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Test ID: HGEMS Hydroxyglutaric Acids, Glutaric Acid, Ethylmalonic Acid, and Methylsuccinic Acid, Serum

Useful For

Evaluation of patients with an abnormal newborn screen showing elevations of glutarylcarnitine (C5-DC)

 

Evaluation of patients with abnormal newborn screens showing elevations of C4- acylcarnitine to aid in the differential diagnosis of short chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies

 

Diagnosis of glutaric acidemia type 1

 

Aids in diagnosis of glutaric acidemia type 2

Method Name

Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)

Reporting Name

HGEM, S

Specimen Type

Serum Red


Necessary Information


Patient's age is required.



Specimen Required


Container/Tube: Red top

Submission Container/Tube: Plastic vial

Specimen Volume: 0.1 mL


Specimen Minimum Volume

0.02 mL

Specimen Stability Information

Specimen Type Temperature Time
Serum Red Refrigerated (preferred) 90 days
  Frozen  90 days
  Ambient  4 days

Clinical Information

Acylcarnitine analysis is included in newborn screening blood testing and is utilized for detection of several inborn errors of metabolism, including fatty acid oxidation disorders (FAOD) and organic acidemias (OA). A limitation of this analytic method is its inability to differentiate between several isomers. Additional testing of 2-hydroxy glutaric acid (2OH-GA), 3-hydroxy glutaric acid (3OH-GA), glutaric acid (GA), methylsuccinic acid (MSA), and ethylmalonic acid (EMA) by LC-MS/MS allows better differentiation among C4 acylcarnitine and glutarylcarnitine/C10-OH isomers.

 

C4 acylcarnitine represents both butyrylcarnitine and isobutyrylcarnitine and is elevated in short chain acyl Co-A dehydrogenase (SCAD) deficiency, isobutyryl-CoA dehydrogenase (IBDH) deficiency and ethylmalonic encephalopathy (EE). SCAD deficiency is a condition affecting fatty acid metabolism, with reported symptoms of hypoglycemia, lethargy, developmental delays, and failure to thrive; there is controversy on whether a biochemical diagnosis necessarily confers clinical symptoms. IBDH deficiency is characterized by cardiomyopathy, hypotonia, and developmental delays, although many individuals with IBDH deficiency are asymptomatic. EE is a rare progressive encephalopathy associated with hypotonia, seizures, and abnormal movements.

 

Individuals with SCAD deficiency demonstrate elevated plasma EMA and MSA levels and individuals with EE show only elevations in EMA, while individuals with IBDH deficiency do not typically have elevations in either EMA or MSA.

 

Glutarylcarnitine (C5-DC) is elevated in glutaric acidemia type 1 (GA-1), but is not differentiated from C10-OH acylcarnitine. GA-1, also known as glutaric aciduria type 1, is caused by a deficiency of glutaryl-CoA dehydrogenase. GA-1 is characterized by bilateral striatal brain injury leading to dystonia, often a result of acute neurologic crises triggered by illness. Individuals with GA-1 typically show elevations of glutaric acid and 3OH-GA, even in those considered to be "low excretors."

 

Glutaric acidemia (GA-2), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is caused by defects in either the electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase. This disease can be severe and is often fatal in the first weeks of life, with typical symptoms of hypoglycemia, muscle weakness, metabolic acidosis, dysmorphic features, cardiac defects or arrhythmias, renal cysts, and fatty infiltration of the liver. GA-2 can have a milder presentation, also known as ethylmalonic-adipic aciduria, with Reye-like illnesses in childhood, and muscle weakness in childhood and adulthood. In addition to elevations in glutaric acid, individuals with GA-2 can also show increased EMA, MSA, and 2OH-GA.

 

The American College of Medical Genetics (ACMG) newborn screening work group published diagnostic algorithms for the follow-up of infants who had a positive newborn screening result. For more information, see www.acmg.net.

Reference Values

2-OH Glutaric acid ≤4.5 nmol/mL

3-OH Glutaric acid ≤0.7 nmol/mL

Glutaric acid ≤0.8 nmol/mL

Methylsuccinic acid ≤0.3 nmol/mL

Ethylmalonic acid ≤1.5 nmol/mL

Interpretation

Elevations of ethylmalonic acid (EMA) and methylsuccinic acid (MSA) are consistent with a diagnosis of short chain acyl Co-A dehydrogenase (SCAD) deficiency.

 

Elevation of EMA is consistent with a diagnosis of ethylmalonic encephalopathy.

 

Normal levels of EMA in the context of elevated C4 is consistent with a diagnosis of isobutyryl-CoA dehydrogenase (IBDH) deficiency.

 

Elevation of glutaric acid (GA) and 3-hydroxy glutaric acid (3OH-GA) are consistent with a diagnosis of glutaric acidemia type 1 (GA-1).

 

Elevation of GA, 2-hydroxy glutaric acid (2OH-GA), 3OH-GA, EMA, and MSA are consistent with a diagnosis of glutaric acidemia (GA-2).

Clinical Reference

1. Rinaldo P, Cowan TM, Matern D: Acylcarnitine profile analysis. 2008:10(2):151-156

2. Kolker S, Christensen E, Leonar JV, et al: Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis 2011:34:677-694

3. Frerman FE, Goodman SI: Chapter 103: Defects of Electron Transfer Flavoprotein and Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase: Glutaric Acidemia Type II. In Scriver's Online Metabolic and Molecular Bases of Inherited Disease. Edited by CR Scriver, AL Beaudet, D Valle, et al. Accessed 8/17/17. Available at www.ommbid.com

Day(s) and Time(s) Performed

Monday, Wednesday; 8 a.m.

Analytic Time

2 days

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

83918

LOINC Code Information

Test ID Test Order Name Order LOINC Value
HGEMS HGEM, S In Process

 

Result ID Test Result Name Result LOINC Value
36055 2-OH Glutaric acid 69845-6
36056 3-OH Glutaric acid 69851-4
36057 Glutaric acid 27301-1
36058 Methylsuccinic acid 69829-0
36059 Ethylmalonic acid 79476-8
36060 Interpretation (HGEMS) 59462-2
36061 Reviewed By 18771-6
Mayo Clinic Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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