Methylmalonic Acid (MMA), Amniotic Fluid
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Methylmalonic acid (MMA) is a specific diagnostic marker for the group of disorders collectively called methylmalonic acidemias, which include at least 9 different complementation groups. Two of them (mut0 and mut-) reflect deficiencies of the apoenzyme portion of the enzyme methylmalonyl-CoA mutase. Two other disorders (CblA and CblB) are associated with abnormalities in the adenosylcobalamin synthesis pathway. CblC, CblD, and CblF deficiencies lead to impaired synthesis of both adenosyl- and methyl-cobalamin. The final 2, CblE and CblG deficiencies, cause impaired synthesis of the enzymes methionine synthase and methionine synthase reductase and are not associated with abnormal MMA concentrations.
Since the first reports of this disorder in 1967, many hundreds of cases have been diagnosed worldwide. Newborn screening identifies approximately 1 in 30,000 live births with a methylmalonic acidemia. The most frequent clinical manifestations are neonatal or infantile metabolic ketoacidosis, failure to thrive, and developmental delay. Excessive protein intake may cause life-threatening episodes of metabolic decompensation and remains a life-long risk unless treatment is closely monitored, including serum and urine MMA levels.
Because the morbidity and mortality of methylmalonic acidemia are high, genetic counseling and prenatal diagnosis are frequently sought by families with 1 or more affected children. The prenatal diagnosis is made on a dual, complementary approach: enzymatic assays in cultured amniocytes or molecular analysis for previously identified familial mutations and direct chemical determination of MMA in cell-free supernatant of amniotic fluid from amniocentesis between 16 and 19 weeks of gestational age.
Specific diagnostic marker for methylmalonic acidemia
A significantly increased amniotic fluid methylmalonic acid concentration supports a diagnosis of methylmalonic acidemia
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
If termination is under consideration, validation of an abnormal result should be done by molecular analysis for previously identified familial mutations or assay of (14)C-propionate fixation and cobalamin uptake in cultured amniocytes, and no medical action should be undertaken before the completion of all in vitro studies.
A prenatal diagnosis of methylmalonic acidemia is made only if there is a commitment to perform molecular analysis for previously identified familial mutations or have the amniocytes analyzed at an independent laboratory (not currently offered at Mayo Medical Laboratories with the exception of MAHMS/89436 Methylmalonic Aciduria and Homocystinuria, cblC Type, Full Gene Analysis).
Previous knowledge of the complementation group (typically labeled as mut0, mut-, CblA, CblB, CblC, etc), associated homocystinuria, responsiveness to vitamin B12 of the affected child, and B12 intake of the mother during the pregnancy are critical to secure an accurate prenatal diagnosis.
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.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Fenton WA, Gravel RA, Rosenblatt DS: Disorders of propionate and methylmalonate metabolism. In Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMBBID) Edited by D Valle, AL Beaudet, B Vogelstein, et al. McGraw-Hill Companies, 2008, Chapter 94 pp 1-47
2. Sweetman L, Rinaldo P: Prenatal diagnosis of organic acidemias with amniotic fluid. Organic Acidemia Association Newsletter 2000;10:8-9
3. Lacey J, Magera M, Matern D: Methylmalonic acid quantitation in serum, urine and amniotic fluid: A method modification with benefits. J Am Soc Mass Spec 2010;21(5):Supplement 1. S44
4. Evans MI, Duquette DA, Rinaldo P, et al: Modulation of B12 dosage and response in fetal treatment of methylmalonic aciduria (MMA): titration of treatment dose to serum and urine MMA. Fetal Diagn Ther 1997;12:21-23