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3MCC Deficiency

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Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

MCC deficiency
3-methylcrotonyl-CoA carboxylase deficiency
3-methylcrotonylglycinuria

ICD-10 Coding

E71.19, Other disorders of branched-chain amino-acid metabolism

Disorder Category

Organic acidemia

Screening

Abnormal Finding

Elevated C5-OH (acylcarnitine)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity: 100%; specificity: NA [Schulze: 2003]

Description

In 3MCC deficiency, a lack of 3-methylcrotonyl-CoA carboxylase activity leads to impaired leucine degradation and subsequent elevations of proximal metabolites, including 3-hydroxyisovaleric acid. With the vast majority of cases identified through newborn screening being asymptomatic without treatment, as high as 90% of all cases [Forsyth: 2016], it is considered by many to be a benign biochemical phenotype rather than a true metabolic disorder. However, there are rare cases that have been reported presenting with developmental delays and recurrent attacks of metabolic acidosis and hypoglycemia. This enzyme requires biotin as a cofactor, and therefore, newborn screens with elevated C5-OH can also be seen in biotinidase deficiency.

Clinical Characteristics

With treatment, those who are symptomatic can still achieve normal development and IQ. However, episodes of metabolic acidosis and hypoglycemia may still occur during infectious illnesses and other causes of metabolic stress.
Without treatment, most will remain asymptomatic with normal growth and development. For the rare cases with true symptoms caused by the enzyme deficiency, recurring metabolic crises associated with illness may result in developmental delays, failure to thrive, or seizures. Symptoms generally begin after three months and before three years of age. Affected children may be healthy between metabolic crises.
Initial signs/symptoms of symptomatic 3MCC deficiency may include:
  • Poor feeding
  • Vomiting
  • Irritability
  • Lethargy
  • Lab findings:
    • Hyperammonemia
    • Low carnitine levels
    • Ketoacidosis
    • Hypoglycemia
If symptomatic cases are not treated promptly and consistently, patients may experience:
  • Failure to thrive
  • Hypotonia
  • Reye-like illness
  • Seizures
  • Coma
  • Developmental delay/intellectual disability

Incidence

The incidence of 3MCC deficiency is approximately 1:50,000.

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for poor feeding, vomiting, or lethargy.
  • Provide emergency treatment/referral for symptoms of hypoglycemia, metabolic acidosis, or seizures.

Confirming the Diagnosis

  • To confirm the diagnosis of 3MCC deficiency, work with Newborn Screening Services (see OH providers [1]).
  • Follow-up testing will include quantitative plasma acylcarnitine profile, serum biotinidase, urine organic acids, and enzyme activity assay in white blood cells.

If the Diagnosis is Confirmed

Resources

Information & Support

Related Portal Content
After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

3-Methylchrotonyl-CoA (3-MCC) Dehydrogenase Deficiency (NECMP)
A guideline for health care professionals treating the sick infant/child who has previously been diagnosed with 3MCCD; developed under the direction of Dr. Harvey Levy, Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School, for the New England Consortium of Metabolic Programs.

3MCC Deficiency (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

For Parents and Patients

3MCC Deficiency - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

Tools

ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) (PDF Document 336 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive, along with resources for consultation and patient education/support; from the American College of Genetics and Genomics

Confirmatory Algorithms for Elevated C5-OH (ACMG) (PDF Document 224 KB)
Basic steps involved in determining the final diagnosis of an infant with a positive newborn screen for this condition; American College of Medical Genetics.

Services for Patients & Families in Ohio (OH)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Helpful Articles

PubMed search for 3MCC deficiency and neonatal screening, last 10 years.

Pasquali M, Monsen G, Richardson L, Alston M, Longo N.
Biochemical findings in common inborn errors of metabolism.
Am J Med Genet C Semin Med Genet. 2006;142C(2):64-76. PubMed abstract

Authors & Reviewers

Initial publication: July 2010; last update/revision: April 2024
Current Authors and Reviewers:
Author: Tyler T Miller, MD
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2019: update: Nicola Longo, MD, Ph.D.A
2012: revision: Kimberly Hart, MS, LCGCA
2010: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Forsyth R, Vockley CW, Edick MJ, Cameron CA, Hiner SJ, Berry SA, Vockley J, Arnold GL.
Outcomes of cases with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency - Report from the Inborn Errors of Metabolism Information System.
Mol Genet Metab. 2016;118(1):15-20. PubMed abstract / Full Text

Pasquali M, Monsen G, Richardson L, Alston M, Longo N.
Biochemical findings in common inborn errors of metabolism.
Am J Med Genet C Semin Med Genet. 2006;142C(2):64-76. PubMed abstract

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract

Thomsen JA, Lund AM, Olesen JH, Mohr M, Rasmussen J.
Is L-Carnitine Supplementation Beneficial in 3-Methylcrotonyl-CoA Carboxylase Deficiency?.
JIMD Rep. 2015;21:79-88. PubMed abstract / Full Text