The overall goal of this project is develop tandem mass spectrometry for newborn screening of the subset of lysosomal storage diseases for which treatment options exist or are being developed. A punch from a dried blood spot on a newborn screening card is used as a source of lysosomal enzymes, and this is incubated with a collection of substrates in a suitable buffer to allow formation of products. The latter are quantified by tandem mass spectrometry with the aid of a set of internal standards. We have developed a tandem mass spectrometry multiplex assay of six lysosomal enzymes. This 6-plex assay will be piloted in the WA state newborn screening laboratory on n=100,000 dried blood spots from random newborns. The next phase is to develop highly sensitive reagents to assay 6 sulfatase enzymes relevant to 6 additional lysosomal storage diseases. We will also develop tandem mass spectrometry assays for tripeptidyl protease I (deficiency causes neuronal ceroid lipofuscinosis 2), lysosomal acid lipase (deficiency causes Wolman disease and cholesterol-ester storage disease). We will then develop a multiplex method for newborn screening of all 13 enzymes using the minimum number of dried blood spot punches and assay buffers. Once this multiplex assay has been developed, we will carry out a second pilot study in the WA state newborn screening lab on n=100,000 dried blood spots from random newborns. We will also carry out exome DNA sequencing using next-generation sequencing on dried blood spots that give an enzyme activity below the cut-off value. This data will allow us to determine the positive predictive values and false positive rates for the screening assay. These pilot studies will explore the feasibility of newborn screening of treatable lysosomal storage diseases.

Public Health Relevance

A subset of lysosomal storage diseases is treatable, and initiation of treatment early in life leads to better treatment outcomes. Newborn screening is the only reliable way to find individuals early in life who would benefit from treatment options. There is general agreement in the field that newborn screening for treatable lysosomal storage diseases is ready for development and implementation. Our research is critical for the worldwide development of newborn screening for lysosomal storage diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Therapeutic Approaches to Genetic Diseases (TAG)
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Sechi, Salvatore
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University of Washington
Schools of Arts and Sciences
United States
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Spacil, Zdenek; Babu Kumar, Arun; Liao, Hsuan-Chieh et al. (2016) Sulfatide Analysis by Mass Spectrometry for Screening of Metachromatic Leukodystrophy in Dried Blood and Urine Samples. Clin Chem 62:279-86
Elliott, Susan; Buroker, Norman; Cournoyer, Jason J et al. (2016) Dataset and standard operating procedure for newborn screening of six lysosomal storage diseases: By tandem mass spectrometry. Data Brief 8:915-24
Kumar, Arun Babu; Masi, Sophia; Ghomashchi, Farideh et al. (2015) Tandem Mass Spectrometry Has a Larger Analytical Range than Fluorescence Assays of Lysosomal Enzymes: Application to Newborn Screening and Diagnosis of Mucopolysaccharidoses Types II, IVA, and VI. Clin Chem 61:1363-71
Kumar, Arun Babu; Spacil, Zdenek; Ghomashchi, Farideh et al. (2015) Fluorimetric assays for N-acetylgalactosamine-6-sulfatase and arylsulfatase B based on the natural substrates for confirmation of mucopolysaccharidoses types IVA and VI. Clin Chim Acta 451:125-8
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