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1
ARUP Institute for Clinical and Experimental Pathology, 500 Chipeta Way, Salt Lake City, UT 84108.
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Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132.
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MDS SCIEX, Concord, ON, L4K 4V8 Canada.
aAuthor for correspondence. Fax 801-584-5207; e-mail kushnmm{at}aruplab.com.
Background: Methylmalonic acid (MMA) is a dicarboxylic acid whose concentration can be increased in blood and urine in patients with an inborn error of metabolism or vitamin B12 deficiency. We developed a method for the selective analysis of dicarboxylic acids that exploits the high specificity of tandem mass spectrometry (MS/MS) and the substantial difference in fragmentation patterns of the isomers methylmalonic (MMA) and succinic acid (SA).
Methods: Dicarboxylic acids were extracted from samples with methyl-tert-butyl ether and derivatized with butanolic HCl to form dibutyl esters. The derivative was injected into the liquid chromatography (LC)-MS/MS system using TurboIonSprayTM (nebulizer-assisted electrospray) ionization and quantified by the multiple reaction monitoring mode of MS/MS.
Results: The assay for MMA was linear up to 150 µmol/L. The total imprecision was 
7.5% at both low and high concentrations. The limits of quantification and detection were 0.1 and 0.05 µmol/L, respectively. The degree of interference from SA could be predicted from the branching ratios of the major product ions.
Conclusions: The method is specific for dicarboxylic acids. The LC-MS/MS analysis for MMA requires minimal chromatographic separation and takes <60 s per sample. The entire analysis, including sample preparation, for a batch of 100 specimens can be performed in <4 h.
The following articles in journals at HighWire Press have cited this article:
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  G. la Marca, S. Malvagia, E. Pasquini, M. Innocenti, M. A. Donati, and E. Zammarchi Rapid 2nd-Tier Test for Measurement of 3-OH-Propionic and Methylmalonic Acids on Dried Blood Spots: Reducing the False-Positive Rate for Propionylcarnitine during Expanded Newborn Screening by Liquid Chromatography-Tandem Mass Spectrometry Clin. Chem., July 1, 2007; 53(7): 1364 - 1369. [Abstract] [Full Text] [PDF]
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 I. C. Macaulay, M. R. Tijssen, D. C. Thijssen-Timmer, A. Gusnanto, M. Steward, P. Burns, C. F. Langford, P. D. Ellis, F. Dudbridge, J.-J. Zwaginga, et al. Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins Blood, April 15, 2007; 109(8): 3260 - 3269. [Abstract] [Full Text] [PDF]
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M. M. Kushnir, A. L. Rockwood, W. L. Roberts, E. G. Pattison, W. E. Owen, A. M. Bunker, and A. W. Meikle Development and Performance Evaluation of a Tandem Mass Spectrometry Assay for 4 Adrenal Steroids Clin. Chem., August 1, 2006; 52(8): 1559 - 1567. [Abstract] [Full Text] [PDF]
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A. Schmedes and I. Brandslund Analysis of methylmalonic Acid in plasma by liquid chromatography-tandem mass spectrometry. Clin. Chem., April 1, 2006; 52(4): 754 - 757. [Abstract] [Full Text] [PDF]
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J. W. Miller, M. G. Garrod, A. L. Rockwood, M. M. Kushnir, L. H. Allen, M. N. Haan, and R. Green Measurement of Total Vitamin B12 and Holotranscobalamin, Singly and in Combination, in Screening for Metabolic Vitamin B12 Deficiency Clin. Chem., February 1, 2006; 52(2): 278 - 285. [Abstract] [Full Text] [PDF]
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M. M. Kushnir, A. L. Rockwood, W. L. Roberts, E. G. Pattison, A. M. Bunker, R. L. Fitzgerald, and A. W. Meikle Performance Characteristics of a Novel Tandem Mass Spectrometry Assay For Serum Testosterone Clin. Chem., January 1, 2006; 52(1): 120 - 128. [Abstract] [Full Text] [PDF]
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 N. Anzai, P. Jutabha, A. Enomoto, H. Yokoyama, H. Nonoguchi, T. Hirata, K. Shiraya, X. He, S. H. Cha, M. Takeda, et al. Functional Characterization of Rat Organic Anion Transporter 5 (Slc22a19) at the Apical Membrane of Renal Proximal Tubules J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 534 - 544. [Abstract] [Full Text] [PDF]
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A. Windelberg, O. Arseth, G. Kvalheim, and P. M. Ueland Automated Assay for the Determination of Methylmalonic Acid, Total Homocysteine, and Related Amino Acids in Human Serum or Plasma by Means of Methylchloroformate Derivatization and Gas Chromatography-Mass Spectrometry Clin. Chem., November 1, 2005; 51(11): 2103 - 2109. [Abstract] [Full Text] [PDF]
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D. H. Chace, T. A. Kalas, and E. W. Naylor Use of Tandem Mass Spectrometry for Multianalyte Screening of Dried Blood Specimens from Newborns Clin. Chem., November 1, 2003; 49(11): 1797 - 1817. [Abstract] [Full Text] [PDF]
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 A. K. Campbell, J. W. Miller, R. Green, M. N. Haan, and L. H. Allen Plasma Vitamin B-12 Concentrations in an Elderly Latino Population Are Predicted by Serum Gastrin Concentrations and Crystalline Vitamin B-12 Intake J. Nutr., September 1, 2003; 133(9): 2770 - 2776. [Abstract] [Full Text] [PDF]
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J. J. Pitt, M. Eggington, and S. G. Kahler Comprehensive Screening of Urine Samples for Inborn Errors of Metabolism by Electrospray Tandem Mass Spectrometry Clin. Chem., November 1, 2002; 48(11): 1970 - 1980. [Abstract] [Full Text] [PDF]
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M. M. Kushnir, B. Shushan, W. L. Roberts, and M. Pasquali Serum Acylcarnitines and Vitamin B12 Deficiency Clin. Chem., July 1, 2002; 48(7): 1126 - 1128. [Full Text] [PDF]
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