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Tandem Mass Spectrometry in Newborn Screening
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Tandem Mass Spectrometry in Newborn Screening

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 30598

Special Issue Editors

Prof. Dr. David S. Millington

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Guest Editor
Duke University Hospital Biochemical Genetics Lab, Durham, NC 27709, USA
Interests: tandem mass spectrometry; liquid chromatography-mass spectrometry; lysosomal storage disease biomarkers; digital microfluidic fluorometry; acylcarnitines; second-tier biochemical testing
Special Issues, Collections and Topics in MDPI journals
Dr. Donald H Chace

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Guest Editor
Medolac Laboratories, Boulder City, NV 89005, USA
Interests: newborn screeening; tandem mass spectrometry; neonatology; disease diagnostics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tandem mass spectrometry (MS/MS) has had a profound impact on newborn screening (NBS) from dried blood spots since its introduction over 20 years ago. Initially, flow-injection electrospray ionization tandem mass spectrometry (FIA-ESI-MS/MS) was employed to target approximately thirteen acylcarnitines and eight amino acids derivatized as their butyl esters. The target analytes were simultaneously analyzed in a methanol extract of a single DBS punch containing isotope-labeled internal standards to aid in quantification. Since then, various adaptations and modifications have been made, including the development of a non-derivatized method, the addition of target analytes such as succinylacetone and orotic acid, plus an entirely new phase of NBS – screening for lysosomal storage disorders (LSDs) by measurement of residual enzyme activities using artificial substrates. Meanwhile, liquid chromatography (LC) with ESI-MS/MS methods has been developed for second-tier testing to improve the positive predictive value of several NBS tests. Furthermore, mass spectrometry plays a vital role in follow-up for patients with presumptive-positive NBS tests, where methods based on GC/MS and LC-MS/MS are routinely employed.

This Special Issue of the International Journal of Newborn Screening (IJNS) will showcase the contributions of MS/MS in NBS. Contributors are welcome to submit manuscripts on any of the aforementioned applications of MS/MS and their impact on the NBS program, any time from now until the deadline of May 31, 2021.

Prof. Dr. David S. Millington
Dr. Donald H. Chace
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 submissions that pass pre-check are 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 1600 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.

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Related Special Issue

Published Papers (5 papers)

