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. 2019 Aug 26;9(1):12366.
doi: 10.1038/s41598-019-48885-9.

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

Osama Y Al-Dirbashi  1   2   3   4 , Majid Alfadhel  5   6   7 , Khalid Al-Thihli  8 , Nahid Al Dhahouri  9 , Claus-Dieter Langhans  10 , Zalikha Al Hammadi  11 , Aisha Al-Shamsi  12 , Jozef Hertecant  9   12 , Jürgen G Okun  10 , Georg F Hoffmann  10 , Fatma Al-Jasmi  9   12
Affiliations

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

Osama Y Al-Dirbashi et al. Sci Rep. .

Abstract

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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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Extracted mass chromatograms obtained with a DBS from healthy individual (A–D), and from a patient with MMA (E–H).
Figure 2
Figure 2
Distribution of MCA and the MCA/CA ratio in DBS from the study population. Open circles represent controls, solid triangles represent MMA and solid squares represent PA. The dashed lines represent arbitrary cutoffs of MCA and MCA/CA ratio of 0.7 μmol/L and 0.01, respectively.
Figure 3
Figure 3
Methylmalonic acid (A), MCA (B) and MCA/CA (C) in daily consecutive DBS samples (n = 11) collected from a vitamin B12 responsive MMA patient before and after starting treatment with IM hydroxycobalamin (1.0 mg/day). Methylmalonic acid (D), MCA (E) and MCA/CA (F) in daily consecutive DBS samples (n = 34) collected from a vitamin B12 non-responsive MMA patient before and after starting treatment with IM hydroxycobalamin (1.0 mg/day).
See this image and copyright information in PMC

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