Understanding acute metabolic decompensation in propionic and methylmalonic acidemias: a deep metabolic phenotyping approach

Abstract

Background: Pathophysiology of life-threatening acute metabolic decompensations (AMD) in propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is insufficiently understood. Here, we study the metabolomes of PA and MMA patients over time, to improve insight in which biochemical processes are at play during AMD. Methods: Longitudinal data from clinical chemistry analyses and metabolic assays over the life-course of 11 PA and 13 MMA patients were studied retrospectively. Direct-infusion high-resolution mass spectrometry was performed on 234 and 154 remnant dried blood spot and plasma samples of PA and MMA patients, respectively. In addition, a systematic literature search was performed on reported biomarkers. All results were integrated in an assessment of biochemical processes at play during AMD. Results: We confirmed many of the metabolite alterations reported in literature, including increases of plasma valine and isoleucine during AMD in PA patients. We revealed that plasma leucine and phenylalanine, and urinary pyruvic acid were increased during AMD in PA patients. 3-hydroxyisovaleric acid correlated positively with plasma ammonia. We found that known diagnostic biomarkers were not significantly further increased, while intermediates of the branched-chain amino acid (BCAA) degradation pathway were significantly increased during AMD. Conclusions: We revealed that during AMD in PA and MMA, BCAA and BCAA intermediates accumulate, while known diagnostic biomarkers remain essentially unaltered. This implies that these acidic BCAA intermediates are responsible for metabolic acidosis. Based on this, we suggest to measure plasma 3-hydroxyisovaleric acid and urinary ketones or 3-hydroxybutyric acid for the biochemical follow-up of a patient's metabolic stability.

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

“…10 In particular, the relative depletion of glutamine in organic acidurias may result from the attempt of replenish alphaketoglutarate in the Krebs cycle. 10,14 In our study, we observed that MCA was directly related also to plasma lysine and glycine levels. Lysine is an essential amino acid and its increase likely reflects a decreased degradation.…”

“…Correlation analysis between MCA with other metabolic parameters displayed the significant correlation with plasma ammonia levels, a result in line with previous studies, that confirms the perturbation of ammonia metabolism in inherited disorders of propionate. 10,11,14 Furthermore, plasma MCA was also positively correlated with lysine and glycine levels as well as with the changes in acyl-carnitine profile (C3 and C3/C2 and C3/C16 ratios), reflecting the mitochondrial accumulation of propionyl-CoA and the relative depletion of acetyl-CoA.…”

“…8,9 Thus far, MCA has been mainly considered a helpful biomarker for diagnosis of inherited disorders of propionate metabolism, but its utility in guiding the adjustment of treatment regimens and in predicting the metabolic status still needs to be established, with only a few works reporting data on urine/plasma MCA in the follow-up of PA and MMA. 5,[10][11][12][13][14][15] In this study, we have prospectively evaluated plasma concentrations of MCA and its correlations with primary and secondary biomarkers, including FGF21, in a large series of PA and MMA patients, on standard treatment and/or after transplantation, to explore the potential contribution of MCA quantification in the long-term management of organic acidemias.…”

SARS-CoV-2 infection in a patient with propionic acidemia

“…Appropriate management of acute metabolic crises is crucial for normal intellectual development in PA patients [ 4 ]. Recent literature confirms that hyperammonemia and metabolic decompensation have a great impact on patients’ outcome, and that even when diagnosis is a result of NBS, outcomes are not necessarily better [ 7 , 21 , 22 ].…”

“…Acute decompensations, whose initial management is critical, can be triggered by fever, vomiting, prolonged fasting, gastroenteritis and other infections [ 5 , 6 ]. The health gains of NBS for PA in overall outcome are modest, even if mortality in patients detected by NBS is lower than in the group detected by selected metabolic screening [ 3 , 5 – 7 ].…”