Special Issue "Newborn Screening for Lysosomal Storage Disorders"

A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (30 September 2018)

Special Issue Editors

Guest Editor
Prof. Dr. David S. Millington

Professor Emeritus of Pediatrics, Medical Genetics Division, Duke Medicine, Durham, NC 27709, USA
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Guest Editor
Dr. Janice Fletcher

Genetics and Molecular Pathology, SA Pathology at Women's and Children's Hospital, 72 King William Road, North Adelaide, South Australia 5006, Australia
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Special Issue Information

Dear Colleagues,

Newborn screening for lysosomal storage disorders (LSDs) has gained significant momentum during the past two years, especially in the United States, during which time the addition of Pompe Disease (GSD II) and Hurler Syndrome (MPS I) to the recommended universal screening panel (RUSP) have been major stimuli.

The main driving force for the expansion of newborn screening to the LSDs has been the emergence of new therapeutic strategies, especially enzyme replacement and hematopoietic stem cell transplantation, that have given new hope to families with affected children. Furthermore, the development of fluorometric enzymatic assays for LSDs in dried blood spots that began with the pioneering work of Nestor Chamoles in 2001 and boosted by Michael Gelb’s tandem mass spectrometry (MS/MS) method that was first applied in 2004 to galactosylceramidase, the enzyme that is deficient in Krabbe Disease, enables early detection of affected newborns who can potentially benefit the most from the new therapies. Modifications that permit multiplexing of LSD enzyme assays using either MS/MS or digital microfluidic fluorometry have facilitated high-throughput prospective screening for multiple LSDs, and both of these methods are now in use in several programs.

In spite of these developments, many have argued against screening for LSDs, citing concerns arising from the expense and variable efficacy of current treatment options and the preponderance of cases detected by NBS with later onset forms of disease, pseudodeficiency alleles, genetic variants of unknown significance and carriers.  Accordingly, post-analytical methods including statistical analytical tools and second-tier biochemical tests have been developed or are under development to help clarify these challenging outcomes of LSD newborn screening.

With so many active developments and improvements in the field of LSD newborn screening, the International Journal of Newborn Screening is planning to dedicate a Special Issue to this topic. Manuscripts on all aspects, including results of established NBS programs, pilot studies, post-analytical methods to improve the positive predictive value, new or improved treatment strategies and outcomes, ethical considerations and counter-arguments to LSD screening are welcome.

