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Test ID 2HGA 2-Hydroxyglutaric Acid Chiral Analysis, Quantitative, Random, Urine


Necessary Information


1. Age and sex of patient are required.

2. Biochemical Genetics Patient Information (T602) is recommended, but not required, to be filled out and sent with the specimen to aid in the interpretation of test results.



Specimen Required


Supplies: Urine Tube, 10 mL (T068)

Container/Tube: Plastic, 10-mL urine tube

Specimen Volume: 10 mL

Pediatric: If the collection volume appears insufficient, submit as much specimen as possible in a single container; the laboratory will determine if volume is sufficient for test.

Collection Instructions:

1. Collect a random urine specimen (first morning void preferred)

2. No preservative


Useful For

Determining type of 2-hydroxyglutaric aciduria by chiral analysis of urine

Highlights

This test provides differentiation of the 3 subtypes of 2-hydroxyglutaric aciduria: D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, and combined D,L-2-hydroxyglutaric aciduria. It also provides a quantitative result of the D- and L-enantiomers of 2-hydroxyglutaric acid via gas chromatography-mass spectrometry analysis.

Method Name

Gas Chromatography Mass Spectrometry (GC-MS)

Reporting Name

D-,L- 2-Hydroxyglutaric Acid, QN, U

Specimen Type

Urine

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Urine Frozen (preferred) 416 days
  Ambient  14 days
  Refrigerated  14 days

Reject Due To

  All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.

Clinical Information

2-Hydroxyglutaric aciduria disorders are a group of cerebral organic acidurias that present biochemically with an elevation of 2-hydroxyglutaric acid (2-HGA) in the urine. There are 2 enantiomers of 2-HGA, the D-form and the L-form. Depending on the genetic defect, individuals may have an elevation of one or both forms of 2-HGA. Routine organic acid analysis (OAU / Organic Acids Screen, Random, Urine), while able to detect 2-HGA, is unable to distinguish between the 2 enantiomers; however, they can be separated with this more specialized biochemical test.

 

L-2-hydroxyglutaric aciduria (L-2-HGA) is caused by defects in L2HGDH and is characterized by progressive cerebellar ataxia and intellectual disability, seizures, and macrocephaly beginning in infancy or early childhood. Symptoms worsen over time, leading to severe disability by early adulthood. Magnetic resonance imaging (MRI) findings include subcortical leukoencephalopathy, generalized cerebellar and cerebral atrophy, and atrophy of the corpus callosum.

 

D-2-hydroxylglutaric aciduria (D-2-HGA) is characterized by elevated levels of D-2-hydroxyglutaric acid (D-2-HG) and typically manifests with developmental delay, seizures, and hypotonia, though can vary widely from asymptomatic to severe. There are 2 types of D-2-HGA depending on the genetic cause. D-2-HGA can either be autosomal recessive, resulting from variants in D2HGDH causing reduced enzymatic activity (type I), or autosomal dominant, with gain-of-function variants in IDH2 causing overproduction of D-2-HG (type II).

 

Combined D,L-2-hydroxylglutaric aciduria (D,L-2-HGA) is the most severe of the 3 types and is caused by defects in SLC25A1, which encodes the mitochondrial citrate carrier. It is characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death.

 

Molecular genetic testing is available (2OHGP / 2-Hydroxyglutaric Aciduria Gene Panel, Varies), which includes analysis of D2HGDH, L2HGDH, IDH2, and SLC25A1 and can be used to confirm abnormal urine results.

Reference Values

Age

D-2-hydroxyglutaric acid (mmol/mol creatinine)

L-2-hydroxyglutaric acid
(mmol/mol creatinine)

