The unifying goal of the proposed studies is the development of assays for the multiplex analysis of enzyme activities of diagnostic value for the detection of inborn errors of metabolism. The assays are based on quantitative analysis of enzymatic products by tandem mass spectrometry as a common analytical platform. In the previous 3-year funding period we have developed tandem mass spectrometric assays for several lysosomal storage diseases using dried blood spots on newborn screening cards. We have also developed mass spectrometric assays for the clinical detection of three porphyrias. Our research on tandem mass spectrometric assays of lysosomal storage diseases has already had a significant impact on the medical community, and some of the assays we developed have been transitioned from our lab to several newborn screening labs in the U.S. and worldwide. The proposed research aims at the detection of syndromes of Hunter, Maroteaux-Lamy, Morquio A, Metachromatic Leukodystrophy, and Sanfilippo A-D using dried blood spots on newborn screening cards. Treatments for these lysosomal storage disorders are either available or being developed and our assays will make it possible for newborn screening laboratories to detect these diseases prior to the development of irreversible symptoms. Also proposed is a continuation of studies of porphyria-linked enzymes aminolevulinic acid dehydratase, porphobilinogen oxidase, and ferrochelatase to develop a complete battery of assays for porphyrias based on tandem mass spectrometry.

Public Health Relevance

The proposed research is aimed at the development of selective and sensitive methods based on enzyme assays and product analysis by tandem mass spectrometry. Technologies and procedures for the early detection of several lysosomal storage diseases are proposed in continuation of our previous successful efforts in this area.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067859-13
Application #
8316182
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Sechi, Salvatore
Project Start
1999-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
13
Fiscal Year
2012
Total Cost
$281,225
Indirect Cost
$89,370
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Fitterer, Braden; Hall, Patricia; Antonishyn, Nick et al. (2014) Incidence and carrier frequency of Sandhoff disease in Saskatchewan determined using a novel substrate with detection by tandem mass spectrometry and molecular genetic analysis. Mol Genet Metab 111:382-9
Chennamaneni, Naveen Kumar; Kumar, Arun Babu; Barcenas, Mariana et al. (2014) Improved reagents for newborn screening of mucopolysaccharidosis types I, II, and VI by tandem mass spectrometry. Anal Chem 86:4508-14
Barcenas, Mariana; Suhr, Teryn R; Scott, C Ronald et al. (2014) Quantification of sulfatides in dried blood and urine spots from metachromatic leukodystrophy patients by liquid chromatography/electrospray tandem mass spectrometry. Clin Chim Acta 433:39-43
Barcenas, Mariana; Xue, Chang; Marushchak-Vlaskin, Tatyana et al. (2014) Tandem mass spectrometry assays of palmitoyl protein thioesterase 1 and tripeptidyl peptidase activity in dried blood spots for the detection of neuronal ceroid lipofuscinoses in newborns. Anal Chem 86:7962-8
Scott, C Ronald; Elliott, Susan; Buroker, Norman et al. (2013) Identification of infants at risk for developing Fabry, Pompe, or mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry. J Pediatr 163:498-503
Spacil, Zdenek; Tatipaka, Haribabu; Barcenas, Mariana et al. (2013) High-throughput assay of 9 lysosomal enzymes for newborn screening. Clin Chem 59:502-11
Kuchar, Ladislav; Asfaw, Befekadu; Poupetova, Helena et al. (2013) Direct tandem mass spectrometric profiling of sulfatides in dry urinary samples for screening of metachromatic leukodystrophy. Clin Chim Acta 425:153-9
Wolfe, Brian J; Ghomashchi, Farideh; Kim, Tim et al. (2012) New substrates and enzyme assays for the detection of mucopolysaccharidosis III (Sanfilippo Syndrome) types A, B, C, and D by tandem mass spectrometry. Bioconjug Chem 23:557-64
Spacil, Zdenek; Elliott, Susan; Reeber, Steven L et al. (2011) Comparative triplex tandem mass spectrometry assays of lysosomal enzyme activities in dried blood spots using fast liquid chromatography: application to newborn screening of Pompe, Fabry, and Hurler diseases. Anal Chem 83:4822-8
Wolfe, Brian J; Blanchard, Sophie; Sadilek, Martin et al. (2011) Tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots: application to screening newborns for mucopolysaccharidosis II (Hunter Syndrome). Anal Chem 83:1152-6

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