scholarly journals The low excretor phenotype of glutaric acidemia type I is a source of false negative newborn screening results and challenging diagnoses

JIMD Reports ◽  
2021 ◽  
Author(s):  
Adam J. Guenzel ◽  
Patricia L. Hall ◽  
Anna I. Scott ◽  
Christina Lam ◽  
Irene J. Chang ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Negative ◽  
Type I ◽  
Glutaric Acidemia Type I

scholarly journals Preliminary Proficiency Testing Results for Succinylacetone in Dried Blood Spots for Newborn Screening for Tyrosinemia Type I

2009 ◽  
Vol 55 (12) ◽  
pp. 2207-2213 ◽  
Author(s):  
Barbara W Adam ◽  
Timothy H Lim ◽  
Elizabeth M Hall ◽  
W Harry Hannon
Keyword(s):  
Newborn Screening ◽  
Proficiency Testing ◽  
False Negative ◽  
Dried Blood Spots ◽  
Screening Tests ◽  
Type I ◽  
Primary Metabolite ◽  
Screening Practices ◽  
Tyrosinemia Type I ◽  
Stable Performance

Abstract Background: Succinylacetone (SUAC) is the primary metabolite accumulated in tyrosinemia type I—an inborn error of metabolism that, if untreated, can cause death from liver failure during the first months of life. Newborn screening laboratories measure SUAC in dried blood spot (DBS) samples to detect asymptomatic tyrosinemia type I. We used panels of SUAC-enriched DBSs to compare and evaluate the performance of these screening tests. Methods: We prepared sets of DBS materials enriched with predetermined SUAC concentrations and distributed samples of these materials, along with a screening practices questionnaire, to laboratories that perform SUAC tests. We compared their reported SUAC concentrations and questionnaire responses to identify screening practices that affect SUAC test outcomes. Results: Data from 2 pilot surveys showed large differences among laboratories in SUAC recoveries, reproducible within-laboratory recoveries, and stable performance of the DBS materials. Results from 257 proficiency test analyses contained a total of 6 false-negative misclassifications. Reported recoveries of added SUAC ranged from 0 to >200%. Low-biased SUAC recoveries were associated with 1 method used by 5 laboratories. All laboratories that reported SUAC recoveries ≥100% used DBS matrix calibrators. Conclusions: The wide ranges of SUAC concentrations reported for pilot and proficiency testing specimens demonstrate a need to harmonize quantitative results among laboratories. Although DBS matrix calibrators are important for optimizing SUAC recoveries, the preparation of these calibrators is not standardized among laboratories. Certified DBS-based SUAC calibrators are needed for accuracy and harmonization.

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

2020 ◽  
Vol 6 (1) ◽  
pp. 10 ◽  
Author(s):  
Dawn S. Peck ◽  
Jean M. Lacey ◽  
Amy L. White ◽  
Gisele Pino ◽  
April L. Studinski ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
Dermatan Sulfate ◽  
False Positive Rate ◽  
False Negative ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Second Tier ◽  
Mps I

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.

scholarly journals Combined Newborn Screening for Succinylacetone, Amino Acids, and Acylcarnitines in Dried Blood Spots

2008 ◽  
Vol 54 (4) ◽  
pp. 657-664 ◽  
Author(s):  
Coleman Turgeon ◽  
Mark J Magera ◽  
Pierre Allard ◽  
Silvia Tortorelli ◽  
Dimitar Gavrilov ◽  
...  
Keyword(s):  
Amino Acids ◽  
Newborn Screening ◽  
False Negative ◽  
Internal Standard ◽  
Early Death ◽  
Cost Effective ◽  
Dried Blood Spots ◽  
Type I ◽  
Blood Spots ◽  
Negative Results

Abstract Background: Tyrosinemia type I (TYR 1) is a disorder causing early death if left untreated. Newborn screening (NBS) for this condition is problematic because determination of the diagnostic marker, succinylacetone (SUAC), requires a separate first-tier or only partially effective second-tier analysis based on tyrosine concentration. To overcome these problems, we developed a new assay that simultaneously determines acylcarnitines (AC), amino acids (AA), and SUAC in dried blood spots (DBS) by flow injection tandem mass spectrometry (MS/MS). Methods: We extracted 3/16-inch DBS punches with 300 μL methanol containing AA and AC stable isotope-labeled internal standards. This extract was derivatized with butanol-HCl. In parallel, we extracted SUAC from the residual filter paper with 100 μL of a 15 mmol/L hydrazine solution containing the internal standard 13C5-SUAC. We combined the derivatized aliquots in acetonitrile for MS/MS analysis of AC and AA with additional SRM experiments for SUAC (m/z 155–137) and 13C5-SUAC (m/z 160–142). Analysis time was 1.2 min. Results: SUAC was increased in retrospectively analyzed NBS samples of 11 TYR 1 patients (length of storage, 52 months to 1 week; SUAC range, 13–81 μmol/L), with Tyr concentrations ranging from 65 to 293 μmol/L in the original NBS analysis. The mean concentration of SUAC in 13 521 control DBS was 1.25 μmol/L. Conclusion: The inclusion of SUAC analysis into routine analysis of AC and AA allows for rapid and cost-effective screening for TYR 1 with no tangible risk of false-negative results.

