Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry

Citrullinemia is the earliest identifiable biochemical abnormality in neonates with intrahepatic cholestasis due to a citrin deficiency (NICCD) and it has been included in newborn screening panels using tandem mass spectrometry. However, only one neonate was positive among 600,000 infants born in Sapporo city and Hokkaido, Japan between 2006 and 2017. We investigated 12 neonates with NICCD who were initially considered normal in newborn mass screening (NBS) by tandem mass spectrometry, but were later diagnosed with NICCD by DNA tests. Using their initial NBS data, we examined citrulline concentrations and ratios of citrulline to total amino acids. Although their citrulline values exceeded the mean of the normal neonates and 80 % of them surpassed +3SD, all were below the cutoff of 40 nmol/mL. The ratios of citrulline to total amino acids significantly elevated in patients with NICCD compared to the control. By evaluating two indicators simultaneously, we could select about 80% of patients with missed NICCD. Introducing an estimated index comprising citrulline values and citrulline to total amino acid ratios could assure NICCD detection by NBS.

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Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry

International Journal of Neonatal Screening ◽

10.3390/ijns4010005 ◽

2018 ◽

Vol 4 (1) ◽

pp. 5 ◽

Cited By ~ 1

Author(s):

Hiroko Shigetomi ◽

Toju Tanaka ◽

Masayoshi Nagao ◽

Hiroyuki Tsutsumi

Keyword(s):

Mass Spectrometry ◽

Early Detection ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Intrahepatic Cholestasis ◽

Tandem Mass ◽

Detection And Diagnosis ◽

Citrin Deficiency ◽

Early Detection And Diagnosis

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National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Follow-Up Testing for Metabolic Disease Identified by Expanded Newborn Screening Using Tandem Mass Spectrometry; Executive Summary

Clinical Chemistry ◽

10.1373/clinchem.2009.131300 ◽

2009 ◽

Vol 55 (9) ◽

pp. 1615-1626 ◽

Cited By ~ 54

Author(s):

Dennis J Dietzen ◽

Piero Rinaldo ◽

Ronald J Whitley ◽

William J Rhead ◽

W Harry Hannon ◽

...

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

Tandem Mass Spectrometry ◽

Organic Acids ◽

Newborn Screening ◽

Tandem Mass ◽

Confirmatory Testing ◽

The Us ◽

The Impact

Abstract Background: Almost all newborns in the US are screened at birth for multiple inborn errors of metabolism using tandem mass spectrometry. Screening tests are designed to be sufficiently sensitive so that cases are not missed. The NACB recognized a need for standard guidelines for laboratory confirmation of a positive newborn screen such that all babies would benefit from equal and optimal follow-up by confirmatory testing. Methods: A committee was formed to review available data pertaining to confirmatory testing. The committee evaluated previously published guidelines, published methodological and clinical studies, clinical case reports, and expert opinion to support optimal confirmatory testing. Grading was based on guidelines adopted from criteria derived from the US Preventive Services Task Force and on the strength of recommendations and the quality of the evidence. Three primary methods of analyte measurement were evaluated for confirmatory testing including measurement of amino acids, organic acids, and carnitine esters. The committee graded the evidence for diagnostic utility of each test for the screened conditions. Results: Ample data and experience were available to make strong recommendations for the practice of analyzing amino acids, organic acids, and acylcarnitines. Likewise, strong recommendations were made for the follow-up test menu for many disorders, particularly those with highest prevalence. Fewer data exist to determine the impact of newborn screening on patient outcomes in all but a few disorders. The guidelines also provide an assessment of developing technology that will fuel a refinement of current practice and ultimate expansion of the diseases detectable by tandem mass spectrometry. Conclusions: Guidelines are provided for optimal follow-up testing for positive newborn screens using tandem mass spectrometry. The committee regards these tests as reliable and currently optimal for follow-up testing. .

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Validation of Accuracy-based Amino Acid Reference Materials in Dried-Blood Spots by Tandem Mass Spectrometry for Newborn Screening Assays

Clinical Chemistry ◽

10.1093/clinchem/45.8.1269 ◽

1999 ◽

Vol 45 (8) ◽

pp. 1269-1277 ◽

Cited By ~ 58

Author(s):

Donald H Chace ◽

Barbara W Adam ◽

S Jay Smith ◽

J Richard Alexander ◽

Steven L Hillman ◽

...

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

Amino Acid ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Dried Blood Spots ◽

Tandem Mass ◽

Blood Spots ◽

Amino Acid Contents ◽

Amino Acid Concentrations

Abstract Background: Advances in technology and the earlier release of newborns from hospitals have pressed the demand for accurate calibration and improved interlaboratory performance for newborn screening tests. As a first step toward standardization of newborn screening aminoacidopathy tests, we have produced six-pool sets of multianalyte dried-blood-spot amino acid reference materials (AARMs) containing predetermined quantities of five amino acids. We describe here the production of the AARMs, validation of their amino acid contents, and characterization of their homogeneity and their stability in storage. Methods: To each of six portions of a pool of washed erythrocytes suspended in serum we added Phe (0–200 mg/L), Leu (0–200 mg/L), Met (0–125 mg/L), Tyr (0–125 mg/L), and Val (0–125 mg/L). Six-pool sets (1300) were prepared, dried, and packaged. We used isotope-dilution mass spectrometry to estimate the endogenous amino acid concentrations of the AARMs and validate their final amino acid concentrations. We used additional tandem mass spectrometry analyses to examine the homogeneity of amino acid distribution in each AARM, and HPLC analyses to evaluate the stability of the amino acid contents of the AARMs. Results: The absolute mean biases across the analytic range for five amino acids were 2.8–9.4%. One-way ANOVAs of the homogeneity results predicted no statistically significant differences in amino acid concentrations within the blood spots or within the pools (P >0.05). Regression slopes (0 ± 0.01) for amino acid concentrations vs storage times and their P values (>0.05) showed no evidence of amino acid degradation at ambient temperatures, 4 °C, or −20 °C during the intervals tested. Conclusion: The validation, homogeneity, and stability of these blood spots support their use as a candidate national reference material for calibration of assays that measure amino acids in dried-blood spots.

