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3-methylcrotonyl-CoA carboxylase 1 deficiency(MCC1D)

MedGen UID:
78691
Concept ID:
C0268600
Disease or Syndrome
Synonyms: 3 Alpha methylcrotonylglycinuria 1; MCC 1 deficiency; MCC1D; MCCC1-Related 3-Methylcrotonyl-CoA Carboxylase Deficiency; MCCD TYPE 1; METHYLCROTONYLGLYCINURIA TYPE I
SNOMED CT: beta-Methylcrotonylglycinuria, type 1 (13144005)
 
Gene (location): MCCC1 (3q27.1)
 
Monarch Initiative: MONDO:0008861
OMIM®: 210200

Definition

3-Methylcrotonylglycinuria is an autosomal recessive disorder of leucine catabolism. The clinical phenotype is highly variable, ranging from neonatal onset with severe neurologic involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. MCC activity in extracts of cultured fibroblasts of patients is usually less than 2% of control (summary by Baumgartner et al., 2001). Also see 3-methylcrotonylglycinuria II (MCC2D; 210210), caused by mutation in the beta subunit of 3-methylcrotonyl-CoA carboxylase (MCCC2; 609014). [from OMIM]

Additional description

From MedlinePlus Genetics
3-methylcrotonyl-CoA carboxylase deficiency (also called MCC deficiency) is an inherited disorder in which the body is unable to process certain proteins. People with this disorder have a shortage of an enzyme that helps break down proteins that contain a particular building block (amino acid) called leucine.

The signs and symptoms of MCC deficiency can vary among individuals, even among individuals in the same family. Some people with the genetic changes that cause MCC deficiency will not develop symptoms until adulthood, while many will never develop signs or symptoms.



Some affected individuals develop signs and symptoms in infancy or early childhood after an event such as an infection, a long period without food, or the introduction of a high-protein diet. Features of MCC deficiency may include feeding difficulties, delayed development, vomiting, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, MCC deficiency can lead to seizures; breathing difficulties; and comas, which can be life-threatening.   https://medlineplus.gov/genetics/condition/3-methylcrotonyl-coa-carboxylase-deficiency

Clinical features

From HPO
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) in the urine. Ketone bodies are insignificant in the blood and urine of normal individuals in the postprandial or overnight-fasted state.
3-hydroxyisovaleric aciduria
MedGen UID:
1746334
Concept ID:
C5421619
Finding
Concentration of 3-hydroxyisovaleric acid in the urine above the normal range.
Elevated urinary 3-methylcrotonylglycine level
MedGen UID:
1782488
Concept ID:
C5539708
Finding
An abnormally increased amount of 3-methylcrotonylglycine in the urine.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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.
Acute hepatic steatosis
MedGen UID:
870572
Concept ID:
C4025020
Disease or Syndrome
An acute form of hepatic steatosis.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, 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 characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Opisthotonus
MedGen UID:
56246
Concept ID:
C0151818
Sign or Symptom
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
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).
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Acute hyperammonemia
MedGen UID:
347900
Concept ID:
C1859506
Finding
An increased concentration of ammonia in the blood with sudden onset.
Episodic metabolic acidosis
MedGen UID:
349179
Concept ID:
C1859516
Finding
Repeated transient episodes of metabolic acidosis, that is, of the buildup of acid or depletion of base due to accumulation of metabolic acids.
Reduced 3-methylcrotonyl CoA carboxylase activity in cultured fibroblasts
MedGen UID:
1051435
Concept ID:
CN375677
Finding
Acitivity of 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) below the lower limit of normal in cultured fibroblasts.

Professional guidelines

PubMed

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
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
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

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

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
Smon A, Repic Lampret B, Groselj U, Zerjav Tansek M, Kovac J, Perko D, Bertok S, Battelino T, Trebusak Podkrajsek K
Clin Biochem 2018 Feb;52:48-55. Epub 2017 Oct 27 doi: 10.1016/j.clinbiochem.2017.10.016. PMID: 29111448
Forsyth R, Vockley CW, Edick MJ, Cameron CA, Hiner SJ, Berry SA, Vockley J, Arnold GL; Inborn Errors of Metabolism Collaborative
Mol Genet Metab 2016 May;118(1):15-20. Epub 2016 Feb 15 doi: 10.1016/j.ymgme.2016.02.002. PMID: 27033733Free PMC Article
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

Diagnosis

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
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
Forsyth R, Vockley CW, Edick MJ, Cameron CA, Hiner SJ, Berry SA, Vockley J, Arnold GL; Inborn Errors of Metabolism Collaborative
Mol Genet Metab 2016 May;118(1):15-20. Epub 2016 Feb 15 doi: 10.1016/j.ymgme.2016.02.002. PMID: 27033733Free PMC Article
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
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

Therapy

Peake RW
Clin Chem 2016 Sep;62(9):1278-9. doi: 10.1373/clinchem.2016.257600. PMID: 27573455

Prognosis

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
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
Forsyth R, Vockley CW, Edick MJ, Cameron CA, Hiner SJ, Berry SA, Vockley J, Arnold GL; Inborn Errors of Metabolism Collaborative
Mol Genet Metab 2016 May;118(1):15-20. Epub 2016 Feb 15 doi: 10.1016/j.ymgme.2016.02.002. PMID: 27033733Free PMC Article
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
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

Clinical prediction guides

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
Forsyth R, Vockley CW, Edick MJ, Cameron CA, Hiner SJ, Berry SA, Vockley J, Arnold GL; Inborn Errors of Metabolism Collaborative
Mol Genet Metab 2016 May;118(1):15-20. Epub 2016 Feb 15 doi: 10.1016/j.ymgme.2016.02.002. PMID: 27033733Free PMC Article
Yang L, Yang J, Zhang T, Weng C, Hong F, Tong F, Yang R, Yin X, Yu P, Huang X, Qi M
Clin Genet 2015 Nov;88(5):484-8. Epub 2014 Dec 23 doi: 10.1111/cge.12535. PMID: 25382614
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
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

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.

    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

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