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Methylcrotonyl-CoA carboxylase deficiency

MedGen UID:
1633312
•Concept ID:
C4551505
•
Disease or Syndrome
Synonyms: 3 Methylcrotonylglycinuria; 3-MCC Deficiency; 3-Methylcrotonyl-CoA Carboxylase Deficiency; Deficiency of methylcrotonoyl-CoA carboxylase
SNOMED CT: 3-Methylcrotonyl-CoA carboxylase deficiency (13144005); Methylcrotonyl-CoA carboxylase deficiency (13144005); BMCC deficiency (13144005); MCC deficiency (13144005); Methylcrotonyl-coenzyme A carboxylase deficiency (13144005)
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).
Autosomal recessive inheritance (Orphanet)
 
Related genes: MCCC2, MCCC1
 
Monarch Initiative: MONDO:0018950
OMIM® Phenotypic series: PS210200
Orphanet: ORPHA6

Definition

An inherited disorder of leucine metabolism with characteristics of a highly variable clinical picture ranging from metabolic crisis in infancy to asymptomatic adults. Patients have a variable clinical phenotype with the vast majority of patients being asymptomatic and a small subgroup displaying symptoms of an organic aciduria, usually in association with environmental triggering factors. This disease is due to mutations in the MCCC1 (3q27.1) or MCCC2 (5q12-q13) genes. Mutations in these genes lead to reduced or absent 3-MCC activity, thereby allowing the toxic byproducts of leucine processing to build up and cause clinical symptoms. Inherited autosomal recessively. [from SNOMEDCT_US]

Professional guidelines

PubMed

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency in Zhejiang province, China.
Cheng Y, Chen P, Yu Z, Yin X, Zhang C, Miao H, Huang X
Clin Chim Acta 2023 Mar 1;542:117266. Epub 2023 Feb 21 doi: 10.1016/j.cca.2023.117266. PMID: 36822454
3-Methylcrotonyl-CoA carboxylase deficiency: Mutational spectrum derived from comprehensive newborn screening.
Fonseca H, Azevedo L, Serrano C, Sousa C, Marcão A, Vilarinho L
Gene 2016 Dec 15;594(2):203-210. Epub 2016 Sep 4 doi: 10.1016/j.gene.2016.09.003. PMID: 27601257
A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency.
Arnold GL, Koeberl DD, Matern D, Barshop B, Braverman N, Burton B, Cederbaum S, Fiegenbaum A, Garganta C, Gibson J, Goodman SI, Harding C, Kahler S, Kronn D, Longo N
Mol Genet Metab 2008 Apr;93(4):363-70. Epub 2007 Dec 21 doi: 10.1016/j.ymgme.2007.11.002. PMID: 18155630

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022

American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

Recent clinical studies

Etiology

3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary?
Wang H, Liu S, Wang B, Yang Y, Yu B, Wang L, Wang T
J Pediatr Endocrinol Metab 2019 Dec 18;32(12):1321-1326. doi: 10.1515/jpem-2018-0536. PMID: 31730530
Primary and maternal 3-methylcrotonyl-CoA carboxylase deficiency: insights from the Israel newborn screening program.
Rips J, Almashanu S, Mandel H, Josephsberg S, Lerman-Sagie T, Zerem A, Podeh B, Anikster Y, Shaag A, Luder A, Staretz Chacham O, Spiegel R
J Inherit Metab Dis 2016 Mar;39(2):211-7. Epub 2015 Nov 13 doi: 10.1007/s10545-015-9899-4. PMID: 26566957
Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency.
Uematsu M, Sakamoto O, Sugawara N, Kumagai N, Morimoto T, Yamaguchi S, Hasegawa Y, Kobayashi H, Ihara K, Yoshino M, Watanabe Y, Inokuchi T, Yokoyama T, Kiwaki K, Nakamura K, Endo F, Tsuchiya S, Ohura T
J Hum Genet 2007;52(12):1040-1043. Epub 2007 Oct 30 doi: 10.1007/s10038-007-0211-9. PMID: 17968484
Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment.
Stadler SC, Polanetz R, Maier EM, Heidenreich SC, Niederer B, Mayerhofer PU, Lagler F, Koch HG, Santer R, Fletcher JM, Ranieri E, Das AM, Spiekerkötter U, Schwab KO, Pötzsch S, Marquardt I, Hennermann JB, Knerr I, Mercimek-Mahmutoglu S, Kohlschmidt N, Liebl B, Fingerhut R, Olgemöller B, Muntau AC, Roscher AA, Röschinger W
Hum Mutat 2006 Aug;27(8):748-59. doi: 10.1002/humu.20349. PMID: 16835865
The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.
Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D
J Clin Invest 2001 Feb;107(4):495-504. doi: 10.1172/JCI11948. PMID: 11181649Free PMC Article

