3-Methylglutaconic Aciduria (3-MGA)

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Barth syndrome (Type II)
Costeff syndrome (Type III)
Dilated cardiomyopathy with ataxia (Type V)
3-methylglutaconic aciduria type IV
3-methylglutaconyl CoA hydratase deficiency (Type I)

ICD-10 Coding

E71.111, 3-methylglutaconic aciduria

Disorder Category

Organic acidemia

Screening

Abnormal Finding

Elevated C5-OH acylcarnitine

Tested By

Tandem mass spectrometry

Description

3-methylglutaconic aciduria (3-MGA) is a general term used to describe any 1 of 5 metabolic disorders that, for different reasons, results in increased 3-MGA levels excreted in the urine.
  • In 3-MGA type I, the enzyme 3-methylglutaconyl-CoA hydratase involved in leucine metabolism is deficient. 3-MGA1 has significant phenotypic heterogeneity ranging from early-onset developmental delays and dystonia to adult-onset neurodegenerative disease.
  • In 3-MGA type II (aka Barth syndrome), the chromosome X encoded enzyme tafazzin involved in mitochondrial energy production is deficient. Patients with 3-MGA2 typically present with severe early-onset dilated cardiomyopathy, neutropenia, skeletal myopathy, and prepubertal growth delay.
  • In 3-MGA type III (aka Costeff syndrome), the OPA3 protein involved in mitochondrial fission and apoptosis is deficient. Clinically this results in early-onset optic atrophy and/or a choreoathetoid movement disorder.
  • In 3-MGA type IV, the remaining unclassified causes of secondary elevated 3-MGA are grouped together and include disorders caused by mutations in POLG1, SUCLA2, TMEM70, and mtDNA.
  • In 3-MGA type V (aka dilated cardiomyopathy with ataxia), the DNAJC19 protein involved in the transport of other proteins across the mitochondrial membrane is deficient. Clinically this results in early-onset dilated cardiomyopathy, ataxia, microcytic anemia, growth failure, and genital anomalies in males.

Clinical Characteristics

Early signs and symptoms vary by type of 3-MGA:

Type I
  • Variable age of symptom onset
  • Developmental delay
  • Dystonia
  • Seizures
  • Adult-onset slowly progressive leukoencephalopathy
Type II (Barth syndrome)
  • Onset in early infancy
  • Dilated cardiomyopathy frequently leading to heart failure
  • Skeletal myopathy or hypotonia
  • Neutropenia
  • Prepubertal growth delay
  • Characteristic facial features
Type III (Costeff optic atrophy syndrome)
  • Onset typically before 10 years of age
  • Optic atrophy with vision loss
  • Extrapyramidal dysfunction
  • Ataxia
  • Spasticity
  • Cognitive impairment
Type IV
  • Signs/symptoms can vary based on the underlying genetic cause
Type V (aka Dilated cardiomyopathy with ataxia)
  • Early infancy/childhood onset
  • Dilated cardiomyopathy
  • Microcytic anemia
  • Ataxia
  • Growth failure
  • Genital anomalies in males
Currently, treatments do not fix the underlying cause for disease for any of the types of 3-MGA. Rather, therapies focus on managing the associated features, including medications to slow cardiac disease (sometimes requiring cardiac transplantation). G-CSF may be used to treat neutropenia in 3-MGA type II, and gastrostomy tubes may be required for patients experiencing feeding difficulties. PT/OT and IEP support for developmental delays and spasticity should be considered as well.

Incidence

  • 3-MGA type I is particularly rare with less than 50 cases reported in the medical literature.
  • 3-MGA type II is estimated to affect 1 out of every 1 million males.
  • 3-MGA type III is very rare in most populations but may be as high as 1:10,000 individuals of Iraqi-Jewish descent.
  • Exact numbers of affected individuals with MGA types IV and V are not known. MGA type V has only been reported in the Hutterite population of North America and Canada.

Inheritance

  • 3-MGA types I, III, and V are autosomal recessive conditions and therefore impart a 25% risk recurrence for most families.
  • 3-MGA type II is X-linked recessive and, therefore, a risk for male offspring of carrier mothers.
  • 3-MGA type IV has multiple genetic causes and, therefore, inheritance depends on the specific causative gene.

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for any symptoms.

Confirming the Diagnosis

  • To confirm the diagnosis of 3-MGA, work with Newborn Screening Services (see UT providers [3]).
  • Follow-up testing may include: 3-MGA type I can be identified by Newborn Screening with an elevated C5-OH, among several other metabolic disorders, which can also be seen on an acylcarnitine profile. Urine organic acids are needed to measure 3-MGA levels, but with some types of 3-MGA may be only mildly elevated. Genetic testing may still be necessary to confirm a diagnosis.

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; 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-Methylglutaconic Aciduria, Type I; MGCA1 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; from Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

Barth Syndrome, aka 3-Methylglutaconic Aciduria, Type II; MGCA2 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; from Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

3-Methylglutaconic Aciduria, Type III; MGCA3 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; from Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

3-Methylglutaconic Aciduria, Type IV; MGCA4 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; from Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

3-Methylglutaconic Aciduria, Type V; MGCA5 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; from 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

Baby's First Test: 3-Methylglutaconic Aciduria
Information about early signs, follow-up testing, treatment, accessing care, and expected outcomes. Provides links to support services.

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

3-Methylglutaconyl-CoA Hydratase Deficiency (GARD)
Includes information about symptoms, inheritance, diagnosis, finding a specialist, related diseases, and support organizations; Genetic and Rare Diseases Information Center of the National Center for Advancing Translational Sciences.

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

Barth Syndrome Foundation
A worldwide volunteer organization dedicated to saving lives through education, advances in treatment, and finding a cure for Barth syndrome (BTHS).

Children’s Cardiomyopathy Foundation
This non-profit organization is focused on pediatric cardiomyopathy, a chronic and potentially life-threatening heart disease. It is a condition that is not well known even though it is a leading cause of heart transplants and sudden cardiac arrest in children.

National Association for Parents of Children with Visual Impairments (National Eye Institute)
Offers emotional support for parents of blind or visually impaired children. Provides information, training and assistance, and help in understanding and using available resources. Publishes Awareness, a quarterly newsletter.

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 Utah (UT)

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

Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E, Wevers RA.
Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.
J Inherit Metab Dis. 2013;36(6):923-8. PubMed abstract

Wortmann SB, Kluijtmans LA, Engelke UF, Wevers RA, Morava E.
The 3-methylglutaconic acidurias: what's new?.
J Inherit Metab Dis. 2012;35(1):13-22. PubMed abstract / Full Text

Authors & Reviewers

Initial publication: July 2021
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Authoring history
2021: first version: Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer