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Received on April 20, 2004
Accepted on June 29, 2004
Automation and Analytical Techniques |
1 Department of Chemistry, University of Washington, Seattle, WA
2 Department of Pediatrics, University of Washington, Seattle, WA
3 Laboratory of Neurochemistry, Buenos Aires, Argentina
4 Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada
5 Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA
* To whom correspondence should be addressed. E-mail: gelb{at}chem.washington.edu.
Background: Newborn screening for deficiency in the lysosomal enzymes that cause Fabry, Gaucher, Krabbe, Niemann-Pick A/B, and Pompe diseases is warranted because treatment for these syndromes is now available or anticipated in the near feature. We describe a multiplex screening method for all five lysosomal enzymes that uses newborn-screening cards containing dried blood spots as the enzyme source.
Methods: We used a cassette of substrates and internal standards to directly quantify the enzymatic activities, and tandem mass spectrometry for enzymatic product detection. Rehydrated dried blood spots were incubated with the enzyme substrates. We used liquid-liquid extraction followed by solid-phase extraction with silica gel to remove buffer components. Acarbose served as inhibitor of an interfering acid 
-glucosidase present in neutrophils, which allowed the lysosomal enzyme implicated in Pompe disease to be selectively analyzed.
Results: We analyzed dried blood spots from 5 patients with Gaucher, 5 with Niemann-Pick A/B, 11 with Pompe, 5 with Fabry, and 12 with Krabbe disease, and in all cases the enzyme activities were below the minimum activities measured in a collection of heterozygous carriers and healthy noncarrier individuals. The enzyme activities measured in 5-9 heterozygous carriers were approximately one-half those measured with 16-32 healthy individuals, but there was partial overlap of each condition between the data sets for carriers and healthy individuals.
Conclusion: For all five diseases, the affected individuals were detected. The assay can be readily automated, and the anticipated reagent and supply costs are well within the budget limits of newborn-screening centers.
The following articles in journals at HighWire Press have cited this article:
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  D. S. Millington Rapid and Effective Screening for Lysosomal Storage Disease: How Close Are We? Clin. Chem., October 1, 2008; 54(10): 1592 - 1594. [Full Text] [PDF]
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A. Dajnoki, A. Muhl, G. Fekete, J. Keutzer, J. Orsini, V. DeJesus, X. K. Zhang, and O. A. Bodamer Newborn Screening for Pompe Disease by Measuring Acid {alpha}-Glucosidase Activity Using Tandem Mass Spectrometry Clin. Chem., October 1, 2008; 54(10): 1624 - 1629. [Abstract] [Full Text] [PDF]
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X. K. Zhang, C. S. Elbin, W.-L. Chuang, S. K. Cooper, C. A. Marashio, C. Beauregard, and J. M. Keutzer Multiplex Enzyme Assay Screening of Dried Blood Spots for Lysosomal Storage Disorders by Using Tandem Mass Spectrometry Clin. Chem., October 1, 2008; 54(10): 1725 - 1728. [Abstract] [Full Text] [PDF]
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 Y.-H. Chien, S.-C. Chiang, X. K. Zhang, J. Keutzer, N.-C. Lee, A.-C. Huang, C.-A. Chen, M.-H. Wu, P.-H. Huang, F.-J. Tsai, et al. Early Detection of Pompe Disease by Newborn Screening Is Feasible: Results From the Taiwan Screening Program Pediatrics, July 1, 2008; 122(1): e39 - e45. [Abstract] [Full Text] [PDF]
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A. R. Kemper, W.-L. Hwu, M. Lloyd-Puryear, and P. S. Kishnani Newborn Screening for Pompe Disease: Synthesis of the Evidence and Development of Screening Recommendations Pediatrics, November 1, 2007; 120(5): e1327 - e1334. [Abstract] [Full Text] [PDF]
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D. Wang, T. Wood, M. Sadilek, C. R. Scott, F. Turecek, and M. H. Gelb Tandem Mass Spectrometry for the Direct Assay of Enzymes in Dried Blood Spots: Application to Newborn Screening for Mucopolysaccharidosis II (Hunter Disease) Clin. Chem., January 1, 2007; 53(1): 137 - 140. [Abstract] [Full Text] [PDF]
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E. Parkinson-Lawrence, M. Fuller, J. J. Hopwood, P. J. Meikle, and D. A. Brooks Immunochemistry of Lysosomal Storage Disorders Clin. Chem., September 1, 2006; 52(9): 1660 - 1668. [Abstract] [Full Text] [PDF]
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 T. M. Cowan Neonatal Screening by Tandem Mass Spectrometry NeoReviews, December 1, 2005; 6(12): e539 - e548. [Full Text] [PDF]
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M. Fuller, M. Lovejoy, J. J. Hopwood, and P. J. Meikle Immunoquantification of {beta}-Glucosidase: Diagnosis and Prediction of Severity in Gaucher Disease Clin. Chem., November 1, 2005; 51(11): 2200 - 2202. [Full Text] [PDF]
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D. S. Millington Newborn Screening for Lysosomal Storage Disorders Clin. Chem., May 1, 2005; 51(5): 808 - 809. [Full Text] [PDF]
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D. Wang, B. Eadala, M. Sadilek, N. A. Chamoles, F. Turecek, C. R. Scott, and M. H. Gelb Tandem Mass Spectrometric Analysis of Dried Blood Spots for Screening of Mucopolysaccharidosis I in Newborns Clin. Chem., May 1, 2005; 51(5): 898 - 900. [Full Text] [PDF]
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P. Clements Mass Spectrometry as a Platform for the Diagnosis of Lysosomal Disorders Clin. Chem., October 1, 2004; 50(10): 1723 - 1724. [Full Text] [PDF]
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