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Maple syrup urine disease(MSUD)

MedGen UID:
6217
Concept ID:
C0024776
Disease or Syndrome
Synonyms: Branched chain ketoaciduria; Branched-chain alpha-keto acid dehydrogenase deficiency; Keto acid decarboxylase deficiency; MSUD
SNOMED CT: Branched chain ketoacid dehydrogenase deficiency (27718001); BCKD - Branched chain alpha-ketoacid dehydrogenase deficiency (27718001); MSUD - Maple syrup urine disease (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); BCKD deficiency (27718001); MSUD (27718001); Ketoacid decarboxylase deficiency (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); DBT (1p21.2)
 
Monarch Initiative: MONDO:0009563
OMIM®: 248600
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 compliance. [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 are mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. There are 5 clinical subtypes of MSUD: the 'classic' neonatal severe form, an 'intermediate' form, an 'intermittent' form, a 'thiamine-responsive' form, and an 'E3-deficient with lactic acidosis' form (246900). All of these subtypes can be caused by mutations in any of the 4 genes mentioned above, except for the E3-deficient form, which is caused only by mutation in the E3 gene (Chuang and Shih, 2001).  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

Clinical features

From HPO
Increased level of hippuric acid in urine
MedGen UID:
1640306
Concept ID:
C4703632
Finding
An increase in the level of hippuric acid in the urine.
Growth abnormality
MedGen UID:
808205
Concept ID:
C0262361
Finding
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
Complete absence of wakefulness and content of conscience, which manifests itself as a lack of response to any kind of external stimuli.
Hallucinations
MedGen UID:
6709
Concept ID:
C0018524
Mental or Behavioral Dysfunction
Perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterestedness, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
The presence of inflammation in the pancreas.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Ketosis
MedGen UID:
7206
Concept ID:
C0022638
Disease or Syndrome
Presence of elevated levels of ketone bodies in the body.
Elevated circulating branched chain amino acid concentration
MedGen UID:
870259
Concept ID:
C4024697
Finding
An increased concentration of a branched chain amino acid in the blood.
Elevated circulating L-alloisoleucine concentration
MedGen UID:
1753697
Concept ID:
C5421646
Finding
Abnormally increased concentration of L-alloisoleucine in the blood circulation.

Professional guidelines

PubMed

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

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

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
Xu J, Jakher Y, Ahrens-Nicklas RC
Int J Mol Sci 2020 Oct 11;21(20) doi: 10.3390/ijms21207490. PMID: 33050626Free 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
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

Liu Q, Li F, Zhou J, Liu X, Peng J, Gong L
Medicine (Baltimore) 2022 Dec 16;101(50):e32174. doi: 10.1097/MD.0000000000032174. PMID: 36550798Free PMC Article
Cannon Homaei S, Barone H, Kleppe R, Betari N, Reif A, Haavik J
Neurosci Biobehav Rev 2022 Jan;132:838-856. Epub 2021 Nov 11 doi: 10.1016/j.neubiorev.2021.11.012. PMID: 34774900
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
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
EFRON ML
N Engl J Med 1965 May 20;272:1058-67 CONTD. doi: 10.1056/NEJM196505202722006. PMID: 14281543

Therapy

Deger İ, Çelik M, Taş İ, Samancı S
Ther Apher Dial 2022 Jun;26(3):658-666. Epub 2022 Feb 24 doi: 10.1111/1744-9987.13816. PMID: 35166449
Marques HP, Barros I, Li J, Murad SD, di Benedetto F
Int J Surg 2020 Oct;82S:163-168. Epub 2020 Mar 31 doi: 10.1016/j.ijsu.2020.03.017. PMID: 32244002
Grünert SC, Rosenbaum-Fabian S, Schumann A, Schwab KO, Mingirulli N, Spiekerkoetter U
Nutr J 2018 May 12;17(1):51. doi: 10.1186/s12937-018-0357-7. PMID: 29753318Free 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
Shaw KN, Lieberman E, Koch R, Donnell GN
Am J Dis Child 1967 Jan;113(1):119-28. doi: 10.1001/archpedi.1967.02090160169027. PMID: 4289134

Prognosis

Al Shidhani A, Al Hinai A, Al Thihli K, Al Mandhari H, Al Yaarubi S, Ullah I, Al-Hashmi N, Al Murshedi F
J Clin Res Pediatr Endocrinol 2023 Aug 23;15(3):302-306. Epub 2021 Nov 5 doi: 10.4274/jcrpe.galenos.2021.2021.0173. PMID: 34738771Free 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
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
Muelly ER, Moore GJ, Bunce SC, Mack J, Bigler DC, Morton DH, Strauss KA
J Clin Invest 2013 Apr;123(4):1809-20. Epub 2013 Mar 8 doi: 10.1172/JCI67217. PMID: 23478409Free PMC Article
Ogier de Baulny H, Saudubray JM
Semin Neonatol 2002 Feb;7(1):65-74. doi: 10.1053/siny.2001.0087. PMID: 12069539

Clinical prediction guides

Margutti AVB, Silva WA Jr, Garcia DF, de Molfetta GA, Marques AA, Amorim T, Prazeres VMG, Boy da Silva RT, Miura IK, Seda Neto J, Santos ES, Santos MLSF, Lourenço CM, Tonon T, Sperb-Ludwig F, de Souza CFM, Schwartz IVD, Camelo JS Jr
Orphanet J Rare Dis 2020 Nov 1;15(1):309. doi: 10.1186/s13023-020-01590-7. PMID: 33131499Free PMC Article
Xu J, Jakher Y, Ahrens-Nicklas RC
Int J Mol Sci 2020 Oct 11;21(20) doi: 10.3390/ijms21207490. PMID: 33050626Free PMC Article
Khalifa OA, Imtiaz F, Ramzan K, Zaki O, Gamal R, Elbaik L, Rihan S, Salam E, Abdul-Mawgoud R, Hassan M, Hassan N, Saleh E, Seoudi D, Moustafa AS
Am J Med Genet A 2020 Nov;182(11):2486-2500. Epub 2020 Aug 19 doi: 10.1002/ajmg.a.61806. PMID: 32812330
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
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

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

    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

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