Serum Proteome Profiling Implicates Dysregulation of Immune Response and Inflammatory Mechanisms in Methylmalonic Acidemia With Brain Injury

ABSTRACT Methylmalonic acidemia (MMA) is the most common organic acidemia in childhood. Brain injury represents the most common clinical manifestation among MMA patients and is often associated with a poor prognosis. Currently, the mechanisms of MMA with brain injury are unclear, and there are no reliable biomarkers available for diagnosing MMA with brain injury. Consequently, a proteomic analysis was performed on the serum from 40 patients with MMA with brain injury (MBI), 15 MMA without brain injury (MNBI), 15 hyperhomocysteinemia patients (HHCY), and 25 healthy controls (CTRL). The differentially expressed proteins were analyzed by bioinformatics, and then the potential biomarkers were validated by the enzyme‐linked immunosorbent assays in another independent cohort. The results showed that a total of 503 proteins were identified in the serum samples, of which 49 differentially expressed proteins were identified in the MBI and MNBI groups. Two key molecules were identified as candidate molecules for further validation. The combination of ACE and MMP9 might be a biomarker panel for MMA with brain injury (AUC 0.847, sensitivity 0.750, specificity 0.867). The down‐regulation of immune response and up‐regulation of inflammatory response were mainly enriched in MMA brain injury patients. Our research indicated that dysregulation of immune response and neuroinflammation might be potential mechanisms of MMA with brain injury. In addition, it provided a candidate biomarker panel for early diagnosing MMA with brain injury, facilitating early intervention and prognosis improvement. image