Exploration of Metabolic Alterations in Methylmalonic Acidemia across Distinct Genetic Backgrounds

Methylmalonic acidemia (MMA) is a rare recessively inherited disorder mainly caused by variants in the MMUT and MMACHC genes, leading to the accumulation of methylmalonic acid. The pathophysiological mechanisms of MMA remain poorly understood, and treatments are symptomatic. This study investigated the comprehensive metabolic remodeling signatures of the MMA subtypes. We applied targeted metabolomics to dried blood spot (DBS) samples obtained from a Chinese cohort of 85 patients, consisting of 42 MUT-MMA, 23 CblC-MMA, and an additional 20 CblC-MMA presenting kidney injury and pulmonary arterial hypertension (PAH) as the initial symptoms. In addition, metabolite alterations were also assessed following treatments adopting a reduction analysis. The targeted metabolomics study highlighted the presence of significant differences among the MMA subtypes. New biomarkers (carbohydrates and short-chain fatty acids) were proposed for MUT, while novel data regarding the alterations of unsaturated fatty acid profiles and biomarkers of phenylalanine, tyrosine, and tryptophan biosynthesis were obtained for CblC disease. We also revealed the metabolic remodeling signatures in MMA patients following treatment. Additionally, key differences were identified between the CblC-MMA-presenting kidney injury and PAH populations, particularly regarding phenylacetylglutamine and isovalerylcarnitine, which may serve as discriminatory biomarkers for these subtypes. These findings provide a robust metabolic framework that facilitates precise subtype diagnosis, therapeutic monitoring, and a mechanistic understanding of MMA heterogeneity.