TEST CATALOG ORDERING & RESULTS SPECIMEN HANDLING CUSTOMER SERVICE EDUCATION & INSIGHTS
Test Catalog

Test ID: CMMPP    
Cobalamin, Methionine, and Methylmalonic Acid Pathways, Plasma

Useful For Suggests clinical disorders or settings where the test may be helpful

Screening and monitoring patients suspected of or confirmed with an inherited disorder of methionine, cobalamin, or propionate metabolism using plasma specimens

 

Evaluating individuals with suspected deficiency of vitamin B12

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Homocysteine, methylmalonic acid (MMA), methylcitric acid, methionine, cysteine, and cystathionine can be used to evaluate patients for inborn errors of methionine, cobalamin, and propionate metabolism. Homocysteine is an intermediary in the sulfur-amino acid metabolism pathways, linking the methionine cycle to the folate cycle.

 

Inborn errors of metabolism that lead to homocysteinemia or homocystinuria include cystathionine beta-synthase deficiency (homocystinuria) and various defects of methionine remethylation.

 

Homocystinuria is an autosomal recessive disorder caused by a deficiency of the enzyme cystathionine beta-synthase. The incidence of homocystinuria is approximately 1 in 200,000 to 335,000 live births. Classical homocystinuria is characterized by a normal presentation at birth followed by failure to thrive and developmental delay. Untreated homocystinuria can lead to ophthalmological problems, developmental delay, seizures, thromboembolic episodes, and skeletal abnormalities. The biochemical phenotype is characterized by increased plasma concentrations of methionine and homocysteine along with decreased concentrations of cystine.

 

Elevated levels of MMA result from inherited defects of enzymes involved in MMA metabolism or inherited or acquired deficiencies of vitamin B12.

 

Enzymatic deficiencies of propionyl-CoA carboxylase and methylmalonyl-CoA mutase are associated with propionic academia (PA) and methylmalonic acidemia mut(0/-) type (MMAmut), respectively. The clinical phenotype includes vomiting, hypotonia, lethargy, apnea, hypothermia, and coma. The biochemical phenotype for MMAmut includes elevations of propionyl carnitine, methylmalonic acid, and methylcitric acid. Patients with PA will have elevations of propionyl carnitine and methylcitric acid with normal MMA concentrations as the enzymatic defect is upstream of methylmalonic-CoA mutase.

 

Inherited conditions of cobalamin (Cbl) absorption and transport are caused by variants in several genes encoding Cbl binding factors and transmembrane transporters and receptors. In addition, inside the cell, Cbl undergoes several steps of modification until it reaches a divergent point beyond which 2 separate paths lead to the formation of the 2 active components of this cofactor: a) adenosylcobalamin (AdoCbl), a cofactor for methylmalonyl-CoA mutase; and b) methylcobalamin (MeCbl), a cofactor for methionine synthase (MS), remethylating homocysteine to methionine.

 

Defects of AdoCbl and MeCbl metabolism after the point where the synthetic pathways separate lead to isolated deficiencies of methylmalonyl-CoA mutase (elevations of propionyl carnitine, MMA, and methylcitric acid) or methionine synthase (elevated homocysteine with low/low normal methionine) respectively. Defects prior to this point are associated with deficiencies of both enzymes and lead to elevation of all markers (propionyl carnitine, MMA, methylcitric acid, and homocysteine).

 

Acquired cobalamin (vitamin B12) deficiency can be a result of pernicious anemia, vegan diet, malabsorption, and decreased intrinsic factor excretion (secondary to gastrectomy) and can be distinguished from most inherited defects (particularly intracellular deficiencies) with the identification of decreased levels of vitamin B12. Elderly patients with cobalamin deficiency may present with megaloblastic anemia, peripheral neuropathy, ataxia, loss of position and vibration senses, memory impairment, depression, and dementia in the absence of anemia. Other conditions such as renal insufficiency, hypovolemia, and bacterial overgrowth of the small intestine also contribute to the possible causes of mild methylmalonic acidemia and aciduria. Additional testing with homocysteine and MMA determinations may help distinguish between vitamin B12 and folate deficiency states.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Age

Total homocysteine
(nmol/mL)

Methyl-malonic acid
(nmol/mL)

