3MCC Deficiency

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

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

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 (usually present in the liver, fibroblasts, and leukocytes) impairs the breakdown of leucine, resulting in metabolic acidosis and occasional hypoglycemia. The phenotype is extremely variable, ranging from patients presenting in infancy with developmental delays or recurrent attacks of metabolic decompensation followed by complete recovery to asymptomatic adults. In most cases, the condition is relatively benign if properly recognized and treated. This enzyme requires biotin and elevated C5-OH and can also be seen in biotinidase deficiency.

Clinical Characteristics

With treatment of 3MCC, normal development and IQ are possible; however, severe episodes of metabolic acidosis/hypoglycemia may still result in seizures and/or intellectual disability.

Without treatment, 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. Some people remain completely asymptomatic.
Initial signs/symptoms of 3MCC deficiency may include:
  • Poor feeding
  • Vomiting
  • Irritability
  • Lethargy
  • Lab findings:
    • Hyperammonemia
    • Low carnitine levels
    • Ketoacidosis
    • Hypoglycemia
    • Hyperglycemia
If not treated promptly and consistently, patients may experience:
  • Failure to thrive
  • Fasting intolerance
  • 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 ID providers [22]).
  • 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

  • For evaluation and ongoing collaborative management, consult Biochemical Genetics (Metabolics) Clinics (see ID providers [2]).
  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill. See 3MCC Deficiency - Information for Parents (STAR-G).
  • Once a diagnosis is confirmed, endocrine testing is completed. Then, long-term care requires a specialist team and testing on a repeating basis (endocrine testing and brain MRIs for males).
  • Oral L-carnitine supplementation
  • Fasting avoidance, low-protein diet in rare cases
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

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

Support

Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board, and nutrition and recipe ideas.

General

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.

3-methylcrotonyl-CoA carboxylase deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Resources for 3MCC Deficiency (Disease InfoSearch)
Compilation of information, articles, and links to support; from Genetic Alliance.

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; American College of Medical Genetics.

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 Idaho (ID)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG)

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: May 2019
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Authoring history
2012: revision: Kimberly Hart, MS, LCGCA
2010: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

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