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

Abstract

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

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

“…The present evidence, though, suggests to rely on clinical assessment, including review of medical history, and the measurement of simple biochemical parameters, such as acid‐base balance (decreased pH and base excess, raised anion gap), urinary ketones and plasma ammonia in the acute setting to discriminate between a metabolically stable or a decompensating situation 45,46 . More recently, measurement of fibroblast growth factor 21 (FGF21) and of 2‐methylcitrate showed potential to predict the development of long‐term complications 47‐49 …”

“…After liver and/or kidney transplantation, the number of metabolic decompensations decreases and some report a shortened hospital admission length during an intermittent illness 42,54,75‐103 . Also biochemical markers (C3, C3/C2 ratio, methylmalonic acid, 2‐methylcitrate, FGF21) seem to improve after transplantation 47,49,75,98,104 . However, acute metabolic decompensations can still occur after transplantation in MMA and PA patients and some of these decompensations have been reported to be lethal 47,102,104‐109 .…”

“…45,46 More recently, measurement of fibroblast growth factor 21 (FGF21) and of 2methylcitrate showed potential to predict the development of long-term complications. [47][48][49] Trigger events leading to metabolic decompensation include infections, causing fever and catabolism. Similarly, prolonged fasting periods are leading to catabolism and should be avoided to prevent metabolic instability.…”

“…42,54, Also biochemical markers (C3, C3/C2 ratio, methylmalonic acid, 2-methylcitrate, FGF21) seem to improve after transplantation. 47,49,75,98,104 However, acute metabolic decompensations can still occur after transplantation in MMA and PA patients and some of these decompensations have been reported to be lethal. 47,102,[104][105][106][107][108][109] Therefore, followup of any transplanted MMA or PA patient by a metabolic clinician is indicated and regular metabolic monitoring seems to be essential.…”

Development of Second-Tier Liquid Chromatography-Tandem Mass Spectrometry Analysis for Expanded Newborn Screening in Japan

“…For practical application of newborn screening projects, identification of patients as early as possible is thought to be essential for initiation of appropriate treatment based on the laboratory data specific to the disease. Thus, data measured by LC-MS/MS for the follow-up of patients have been obtained from several screening laboratories [ 3 , 8 , 17 , 22 ]. Our methods can be applied to serum sample measurements, and serum and DBS concentrations of metabolites, such as MMA, tHcy, 3HGA, allo-Ile, argininosuccinic acid, and succinylacetone, by LC-MS/MS have been provided to hospitals for patient follow-up from our laboratories.…”