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Test ID: HGEM Hydroxyglutaric Acids, Glutaric Acid, Ethylmalonic Acid, and Methylsuccinic Acid, Blood Spot

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, BS

Specimen Type

Whole blood


Specimen Required


Supplies: Card-Blood Spot Collection (Filter Paper) (T493)

Container/Tube:

Preferred: Card-Blood Spot Collection (Filter Paper) (T493)

Acceptable: Ahlstrom 226 filter paper, Munktell filter paper, Whatman Protein Saver 903 paper, available newborn screening card, blood collected in tubes containing heparin or EDTA and dried on filter paper

Specimen Volume: 2 blood spots

Collection Instructions:

1. Completely fill at least 2 circles on the filter paper card (approximately 100 microliters blood per circle).

2. Let blood dry on filter paper at room temperature in a horizontal position for 3 or more hours.

3. Do not stack wet specimens.

4. Do not expose specimen to heat or direct sunlight.

5. Keep specimen dry.


Specimen Minimum Volume

1 blood spot

Specimen Stability Information

Specimen Type Temperature Time
Whole blood Ambient (preferred) 123 days
  Frozen  123 days
  Refrigerated  123 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, is caused by a deficiency of glutaryl-CoA dehydrogenase and 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 ≤25 nmol/mL

3-OH Glutaric acid ≤1.5 nmol/mL

Glutaric acid ≤1.5 nmol/mL

Methylsuccinic acid ≤0.45 nmol/mL

Ethylmalonic acid ≤3.5 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
HGEM HGEM, BS In Process

 

Result ID Test Result Name Result LOINC Value
36048 2-OH Glutaric acid 75037-2
36049 3-OH Glutaric acid 82505-9
36050 Glutaric acid 82504-2
36051 Methylsuccinic acid 82503-4
36052 Ethylmalonic acid 82502-6
36053 Interpretation (HGEM) 59462-2
36054 Reviewed By No LOINC Needed

Forms

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

2. Biochemical Genetics Patient Information (T602) in Special Instructions.