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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Measuring Non-reducing Terminal Glycosaminoglycan ...
Measuring Non-reducing Terminal Glycosaminoglycan Fragments increases specificity and differentiates Mucopolysaccharidosis Type I (MPS I) from Mucopolysaccharidosis Type II (MPS II)
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This document discusses the measurement of non-reducing terminal glycosaminoglycan (GAG) fragments as a method to increase specificity and differentiate between Mucopolysaccharidosis Type I (MPS I) and Mucopolysaccharidosis Type II (MPS II). MPS disorders are lysosomal storage diseases that disrupt the catabolism of GAGs. The primary screening for MPS diseases is done through enzyme activity testing, but additional methods are needed to identify false positives. Traditional second-tier tests rely on elevations of broad classes of GAGs, which cannot differentiate between MPS I and MPS II. However, recent discovery of terminal non-reducing fragments cleaved from GAGs in affected patients presents an opportunity to measure these markers for specific MPS disease subtypes.<br /><br />The document describes the specificity of the MPS I and MPS II markers and the materials and methods used for measurement. The MPS I marker is tested using whole blood dried blood spots (DBS) enriched with fibroblast-generated MPS I biomarker, while the MPS II marker is tested using DBS enriched with fibroblast-generated MPS II biomarker. Both markers use Chondroitin disaccharide-d4 as the internal standard and 1-phenyl-3-methyl-5-pyrazolone (PMP) as the derivatizing agent.<br /><br />The results show the marker ratio values for MPS I and MPS II in different patient sets. The cutoff ratios for the markers are established based on statistical analysis and clinical specificity. The document also discusses ongoing studies and future steps, such as correlation studies with genotype and validation of biomarkers in urine samples.<br /><br />The document includes chromatograms showing the separation of the isobaric MPS I and MPS II markers and their absence in healthy newborns. Results from MPS I and MPS II affected patients show the presence of the corresponding markers. Control stability data also demonstrate the long-term stability of the markers.<br /><br />In conclusion, measuring non-reducing terminal glycosaminoglycan fragments can increase specificity and differentiate between MPS I and MPS II. The validated methods described in the document provide a valuable tool for newborn screening and further research in MPS diseases.
Asset Subtitle
Presenting Author - Taraka Donti, PhD, FACMG; Co-Author - Sara E. Smith, BS, MPS, PhD; Co-Author - Sasha Chernenkoff, BS; Co-Author - Madeline Ellgass, MS; Co-Author - Madhuri Hegde, PhD, FACMG;
Meta Tag
Biochemical genetics
Genetic Testing
Lysosomal Diseases
Metabolic Disorder
Co-Author
Sara E. Smith, BS, MPS, PhD
Co-Author
Sasha Chernenkoff, BS
Co-Author
Madeline Ellgass, MS
Co-Author
Madhuri Hegde, PhD, FACMG
Presenting Author
Taraka Donti, PhD, FACMG
Keywords
non-reducing terminal glycosaminoglycan fragments
Mucopolysaccharidosis Type I
MPS I
Mucopolysaccharidosis Type II
MPS II
lysosomal storage diseases
enzyme activity testing
false positives
terminal non-reducing fragments
specific MPS disease subtypes
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