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Newborn screening for lysosomal storage disorders by tandem mass spectrometry in North East Italy

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Background

Lysosomal storage diseases (LSDs) are inborn errors of metabolism resulting from 50 different inherited disorders. The increasing availability of treatments and the importance of early intervention have stimulated newborn screening (NBS) to diagnose LSDs and permit early intervention to prevent irreversible impairment or severe disability. We present our experience screening newborns in North East Italy to identify neonates with Mucopolysaccharidosis type I (MPS I) and Pompe, Fabry, and Gaucher diseases.

Methods

Activities of acid β-glucocerebrosidase (ABG; Gaucher), acid α-glucosidase (GAA; Pompe), acid α-galactosidase (GLA; Fabry), and acid α-L-iduronidase (IDUA; MPS-I) in dried blood spots (DBS) from all newborns during a 17-month period were determined by multiplexed tandem mass spectrometry (MS/MS) using the NeoLSD® assay system. Enzymatic activity cutoff values were determined from 3500 anonymous newborn DBS. In the screening study, samples were retested if the value was below cutoff and a second spot was requested, with referral for confirmatory testing and medical evaluation if a low value was obtained.

Results

From September 2015 to January 2017, 44,411 newborns were screened for the four LSDs. We recalled 40 neonates (0.09%) for collection of a second DBS. Low activity was confirmed in 20, who had confirmatory testing. Ten of 20 had pathogenic mutations: two Pompe, two Gaucher, five Fabry, and one MPS-I. The incidences of Pompe and Gaucher diseases were similar (1/22,205), with Fabry disease the most frequent (1/8882) and MPS-I the rarest (1/44411). The combined incidence of the four disorders was 1/4411 births.

Conclusions

Simultaneously determining multiple enzyme activities by MS/MS, with a focus on specific biochemical markers, successfully detected newborns with LSDs. The high incidence of these disorders supports this screening program.

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Abbreviations

ABG:

Acid β-glucocerebrosidase

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

CPK:

Creatine phosphokinase

CRIM:

Cross-reactive immunological material

DBS:

Dried blood spot

EA:

Ethyl acetate

ECG:

Electrocardiogram

ENBS:

Expanded newborn screening

ERT:

Enzyme replacement therapy

GAA:

Acid α-glucosidase

GlcSPh:

Glucosylsphingosine

IDUA:

Acid α-L-iduronidase

LSD:

Lysosomal storage disease

LysoGb3:

Globotriaosylsphingosine

MeOH:

Methanol

MOM:

Multiple of the median

MPS I:

Mucopolysaccharidosis type I

NBS:

Newborn screening

MRM:

Multiple reaction monitoring

PPV:

Positive predictive value

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Acknowledgements

We thank PerkinElmer, who provided the reagent kit and technical support for this study. We also thank Ray Hill, an independent medical writer on behalf of Springer Healthcare Communications, who provided medical writing support funded by Cometa A.S.M.M.E. – Associazione Studio Malattie Metaboliche Ereditarie – ONLUS. Sheridan Henness, PhD, of Springer Healthcare Communications assisted with post-submission revisions of the manuscript, which were funded by Cometa A.S.M.M.E. – Associazione Studio Malattie Metaboliche Ereditarie – ONLUS.

Funding

Medical writing support was funded by Cometa A.S.M.M.E. – Associazione Studio Malattie Metaboliche Ereditarie – ONLUS, Padova Italy.

Author information

Author notes

  1. Robert J. Desnick and Alessandro P. Burlina contributed equally to this work.

Authors and Affiliations

  1. Division of Inherited Metabolic Diseases, Regional Center for Expanded Neonatal Screening Department of Women and Children’s Health, University Hospital of Padova, Via Orus 2/B, 35129, Padova, Italy

    Alberto B. Burlina, Giulia Polo, Chiara Cazzorla & Laura Rubert

  2. Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, Via Giustiniani, 3, 35128, Padova, Italy

    Leonardo Salviati & Roberta Zordan

  3. IRP Città della Speranza, Corso Stati Uniti, 4, 35129, Padova, Italy

    Leonardo Salviati & Roberta Zordan

  4. Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council, Via Ugo La Malfa, 153, 90146, Palermo, Italy

    Giovanni Duro & Carmela Zizzo

  5. Regional Coordinator Centre for Rare Diseases, Scientific Coordinator - Academic Medical Center Hospital, Udine, Italy

    Andrea Dardis & Bruno Bembi

  6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Robert J. Desnick

  7. Neurological Unit, St. Bassiano Hospital, Via dei Lotti, 40, 36061, Bassano del Grappa, Italy

    Alessandro P. Burlina

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  1. Alberto B. Burlina
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Corresponding author

Correspondence to Alberto B. Burlina.

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Conflict of interest

Alberto B Burlina has received speaker honoraria and travel support from Sanofi Genzyme, Biomarin and Actelion. He is a member of the European Advisory Board of Nutricia Danone and Biomarin.

Alessandro P Burlina has received speaker honoraria and travel support from Sanofi Genzyme and Amicus Therapeutics. He is a member of the European Advisory Board of the Fabry Registry, which is sponsored by Sanofi Genzyme.

Giulia Polo has received speaker honoraria and travel support from PerkinElmer and Actelion.

Bruno Bembi has received speaker honoraria and travel support from Sanofi Genzyme, and Actelion.

Giovanni Duro has received speaker honoraria, travel support and research grants from Sanofi Genzyme.

Robert J Desnick is a consultant for Sanofi Genzyme, Amicus Therapeutics, Alexion Pharmaceuticals, and Sangamo Therapeutics and receives research support from Sanofi Genzyme and Sangamo Therapeutics, and has founder stock in Amicus Therapeutics.

Leonardo Salviati, Roberta Zordan, Chiara Cazzorla, Laura Rubert, Carmela Zizzo, and Andrea Dardis, declare that they have no conflict of interest.

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Communicated by: Piero Rinaldo

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Burlina, A.B., Polo, G., Salviati, L. et al. Newborn screening for lysosomal storage disorders by tandem mass spectrometry in North East Italy. J Inherit Metab Dis 41, 209–219 (2018). https://doi.org/10.1007/s10545-017-0098-3

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