Identification of potential interferents of methylmalonic acid: A previously unrecognized pitfall in clinical diagnostics and newborn screening

Peter, Markus; Godejohann, Markus; Janda, Joachim; Galla, Zsolt; Rácz, Gábor; Klinke, Glynis; Szatmári, Ildikó; Zsidegh, Petra; Kohlmüller, Dirk; Kölker, Stefan; Hoffmann, Georg F.; Gramer, Gwendolyn; Okun, Jürgen G.

doi:10.1016/j.clinbiochem.2022.09.010

Cited by 4 publications

(11 citation statements)

References 23 publications

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“…Using hyphenated HPLC-NMR spectroscopy, Monostory et al [72] identified a previously unknown interference in the routine analysis of the dried blood spots (DBSs) used in inborn screening, affecting the methylmalonic acid determination of PA patients. Thus, their paper reports on the identification of five isobaric (same molecular mass) compounds in serum and urine from MMA and PA patients, which elute close to methylmalonic acid, inducing errors in the identification and quantitation of the latter.…”

Section: Non-localized Ex Vivo Nuclear Magnetic Resonance Spectroscop...mentioning

confidence: 99%

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NMR Spectroscopy in Diagnosis and Monitoring of Methylmalonic and Propionic Acidemias

Deleanu,

Nicolescu

2024

Biomolecules

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Although both localized nuclear magnetic resonance spectroscopy (MRS) and non-localized nuclear magnetic resonance spectroscopy (NMR) generate the same information, i.e., spectra generated by various groups from the structure of metabolites, they are rarely employed in the same study or by the same research group. As our review reveals, these techniques have never been applied in the same study of methylmalonic acidemia (MMA), propionic acidemia (PA) or vitamin B12 deficiency patients. On the other hand, MRS and NMR provide complementary information which is very valuable in the assessment of the severity of disease and efficiency of its treatment. Thus, MRS provides intracellular metabolic information from localized regions of the brain, while NMR provides extracellular metabolic information from biological fluids like urine, blood or cerebrospinal fluid. This paper presents an up-to-date review of the NMR and MRS studies reported to date for methylmalonic and propionic acidemias. Vitamin B12 deficiency, although in most of its cases not inherited, shares similarities in its metabolic effects with MMA and it is also covered in this review.

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Section: Non-localized Ex Vivo Nuclear Magnetic Resonance Spectroscop...mentioning

confidence: 99%

“…Out of these isobaric compounds, only succinate has been previously reported to interfere with methylmalonic acid in the MS analysis of DBSs. The study used both DBSs and urine and performed several NMR experiments including 1 H NMR, HSQC, HMBC and TOCSY, recorded at 500 and 600 MHz [72].…”

Section: Non-localized Ex Vivo Nuclear Magnetic Resonance Spectroscop...mentioning

confidence: 99%

NMR Spectroscopy in Diagnosis and Monitoring of Methylmalonic and Propionic Acidemias

Deleanu,

Nicolescu

2024

Biomolecules

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“…Diagnostic specificity can be further increased by confirmatory assays utilizing chromatographic separation of diagnostically important analytes (including MMA, MCA, HCY and rarely 3-hydroxy-propionic acid) from their isobaric substances, i.e., from those having the same molecular mass [25,68,69]. In addition to succinate, the only metabolite considered earlier as an interference for MMA, further five potential isobaric interferents have been identified recently [70]. The urinary organic acid assay by means of GC-MS performs well in separating isobaric interferences that could compromise diagnosis and an accurate quantification [65].…”

Section: Nbs Protocols and New Candidate Markersmentioning

confidence: 99%

Vitamin B12 (Cobalamin): Its Fate from Ingestion to Metabolism with Particular Emphasis on Diagnostic Approaches of Acquired Neonatal/Infantile Deficiency Detected by Newborn Screening

et al. 2022

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Acquired vitamin B12 (vB12) deficiency (vB12D) of newborns is relatively frequent as compared with the incidence of inherited diseases included in newborn screening (NBS) of different countries across the globe. Infants may present signs of vB12D before 6 months of age with anemia and/or neurologic symptoms when not diagnosed in asymptomatic state. The possibility of identifying vitamin deficient mothers after their pregnancy during the breastfeeding period could be an additional benefit of the newborn screening. Vitamin supplementation is widely available and easy to administer. However, in many laboratories, vB12D is not included in the national screening program. Optimized screening requires either second-tier testing or analysis of new urine and blood samples combined with multiple clinical and laboratory follow ups. Our scope was to review the physiologic fate of vB12 and the pathobiochemical consequences of vB12D in the human body. Particular emphasis was put on the latest approaches for diagnosis and treatment of vB12D in NBS.

