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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067859-17
Application #
9277449
Study Section
Therapeutic Approaches to Genetic Diseases Study Section (TAG)
Program Officer
Sechi, Salvatore
Project Start
1999-08-01
Project End
2018-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
17
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Liu, Yang; Yi, Fan; Kumar, Arun Babu et al. (2017) Multiplex Tandem Mass Spectrometry Enzymatic Activity Assay for Newborn Screening of the Mucopolysaccharidoses and Type 2 Neuronal Ceroid Lipofuscinosis. Clin Chem 63:1118-1126
Schielen, Peter C J I; Kemper, Evelien A; Gelb, Michael H (2017) Newborn Screening for Lysosomal Storage Diseases: A Concise Review of the Literature on Screening Methods, Therapeutic Possibilities and Regional Programs. Int J Neonatal Screen 3:
Lin, Na; Huang, Jingyu; Violante, Sara et al. (2017) Liquid Chromatography-Tandem Mass Spectrometry Assay of Leukocyte Acid ?-Glucosidase for Post-Newborn Screening Evaluation of Pompe Disease. Clin Chem 63:842-851
Liao, Hsuan-Chieh; Spacil, Zdenek; Ghomashchi, Farideh et al. (2017) Lymphocyte Galactocerebrosidase Activity by LC-MS/MS for Post-Newborn Screening Evaluation of Krabbe Disease. Clin Chem 63:1363-1369
Escolar, M L; Kiely, B T; Shawgo, E et al. (2017) Psychosine, a marker of Krabbe phenotype and treatment effect. Mol Genet Metab 121:271-278
Liao, Hsuan-Chieh; Chan, Min-Ju; Yang, Chia-Feng et al. (2017) Mass Spectrometry but Not Fluorimetry Distinguishes Affected and Pseudodeficiency Patients in Newborn Screening for Pompe Disease. Clin Chem 63:1271-1277
Orsini, Joseph J; Saavedra-Matiz, Carlos A; Gelb, Michael H et al. (2016) Newborn screening for Krabbe's disease. J Neurosci Res 94:1063-75
Elliott, Susan; Buroker, Norman; Cournoyer, Jason J et al. (2016) Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry. Mol Genet Metab 118:304-9
Peake, Roy W A; Marsden, Deborah L; Bodamer, Olaf A et al. (2016) Newborn Screening for Lysosomal Storage Disorders: Quo Vadis? Clin Chem 62:1430-1438
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

Showing the most recent 10 out of 51 publications