0-11 months

≤14.11

≤17.38

12-23 months

≤13.76

≤17.03

24-35 months

≤13.38

≤16.63

3 years

≤12.96

≤16.18

4 years

≤12.20

≤15.35

5 years

≤11.40

≤14.44

6 years

≤10.56

≤13.46

7 years

≤9.71

≤12.43

8 years

≤8.93

≤11.44

9 years

≤8.21

≤10.50

10 years

≤7.56

≤9.66

11 years

≤6.99

≤8.94

12 years

≤6.47

≤8.33

13 years

≤6.01

≤7.83

14 years

≤5.60

≤7.44

15 years

≤5.23

≤7.14

16 years

≤4.91

≤6.93

17 years

≤4.63

≤6.78

18 years

≤4.40

≤6.69

19 years

≤4.21

≤6.63

20 years

≤4.07

≤6.60

21 years

≤3.96

≤6.59

22 years

≤3.88

≤6.58

23 years

≤3.81

≤6.56

24 years

≤3.76

≤6.54

25 years

≤3.71

≤6.50

26 years

≤3.67

≤6.44

27 years

≤3.63

≤6.37

28 years

≤3.59

≤6.27

29 years

≤3.56

≤6.15

30 years

≤3.54

≤6.02

31 years

≤3.52

≤5.87

32 years

≤3.50

≤5.72

33 years

≤3.49

≤5.57

34 years

≤3.48

≤5.41

35 years

≤3.46

≤5.26

36 years

≤3.45

≤5.13

37 years

≤3.43

≤5.00

38 years

≤3.42

≤4.88

39 years

≤3.40

≤4.78

40 years

≤3.39

≤4.70

41 years

≤3.37

≤4.62

42 years

≤3.35

≤4.55

43 years

≤3.33

≤4.50

44 years

≤3.30

≤4.44

45 years

≤3.28

≤4.40

46 years

≤3.24

≤4.35

47 years

≤3.21

≤4.31

48 years

≤3.17

≤4.27

49 years

≤3.13

≤4.23

50 years

≤3.10

≤4.19

51 years

≤3.07

≤4.16

52 years

≤3.04

≤4.12

53 years

≤3.01

≤4.10

54 years

≤2.99

≤4.07

55 years

≤2.97

≤4.04

56 years

≤2.95

≤4.01

57 years

≤2.93

≤3.98

58 years

≤2.91

≤3.94

59 years

≤2.89

≤3.91

60 years

≤2.87

≤3.87

61 years

≤2.85

≤3.84

62 years

≤2.83

≤3.80

63 years

≤2.79

≤3.78

64 years

≤2.76

≤3.75

65 years

≤2.71

≤3.73

66 years

≤2.67

≤3.72

67 years

≤2.61

≤3.71

68 years

≤2.56

≤3.69

69 years

≤2.50

≤3.68

70 years

≤2.44

≤3.66

71 years

≤2.38

≤3.64

72 years

≤2.32

≤3.61

73 years

≤2.26

≤3.56

74 years

≤2.21

≤3.50

75 years

≤2.16

≤3.43

76 years

≤2.10

≤3.35

77 years

≤2.05

≤3.26

78 years

≤2.00

≤3.17

79 years

≤1.94

≤3.08

80 years

≤1.89

≤2.99

81 years

≤1.84

≤2.91

82 years

≤1.80

≤2.84

83 years

≤1.75

≤2.78

84 years

≤1.71

≤2.73

85 years

≤1.68

≤2.69

86 years

≤1.65

≤2.67

87 years

≤1.64

≤2.65

88 years

≤1.63

≤2.64

≥89 years

≤1.62

≤2.64

Interpretation

The values for the D-2-hydroxyglutaric acid and L-2-hydroxyglutaric acid concentrations are reported. The interpretation of the result must be correlated with clinical and other laboratory findings.

Cautions

No significant cautionary statements

Clinical Reference

1. Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C. Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis. 2012;35(4):571-587. doi:10.1007/s10545-012-9462-5

2. Muhlhausen C, Salomons GS, Lukacs Z, et al. Combined D2-/L2-hydroxyglutaric aciduria (SLC25A1 deficiency): clinical course and effects of citrate treatment. J Inherit Metab Dis. 2014;37(5):775-781. doi:10.1007/s10545-014-9702-y

3. Struys EA. D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect. J Inherit Metab Dis. 2006;29(1):21-29. doi:10.1007/s10545-006-0317-9

4. Perales-Clemente E, Hewitt AL, Studinski AL, et al. Bilateral subdural hematomas and retinal hemorrhages mimicking nonaccidental trauma in a patient with D-2-hydroxyglutaric aciduria. JIMD Rep. 2020;58(1):21-28. doi:10.1002/jmd2.12188

Method Description

Urine volumes are spiked with a mixture of internal standards and evaporated. The dry residue is derivatized to form the diastereomeric molecules, then acidified and extracted. After evaporation, the dry residue is derivatized esters at the carboxylic acid moiety. Specimens are then analyzed by capillary gas chromatography mass spectrometry selected ion monitoring using chemical ionization, with chromatographic separation of the L,L- and D,L-diastereoisomers of derivatized 2-hydroxyglutaric acid (2-HGA), corresponding to L-2-HGA and D-2-HGA, respectively.(Unpublished Mayo method)

Day(s) Performed

Thursday

Report Available

3 to 9 days

Test Classification

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

CPT Code Information

83921 x 2

NY State Approved

Yes

Forms

1. Biochemical Genetics Patient Information (T602)

2. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.