Prof. Dr. David S. Millington
Dr. Janice Fletcher
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Neonatal Screening is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 500 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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Open AccessArticle Performance of the Four-Plex Tandem Mass Spectrometry Lysosomal Storage Disease Newborn Screening Test: The Necessity of Adding a 2nd Tier Test for Pompe Disease
Int. J. Neonatal Screen. 2018, 4(4), 41; https://doi.org/10.3390/ijns4040041
Received: 26 September 2018 / Revised: 18 November 2018 / Accepted: 13 December 2018 / Published: 18 December 2018
Cited by 1 | PDF Full-text (663 KB) | HTML Full-text | XML Full-text
Abstract
Early diagnosis of lysosomal storage diseases (LSDs) through newborn screening (NBS) has been adapted widely. The National Taiwan University Hospital Newborn Screening Center launched the four-plex tandem mass spectrometry LSD newborn screening test in 2015. The test determined activities of acid α-glucosidase (GAA; [...] Read more.
Early diagnosis of lysosomal storage diseases (LSDs) through newborn screening (NBS) has been adapted widely. The National Taiwan University Hospital Newborn Screening Center launched the four-plex tandem mass spectrometry LSD newborn screening test in 2015. The test determined activities of acid α-glucosidase (GAA; Pompe), acid α-galactosidase (GLA; Fabry), acid β-glucocerebrosidase (ABG; Gaucher), and acid α-l-iduronidase (IDUA; MPS-I) in dried blood spots (DBS). Through 2017, 64,148 newborns were screened for these four LSDs. The screening algorithm includes enzyme activity/ratio as the cutoffs for the first screening test and a second-tier test for Pompe disease screening. The second-tier Pompe disease screening test measured activity inhibition by acarbose. Twenty-nine newborns required a confirmatory test; six were confirmed to have Pompe disease, and nine were confirmed to have Fabry disease. The screen-positive rate for Pompe disease was 0.031%. Therefore, in Pompe disease newborn screening, a validated 2nd tier test is necessary to decrease false positives. Full article
(This article belongs to the Special Issue Newborn Screening for Lysosomal Storage Disorders)
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Open AccessArticle Newborn Screening for Lysosomal Storage Diseases: Methodologies, Screen Positive Rates, Normalization of Datasets, Second-Tier Tests, and Post-Analysis Tools
Int. J. Neonatal Screen. 2018, 4(3), 23; https://doi.org/10.3390/ijns4030023
Received: 27 May 2018 / Revised: 18 June 2018 / Accepted: 21 June 2018 / Published: 9 July 2018
Cited by 1 | PDF Full-text (244 KB) | HTML Full-text | XML Full-text
Abstract
All of the worldwide newborn screening (NBS) for lysosomal storage diseases (LSDs) is done by measurement of lysosomal enzymatic activities in dried blood spots (DBS). Substrates used for these assays are discussed. While the positive predictive value (PPV) is the gold standard for [...] Read more.
All of the worldwide newborn screening (NBS) for lysosomal storage diseases (LSDs) is done by measurement of lysosomal enzymatic activities in dried blood spots (DBS). Substrates used for these assays are discussed. While the positive predictive value (PPV) is the gold standard for evaluating medical tests, current PPVs for NBS of LSDs cannot be used as a performance metric due to statistical sampling errors and uncertainty in the onset of disease symptoms. Instead, we consider the rate of screen positives as the only currently reliable way to compare LSD NBS results across labs worldwide. It has been suggested that the expression of enzymatic activity data as multiple-of-the-mean is a way to normalize datasets obtained using different assay platforms, so that results can be compared, and universal cutoffs can be developed. We show that this is often not the case, and normalization is currently not feasible. We summarize the recent use of pattern matching statistical analysis together with measurement of an expanded group of enzymatic activities and biomarkers to greatly reduce the number of false positives for NBS of LSDs. We provide data to show that these post-enzymatic activity assay methods are more powerful than genotype analysis for the stratification of NBS for LSDs. Full article
(This article belongs to the Special Issue Newborn Screening for Lysosomal Storage Disorders)

