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

Disorder Category

A fatty acid oxidation disorder

Screening

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

Specialty Care Collaboration

Initial consultation with the following service(s): Pediatric Genetics (see RI providers [5]); 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

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