Glutaric Acidemia, Type I, Missed by Newborn Screening in an Infant With Dystonia Following Promethazine Administration

PEDIATRICS ◽  
2001 ◽  
Vol 107 (5) ◽  
pp. 1184-1187 ◽  
Author(s):  
W. E. Smith ◽  
D. S. Millington ◽  
D. D. Koeberl ◽  
P. S. Lesser
Keyword(s):  
Newborn Screening ◽  
Type I ◽  
Glutaric Acidemia Type I

scholarly journals Maternal glutaric acidemia, type I identified by newborn screening

2008 ◽  
Vol 94 (1) ◽  
pp. 132-134 ◽  
Author(s):  
Eric A. Crombez ◽  
Stephen D. Cederbaum ◽  
Elaine Spector ◽  
Erica Chan ◽  
Denise Salazar ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Type I ◽  
Glutaric Acidemia Type I

scholarly journals Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families

2021 ◽  
Vol 7 (2) ◽  
pp. 32
Author(s):  
Johannes Spenger ◽  
Esther M. Maier ◽  
Katharina Wechselberger ◽  
Florian Bauder ◽  
Melanie Kocher ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Biological Diversity ◽  
False Negative ◽  
Autosomal Recessive Disorder ◽  
Dried Blood Spots ◽  
Glutaric Aciduria Type ◽  
Type I ◽  
Gene Encoding ◽  
Glutaric Aciduria ◽  
Glutaric Aciduria Type I

Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the amino acids lysine and tryptophan caused by mutations of the GCDH gene encoding glutaryl-CoA-dehydrogenase. Newborn screening (NBS) for this condition is based on elevated levels of glutarylcarnitine (C5DC) in dried blood spots (DBS). Here we report four cases from three families in whom a correctly performed NBS did not detect the condition. Glutarylcarnitine concentrations were either normal (slightly below) or slightly above the cut-off. Ratios to other acylcarnitines were also not persistently elevated. Therefore, three cases were defined as screen negative, and one case was defined as normal, after a normal control DBS sample. One patient was diagnosed after an acute encephalopathic crisis, and the other three patients had an insidious onset of the disease. GA-1 was genetically confirmed in all cases. Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1, by adjusting cut-offs and introducing various ratios, the biological diversity still leads to false-negative NBS results for GA-1.

Rhabdomyolysis, Acute Kidney Injury, and a Novel Frameshift Mutation in a Child with Glutaric Acidemia Type I

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Linlin Huang ◽  
Ting Shi ◽  
Ying Li ◽  
Xiaozhong Li
Keyword(s):  
Acute Kidney Injury ◽  
Case Report ◽  
Frameshift Mutation ◽  
Novel Mutation ◽  
Kidney Injury ◽  
Febrile Illness ◽  
Type I ◽  
Continuous Venovenous Hemodiafiltration ◽  
Glutaric Acidemia Type I ◽  
Acute Decompensation

This is a case report of a girl with glutaric acidemia type I (GA-I) who experienced rhabdomyolysis and acute kidney injury (AKI). Her first acute metabolic crisis occurred at the age of 5 months, which mainly manifested as irritable crying, poor appetite, and hyperlactatemia. Mutation analysis showed 2 pathogenic mutations in the glutaryl-CoA dehydrogenase (GCDH) gene, which were c.383G>A (p.R128Q) and c.873delC (p.N291Kfs*41), the latter of which is a novel frameshift mutation of GA-I. She had a febrile illness at the age of 12 months, followed by AKI and severe rhabdomyolysis. Four days of continuous venovenous hemodiafiltration (CVVHDF) helped to overcome this acute decompensation. This case report describes a novel mutation in the GCDH gene, that is, c.873delC (p.N291Kfs*41). Also, it highlights the fact that patients with GA-I have a high risk of rhabdomyolysis and AKI, which may be induced by febrile diseases and hyperosmotic dehydration; CVVHDF can help to overcome this acute decompensation.

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

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.

scholarly journals Early Detection of Glutaric Aciduria Type I by Newborn Screening in Taiwan

2008 ◽  
Vol 107 (2) ◽  
pp. 139-144 ◽  
Author(s):  
Chin-Tung Hsieh ◽  
Wuh-Liang Hwu ◽  
Yuan-Te Huang ◽  
Ai-Chu Huang ◽  
Shiao-Fang Wang ◽  
...  
Keyword(s):  
Early Detection ◽  
Newborn Screening ◽  
Glutaric Aciduria Type ◽  
Type I ◽  
Glutaric Aciduria ◽  
Glutaric Aciduria Type I
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