givler B, Chopko S, Hailey J, Muelly ER, Shellmer DA, Radcliff Z, Rodrigues A, Loeven K, Heaps AD, Mazariegos GV, Morton DH
Mol Genet Metab 2020 Mar;129(3):193-206. Epub 2020 Jan 16 doi: 10.1016/j.ymgme.2020.01.006. PMID: 31980395
Abiri M, Saei H, Eghbali M, Karamzadeh R, Shirzadeh T, Sharifi Z, Zeinali S
Metab Brain Dis 2019 Aug;34(4):1145-1156. Epub 2019 May 22 doi: 10.1007/s11011-019-00435-y. PMID: 31119508
Chokoshvili D, Vears D, Borry P
Prenat Diagn 2018 Jan;38(1):59-66. Epub 2017 Jul 27 doi: 10.1002/pd.5109. PMID: 28685505
Brunetti-Pierri N, Lanpher B, Erez A, Ananieva EA, Islam M, Marini JC, Sun Q, Yu C, Hegde M, Li J, Wynn RM, Chuang DT, Hutson S, Lee B
Hum Mol Genet 2011 Feb 15;20(4):631-40. Epub 2010 Nov 23 doi: 10.1093/hmg/ddq507. PMID: 21098507Free PMC Article
Painter MJ, Bergman I, Crumrine P
Pediatr Clin North Am 1986 Feb;33(1):91-109. doi: 10.1016/s0031-3955(16)34971-9. PMID: 3513103

Recent systematic reviews

Hassona Y, Alqaisi D, Flaifl Y, Alkilani A
BMC Oral Health 2024 Mar 21;24(1):362. doi: 10.1186/s12903-024-04135-7. PMID: 38515181Free PMC Article
Hassan A
Tremor Other Hyperkinet Mov (N Y) 2023;13:9. Epub 2023 Mar 28 doi: 10.5334/tohm.747. PMID: 37008993Free PMC Article
Zeltner NA, Huemer M, Baumgartner MR, Landolt MA
Orphanet J Rare Dis 2014 Oct 25;9:159. doi: 10.1186/s13023-014-0159-8. PMID: 25344299Free PMC Article
Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H
J Inherit Metab Dis 2014 Nov;37(6):889-98. Epub 2014 Jul 15 doi: 10.1007/s10545-014-9729-0. PMID: 25022222

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2021
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Increased Leucine, Maple Syrup Urine Disease, 2021
    • ACMG Algorithm, 2021
      American College of Medical Genetics and Genomics, Algorithm, Leucine Elevated, 2021
    • GMDI/SERN, 2021
      MSUD Nutrition Management Guidelines
    • ACMG ACT, 2011
      American College of Medical Genetics ACT Sheet, Carrier Screening ACT Sheet Ashkenazi Jewish Genetic Disorders

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...