2-Methylcitric
acid
(nmol/mL)

Total cysteine
(nmol/mL)

Methionine (nmol/mL)

Cystathionine
(nmol/mL)

 

Female

Male

Female

Male

0-11 months

3.1-8.3

3.2-9.7

0.08-0.32

0.02-0.35

142.8-258.8

14.7-43.1

14.5-42.3

0.07-0.38

12-23 months

3.2-8.3

3.3-9.6

0.08-0.31

0.02-0.35

143.7-258.7

14.7-43.1

14.5-42.2

0.07-0.38

24-35 months

3.2-8.2

3.3-9.6

0.08-0.31

0.02-0.35

144.8-258.6

14.7-43.0

14.5-42.1

0.07-0.38

3 years

3.2-8.2

3.3-9.6

0.08-0.31

0.02-0.35

146.0-258.5

14.7-43.0

14.5-42.0

0.07-0.38

4 years

3.3-8.2

3.4-9.5

0.08-0.30

0.02-0.35

148.2-258.4

14.7-42.8

14.5-41.8

0.07-0.38

5 years

3.4-8.1

3.5-9.4

0.08-0.30

0.02-0.35

150.6-258.3

14.8-42.7

14.5-41.6

0.07-0.38

6 years

3.5-8.1

3.6-9.4

0.08-0.29

0.02-0.35

153.2-258.3

14.8-42.5

14.5-41.4

0.07-0.38

7 years

3.5-8.1

3.7-9.4

0.08-0.29

0.02-0.35

155.8-258.4

14.8-42.2

14.5-41.1

0.07-0.38

8 years

3.6-8.2

3.8-9.3

0.08-0.28

0.02-0.35

158.5-258.7

14.9-42.0

14.6-40.9

0.07-0.37

9 years

3.7-8.2

3.9-9.4

0.09-0.28

0.02-0.35

161.0-259.1

14.9-41.7

14.6-40.7

0.07-0.37

10 years

3.8-8.3

4.1-9.4

0.09-0.28

0.02-0.35

163.5-259.7

15.0-41.4

14.7-40.6

0.07-0.37

11 years

3.9-8.4

4.3-9.4

0.09-0.28

0.02-0.35

165.9-260.5

15.1-41.0

14.8-40.4

0.07-0.37

12 years

3.9-8.6

4.4-9.5

0.09-0.27

0.02-0.35

168.4-261.4

15.1-40.7

14.9-40.3

0.07-0.37

13 years

4.0-8.7

4.6-9.6

0.09-0.27

0.02-0.35

170.9-262.4

15.2-40.3

15.1-40.1

0.07-0.36

14 years

4.1-8.8

4.8-9.7

0.09-0.27

0.02-0.35

173.6-263.6

15.3-39.9

15.3-40.0

0.07-0.36

15 years

4.2-8.9

5.0-9.8

0.09-0.27

0.02-0.35

176.4-264.7

15.4-39.5

15.5-39.9

0.07-0.36

16 years

4.2-9.1

5.2-9.9

0.09-0.27

0.02-0.35

179.3-265.9

15.5-39.1

15.8-39.7

0.07-0.35

17 years

4.3-9.2

5.4-10.0

0.09-0.27

0.02-0.35

182.2-267.1

15.6-38.7

16.1-39.6

0.07-0.35

18 years

4.3-9.3

5.6-10.1

0.08-0.27

0.02-0.35

184.9-268.3

15.7-38.2

16.4-39.4

0.07-0.35

19 years

4.4-9.5

5.7-10.3

0.08-0.26

0.02-0.35

187.4-269.4

15.7-37.8

16.7-39.3

0.07-0.34

20 years

4.4-9.6

5.9-10.5

0.08-0.26

0.02-0.35

189.5-270.5

15.8-37.3

17.0-39.1

0.07-0.34

21 years

4.4-9.8

6.0-10.6

0.08-0.26

0.02-0.35

191.2-271.7

15.9-36.8

17.3-38.9

0.07-0.33

22 years

4.4-9.9

6.1-10.8

0.08-0.27

0.02-0.35

192.5-272.8

15.9-36.3

17.6-38.7

0.07-0.33

23 years

4.4-10.1

6.2-11.0

0.08-0.27

0.02-0.35

193.5-274.1

15.9-35.8

17.9-38.5

0.07-0.33

24 years

4.4-10.3

6.2-11.1

0.08-0.27

0.02-0.35

194.2-275.4

15.9-35.3

18.1-38.3

0.07-0.32

25 years

4.4-10.4

6.3-11.3

0.08-0.28

0.02-0.35

194.8-277.0

15.9-34.8

18.2-38.1

0.07-0.32

26 years

