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.

中文翻译：

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了解丙酸和甲基丙二酸血症急性代谢失代偿：深度代谢表型分析方法。

背景技术对丙酸血症（PA）和孤立的甲基丙二酸血症（MMA）中威胁生命的急性代谢失代偿（AMD）的病理生理学了解不足。在这里，我们研究随时间推移的PA和MMA患者的代谢组，以提高对AMD期间哪些生化过程起作用的认识。方法回顾性研究11例PA和13例MMA患者一生中的临床化学分析和代谢分析的纵向数据。直接输注高分辨率质谱法分别对PA和MMA患者的234和154残留干血点和血浆样本进行了分析。另外，对报道的生物标志物进行了系统的文献检索。所有结果都整合到了AMD进行的生化过程评估中。结果我们证实了文献中报道的许多代谢物改变，包括PA患者AMD期间血浆缬氨酸和异亮氨酸的增加。我们发现，PA患者在AMD期间血浆亮氨酸和苯丙氨酸以及尿液丙酮酸增加。3-羟基异戊酸与血浆氨呈正相关。我们发现，在AMD期间，已知的诊断性生物标志物并没有显着增加，而支链氨基酸（BCAA）降解途径的中间体显着增加。结论我们揭示了在PA和MMA的AMD期间，BCAA和BCAA中间体不断积累，而已知的诊断性生物标志物基本上保持不变。这意味着这些酸性BCAA中间体与代谢性酸中毒有关。基于此，