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Glutaric Acidemia Type 2

Other Names

Glutaric acidemia II (GA2, GA II)

Glutaric aciduria type 2

Multiple acyl-CoA dehydrogenase deficiency (MAD, MADD)

Electron transfer flavoprotein dehydrogenase deficiency (ETFA, ETFB, ETFDH)

Diagnosis Coding

E71.313, glutaric aciduria type II

Disorder Category

A fatty acid oxidation disorder

Screening

Finding

Elevated C4 and C5

Tested By

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

Overview

Glutaric acidemia type 2 is caused by a deficiency of one of three electron transfer flavoprotein enzymes (ETFA, ETFB, or ETFDH). Patients are unable to produce energy from fats and proteins resulting in hypoglycemia, weakness, and in severe cases infant death. Three forms of the condition exist - neonatal onset with congenital anomalies, neonatal onset without anomalies, and a late-onset or mild form that may be amenable to treatment. More recently, a form due to defective transport of riboflavin (the cofactor of the ETF complex) has been reported (Brown-Vialetto-Van Laere and Fazio Londe syndrome) [Bosch: 2011]. The differences in clinical presentation relate to the amount of residual enzyme activity.

Incidence

Prevalence is about 1:250,000 live births. [Schulze: 2003]

Inheritance

Autosomal recessive

Maternal & Family History

Sudden infant death syndrome (SIDS) in siblings is possible.

Prenatal Testing

Amniocentesis for DNA analysis.

Clinical Characteristics

With treatment, possible only in the milder forms, some of the neurologic sequelae and the carnitine deficiency may be avoided. Death within the first few weeks is almost invariable in those with the neonatal or congenital anomaly form. Without treatment, patients with the neonatal variety will die during an acute attack. Patients with the late-onset form will experience exercise intolerance.

Initial signs and symptoms may include: In the neonatal with anomalies form:
  • Facial dysmorphism - high forehead, depressed nasal bridge, low-set abnormally formed ears
  • Rocker bottom feet
  • Muscular defects of the abdominal wall
  • Renal anomalies
  • Anomalies of the external genitalia and
  • Virtually all patients with congenital anomalies will die within a week of birth.
In the neonatal without anomalies form, illness generally presents within the first few days, including:
  • Hypotonia
  • Tachypnea
  • Metabolic acidosis
  • Hepatomegaly
  • Sweaty feet odor
  • Lab findings:
    • Metabolic acidosis
    • Hypoglycemia
Those with mild or late-onset form may present with:
  • Exercise-induced muscle pain
  • Movement disorder
Treatment consists of fasting avoidance, carnitine and riboflavin supplements.

Follow-up Testing after Positive Screen

Quantitative plasma acylcarnitine profile, urine organic acid and acylglycine analysis, confirmation with ETF/ETF-QO enzyme assay and/or gene sequencing. If negative, consider riboflavin transporter deficiency if biochemical abnormalities (plasma acylcarnitine profile) are persistent.

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Glutaric Acidemia Type 2 - Information for Parents (STAR-G) for additional information).
  • Support implementation and maintenance of low fat, low proteindiet.
  • Oral L-carnitine, riboflavin, or glycine supplements may be indicated.
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Collaboration

Initial consultation with the following service(s): Pediatric Genetics (see RI providers [4]); and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Genetic counseling for the family.

Resources

Information & Support

For Professionals

ACT Sheet for Glutaric Acidemia Type 2 (C4 & C5) (ACMG) (PDF Document 347 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Resources for Glutaric Acidemia Type 2 (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

Glutaric Acidemia Type 2 (OMIM)
Extensive review of literature that provides technical information on genetic disorders; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

Genetics in Primary Care Institute (AAP)
Contains health supervision guidelines and other useful resources for the care of children with genetic disorders; American Academy of Pediatrics.

For Parents and Patients

Support

Fatty Oxidation Disorders (FOD) Family Support Group
Information for families about fatty acid oxidation disorders, support groups, coping, finances, and links to other sites.

General

Glutaric Acidemia Type 2 - 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.

Glutaric Acidemia Type 2 (Genetics Home Reference)
Excellent, detailed review for patients and families; sponsored by the National Library of Medicine.

Tools

ACT Sheet for Glutaric Acidemia Type 2 (C4 & C5) (ACMG) (PDF Document 347 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Services for Patients & Families in Rhode Island (RI)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).
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 glutaric acidemia type 2 and neonatal screening, last 5 years.

Authors & Reviewers

Current Authors and Reviewers:
Reviewer: Kimberly Hart, MS, LCGC
Authoring history
2011: first version: Nicola Longo, MD, Ph.D.R
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL, Stroomer AE, Wanders RJ, Visser G, Wijburg FA, Duran M, Waterham HR.
Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment.
J Inherit Metab Dis. 2011;34(1):159-64. PubMed abstract / Full Text
High dose riboflavin is a potential treatment for the Brown-Vialetto-Van Laere syndrome, as well as for the Fazio Londe syndrome, which is considered to be the same disease entity without the deafness.

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