Diagnosis

Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency in Zhejiang province, China.
Cheng Y, Chen P, Yu Z, Yin X, Zhang C, Miao H, Huang X
Clin Chim Acta 2023 Mar 1;542:117266. Epub 2023 Feb 21 doi: 10.1016/j.cca.2023.117266. PMID: 36822454
3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary?
Wang H, Liu S, Wang B, Yang Y, Yu B, Wang L, Wang T
J Pediatr Endocrinol Metab 2019 Dec 18;32(12):1321-1326. doi: 10.1515/jpem-2018-0536. PMID: 31730530
Primary and maternal 3-methylcrotonyl-CoA carboxylase deficiency: insights from the Israel newborn screening program.
Rips J, Almashanu S, Mandel H, Josephsberg S, Lerman-Sagie T, Zerem A, Podeh B, Anikster Y, Shaag A, Luder A, Staretz Chacham O, Spiegel R
J Inherit Metab Dis 2016 Mar;39(2):211-7. Epub 2015 Nov 13 doi: 10.1007/s10545-015-9899-4. PMID: 26566957
3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.
Grünert SC, Stucki M, Morscher RJ, Suormala T, Bürer C, Burda P, Christensen E, Ficicioglu C, Herwig J, Kölker S, Möslinger D, Pasquini E, Santer R, Schwab KO, Wilcken B, Fowler B, Yue WW, Baumgartner MR
Orphanet J Rare Dis 2012 May 29;7:31. doi: 10.1186/1750-1172-7-31. PMID: 22642865Free PMC Article
A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency.
Arnold GL, Koeberl DD, Matern D, Barshop B, Braverman N, Burton B, Cederbaum S, Fiegenbaum A, Garganta C, Gibson J, Goodman SI, Harding C, Kahler S, Kronn D, Longo N
Mol Genet Metab 2008 Apr;93(4):363-70. Epub 2007 Dec 21 doi: 10.1016/j.ymgme.2007.11.002. PMID: 18155630

Therapy

A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency.
Arnold GL, Koeberl DD, Matern D, Barshop B, Braverman N, Burton B, Cederbaum S, Fiegenbaum A, Garganta C, Gibson J, Goodman SI, Harding C, Kahler S, Kronn D, Longo N
Mol Genet Metab 2008 Apr;93(4):363-70. Epub 2007 Dec 21 doi: 10.1016/j.ymgme.2007.11.002. PMID: 18155630
Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy.
Baumgartner MR, Dantas MF, Suormala T, Almashanu S, Giunta C, Friebel D, Gebhardt B, Fowler B, Hoffmann GF, Baumgartner ER, Valle D
Am J Hum Genet 2004 Nov;75(5):790-800. Epub 2004 Sep 9 doi: 10.1086/425181. PMID: 15359379Free PMC Article
Metabolic stroke in isolated 3-methylcrotonyl-CoA carboxylase deficiency.
Steen C, Baumgartner ER, Duran M, Lehnert W, Suormala T, Fingerhut R, Stehn M, Kohlschütter A
Eur J Pediatr 1999 Sep;158(9):730-3. doi: 10.1007/s004310051189. PMID: 10485305
Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency: long-term outcome in a case with neonatal onset.
Lehnert W, Niederhoff H, Suormala T, Baumgartner ER
Eur J Pediatr 1996 Jul;155(7):568-72. doi: 10.1007/BF01957906. PMID: 8831079
Glycine and L-carnitine therapy in 3-methylcrotonyl-CoA carboxylase deficiency.
Rutledge SL, Berry GT, Stanley CA, van Hove JL, Millington D
J Inherit Metab Dis 1995;18(3):299-305. doi: 10.1007/BF00710419. PMID: 7474896

