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Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

  • Jürgen G. OkunEmail author
  • Hongying Gan-Schreier
  • Tawfeq Ben-Omran
  • Kathrin V. Schmidt
  • Junmin Fang-Hoffmann
  • Gwendolyn Gramer
  • Ghassan Abdoh
  • Noora Shahbeck
  • Hilal Al Rifai
  • Abdul Latif Al Khal
  • Gisela Haege
  • Chuan-Chi Chiang
  • David C. Kasper
  • Bridget Wilcken
  • Peter Burgard
  • Georg F. Hoffmann
Research Report
Part of the JIMD Reports book series (JIMD, volume 32)

Abstract

Background: In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine β-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening.

Methods: We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met values >P97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy.

Results: Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly.

Conclusion: The finally derived two-tier algorithm using Met to Phe ratio as first- and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening.

Keywords

Classical homocystinuria Cystathionine β-synthase Dried blood spots Homocysteine Newborn screening Two-tier strategy 

Abbreviations

CBS

Cystathionine β-synthase

DBS

Dried blood spots

ESI-MS/MS

Electrospray ionization-tandem mass spectrometry

HCU

Classical homocystinuria

Hcy

Homocysteine

HPLC

High-performance liquid chromatography

LC-MS/MS

Liquid chromatography-tandem mass spectrometry

Met

Methionine

Phe

Phenylalanine

Notes

Acknowledgements

We thank Deborah Treiber and all members of the Newborn Screening Laboratory in Heidelberg as well as the team in the Newborn Screening Units in Austria, Australia, the Netherlands (especially Bert Elvers), Qatar, and Taiwan for excellent assistance and continuous reliable work.

This extensive study over more than a decade was only made possible by the continuous and generous support of the Dietmar Hopp Foundation to Georg F. Hoffmann.

Supplementary material

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Jürgen G. Okun
    • 1
    Email author
  • Hongying Gan-Schreier
    • 1
  • Tawfeq Ben-Omran
    • 2
  • Kathrin V. Schmidt
    • 1
  • Junmin Fang-Hoffmann
    • 1
  • Gwendolyn Gramer
    • 1
  • Ghassan Abdoh
    • 2
  • Noora Shahbeck
    • 2
  • Hilal Al Rifai
    • 2
  • Abdul Latif Al Khal
    • 2
  • Gisela Haege
    • 1
  • Chuan-Chi Chiang
    • 3
  • David C. Kasper
    • 4
  • Bridget Wilcken
    • 5
  • Peter Burgard
    • 1
  • Georg F. Hoffmann
    • 1
  1. 1.Department of General Pediatrics, Division of Inherited Metabolic DiseasesUniversity Children’s HospitalHeidelbergGermany
  2. 2.Department of PediatricsHamad Medical CorporationDohaQatar
  3. 3.Chinese Foundation of HealthTaipei CityTaiwan
  4. 4.Department of Pediatrics and Adolescent MedicineMedical University of ViennaViennaAustria
  5. 5.NSW Newborn Screening ProgrammeThe Children’s Hospital at WestmeadWestmeadAustralia

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