Glutaric Acidemia Type 2

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Electron transfer flavoprotein dehydrogenase deficiency (ETFA, ETFB, ETFDH)
Glutaric acidemia II (GA2, GA II)
Glutaric aciduria type 2
Multiple acyl-CoA dehydrogenase deficiency (MAD, MADD)

ICD-10 Coding

E71.313, Glutaric aciduria type II

Disorder Category

Fatty acid oxidation disorder

Screening

Abnormal Finding

Elevated C4 and C5

Tested By

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

Description

Glutaric acidemia type 2 is caused by a deficiency of 1 of 3 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.

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.

Symptoms are usually triggered by illness (high fever, vomiting, dehydration); crises may also be triggered by vaccinations and surgery. Children may be healthy until the first metabolic crisis. Profuse sweating may occur in some affected children. Acute decompensation has not been reported after 6 years of age, although some undiagnosed patients have presented with a leukoencephalopathy after this age. [Kölker: 2006]
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
  • Renal anomalies
  • Anomalies of the external genitalia
  • 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.

Incidence

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

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for facial dysmorphism, poor feeding, vomiting, lethargy, odor of sweaty feet.
  • Provide emergency treatment/referral for signs or symptoms of hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia, cardiomyopathy. See ACT Sheet for Glutaric Aciduria Type 2 (C4 & C5) (ACMG) (PDF Document 347 KB)

Confirming the Diagnosis

  • To confirm the diagnosis, work with Newborn Screening Services (see NW providers [1]).
  • Follow-up testing includes 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.

If the Diagnosis is Confirmed

  • For evaluation and ongoing collaborative management, consult Medical Genetics (see NW providers [1]).
  • 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. for additional information).
  • Support implementation and maintenance of low fat, low protein diet.
  • Glucose, intralipids, carnitine, and fluids given intravenously may be indicated during episodes of acute, intercurrent illness.
  • 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.

Resources

Information & Support

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

Glutaric Acidemia Type 2 (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

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

Tools

ACT Sheet for Glutaric Aciduria 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.

Confirmatory Algorithms for Glutaric Acidemia Type 2 (ACMG) (PDF Document 190 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Services for Patients & Families Nationwide (NW)

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.

Authors & Reviewers

Initial publication: March 2007; last update/revision: July 2012
Current Authors and Reviewers:
Authors: Kimberly Hart, MS, LCGC
Nicola Longo, MD, Ph.D.

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.

Kölker S, Garbade SF, Greenberg CR, Leonard JV, Saudubray JM, Ribes A, Kalkanoglu HS, Lund AM, Merinero B, Wajner M, Troncoso M, Williams M, Walter JH, Campistol J, Martí-Herrero M, Caswill M, Burlina AB, Lagler F, Maier EM, Schwahn B, Tokatli A, Dursun A, Coskun T, Chalmers RA, Koeller DM, Zschocke J, Christensen E, Burgard P, Hoffmann GF.
Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.
Pediatr Res. 2006;59(6):840-7. 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