Prognosis

3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary?
Wang H, Liu S, Wang B, Yang Y, Yu B, Wang L, Wang T
J Pediatr Endocrinol Metab 2019 Dec 18;32(12):1321-1326. doi: 10.1515/jpem-2018-0536. PMID: 31730530
A 3-methylcrotonyl-CoA carboxylase deficient human skin fibroblast transcriptome reveals underlying mitochondrial dysfunction and oxidative stress.
Zandberg L, van Dyk HC, van der Westhuizen FH, van Dijk AA
Int J Biochem Cell Biol 2016 Sep;78:116-129. Epub 2016 Jul 12 doi: 10.1016/j.biocel.2016.07.010. PMID: 27417235
Analysis of cases of 3-methylcrotonyl CoA carboxylase deficiency (3-MCCD) in the California newborn screening program reported in the state database.
Lam C, Carter JM, Cederbaum SD, Neidich J, Gallant NM, Lorey F, Feuchtbaum L, Wong DA
Mol Genet Metab 2013 Dec;110(4):477-83. Epub 2013 Sep 17 doi: 10.1016/j.ymgme.2013.09.006. PMID: 24103308
3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.
Grünert SC, Stucki M, Morscher RJ, Suormala T, Bürer C, Burda P, Christensen E, Ficicioglu C, Herwig J, Kölker S, Möslinger D, Pasquini E, Santer R, Schwab KO, Wilcken B, Fowler B, Yue WW, Baumgartner MR
Orphanet J Rare Dis 2012 May 29;7:31. doi: 10.1186/1750-1172-7-31. PMID: 22642865Free PMC Article
Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome.
Baykal T, Gokcay GH, Ince Z, Dantas MF, Fowler B, Baumgartner MR, Demir F, Can G, Demirkol M
J Inherit Metab Dis 2005;28(2):229-33. doi: 10.1007/s10545-005-4559-8. PMID: 15877210

Clinical prediction guides

A 3-methylcrotonyl-CoA carboxylase deficient human skin fibroblast transcriptome reveals underlying mitochondrial dysfunction and oxidative stress.
Zandberg L, van Dyk HC, van der Westhuizen FH, van Dijk AA
Int J Biochem Cell Biol 2016 Sep;78:116-129. Epub 2016 Jul 12 doi: 10.1016/j.biocel.2016.07.010. PMID: 27417235
An asymptomatic mother diagnosed with 3-methylcrotonyl-CoA carboxylase deficiency after newborn screening.
Kör D, Mungan NÖ, Yılmaz BŞ, Öktem M
J Pediatr Endocrinol Metab 2015 May;28(5-6):669-71. doi: 10.1515/jpem-2014-0302. PMID: 25381946
3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.
Grünert SC, Stucki M, Morscher RJ, Suormala T, Bürer C, Burda P, Christensen E, Ficicioglu C, Herwig J, Kölker S, Möslinger D, Pasquini E, Santer R, Schwab KO, Wilcken B, Fowler B, Yue WW, Baumgartner MR
Orphanet J Rare Dis 2012 May 29;7:31. doi: 10.1186/1750-1172-7-31. PMID: 22642865Free PMC Article
Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency.
Uematsu M, Sakamoto O, Sugawara N, Kumagai N, Morimoto T, Yamaguchi S, Hasegawa Y, Kobayashi H, Ihara K, Yoshino M, Watanabe Y, Inokuchi T, Yokoyama T, Kiwaki K, Nakamura K, Endo F, Tsuchiya S, Ohura T
J Hum Genet 2007;52(12):1040-1043. Epub 2007 Oct 30 doi: 10.1007/s10038-007-0211-9. PMID: 17968484
3-Hydroxyisovalerylcarnitine in 3-methylcrotonyl-CoA carboxylase deficiency.
van Hove JL, Rutledge SL, Nada MA, Kahler SG, Millington DS
J Inherit Metab Dis 1995;18(5):592-601. doi: 10.1007/BF02436004. PMID: 8598640

Supplemental Content

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    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.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

    Reviews

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    • GTR
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      Clinical tests in GTR
    • PMC Articles
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