4.4-10.6

6.3-11.4

0.08-0.28

0.02-0.35

195.3-278.6

15.9-34.3

18.4-37.9

0.07-0.32

27 years

4.3-10.8

6.4-11.6

0.08-0.28

0.02-0.35

196.0-280.5

16.0-33.8

18.5-37.7

0.07-0.31

28 years

4.3-11.0

6.4-11.7

0.08-0.29

0.02-0.35

196.7-282.4

16.0-33.4

18.7-37.5

0.07-0.31

29 years

4.3-11.2

6.4-11.8

0.08-0.29

0.02-0.35

197.7-284.3

16.0-33.0

18.8-37.3

0.07-0.31

30 years

4.3-11.4

6.4-11.9

0.08-0.30

0.02-0.35

198.8-286.3

16.1- 32.6

18.9-37.1

0.07-0.30

31 years

4.4-11.6

6.4-12.1

0.08-0.30

0.02-0.35

200.2-288.2

16.1-32.2

19.0-36.9

0.07-0.30

32 years

4.4-11.8

6.4-12.2

0.08-0.31

0.02-0.35

201.7-290.0

16.1-31.8

19.1-36.7

0.07-0.30

33 years

4.4-11.9

6.4-12.3

0.08-0.31

0.02-0.35

203.4-291.5

16.1-31.5

19.2-36.5

0.07-0.29

34 years

4.5-12.1

6.4-12.4

0.08-0.31

0.02-0.35

205.2-292.9

16.1-31.2

19.3-36.3

0.07-0.29

35 years

4.5-12.2

6.4-12.6

0.08-0.32

0.02-0.35

207.2-294.1

16.1-30.8

19.4-36.1

0.07-0.28

36 years

4.6-12.4

6.4-12.8

0.08-0.32

0.02-0.35

209.3-295.1

16.1-30.5

19.5-35.9

0.07-0.28

37 years

4.6-12.5

6.4-12.9

0.08-0.33

0.02-0.35

211.5-296.0

16.1-30.2

19.6-35.6

0.07-0.27

38 years

4.7-12.7

6.4-13.1

0.08-0.33

0.02-0.35

213.8-296.9

16.1-29.9

19.7-35.4

0.07-0.27

39 years

4.7-12.8

6.4-13.2

0.08-0.34

0.02-0.35

216.3-297.7

16.1-29.7

19.8-35.2

0.07-0.27

40 years

4.8-13.0

6.5-13.4

0.08-0.34

0.02-0.35

218.9-298.7

16.1-29.4

19.9-35.0

0.07-0.27

41 years

4.8-13.2

6.5-13.5

0.08-0.35

0.02-0.35

221.6-299.7

16.1-29.2

20.0-34.8

0.07-0.27

42 years

4.8-13.4

6.5-13.7

0.08-0.36

0.02-0.35

224.3-300.8

16.2-29.0

20.1-34.6

0.07-0.26

43 years

4.9-13.5

6.6-13.9

0.08-0.36

0.02-0.35

227.0-302.0

16.2-28.8

20.2-34.4

0.07-0.26

44 years

4.9-13.7

6.6-14.0

0.08-0.37

0.02-0.35

229.8-303.5

16.3-28.6

20.3-34.2

0.07-0.26

45 years

4.9-13.9

6.6-14.2

0.08-0.38

0.02-0.35

232.6-305.2

16.3-28.5

20.3-34.0

0.07-0.26

46 years

4.9-14.0

6.7-14.4

0.08-0.38

0.02-0.35

235.3-307.3

16.4-28.4

20.4-33.8

0.07-0.26

47 years

4.9-14.2

6.7-14.5

0.08-0.39

0.02-0.35

238.0-309.7

16.4-28.2

20.4-33.6

0.07-0.26

48 years

5.0-14.3

6.8-14.7

0.08-0.39

0.02-0.35

240.8-312.6

16.5-28.1

20.5-33.3

0.07-0.26

49 years

5.0-14.4

6.8-14.9

0.08-0.40

0.02-0.35

243.5-315.9

16.5-28.0

20.5-33.1

0.07-0.26

50 years

5.0-14.5

6.8-15.0

0.08-0.40

0.02-0.35

246.2-319.7

16.5-27.9

20.6-32.8

0.07-0.26

51 years

5.1-14.6

6.8-15.2

0.08-0.41

0.02-0.35

248.9-323.8

16.5-27.8

20.6-32.5

0.07-0.26

52 years

5.1-14.7

6.9-15.4

0.08-0.41

0.02-0.35

251.5-328.1

16.5-27.6

20.7-32.3

0.07-0.26

53 years

