A False-Positive Case of Methylmalonic Aciduria by Tandem Mass Spectrometry Newborn Screening Dependent on Maternal Malnutrition in Pregnancy.

Claudia Rossi,Vincenzo De Laurenzi,Daniela Semeraro,Damiana Pieragostino,Silvia Valentinuzzi,Mirco Zucchelli,Ilaria Cicalini,Ada Consalvo,Carlo Dionisi-Vici,Diego Gazzolo,Giorgia Gasparroni,Cristiano Rizzo,Patrizia Brindisino

doi:10.3390/ijerph17103601

Abstract

Methylmalonic Acidurias (MMAs) are a group of inborn errors of metabolism (IEMs), specifically of propionate catabolism characterized by gastrointestinal and neurometabolic manifestations resulting from a deficiency in the function of methylmalonyl-CoA mutase, methylmalonyl-CoA epimerase, and cobalamin metabolism. In Expanded Newborn Screening (NBS), increased levels of propionylcarnitine (C3) and/or of its ratios by MS/MS analysis of dried blood spots (DBS) samples are suggestive for either Propionic Acidemia or MMAs. C3 elevation is not considered a specific marker for these disorders, resulting in high false-positive rates. The use of analyte ratios improves specificity, but it still cannot resolve the diagnostic issue. Second-tier testing are strongly recommended as confirmation of primary NBS results and for a differential diagnosis. LC-MS/MS analysis allows the quantification of more specific markers of the disorder. Here, we report the case of a newborn with a suspected MMA at Expanded NBS and at second-tier test. Given the urgent situation, in-depth diagnostic investigations were performed. Further investigations surprisingly revealed a Vitamin B12 deficiency due to a maternal malnutrition during pregnancy. This case emphasized that metabolic alterations at NBS may not only be influenced by genome and related to IEMs, but also to external factors and to maternal conditions.

Highlights

Organic acidemias (OAs), known as organic acidurias, are a class of inherited disorders of intermediary metabolism resulting primarily from deficiencies of specific enzymes or transport protein inInt
Parameters were within normal ranges according to local standards, and neurological evaluation amino acids (AAs), C2, and urinary fatty acids were within normality ranges at the stage under showed axial hypotonia previously diagnosed at birth
In agreement with laboratory collection protocol, samples for Newborn Screening (NBS) are collected at 48–72 h after birth by heel-pricking blood specimen onto Ahlstrom 226 filter paper provided by PerkinElmer

Summary

Introduction

Organic acidemias (OAs), known as organic acidurias, are a class of inherited disorders of intermediary metabolism resulting primarily from deficiencies of specific enzymes or transport protein in. Second-tier tests are usually performed by Liquid Chromatography coupled to MS/MS (LC-MS/MS) and are able to identify additional analytes, not measured in primary NBS test, as more specific markers of the suspected disease, leading to a better interpretation of the abnormal results [8]. The introduction of second-tier testing for the suspicion of MMAs or PA is considered an important strategy to cope with C3 false positive results at NBS [8]. Given the urgent situation and considering the increasing marker alteration, in-depth diagnostic investigations by further specific biochemical tests were performed. NBS and the increased levels of mma and hcy at the second-tier test, which doubled in a couple of Clinical days. We suspected a metabolic disease due to altered expanded newborn screening characterized by increased levels of C3, C3/C2, C16:1OH\C17 (3-Hydroxy-hexadecenoylcarnitine), and methionine

Clinical

Routine Newborn Screening Analysis and Second-Tier Testing

NBS Analysis and Second-Tier Testing of The Suspected Neonate

Biochemical Diagnostic Confirmations

Discussion

Conclusions