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Serum Proteome Profiling Implicates Dysregulation of Immune Response and Inflammatory Mechanisms in Methylmalonic
Yumei Su1, Jing Wei2, Shuqi Sun1
1Department of Clinical Laboratory, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
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.
Insights
Methylmalonic acidemia (MMA) with brain injury may be diagnosed using a new biomarker panel of ACE and MMP9. This discovery aids early intervention for better outcomes in children with MMA.
Area of Science:
- Biochemistry
- Neuroscience
- Pediatrics
Background:
- Methylmalonic acidemia (MMA) is a common childhood organic acidemia.
- Brain injury is a frequent and severe complication of MMA, often leading to poor prognosis.
- Current understanding of MMA-related brain injury mechanisms and diagnostic biomarkers is limited.
Purpose of the Study:
- To identify potential serum biomarkers for diagnosing MMA with brain injury (MBI).
- To investigate the underlying mechanisms of brain injury in MMA patients.
- To validate candidate biomarkers for early diagnosis and intervention.
Main Methods:
- Serum proteomic analysis was conducted on MMA patients with (MBI) and without (MNBI) brain injury, hyperhomocysteinemia patients (HHCY), and healthy controls (CTRL).
- Bioinformatic analysis identified differentially expressed proteins.
- Candidate biomarkers were validated using enzyme-linked immunosorbent assays (ELISA) in an independent cohort.
Main Results:
- A total of 503 proteins were identified, with 49 differentially expressed between MBI and MNBI groups.
- A combination of ACE and MMP9 showed potential as a biomarker panel for MBI (AUC 0.847).
- Enriched pathways indicated down-regulation of immune response and up-regulation of inflammatory response in MBI patients.
Conclusions:
- Dysregulation of immune response and neuroinflammation are potential mechanisms underlying MMA with brain injury.
- The ACE and MMP9 biomarker panel offers a promising tool for early diagnosis of MBI.
- Early diagnosis can facilitate timely intervention, potentially improving patient prognosis.
