Abstract
All newborn screening (NBS) for mucopolysaccharidosis-I (MPS-I) is carried out by the measurement of α-iduronidase (IDUA) enzymatic activity in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and studies from the Mayo Clinic have shown that the false positive rate can be greatly reduced by including a second-tier analysis of glycosaminoglycans (GAGs) in DBS as part of NBS. In the present study, we obtained newborn DBS from 13 patients with severe MPS-I and 2 with attenuated phenotypes. These samples were submitted to four different GAG mass spectrometry analyses in a comparative study: (1) internal disaccharide; (2) endogenous disaccharide; (3) Sensi-Pro; (4) Sensi-Pro Lite (a variation of Sensi-Pro with a simplified workflow). Patients with attenuated MPS-I show less GAG elevation than those with severe disease, and all MPS-I patients were separated from the reference range using all four methods. The minimal differential factor (lowest GAG marker level in MPS-I samples divided by highest level in the reference range of 30 random newborns) was about two for internal disaccharide, Sensi-Pro, and Sensi-Pro Lite methods. The endogenous disaccharide was clearly the best method with a minimal differential of 16-fold. This study supports use of second-tier GAG analysis of newborn DBS, especially the endogenous disaccharide method, as part of NBS to reduce the false positive rate.
Highlights
Worldwide newborn screening (NBS) of MPS-I (OMIM Entry #607014) is done exclusively by the first-tier measurement of α-iduronidase enzymatic activity (IDUA, EC 3.2.1.76) in dried blood spots (DBS), either by tandem mass spectrometry (MS/MS) or by digital microfluidics fluorometry [1,2]
MS/MS measurement of psychosine in DBS greatly reduces the number of false positives in NBS of Krabbe disease, as well as helping to stratify patients into early versus late-onset disease [5]
GAG analysis in DBS is currently not used for first-tier NBS of MPS-I because the analysis time per sample is still too long, and the false positive rate is well above that seen with IDUA measurement [6,7]
Summary
Worldwide newborn screening (NBS) of MPS-I (OMIM Entry #607014) is done exclusively by the first-tier measurement of α-iduronidase enzymatic activity (IDUA, EC 3.2.1.76) in dried blood spots (DBS), either by tandem mass spectrometry (MS/MS) or by digital microfluidics fluorometry [1,2]. Many of the hits from MS/MS- and fluorometry-based enzyme analysis are false positives, because of the partial overlap of the reference and affected ranges [3] and because of the presence of pseudodeficiencies [4]. This is the typical situation with NBS for lysosomal storage diseases. GAG analysis in DBS is currently not used for first-tier NBS of MPS-I because the analysis time per sample is still too long, and the false positive rate is well above that seen with IDUA measurement [6,7]. We report data on the levels of GAG-derived biomarkers in newborn DBS from MPS-I patients using four different MS/MS approaches
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