Review

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Open AccessReview Newborn Screening for Lysosomal Storage Disorders: Methodologies for Measurement of Enzymatic Activities in Dried Blood Spots
Int. J. Neonatal Screen. 2019, 5(1), 1; https://doi.org/10.3390/ijns5010001
Received: 26 November 2018 / Accepted: 19 December 2018 / Published: 21 December 2018
PDF Full-text (593 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
All worldwide newborn screening (NBS) for lysosomal storage diseases (LSDs) is performed as a first-tier test by measurement of lysosomal enzymatic activities in dried blood spots (DBS). The currently two available methodologies used for measurement of enzymatic activities are tandem mass spectrometry (MS/MS) [...] Read more.
All worldwide newborn screening (NBS) for lysosomal storage diseases (LSDs) is performed as a first-tier test by measurement of lysosomal enzymatic activities in dried blood spots (DBS). The currently two available methodologies used for measurement of enzymatic activities are tandem mass spectrometry (MS/MS) and digital microfluidics fluorimetry (DMF-F). In this chapter we summarize the workflows for the two platforms. Neither platform is fully automated, but the relative ease of workflow will be dependent upon the specific operation of each newborn screening laboratory on a case-by-case basis. We provide the screen positive rate (the number of below cutoff newborns per 100,000 newborns) from all NBS laboratories worldwide carrying out MS/MS-based NBS of one or more LSDs. The analytical precision of the MS/MS method is higher than that for DMF-F as shown by analysis of a common set of quality control DBS by the Centers for Disease Control and Prevention (CDC). Both the MS/MS and DMF-F platforms enable multiplexing of the LSD enzymes. An advantage of MS/MS over DMF-F is the ability to include assays of enzymatic activities and biomarkers for which no fluorimetric methods exist. Advantages of DMF-F over MS/MS are: (1) simple to use technology with same-day turn-around time for the lysosomal enzymes with the fastest rates compared to MS/MS requiring overnight analytical runs.; (2) the DMF-F instrumentation, because of its simplicity, requires less maintenance than the MS/MS platform. Full article
(This article belongs to the Special Issue Newborn Screening for Lysosomal Storage Disorders)
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Open AccessReview Current State of the Art of Newborn Screening for Lysosomal Storage Disorders
Int. J. Neonatal Screen. 2018, 4(3), 24; https://doi.org/10.3390/ijns4030024
Received: 24 June 2018 / Revised: 10 July 2018 / Accepted: 12 July 2018 / Published: 18 July 2018
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Abstract
Prospective full-population newborn screening for multiple lysosomal storage disorders (LSDs) is currently practiced in a few NBS programs, and several others are actively pursuing this course of action. Two platforms suitable for multiple LSD screening—tandem mass spectrometry (MS/MS) and digital microfluidic fluorometry (DMF)—are [...] Read more.
Prospective full-population newborn screening for multiple lysosomal storage disorders (LSDs) is currently practiced in a few NBS programs, and several others are actively pursuing this course of action. Two platforms suitable for multiple LSD screening—tandem mass spectrometry (MS/MS) and digital microfluidic fluorometry (DMF)—are now commercially available with reagent kits. In this article, we review the methods currently used for prospective NBS for LSDs and objectively compare their workflows and the results from two programs in the United States that screen for the same four LSDs, one using MS/MS and the other DMF. The results show that the DMF platform workflow is simpler and generates results faster than MS/MS, enabling results reporting on the same day as specimen analysis. Furthermore, the performance metrics for both platforms while not identical, are broadly similar and do not indicate the superior performance of one method over the other. Results show a preponderance of inconclusive results for Pompe and Fabry diseases and for Hurler syndrome, due to genetic heterogeneity and other factors that can lead to low enzyme activities, regardless of the screening method. We conclude that either platform is a good choice but caution that post-analytical tools will need to be applied to improve the positive predictive value for these conditions. Full article
(This article belongs to the Special Issue Newborn Screening for Lysosomal Storage Disorders)
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Open AccessReview Newborn Screening for Lysosomal Disease: Mission Creep and a Taste of Things to Come?
Int. J. Neonatal Screen. 2018, 4(3), 21; https://doi.org/10.3390/ijns4030021
Received: 21 May 2018 / Revised: 13 June 2018 / Accepted: 26 June 2018 / Published: 27 June 2018
PDF Full-text (173 KB) | HTML Full-text | XML Full-text
Abstract
Newborn screening for several lysosomal disorders can now be accomplished successfully for case finding. However, many cases identified do not require immediate intervention and it is not yet clear, for some disorders, if there is a benefit in early diagnosis for those cases, [...] Read more.
Newborn screening for several lysosomal disorders can now be accomplished successfully for case finding. However, many cases identified do not require immediate intervention and it is not yet clear, for some disorders, if there is a benefit in early diagnosis for those cases, or what should be called a benefit. Diagnosing adult-onset cases, especially when there are quite imperfect genotype-phenotype correlations, represents a significant expansion of what has heretofore been considered the aim of newborn screening. This mission creep should be carefully discussed, and certain aspects of newborn screening strengthened. We should all proceed with caution in this field. Full article
(This article belongs to the Special Issue Newborn Screening for Lysosomal Storage Disorders)
Int. J. Neonatal Screen. EISSN 2409-515X Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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