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Evaluating children with signs and symptoms of methylmalonic acidemia
Additional confirmatory testing must be performed.
Evaluating individuals with signs and symptoms associated with a variety of causes of cobalamin (vitamin B12) deficiency
Several studies have suggested that the determination of serum or urinary methylmalonic acid could be a more reliable marker of cobalamin deficiency than direct cobalamin determination.
Elevated levels of methylmalonic acid (MMA) result from inherited defects of enzymes involved in MMA metabolism or inherited or acquired deficiencies of vitamin B12 (cobalamin) or its downstream metabolites. Of the 2, nutritional deficiencies are much more common and can be due to intestinal malabsorption, impaired digestion, or poor diet. Elderly patients with cobalamin deficiency may present with 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.
MMA is also a specific diagnostic marker for the group of disorders collectively called methylmalonic acidemia, which include at least 7 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 of the adenosylcobalamin synthesis pathway. CblC, CblD, and CblF deficiencies lead to impaired synthesis of both adenosyl- and methylcobalamin.
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 lifelong risk unless treatment is closely monitored, including serum and urine MMA levels.
< or =0.40 nmol/mL
In pediatric patients, markedly elevated methylmalonic acid values indicate a probable diagnosis of methylmalonic acidemia. Additional confirmatory testing must be performed.
In adults, moderately elevated values indicate a likely cobalamin (vitamin B12) deficiency.
Diet, nutritional status, and age should be considered in the evaluation of serum or urine methylmalonic acid level.
1. Fenton WA, Gravel RA, Rosenblatt DS: Disorders of Propionate and Methylmalonate Metabolism. In The Online Metabolic and Molecular Basis of Inherited Disease (OMBBID). Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, NY, McGraw-Hill, 2014. Available from http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62677098. Accessed August 24, 2015
2. Klee GG: Cobalamin and folate evaluation measurement of methylmalonic acid and homocysteine vs vitamin B12 and folate. Clin Chem 2000:46(8):1277-1283
3. Watkins D, Rosenblatt DS: Inherited Disorders of Folate and Cobalamin Transport and Metabolism. In Scriver’s The Online Metabolic and Molecular Basis of Inherited Disease (OMBBID). Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, NY, McGraw-Hill, 2014. Available from http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62646147. Accessed August 24, 2015