Test Catalog

Test ID: HCMM    
Homocysteine (Total), Methylmalonic Acid, and Methylcitric Acid, Blood Spot

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

Second-tier assay of newborn screening specimens when abnormal propionyl carnitine or methionine concentrations are identified in a primary newborn screen

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

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, mental retardation, seizures, thromboembolic episodes, and skeletal abnormalities. The biochemical phenotype is characterized by increased plasma concentrations of methionine and homocysteine (free and total) along with decreased concentrations of cystine.


Methylmalonic acidemia (MMA) and propionic acidemia (PA) are defects of propionate metabolism caused by deficiencies in methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. The clinical phenotype includes vomiting, hypotonia, lethargy, apnea, hypothermia, and coma. The biochemical phenotype for MMA includes elevations of propionyl carnitine, methylmalonic acid, and methylcitric acid. Patients with PA will have elevations of propionyl carnitine and methylcitric acid with normal methylmalonic acid concentrations as the enzymatic defect is upstream of methylmalonic-CoA mutase.


Newborn screening for inborn errors of methionine and propionic acid metabolism relies on elevations of methionine and propionyl carnitine. These analytes are not specific for these conditions and are prone to false-positive results, leading to increased cost, stress, and anxiety for families who are subjected to follow-up testing. Homocysteine, methylmalonic acid, and methylcitric acid are more specific markers for inborn errors of methionine and propionic acid metabolism. Molecular genetic testing can be used to confirm a biochemical diagnosis for homocystinuria, methylmalonic acidemia, and propionic acidemia.

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.


<9.0 nmol/mL



<4.0 nmol/mL



<1.0 nmol/mL


An interpretive report will also be provided.

Interpretation Provides information to assist in interpretation of the test results

Elevated homocysteine, methylcitric acid, or methylmalonic acid concentrations are indicative of an underlying metabolic disorder.

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 affected individuals undergoing treatment.

Supportive Data

In a Mayo study that analyzed specimens from 200 unaffected neonates, clear clinical discrimination was observed when compared to patients with defects of propionate or methionine metabolism. The 99.5 percentile, determined from the analysis of 200 dried blood spots of unaffected controls, for methylmalonic acid (MMA), methylcitric acid (MCA), and homocysteine (HCY), are 1.58 nmol/mL, 0.62 nmol/mL, and 9.9 nmol/mL, respectively, providing clear clinical discrimination from patients with defects of propionate or methionine metabolism (eg, methylmalonic acidemia: MMA=31.9 nmol/mL; propionic acidemia: MCA=12.8 nmol/mL; homocystinuria: HCY=189 nmol/mL).

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

1. Pasquali M, Longo N: Newborn screening and inborn errors of metabolism. In: Rifai N, Horvath AR, Wittwer CT, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. Elsevier; 2018:1697-1730

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. Harvey Mudd S, Levy HL, Kraus JP: Disorders of transsulfuration. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed September 17, 2020. Available at https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225084718

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