3-Methylglutaconic Aciduria (3MGA)

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)

Diagnosis Coding

E71.111, 3-methylglutaconic aciduria

Disorder Category

An organic acidemia

Screening

Finding

Elevated C5-OH acylcarnitine

Tested By

Tandem mass spectrometry

Overview

3-methylglutaconic aciduria (3-MGA) is a general term used to describe any 1 of 5 metabolic disorders that, for different reasons, result 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.

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 affect1 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.

Prenatal Testing

If there is a positive family history for any 3-MGA type, prenatal targeted genetic testing can be performed via CVS or amniocentesis.

Other Testing

Most recent cases in the US will be identified by Newborn Screening. 3-MGA can also be measured on urine organic acids, along with 3-methylglutaric, which may also be elevated. 3-MGA type I may also have elevations in 3-hydroxyisovaleric acid. Supportive findings of 3-MGA type II include lactic acidosis, neutropenia, and elevated 2-ethylhydracrylic, while increased monolysocardiolipin:cardiolipin ratio is pathognomonic.

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

Treatment
Currently, available treatments do not aim to fix the underlying cause for disease in all 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.

Follow-up Testing after Positive Screen

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.

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Educate the family regarding potential cardiac signs and symptoms, as well as developmental delay, poor growth, abnormal movements, and the need for close follow-up. Also, may discuss risk recurrence depending on the inheritance pattern.

Specialty Care Collaboration

Initial consultation and ongoing collaboration with the following service(s): Pediatric Genetics (see UT providers [6]) or Pediatric Metabolics (see UT providers [2]) and, for some types, Pediatric Cardiology (see UT providers [6]).

Resources

Information & Support

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.

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