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Analysis of a second-tier test panel in dried blood spot samples using liquid chromatography-tandem mass spectrometry in Catalonia’s newborn screening programme

  • Sonia Pajares-García , José Manuel González de Aledo-Castillo ORCID logo , José Eduardo Flores-Jiménez , Tatiana Collado , Judit Pérez , Abraham José Paredes-Fuentes , Ana Argudo-Ramírez , Rosa María López-Galera , Blanca Prats and Judit García-Villoria EMAIL logo
Published/Copyright: October 6, 2023
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 62 Issue 3

Abstract

Objectives

Acylcarnitine and amino acid analyses of dried blood spot (DBS) samples using tandem mass spectrometry in newborn screening (NBS) programmes can generate false positive (FP) results. Therefore, implementation of second-tier tests (2TTs) using DBS samples has become increasingly important to avoid FPs. The most widely used 2TT metabolites include methylmalonic acid, 3-hydroxypropionic acid, methylcitric acid, and homocysteine.

Methods

We simultaneously measured 46 underivatised metabolites, including organic acids, acylglycine and acylcarnitine isomers, homocysteine, and orotic acid, in DBS samples using tandem mass spectrometry. To validate this method, we analysed samples from 147 healthy newborns, 160 patients with genetic disorders diagnosed via NBS, 20 patients with acquired vitamin B12 deficiency, 10 newborns receiving antibiotic treatment, and nine external quality control samples.

Results

The validation study revealed that 31 metabolites showed good analytical performance. Furthermore, this method detected key metabolites for all diseases associated with increased levels of the following acylcarnitines: C3, C4, C5, C4DC/C5OH, and C5DC. The sensitivity of this method to detect all diseases was 100 %, and the specificity was 74–99 %, except for glutaric aciduria type 1. This method can also be used to diagnose mitochondrial fatty acid β-oxidation disorders (FAODs) and urea cycle defects (UCDs).

Conclusions

We have described a 2TT panel of 31 metabolites in DBS samples based on an easy and rapid method without derivatisation. Its implementation allowed us to distinguish between different organic acidurias, some FAODs, and UCDs. This new strategy has increased the efficiency of our NBS programme by reducing FP and false negative results, second sample requests, and the time required for diagnosis.

Keywords: second-tier test; newborn screening; organic acids; acylcarnitines; acylglycines; mass spectrometry
Corresponding author: Judit García-Villoria, Department of Biochemistry and Molecular Genetics, Section of Inborn Errors of Metabolism-IBC, Hospital Clinic, C/ Mejía Lequerica s/n, Edificio Helios III, 08028 Barcelona, Spain; Center for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain; and Biomedical Research Institute, August Pi i Sunyer (IDIBAPS), Barcelona, Spain, Phone: +0034 932277585, Fax: +0034 932275668, E-mail:

Funding source: Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) and the CERCA Programme/Generalitat de Catalunya

Funding source: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación, Spain)

Acknowledgments

Thanks are due to C. Martínez, G. Delgado, Y. Quintero, E. Ramon, N. Castillo, A. Muniente, and S. Richard, for the excellent technical assistance in the primary screening and helping in the second-tier analysis.

  1. Research ethics: The local Institutional Review Board deemed the study exempt from review.

  2. Informed consent: Informed consent was obtained from all individuals included in this study.

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: The authors state no conflict of interest.

  5. Research funding: This research was supported, in part, by Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), an initiative of the Instituto de Salud Carlos III (Ministerio de Ciencia e Innovación, Spain), and by the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) and the CERCA Programme/Generalitat de Catalunya.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2023-0216).

Received: 2023-02-28
Accepted: 2023-09-21
Published Online: 2023-10-06
Published in Print: 2024-02-26

© 2023 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2023-0216
Keywords for this article
second-tier test; newborn screening; organic acids; acylcarnitines; acylglycines; mass spectrometry

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Unraveling the mystery of blood groups and COVID-19
  4. Reviews
  5. Serum hepcidin levels in chronic liver disease: a systematic review and meta-analysis
  6. Platelet distribution width (PDW) as a significant correlate of COVID-19 infection severity and mortality
  7. Mini Reviews
  8. ABO blood group-related mechanism of infection of SARS-CoV-2: an overview of systematic reviews
  9. Opinion Paper
  10. Personalized laboratory medicine in the digital health era: recent developments and future challenges
  11. Guidelines and Recommendations
  12. Algorithm of differential diagnosis of anemia involving laboratory medicine specialists to advance diagnostic excellence
  13. General Clinical Chemistry and Laboratory Medicine
  14. Rescaling creatinine makes GFR estimation equations generally applicable across populations – validation results for the Lund-Malmö equation in a French cohort of sub-Saharan ancestry
  15. Periodic verification of results’ comparability between several analyzers: experience in the application of the EP31-A-IR guideline
  16. Machine learning to optimize cerebrospinal fluid dilution for analysis of MRZH reaction
  17. Diagnostic performance of automated red cell parameters in predicting bone marrow iron stores
  18. Reliability of hemoglobin A2 value as measured by the Premier Resolution system for screening of β-thalassemia carriers
  19. Amino acid sequence homology of monoclonal serum free light chain dimers and tissue deposited light chains in AL amyloidosis: a pilot study
  20. Development of high-performance point-of-care aqueous VEGF detection system and proof-of-concept validation in RVO patients
  21. Detection rate of IGF-1 variants and their implication to protein binding: study of over 240,000 patients
  22. Analysis of a second-tier test panel in dried blood spot samples using liquid chromatography-tandem mass spectrometry in Catalonia’s newborn screening programme
  23. Targeted quantitative lipidomic uncovers lipid biomarkers for predicting the presence of compensated cirrhosis and discriminating decompensated cirrhosis from compensated cirrhosis
  24. Reference Values and Biological Variations
  25. Establishment of reference intervals for free light chains and immunoglobulins in Saudi population
  26. Cancer Diagnostics
  27. A predictive and prognostic model for surgical outcome and prognosis in ovarian cancer computed by clinico-pathological and serological parameters (CA125, HE4, mesothelin)
  28. M-protein diagnostics in multiple myeloma patients using ultra-sensitive targeted mass spectrometry and an off-the-shelf calibrator
  29. Cardiovascular Diseases
  30. Bioactive adrenomedullin (bio-ADM) is associated with endothelial dysfunction in infants and children with complex congenital heart disease undergoing open-heart surgery on cardiopulmonary bypass
  31. Infectious Diseases
  32. Monocyte distribution width as an early predictor of short-term outcome in adult patients with sepsis
  33. Analytical and clinical evaluations of SNIBE Maglumi chemiluminescent immunoassay for the detection of SARS-CoV-2 antigen in salivary samples
  34. Letters to the Editor
  35. Predicting hemoglobinopathies using ChatGPT
  36. Managing the Quality Control of multiple instruments
  37. Lipid droplets may interfere with urinary red blood cell and crystal counts by urinary flow cytometry
  38. Assessment of the lipemia index determined by the Atellica CH 930 analyzer for the detection of monoclonal immunoglobulins
  39. Concerning quality demands of arterial partial pressure of oxygen
  40. Navigating between perpendicular drop and tangent skimming methods for M-protein quantification: a call for clarification of guidelines
  41. Early detection of peripheral invasive candidiasis further to cytographic interferences in Sysmex XN-9000 hematology analyzer
  42. Congress Abstracts
  43. Annual meeting of the Royal Belgian Society of Laboratory Medicine: “Symphony of the Heart”
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