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3-methylcrotonyl-CoA carboxylase 2 deficiency(MCC2D)

MedGen UID:
347898
Concept ID:
C1859499
Disease or Syndrome
Synonyms: 3 alpha methylcrotonyl-CoA carboxylase 2 deficiency; 3 alpha methylcrotonylglycinuria 2; MCC 2 deficiency; MCCC2-Related 3-Methylcrotonyl-CoA Carboxylase Deficiency; Methylcrotonylglycinuria type 2; METHYLCROTONYLGLYCINURIA, TYPE II
 
Gene (location): MCCC2 (5q13.2)
 
Monarch Initiative: MONDO:0008862
OMIM®: 210210

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 I (MCC1D; 210200), caused by mutation in the alpha subunit of 3-methylcrotonyl-CoA carboxylase (MCCC1; 609010). [from OMIM]

Additional description

From MedlinePlus Genetics
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.



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.

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.  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.
Inborn organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Hyperglycinuria
MedGen UID:
107456
Concept ID:
C0543541
Disease or Syndrome
The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria (IG; 242600), a benign inborn error of amino acid transport, is also a normal finding in neonates and infants under 6 months of age (Chesney, 2001). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG) (summary by Broer et al., 2008). A phenotype of combined glucosuria and glycinuria has been described (see 138070).
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
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Cerebral palsy
MedGen UID:
854
Concept ID:
C0007789
Disease or Syndrome
Cerebral palsy describes a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, and behavior, by epilepsy, and by secondary musculoskeletal problems.
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.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Seborrheic dermatitis
MedGen UID:
19912
Concept ID:
C0036508
Disease or Syndrome
Seborrheic dermatitis is a form of eczema which is closely related to dandruff. It causes dry or greasy peeling of the scalp, eyebrows, and face, and sometimes trunk.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Ketoacidosis
MedGen UID:
67434
Concept ID:
C0220982
Disease or Syndrome
Acidosis resulting from accumulation of ketone bodies.
Hyperleucinemia
MedGen UID:
451032
Concept ID:
C0268576
Disease or Syndrome
An increased concentration of leucine in the blood.
Decreased circulating carnitine concentration
MedGen UID:
222973
Concept ID:
C1142132
Finding
Concentration of carnitine in the blood circulation below the lower limit of normal.
Acute hyperammonemia
MedGen UID:
347900
Concept ID:
C1859506
Finding
An increased concentration of ammonia in the blood with sudden onset.
Propionyl-CoA carboxylase deficiency
MedGen UID:
1638582
Concept ID:
C4551877
Finding
Propionic acidemia is an autosomal recessive metabolic disorder caused by defective functioning in the mitochondrial enzyme propionyl CoA carboxylase (PCC), resulting in the accumulation of propionic acid metabolites, and dysfunction in the respiratory chain and urea cycle pathways. The disorder is clinically heterogeneous. A neonatal-onset form is characterized by poor feeding, vomiting, and fatigue in the first days of life in a previously healthy infant, and if untreated, may be followed by lethargy, seizures, coma, and death. The neonatal form is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenia. A late-onset form in older children and adults has a milder phenotype, is less common, and may present with developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal ganglia infarction, which may result in dystonia and choreoathetosis, and cardiomyopathy. Metabolically unstable individuals can have an acute decompensation that resembles the neonatal presentation, often precipitated by a catabolic stress such as infection, injury, or surgery, or an excessive intake of intact (i.e., complete, dietary, or natural) protein. Long-term manifestations of neonatal and late onset of propionic acidemia can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other less common manifestations include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure (summary by Jurecki et al., 2019).
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.

Professional guidelines

PubMed

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

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

Kim MJ, Kim SY, Lee JS, Kang S, Park LJ, Choi W, Jung JY, Kim T, Park SS, Ko JM, Seong MW, Chae JH
Ann Lab Med 2023 May 1;43(3):280-289. Epub 2022 Dec 22 doi: 10.3343/alm.2023.43.3.280. PMID: 36544340Free PMC Article

Diagnosis

Kim MJ, Kim SY, Lee JS, Kang S, Park LJ, Choi W, Jung JY, Kim T, Park SS, Ko JM, Seong MW, Chae JH
Ann Lab Med 2023 May 1;43(3):280-289. Epub 2022 Dec 22 doi: 10.3343/alm.2023.43.3.280. PMID: 36544340Free PMC Article
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

Prognosis

Kim MJ, Kim SY, Lee JS, Kang S, Park LJ, Choi W, Jung JY, Kim T, Park SS, Ko JM, Seong MW, Chae JH
Ann Lab Med 2023 May 1;43(3):280-289. Epub 2022 Dec 22 doi: 10.3343/alm.2023.43.3.280. PMID: 36544340Free PMC Article
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

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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