Quantification of methylcitrate in dried urine spots by liquid chromatography tandem mass spectrometry for the diagnosis of propionic and methylmalonic acidemias

Dhahouri, Nahid Al; Langhans, Claus-Dieter; Hammadi, Zalikha Al; Okun, Jürgen G.; Hoffmann, Georg F.; Al‐Jasmi, Fatma; Al-Dirbashi, Osama Y.

doi:10.1016/j.cca.2018.09.017

Cited by 20 publications

(23 citation statements)

References 17 publications

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“…4 As primary disease biomarker, MCA has been so far mainly utilized for the biochemical diagnosis of propionate disorders or as a second-tier test in newborn screening. [18][19][20][21][22][23] However, its utility for patients monitoring at follow-up still needs to be better evaluated. Zwickler et al analyzed urinary MCA in MMA and found that the excretion of MCA was significantly increased in patients presenting signs of metabolic decompensation, with no clear-cut differences for other primary disease biomarkers.…”

Section: Discussionmentioning

confidence: 99%

“…The panel of current guidelines recommends primary and secondary parameters, such as blood gases, plasma ammonia, lactate, amino acids, acylcarnitines, and in MMA, methylmalonic acid determination in plasma and urine 4 . As primary disease biomarker, MCA has been so far mainly utilized for the biochemical diagnosis of propionate disorders or as a second‐tier test in newborn screening 18‐23 . However, its utility for patients monitoring at follow‐up still needs to be better evaluated.…”

Section: Discussionmentioning

confidence: 99%

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Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia

Maines

Catesini

Boenzi

et al. 2020

J of Inher Metab Disea

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Methylcitric acid (MCA) analysis has been mainly utilized for the diagnosis of propionate disorders or as a second-tier test in newborn screening, but its utility for patients monitoring still needs to be established. We explored the potential contribution of MCA in the long-term management of organic acidurias. We prospectively evaluated plasma MCA and its relationship with disease biomarkers, clinical status, and disease burden in 22 patients, 13 with propionic acidemia (PA) and nine with methylmalonic acidemia (MMA) on standard treatment and/or after transplantation. Samples were collected at scheduled routine controls or during episodes of metabolic decompensation (MD), 10 patients were evaluated after transplantation (six liver, two combined liver and kidney, 2 kidney). MCA levels were higher in PA compared to MMA and its levels were not influenced by the clinical status (MD vs well state). In MMA, MCA was higher in elder patients and, along with fibroblast growth factor 21 (FGF21) and plasma methylmalonic acid, negatively correlated with GFR. In both diseases, MCA correlated with ammonia, glycine, lysine, C3, and

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia

Maines

Catesini

Boenzi

et al. 2020

J of Inher Metab Disea

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“…Recently we developed methods for the analysis of MCA in dried blood spot (DBS) and dried urine spot samples and showed that this marker improves newborn screening for disorders of propionate metabolism 12–14 . MCA and its physiological counterpart, citric acid (CA) are produced in Krebs cycle in a reaction catalyzed by the same enzyme, namely citrate synthase 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Assessment of methylcitrate and methylcitrate to citrate ratio in dried blood spots as biomarkers for inborn errors of propionate metabolism

Al-Dirbashi

Alfadhel

Al‐Thihli

et al. 2019

Sci Rep

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Deficiency of propionyl-CoA carboxylase causes propionic acidemia and deficiencies of methylmalonyl-CoA mutase or its cofactor adenosylcobalamin cause methylmalonic acidemia. These inherited disorders lead to pathological accumulation of propionyl-CoA which is converted in Krebs cycle to methylcitrate (MCA) in a reaction catalyzed by citrate synthase. In healthy individuals where no propionyl-CoA accumulation occurs, this enzyme drives the condensation of acetyl-CoA with oxaloacetate to produce citric acid (CA), a normal Krebs cycle intermediate. The competitive synthesis of CA and MCA through the same enzymatic mechanism implies that increase in MCA production is accompanied by decrease in CA levels. In this study, we assessed MCA concentration and the ratio of MCA/CA as plausible markers for propionic and methylmalonic acidemias. We measured MCA and CA in dried blood spots using liquid chromatography tandem mass spectrometry. The reference ranges of MCA, CA and MCA/CA in 123 healthy individuals were ≤0.63 µmol/L, 36.6–126.4 µmol/L and 0.0019–0.0074, respectively. In patients with propionic and methylmalnic acidemias (n = 7), MCA concentration ranged between 1.0–12.0 µmol/L whereas MCA/CA was between 0.012–0.279. This is the first report to describe the potential role of MCA and MCA/CA in dried blood spots as diagnostic and monitoring biomarkers for inherited disorders of propionyl-CoA metabolism.

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“…The extraction of total FAs from a diminutive plasma volume (10 μL) was done as previously described [ 25 ]. Coupling of DAABD-AE with FAs was achieved using published conditions with minor modifications to accommodate the qualitative and quantitative diversity of analytes in this study [ 20 , 21 , 25 , 35 , 36 ]. This modification involved a facile single-step derivatization protocol that involves the use of premixed reagents added directly to the residual plasma extract followed by incubation at 60 °C for 1 h. When various DAABD-AE concentrations were tested, we confirmed that 2.0 mmol/L is adequate to achieve the desired derivatization yield.…”

Section: Resultsmentioning

confidence: 99%

“…With liquid chromatography (LC) as a front-end technology, LC-MS/MS methods represent powerful alternatives to GC and GC-MS due to the simpler workflow, better sensitivity, and faster analytical time [ 17 ]. Over the past years, applications of LC-MS/MS have expanded significantly in clinical laboratories in areas, such as therapeutic drug monitoring, drugs of abuse, clinical toxicology, and inborn errors of metabolism [ 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted Metabolomic Profiling of Total Fatty Acids in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry

et al. 2020

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This article reports a targeted metabolomic method for total plasma fatty acids (FAs) of clinical or nutritional relevance. Thirty-six saturated, unsaturated, or branched-chain FAs with a chain length of C8-C28 were quantified using reversed-phase liquid chromatography-tandem mass spectrometry. FAs in plasma (10 μL) were acid-hydrolyzed, extracted, and derivatized with DAABD-AE (4-[2-(N,N-Dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole) at 60 °C for 1 h. Derivatization resulted in a staggering nine orders of magnitude higher sensitivity compared to underivatized analytes. FAs were measured by multiple-reaction monitoring using stable isotope internal standards. With physiological and pathological analyte levels in mind, linearity was established using spiked plasma. Intra-day (n = 15) and inter-day (n = 20) imprecisions expressed as variation coefficient were ≤10.2% with recovery ranging between 94.5–106.4%. Limits of detection and limit of quantitation ranged between 4.2–14.0 and 15.1–51.3 pmol per injection, respectively. Age-stratified reference intervals were established in four categories: <1 month, 1–12 month, 1–18 year, and >18 year. This method was assessed using samples from patients with disorders affecting FAs metabolism. For the first time, C28:0 and C28:0/C22:0 ratio were evaluated as novel disease biomarkers. This method can potentially be utilized in diagnosing patients with inborn errors of metabolism, chronic disease risk estimation, or nutritional applications.

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Quantification of methylcitrate in dried urine spots by liquid chromatography tandem mass spectrometry for the diagnosis of propionic and methylmalonic acidemias

Cited by 20 publications

References 17 publications

Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia

Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia

Assessment of methylcitrate and methylcitrate to citrate ratio in dried blood spots as biomarkers for inborn errors of propionate metabolism

Targeted Metabolomic Profiling of Total Fatty Acids in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry

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