Investigation of newborns with abnormal results in a newborn screening program for four lysosomal storage diseases in Brazil

Abstract

Lysosomal storage diseases (LSDs) are genetic disorders, clinically heterogeneous, mainly caused by defects in genes encoding lysosomal enzymes that degrade macromolecules. Several LSDs already have specific therapies that may improve clinical outcomes, especially if introduced early in life. With this aim, screening methods have been established and newborn screening (NBS) for some LSDs has been developed. Such programs should include additional procedures for the confirmation (or not) of the cases that had an abnormal result in the initial screening. We present here the methods and results of the additional investigation performed in four babies with positive initial screening results in a program of NBS for LSDs performed by a private laboratory in over 10,000 newborns in Brazil. The suspicion in these cases was of Mucopolysaccharidosis I - MPS I (in two babies), Pompe disease and Gaucher disease (one baby each). One case of pseudodeficiency for MPS I, 1 carrier for MPS I, 1 case of pseudodeficiency for Pompe disease and 1 carrier for Gaucher disease were identified. This report illustrates the challenges that may be encountered by NBS programs for LSDs, and the need of a comprehensive protocol for the rapid and precise investigation of the babies who have an abnormal screening result.

Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

“…Similar results were reported by Burton et al [5], with 151 infants out of 219,793 screened referred for confirmatory MPS I testing and an incidence of 1/7326 for IDUA pseudodeficiency and 1/219,793 for MPS I. These findings are reproduced in several additional reports [24][25][26][27][28]. With the overall incidence of pseudodeficiency being approximately 16 times higher than true disease, newborn screening programs and clinicians involved in the evaluation of referred infants will continue to be overwhelmed with false-positive results if the enzymatic screen alone is utilized.…”

Diagnosis of Mucopolysaccharidoses

“…Screening for MPS is also routine in Taiwan, including MPS I, II and VI [126,127] and in some regions of Italy [120,128]. Pilot studies for screening of MPS, mainly for MPS I, were performed in Austria [129], Belgium [130], Brazil [100], Mexico [131] and few other countries.…”

“…Screening for MPS is also routine in Taiwan, including MPS I, II and VI [126,127] and in some regions of Italy [120,128]. Pilot studies for screening of MPS, mainly for MPS I, were performed in Austria [129], Belgium [130], Brazil [100], Mexico [131] and few other countries. The current major methodologies employed for the screening of MPS are the quantification of the lysosomal enzymes by digital microfluidics (DMF) with currently available assays for MPS I a nd II, although this platform is limited by the number of enzymes that can be multiplexed in a single assay [132][133][134].…”

Newborn Screening for Pompe Disease

“…The cutoff value for AαGlu was defined as less than 30% of the mean enzyme activity in samples from 1000 unaffected babies. One case was identified to be pseudodeficiency, and no infants were identified with PD [48,55].…”