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Research

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14 pages, 1416 KiB  
Article
Expanded Newborn Screening in Italy Using Tandem Mass Spectrometry: Two Years of National Experience
by Margherita Ruoppolo, Sabrina Malvagia, Sara Boenzi, Carla Carducci, Carlo Dionisi-Vici, Francesca Teofoli, Alberto Burlina, Antonio Angeloni, Tommaso Aronica, Andrea Bordugo, Ines Bucci, Marta Camilot, Maria Teresa Carbone, Roberta Cardinali, Claudia Carducci, Michela Cassanello, Cinzia Castana, Chiara Cazzorla, Renzo Ciatti, Simona Ferrari, Giulia Frisso, Silvia Funghini, Francesca Furlan, Serena Gasperini, Vincenza Gragnaniello, Chiara Guzzetti, Giancarlo La Marca, Luisa La Spina, Tania Lorè, Concetta Meli, MariaAnna Messina, Amelia Morrone, Francesca Nardecchia, Rita Ortolano, Giancarlo Parenti, Enza Pavanello, Damiana Pieragostino, Sara Pillai, Francesco Porta, Francesca Righetti, Claudia Rossi, Valentina Rovelli, Alessandro Salina, Laura Santoro, Pina Sauro, Maria Cristina Schiaffino, Simonetta Simonetti, Monica Vincenzi, Elisabetta Tarsi and Anna Paola Ucchedduadd Show full author list remove Hide full author list
Int. J. Neonatal Screen. 2022, 8(3), 47; https://doi.org/10.3390/ijns8030047 - 9 Aug 2022
Cited by 21 | Viewed by 5861
Abstract
Newborn screening (NBS) for inborn errors of metabolism is one of the most advanced tools for secondary prevention in medicine, as it allows early diagnosis and prompt treatment initiation. The expanded newborn screening was introduced in Italy between 2016 and 2017 (Law 167/2016; [...] Read more.
Newborn screening (NBS) for inborn errors of metabolism is one of the most advanced tools for secondary prevention in medicine, as it allows early diagnosis and prompt treatment initiation. The expanded newborn screening was introduced in Italy between 2016 and 2017 (Law 167/2016; DM 13 October 2016; DPCM 12-1-2017). A total of 1,586,578 infants born in Italy were screened between January 2017 and December 2020. For this survey, we collected data from 15 Italian screening laboratories, focusing on the metabolic disorders identified by tandem mass spectrometry (MS/MS) based analysis between January 2019 and December 2020. Aminoacidemias were the most common inborn errors in Italy, and an equal percentage was observed in detecting organic acidemias and mitochondrial fatty acids beta-oxidation defects. Second-tier tests are widely used in most laboratories to reduce false positives. For example, second-tier tests for methylmalonic acid and homocysteine considerably improved the screening of CblC without increasing unnecessary recalls. Finally, the newborn screening allowed us to identify conditions that are mainly secondary to a maternal deficiency. We describe the goals reached since the introduction of the screening in Italy by exchanging knowledge and experiences among the laboratories. Full article
(This article belongs to the Special Issue Tandem Mass Spectrometry in Newborn Screening)
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17 pages, 13947 KiB  
Article
Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis Type II
by Zackary M. Herbst, Leslie Urdaneta, Terri Klein, Barbara K. Burton, Khaja Basheeruddin, Hsuan-Chieh Liao, Maria Fuller and Michael H. Gelb
Int. J. Neonatal Screen. 2022, 8(1), 9; https://doi.org/10.3390/ijns8010009 - 21 Jan 2022
Cited by 16 | Viewed by 5027
Abstract
All newborn screening (NBS) for mucopolysaccharidosis-I and -II (MPS-I and MPS-II) is carried out via the measurement of α-iduronidase (IDUA) and iduronate-2-sulfatase (IDS) enzymatic activity, respectively, in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and data [...] Read more.
All newborn screening (NBS) for mucopolysaccharidosis-I and -II (MPS-I and MPS-II) is carried out via the measurement of α-iduronidase (IDUA) and iduronate-2-sulfatase (IDS) enzymatic activity, respectively, in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and data from recent MPS-II population screenings and studies from the Mayo Clinic show that the false positive rate can be dramatically reduced by the inclusion of a second-tier analysis of glycosaminoglycans (GAGs) in DBS as part of NBS. In the present study, which focused on MPS-II, we obtained newborn DBS from 17 patients with severe MPS-II, 1 with attenuated MPS-II, and 6 patients with various IDS pseudodeficiencies. These samples were submitted to two different GAG mass spectrometry analyses in a comparative study: (1) internal disaccharide biomarkers and (2) endogenous biomarkers. For both of these methods, the biomarker levels in six patients with pseudodeficiencies were below the range measured in MPS-II patients. One patient with attenuated MPS-II was not distinguishable from severe disease patients, but all MPS-II patients were distinguishable from the reference range using both methods. The minimal differential factor (lowest GAG marker level in MPS-II samples divided by highest level in the reference range of 60 random newborns) was 3.01-fold for the internal disaccharide method. The endogenous biomarker method demonstrated an improved minimum differential of 5.41-fold. The minimum differential factors between MPS-II patients and patients with pseudodeficiencies for the internal disaccharide and endogenous biomarker methods were 3.77-fold and 2.06-fold, respectively. This study supports use of the second-tier GAG analysis of newborn DBS, especially the endogenous disaccharide method, as part of NBS to reduce the false positive rate. Full article
(This article belongs to the Special Issue Tandem Mass Spectrometry in Newborn Screening)
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14 pages, 1479 KiB  
Article
Successful Implementation of Expanded Newborn Screening in the Philippines Using Tandem Mass Spectrometry
by Carmencita D. Padilla, Bradford L. Therrell, Jr., Maria Melanie Liberty B. Alcausin, Mary Anne D. Chiong, Mary Ann R. Abacan, Ma. Elouisa L. Reyes, Charity M. Jomento, Maria Truda T. Dizon-Escoreal, Margarita Aziza E. Canlas, Michelle E. Abadingo, J. Edgar Winston C. Posecion, Conchita G. Abarquez, Alma P. Andal, Anna Lea G. Elizaga, Bernadette C. Halili-Mendoza, Maria Paz Virginia K. Otayza and David S. Millington
Int. J. Neonatal Screen. 2022, 8(1), 8; https://doi.org/10.3390/ijns8010008 - 19 Jan 2022
Cited by 13 | Viewed by 7868
Abstract
Newborn bloodspot screening (NBS) began as a research project in the Philippines in 1996 and was mandated by law in 2004. The program initially included screening for five conditions, with a sixth added in 2012. As screening technology and medical knowledge have advanced, [...] Read more.
Newborn bloodspot screening (NBS) began as a research project in the Philippines in 1996 and was mandated by law in 2004. The program initially included screening for five conditions, with a sixth added in 2012. As screening technology and medical knowledge have advanced, NBS programs in countries with developed economies have also expanded, not only in the number of newborns screened but also in the number of conditions included in the screening. Various approaches have been taken regarding selection of conditions to be screened. With limited resources, low- and middle-income countries face significant challenges in selecting conditions for screening and in implementing sustainable screening programs. Building on expansion experiences in the U.S. and data from California on Filipinos born and screened there, the Philippine NBS program has recently completed its expansion to include 29 screening conditions. This report focuses on those conditions detectable through tandem mass spectrometry. Expanded screening was implemented in a stepwise fashion across the seven newborn screening laboratories in the Philippines. A university-based biochemical genetics laboratory provides confirmatory testing. Follow-up care for confirmed cases is monitored and provided through the NBS continuity clinics across the archipelago. Pre-COVID-19 pandemic, the coverage was 91.6% but dropped to 80.4% by the end of 2020 due to closure of borders between cities, provinces, and islands. Full article
(This article belongs to the Special Issue Tandem Mass Spectrometry in Newborn Screening)
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27 pages, 2897 KiB  
Article
Neonatal Urine Screening Program in the Province of Quebec: Technological Upgrade from Thin Layer Chromatography to Tandem Mass Spectrometry
by Christiane Auray-Blais, Michel Boutin, Pamela Lavoie and Bruno Maranda
Int. J. Neonatal Screen. 2021, 7(1), 18; https://doi.org/10.3390/ijns7010018 - 20 Mar 2021
Cited by 7 | Viewed by 4150
Abstract
The Quebec Neonatal Urine Screening Program was initiated in 1971 with overall screening inception of newborns in 1973. Forty-seven years later, over 3.5 million babies have been screened for up to 25 inborn errors of metabolism divided into two groups: (1) urea cycle [...] Read more.
The Quebec Neonatal Urine Screening Program was initiated in 1971 with overall screening inception of newborns in 1973. Forty-seven years later, over 3.5 million babies have been screened for up to 25 inborn errors of metabolism divided into two groups: (1) urea cycle disorders and organic acidurias; and (2) disorders of amino acid metabolism and transport. The main goal of this preventive genetic medicine program is the detection of treatable diseases before the onset of clinical symptoms. Urine specimens from 21-day-old babies are collected and dried on filter paper by parents at home. The participation is voluntary with a high compliance rate over the years (~90%). Specimens are analyzed by thin layer chromatography (TLC). The main objective of this evaluative research project was to assess the feasibility of a technological upgrade towards mass spectrometry. A 2.85-min flow injection method was devised, normal values established, and abnormal profiles confirmed using second-tier tests. The validated assays are sensitive, specific, and suitable for populational screening, as well as for high-risk screening laboratories. Triple H syndrome, which would not be detected in newborns by blood screening at two days of age was found to be positive in the urine of an affected patient. Full article
(This article belongs to the Special Issue Tandem Mass Spectrometry in Newborn Screening)
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Review