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Use of Tandem Mass Spectrometry for Multianalyte Screening of Dried Blood Specimens from Newborns

Clinical Chemistry ◽

10.1373/clinchem.2003.022178 ◽

2003 ◽

Vol 49 (11) ◽

pp. 1797-1817 ◽

Cited By ~ 396

Author(s):

Donald H Chace ◽

Theodore A Kalas ◽

Edwin W Naylor

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Metabolic Disorders ◽

Tandem Mass ◽

Screening Programs ◽

The Past ◽

Metabolic Screening ◽

Blood Specimens

Abstract Background: Over the past decade laboratories that test for metabolic disorders have introduced tandem mass spectrometry (MS/MS), which is more sensitive, specific, reliable, and comprehensive than traditional assays, into their newborn-screening programs. MS/MS is rapidly replacing these one-analysis, one-metabolite, one-disease classic screening techniques with a one-analysis, many-metabolites, many-diseases approach that also facilitates the ability to add new disorders to existing newborn-screening panels. Methods: During the past few years experts have authored many valuable articles describing various approaches to newborn metabolic screening by MS/MS. We attempted to document key developments in the introduction and validation of MS/MS screening for metabolic disorders. Our approach used the perspective of the metabolite and which diseases may be present from its detection rather than a more traditional approach of describing a disease and noting which metabolites are increased when it is present. Content: This review cites important historical developments in the introduction and validation of MS/MS screening for metabolic disorders. It also offers a basic technical understanding of MS/MS as it is applied to multianalyte metabolic screening and explains why MS/MS is well suited for analysis of amino acids and acylcarnitines in dried filter-paper blood specimens. It also describes amino acids and acylcarnitines as they are detected and measured by MS/MS and their significance to the identification of specific amino acid, fatty acid, and organic acid disorders. Conclusions: Multianalyte technologies such as MS/MS are suitable for newborn screening and other mass screening programs because they improve the detection of many diseases in the current screening panel while enabling expansion to disorders that are now recognized as important and need to be identified in pediatric medicine.

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Comparison of amino acids and acylcarnitines assay methods used in newborn screening assays by tandem mass spectrometry

Clinica Chimica Acta ◽

10.1016/j.cca.2010.01.034 ◽

2010 ◽

Vol 411 (9-10) ◽

pp. 684-689 ◽

Cited By ~ 38

Author(s):

Víctor R. De Jesús ◽

Donald H. Chace ◽

Timothy H. Lim ◽

Joanne V. Mei ◽

W. Harry Hannon

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Tandem Mass ◽

Assay Methods ◽

Screening Assays

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A quantitative method for acylcarnitines and amino acids using high resolution chromatography and tandem mass spectrometry in newborn screening dried blood spot analysis

Journal of Chromatography B ◽

10.1016/j.jchromb.2012.07.008 ◽

2012 ◽

Vol 903 ◽

pp. 142-149 ◽

Cited By ~ 19

Author(s):

John H. Miller ◽

Philip A. Poston ◽

H. Thomas Karnes

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

High Resolution ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Quantitative Method ◽

Dried Blood Spot ◽

Tandem Mass ◽

Blood Spot ◽

Spot Analysis

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Reference values of amino acids, acylcarnitines and succinylacetone by tandem mass spectrometry for use in newborn screening in southwest Colombia

10.25100/cm.v48i3.2180 ◽

2017 ◽

Vol v48 (i3) ◽

pp. 113-119 ◽

Cited By ~ 2

Author(s):

Nora Cespedes ◽

Angela Valencia ◽

Carlos Alberto Echeverry ◽

Maria Isabel Arce-Plata ◽

Cristobal Colon ◽

...

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Reference Values ◽

Tandem Mass

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Validation of an Automated Extraction Procedure for Amino Acids and Acylcarnitines for Use with Tandem Mass Spectrometry for Newborn Screening

10.31038/edmj.2019314 ◽

2019 ◽

Vol 3 (1) ◽

Keyword(s):

Mass Spectrometry ◽

Amino Acids ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Extraction Procedure ◽

Tandem Mass ◽

Automated Extraction

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Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0694 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Yiming Lin ◽

Weifeng Zhang ◽

Zhixu Chen ◽

Chunmei Lin ◽

Weihua Lin ◽

...

Keyword(s):

Mass Spectrometry ◽

Genetic Analysis ◽

Tandem Mass Spectrometry ◽

Newborn Screening ◽

Dehydrogenase Deficiency ◽

Late Onset ◽

False Negative ◽

Tandem Mass ◽

Lipid Storage Myopathy ◽

Molecular Features

Abstract Objectives Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. Methods From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. Results Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). Conclusions These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.

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