Current State of the Art of Newborn Screening for Lysosomal Storage Disorders

David Millington,Deeksha Bali

doi:10.3390/ijns4030024

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 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.

Highlights

Newborn screening (NBS) for inborn errors of metabolism (IEM) began over 50 years ago with Robert Guthrie’s bacterial inhibition test to detect phenylketonuria by means of elevated phenylalanine concentrations in dried blood spots collected during the first few days of life [1]
This option requires the application of a benchtop microfluorometer that accepts 96-well microtiter plates to measure the release of the fluorophore 4-methylumbelliferone (4-MU) from a synthetic substrate targeted to a specific lysosomal storage disorders (LSDs) enzyme in a DBS extract after an 18 h incubation
There are, some notable differences between programs with Missouri reporting greater than 2-fold higher incidences of Pompe and Fabry

Summary

Introduction

Newborn screening (NBS) for inborn errors of metabolism (IEM) began over 50 years ago with Robert Guthrie’s bacterial inhibition test to detect phenylketonuria by means of elevated phenylalanine concentrations in dried blood spots collected during the first few days of life [1]. During the ensuing period covering more than 30 years, a few additional tests for conditions that satisfied criteria published by Wilson and Jungner in 1968 [2] were added to the panel. The concept of multiplex testing was introduced using tandem mass spectrometry (MS/MS) [3,4]—a method that detects multiple acylcarnitines and amino acids simultaneously and recognizes more than 30 IEM [5,6,7]. Many of the conditions detectable by MS/MS do not satisfy the Wilson and Jungner criteria.

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Conclusion