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15 pages, 288 KiB  
Review
Liquid Chromatography–Tandem Mass Spectrometry in Newborn Screening Laboratories
by Michael H. Gelb, Khaja Basheeruddin, Alberto Burlina, Hsiao-Jan Chen, Yin-Hsiu Chien, George Dizikes, Christine Dorley, Roberto Giugliani, Amy Hietala, Xinying Hong, Shu-Min Kao, Hamid Khaledi, Tracy Klug, Francyne Kubaski, Hsuan-Chieh Liao, Monica Martin, Adrienne Manning, Joseph Orsini, Yin Peng, Enzo Ranieri, Andreas Rohrwasser, Nicolas Szabo-Fresnais, Coleman T. Turgeon, Frédérick M. Vaz, Li-yun Wang and Dietrich Maternadd Show full author list remove Hide full author list
Int. J. Neonatal Screen. 2022, 8(4), 62; https://doi.org/10.3390/ijns8040062 - 28 Nov 2022
Cited by 17 | Viewed by 5971
Abstract
Tandem mass spectrometry (MS/MS) is the most universal platform currently available for the analysis of enzymatic activities and biomarkers in dried blood spots (DBS) for applications in newborn screening (NBS). Among the MS/MS applications in NBS, the most common is flow-injection analysis (FIA-) [...] Read more.
Tandem mass spectrometry (MS/MS) is the most universal platform currently available for the analysis of enzymatic activities and biomarkers in dried blood spots (DBS) for applications in newborn screening (NBS). Among the MS/MS applications in NBS, the most common is flow-injection analysis (FIA-) MS/MS, where the sample is introduced as a bolus injection into the mass spectrometer without the prior fractionation of analytes. Liquid chromatography combined with MS/MS (LC-MS/MS) has been employed for second-tier tests to reduce the false-positive rate associated with several nonspecific screening markers, beginning two decades ago. More recently, LC-MS/MS has been applied to primary screening for new conditions for which FIA-MS/MS or other methods, including genomic screening, are not yet adequate. In addition to providing a list of the currently used LC-MS/MS-based assays for NBS, the authors share their experience regarding the maintenance requirements of LC-MS/MS vs. FIA-MS/MS systems. The consensus is that the maintenance of LC-MS/MS and FIA-MS/MS instrumentation is similar, and LC-MS/MS has the advantage of allowing for a larger number of diseases to be screened for in a multiplex, cost-effective fashion with a high throughput and an adequate turnaround time. Full article
(This article belongs to the Special Issue Tandem Mass Spectrometry in Newborn Screening)
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