5.1-14.8

6.9-15.5

0.08-0.42

0.02-0.35

254.0-332.4

16.5-27.5

20.8-32.1

0.07-0.26

54 years

5.2-14.9

6.9-15.6

0.08-0.42

0.02-0.35

256.4-336.5

16.5-27.4

21.0-31.9

0.07-0.25

55 years

5.2-15.0

6.9-15.7

0.08-0.43

0.02-0.35

258.6-340.2

16.5-27.3

21.1-31.7

0.07-0.25

56 years

5.3-15.0

6.9-15.8

0.08-0.43

0.02-0.35

260.6-343.6

16.6-27.2

21.2-31.5

0.07-0.25

57 years

5.3-15.1

6.9-15.9

0.08-0.44

0.02-0.35

262.5-346.5

16.6-27.1

21.2-31.3

0.07-0.25

58 years

5.3-15.2

6.9-16.0

0.08-0.44

0.02-0.35

264.3-349.0

16.6-27.1

21.3-31.0

0.07-0.25

59 years

5.4-15.2

6.9-16.0

0.08-0.44

0.02-0.35

266.2-351.1

16.7-27.1

21.3-30.8

0.07-0.25

60 years

5.4-15.3

6.9-16.1

0.08-0.45

0.02-0.35

268.3-353.1

16.8-27.1

21.3-30.6

0.07-0.25

61 years

5.4-15.4

7.0-16.2

0.09-0.45

0.02-0.35

270.8-355.1

16.9-27.2

21.3-30.3

0.07-0.25

62 years

5.5-15.4

7.0-16.2

0.09-0.46

0.02-0.35

273.8-357.3

17.0-27.2

21.2-30.0

0.08-0.25

63 years

5.5-15.5

7.0-16.3

0.09-0.46

0.02-0.35

277.5-359.7

17.1-27.3

21.2-29.8

0.08-0.25

64 years

5.6-15.5

7.1-16.3

0.09-0.46

0.02-0.35

281.9-362.3

17.2-27.4

21.1-29.5

0.08-0.25

65 years

5.6-15.6

7.1-16.3

0.09-0.47

0.02-0.35

286.9-365.2

17.3-27.6

21.1-29.2

0.08-0.25

66 years

5.7-15.6

7.1-16.3

0.09-0.47

0.02-0.35

292.4-368.3

17.4-27.7

21.1-29.0

0.08-0.25

67 years

5.7-15.7

7.2-16.3

0.09-0.47

0.02-0.35

298.1-371.6

17.5-27.8

21.0-28.7

0.09-0.25

68 years

5.8-15.7

7.2-16.3

0.09-0.47

0.02-0.35

303.6-374.8

17.7-27.9

21.0-28.5

0.09-0.25

69 years

5.9-15.7

7.2-16.3

0.09-0.47

0.02-0.35

308.7-377.8

17.8-28.0

21.0-28.4

0.09-0.25

70 years

6.0-15.8

7.3-16.3

0.09-0.48

0.02-0.35

313.1-380.7

18.0-28.1

21.0-28.3

0.09-0.25

71 years

6.1-15.8

7.3-16.3

0.09-0.48

0.02-0.35

316.5-383.2

18.1-28.2

20.9-28.2

0.09-0.25

72 years

6.2-15.8

7.3-16.3

0.09-0.48

0.02-0.35

318.9-385.3

18.3-28.3

20.9-28.0

0.09-0.25

73 years

6.3-15.9

7.3-16.3

0.09-0.48

0.02-0.35

320.1-387.0

18.5-28.4

20.8-27.9

0.10-0.26

74 years

6.4-15.9

7.3-16.3

0.09-0.48

0.02-0.35

320.6-388.3

18.8-28.5

20.8-27.8

0.10-0.26

75 years

6.5-15.9

7.3-16.3

0.09-0.48

0.02-0.35

320.3-389.3

19.1-28.5

20.8-27.7

0.10-0.26

76 years

6.6-15.9

7.3-16.3

0.09-0.48

0.02-0.35

319.6-389.9

19.3-28.6

20.8-27.5

0.10-0.26

77 years

6.7-16.0

7.4-16.3

0.10-0.48

0.02-0.35

319.1-390.2

19.6-28.6

20.9-27.4

0.10-0.26

78 years

6.8-16.0

7.4-16.3

0.10-0.48

0.02-0.35

318.5-390.5

20.0-28.7

20.9-27.2

0.11-0.26

79 years

6.9-16.0

7.5-16.3

0.10-0.48

0.02-0.35

317.9-390.6

20.3-28.7

21.0-27.1

0.11-0.26

80 years

7.0-16.0

