Determination of Total Homocysteine, Methylmalonic Acid, and 2-Methylcitric Acid in Dried Blood Spots by Tandem Mass Spectrometry

Turgeon, Coleman T.; Magera, Mark J.; Cuthbert, Carla; Loken, Perry R; Gavrilov, Dimitar; Tortorelli, Silvia; Raymond, Kimiyo; Oglesbee, Devin; Rinaldo, Piero; Matern, Dietrich

doi:10.1373/clinchem.2010.148957

Cited by 128 publications

(167 citation statements)

References 31 publications

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“…In the present study taking the 99.5th Met centile (42 mmol/ l) as a cut-off, 4 out of 34 (11.8%) affected babies would have been missed. Met cut-off values as low as 40 mmol/l have been proposed to yield higher sensitivity (Huemer et al 2015 and the references therein: McHugh et al 2011;Turgeon et al 2010) but methionine seems to be to insecure as a first-tier parameter. The false negative rate is likely to be higher with early (<5 days) than with later blood sampling (5-7th day of life).…”

Section: Discussionmentioning

confidence: 99%

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

et al. 2016

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Background: In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine bsynthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening.Methods: We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met values >P97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy.Results: Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly.Conclusion: The finally derived two-tier algorithm using Met to Phe ratio as first-and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening. Abbreviations CBSCystathionine b-synthase DBS Dried blood spots ESI-MS/ MS Electrospray ionization-tandem mass spectrometry HCU Classical homocystinuria Hcy Homocysteine

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Section: Discussionmentioning

confidence: 99%

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

et al. 2016

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“…Defects in methionine metabolism were tested via measurement of total homocysteine collected on a dried blood spot (DBS) card and Liquid Chromatography-Tandem Mass Spectrometry at Mayo Medical Laboratories (Rochester, MN) as described previously [11] .…”

Section: Total Homocysteine Testingmentioning

confidence: 99%

Discovery of a novel cystathionine-beta-synthase mutation and diagnosis of homocystinuria by whole exome sequencing in a family from rural Honduras

Turner

Dinulos

Vallee

et al. 2015

CRCP

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Objective: Lack of newborn screening, limited access to healthcare, and complex presentation has resulted in gross under-diagnosis of in-born metabolism disorders in many Central American countries. In this study we describe the use of advanced clinical genomics to identify a novel cystathionine-beta-synthase (CBS) mutation with limited clinical information from a small highly consanguineous indigenous community in rural Honduras. Methods:We performed chromosomal microarray analysis and whole exome sequencing on three affected siblings and their mother. Confirmatory Sanger sequencing for CBS exon 10 was performed on genomic DNA from extended family within the community. Results:We identified a novel homozygous missense mutation (p.Tyr308Thrfs*11) in CBS that resulted in the diagnosis of homocystinuria in three siblings. Patients were nonresponsive to standard pyridoxine treatment. We discovered an elevated coefficient of inbreeding (F ≥ 0.20) suggestive of an unreported highly consanguineous population. Genotyping identified ~47% of extended family as carriers of this novel mutation. Conclusion:Expanded use of whole exome sequencing from buccal cell genomic DNA allowed for the discovery of a novel mutation resulting in a rare recessive disorder in an isolated under-served population. Clinical phenotypes and treatment response of patients with this novel homozygous mutation add to our clinical understanding of homocystinuria.

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“…taken, and acylcarnitine and MeCit levels were analyzed by tandem mass spectrometry as published previously (Turgeon et al, 2008(Turgeon et al, , 2010.…”

Section: Metabolic Assaysmentioning

confidence: 99%

“…Patients with PA are usually identified within the first few days of life when newborn screening reveals high levels of C3 and MeCit (Turgeon et al, 2008(Turgeon et al, , 2010. Clinical signs of PA generally manifest within the first few weeks of life with hypotonia, metabolic acidosis, lethargy, vomiting, poor feeding, and failure to thrive .…”

Section: Introductionmentioning

confidence: 99%

Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

et al. 2014

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Propionic acidemia (PA) is an autosomal recessive inborn error of metabolism caused by deficiency of propionyl-CoA carboxylase (PCC). This enzyme is composed of six PCCA and six PCCB subunits and mediates a critical step in catabolism of odd chain fatty acids and certain amino acids. Current treatment options for PA are limited to stringent dietary restriction of protein consumption and some patients undergo elective liver transplantation. We previously generated a hypomorphic model of PA, designated Pcca

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Determination of Total Homocysteine, Methylmalonic Acid, and 2-Methylcitric Acid in Dried Blood Spots by Tandem Mass Spectrometry

Cited by 128 publications

References 31 publications

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

Discovery of a novel cystathionine-beta-synthase mutation and diagnosis of homocystinuria by whole exome sequencing in a family from rural Honduras

Effects of Adeno-Associated Virus Serotype and Tissue-Specific Expression on Circulating Biomarkers of Propionic Acidemia

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