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“…Reducing the number and impact of false positives remains a central challenge to NBS and is the major purpose of second‐tier testing of the original dried blood spot (DBS) from all newborns with a positive NBS result 7,8 . In contrast to first‐tier screening using direct injection analysis, second‐tier tests often use liquid chromatography–tandem mass spectrometry (LC–MS/MS) to increase specificity by distinguishing isomeric compounds 9–12 and evaluating additional disease‐related metabolites 3,13 …”

Section: Introductionmentioning

confidence: 99%

“…5,6 Reducing the number and impact of false positives remains a central challenge to NBS and is the major purpose of second-tier testing of the original dried blood spot (DBS) from all newborns with a positive NBS result. 7,8 In contrast to first-tier screening using direct injection analysis, second-tier tests often use liquid chromatography-tandem mass spectrometry (LC-MS/MS) to increase specificity by distinguishing isomeric compounds [9][10][11][12] and evaluating additional disease-related metabolites. 3,13 False-positive cases can also be reduced using postanalytic tools applied to first-tier screening data with the Collaborative Laboratory Integrated Reports (CLIR), [14][15][16] and more recently using machine learningbased methodologies.…”

Section: Introductionmentioning

confidence: 99%

Validation of a targeted metabolomics panel for improved second‐tier newborn screening

Mak

Peng

et al. 2023

J of Inher Metab Disea

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Improved second‐tier assays are needed to reduce the number of false positives in newborn screening (NBS) for inherited metabolic disorders including those on the Recommended Uniform Screening Panel (RUSP). We developed an expanded metabolite panel for second‐tier testing of dried blood spot (DBS) samples from screen‐positive cases reported by the California NBS program, consisting of true‐ and false‐positives from four disorders: glutaric acidemia type I (GA1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD). This panel was assembled from known disease markers and new features discovered by untargeted metabolomics and applied to second‐tier analysis of single DBS punches using liquid chromatography–tandem mass spectrometry (LC–MS/MS) in a 3‐min run. Additionally, we trained a Random Forest (RF) machine learning classifier to improve separation of true‐ and false positive cases. Targeted metabolomic analysis of 121 analytes from DBS extracts in combination with RF classification at a sensitivity of 100% reduced false positives for GA1 by 83%, MMA by 84%, OTCD by 100%, and VLCADD by 51%. This performance was driven by a combination of known disease markers (3‐hydroxyglutaric acid, methylmalonic acid, citrulline, and C14:1), other amino acids and acylcarnitines, and novel metabolites identified to be isobaric to several long‐chain acylcarnitine and hydroxy‐acylcarnitine species. These findings establish the effectiveness of this second‐tier test to improve screening for these four conditions and demonstrate the utility of supervised machine learning in reducing false‐positives for conditions lacking clearly discriminating markers, with future studies aimed at optimizing and expanding the panel to additional disease targets.

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Identification of potential interferents of methylmalonic acid: A previously unrecognized pitfall in clinical diagnostics and newborn screening

Cited by 4 publications

References 23 publications

NMR Spectroscopy in Diagnosis and Monitoring of Methylmalonic and Propionic Acidemias

NMR Spectroscopy in Diagnosis and Monitoring of Methylmalonic and Propionic Acidemias

Vitamin B12 (Cobalamin): Its Fate from Ingestion to Metabolism with Particular Emphasis on Diagnostic Approaches of Acquired Neonatal/Infantile Deficiency Detected by Newborn Screening

Validation of a targeted metabolomics panel for improved second‐tier newborn screening

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