7.5-16.3

0.10-0.48

0.02-0.35

317.9-390.6

20.3-28.7

21.0-27.1

0.11-0.26

81 years

7.1-16.0

7.7-16.2

0.10-0.48

0.02-0.35

317.9-390.6

20.3-28.7

21.0-27.1

0.11-0.26

82 years

7.2-16.0

7.8-16.2

0.10-0.48

0.02-0.35

317.9-390.6

20.3-28.7

21.0-27.1

0.11-0.26

83 years

7.2-16.0

7.9-16.2

0.10-0.48

0.02-0.35

317.9-390.6

20.3-28.7

21.0-27.1

0.11-0.26

84 years

7.3-16.0

8.0-16.2

0.10-0.48

0.02-0.35

317.9-390.6

20.3-28.7

21.0-27.1

0.11-0.26

85 years

7.3-16.0

8.2-16.2

0.10-0.48

0.02-0.35

317.9-390.6

20.3-28.7

21.0-27.1

0.11-0.26

>85 years

7.4-16.0

8.3-16.2

0.10-0.48

0.02-0.35

317.9-390.6

20.3-28.7

21.0-27.1

0.11-0.26

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

 

When abnormal results are detected, a detailed interpretation is given, including an overview of the results and of their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing, and in vitro confirmatory studies (complementation studies, molecular analysis), and a phone number to reach one of the laboratory directors in case the referring physician has additional questions.

 

Abnormal results are not sufficient to conclusively establish a diagnosis of a particular disease. To verify a preliminary diagnosis based on the analysis, independent biochemical (eg, complementation studies) or molecular genetic analyses are required.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Normal levels may be seen in patients undergoing treatment.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Turgeon CT, Magera MJ, Cuthbert CD, et al: Determination of total homocysteine, methylmalonic acid, and 2-methylcitric acid in dried blood spots by tandem mass spectrometry. Clin Chem. 2010;56(11):1686-1695

2. Tortorelli S, Turgeon CT, Lim JS, et al: Two-tier approach to the newborn screening of methylenetetrahydrofolate reductase deficiency and other remethylation disorders with tandem mass spectrometry. J Pediatr. 2010;157(2):271-275

3. Solomon LR: Disorders of cobalamin (vitamin B12) metabolism: Emerging concepts in pathophysiology, diagnosis and treatment. Blood Rev. 2007;21:113-130

4. Baric I, Staufner C, Augoustides-Savvopoulou P, Chien YH, Dobbelaere D, Grunert SC: Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders. J Inherit Metab Dis. 2017;40(1):5-20

5. Sloan JS, Carrillo N, Adams D, Venditti CP: Disorders of intracellular cobalamin metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2008. Updated September 6, 2018. Accessed May 15, 2020. Available at https://www.ncbi.nlm.nih.gov/books/NBK1328/

Special Instructions Library of PDFs including pertinent information and forms related to the test