MSACL 2016 US Abstract

Tandem Mass Spectrometry for Newborn Screening and Diagnosis of Lysosomal Storage Diseases

Michael Gelb (Presenter)
Univ. of Washington

Bio: Professor in Chemistry and Biochemistry for the past 30 yrs. Expertise in the areas of mass spectrometry in clinical medicine and newborn screening, lipid enzymology, drug discovery.

Authorship: Michael Gelb, Zdenek Spacil, Arun Kumar, Joyce Liao
University of Washington

Short Abstract

Our lab has developed all of the mass spectrometry methods being used in newborn screening of lysosomal storage diseases worldwide. We are continuing to develop these assays and to carry out large scale pilot studies to test the feasibility of newborn screening for lysosomal storage diseases. Mass spectrometry has emerged as the most broadly used and reliable newborn screening method for lysosomal storage diseases.

Long Abstract


Lysosomal storage diseases are a family of inborn errors of metabolism where metabolites build up in cells due to the deficiency of an enzyme that catalyzes metabolite degradation. Treatments for a subset of lysosomal storage diseases have been developed over the past decade, and clinical outcomes are usually better if treatment is initiated early in the disease progress period. Thus, several states and countries have expanded their newborn screening program to include one or more lysosomal storage diseases.


We have developed a panel of assays for direct measurement of lysosomal enzymatic activity in dried blood spots. The method uses tandem mass spectrometry with electrospray ionization to quantify products of enzymatic reactions with the aid of chemically identical internal standards. Mass spectrometry allows enzymatic products to be quantified very accurately and in a multiplex fashion such that several enzymes can be assayed using a single dried blood spot from a newborn screening card.

We also use tandem mass spectrometry to quantify metabolites that accumulate in dried blood spots as a result of a deficient metabolic enzyme. This method is being tested for the possible newborn screening of metachromatic leukodystrophy.


The products of up to 12 lysosomal enzymes can be analyzed in one or two reaction mixtures containing a dried blood spot punch and a cocktail containing several enzyme substrates and internal standards. Both flow-injection and liquid chromatography are used to introduce the sample into the mass spectrometer for enzymatic product quantification. We use enzymatic rate assays for newborn screening of the following lysosomal storage diseases: Fabry, Pompe, Niemann-Pick-A/B, Krabbe, Gaucher, MPS-I, MPS-II, MPS-IIIA, MPS-IIIB, MPS-IVA, MPS-VI, and MPS-VII. Sulfatide accumulation in dried blood spots is analyzed by LC-MS/MS for newborn screening of metachromatic leukodystrophy. Our recent pilot studies, completed and in progress, on up to 100,000 dried blood spots show that these MS/MS methods provide reliable newborn screening for several lysosomal storage diseases. The number of false positives is substantial lower than the number obtained using fluorimetric methods to measure enzymatic activities.

We have also shown that tandem mass spectrometry greatly out-performs fluorimetric assays for high accuracy assay of lysosomal enzymatic activity in blood cells obtained in second-tier diagnosis labs from patients that have scored positive in a newborn screening program. High accuracy assays are critical for prediction of disease severity and the determination of the optimum treatment strategy.


Tandem mass spectrometry has emerged in the past 4-5 yrs as a powerful technique for newborn screening and diagnosis of inborn errors of metabolism, in particular lysosomal storage diseases. Several states in the USA (IL, WA, NJ, PA, NY, OH, KY, TN, FL) and a few countries outside of the USA have started to adopt these methods in order to expand their newborn screening programs to include lysosomal storage diseases. Commercialization of newborn screening kits for lysosomal storage diseases based on mass spectrometry is far along with product launching set for 2016.

References & Acknowledgements:

This work was supported by grants from the National Institutes of Health (DK067859), Shire and BioMarin.

Financial Disclosure

GrantsyesPerkin Elmer, Shire, BioMarin
SalaryyesPerkin Elmer
Board Memberno

IP Royalty: yes

IP Desc:IP for newborn screening of lysosomal storage diseases

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