Fibroblast growth factor 21 and growth differentiation factor 15 as biomarkers for oxidative stress in children with methylmalonic acidemia

Methylmalonic acidemia (MMA) is a rare autosomal recessive inborn error of metabolism commonly presenting in infancy with episodes of metabolic acidosis that can lead to considerable morbidity and early mortality. Oxidative stress is a major aspect in the pathogenesis of MMA. We aimed to evaluate the clinical utility of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) and correlate their levels with established biomarkers of oxidative stress, such as reduced glutathione (GSH) and reduced/oxidized (GSH/GSSG) glutathione ratio in MMA children in a clinical setting. Nineteen MMA pediatric patients (median 5.7; IOR 2.9–7.3 years) were recruited. Thirty age and sex matched healthy children were further recruited as a comparator group. Total glutathione, reduced glutathione, FGF21 and GDF15 were assayed for both cohorts. Total and reduced glutathione were significantly reduced in MMA patients compared to controls (P < 0.001 for both), while FGF21 and GDF15 were significantly elevated (P = 0.037 and < 0.001, respectively). Both FGF21 and GDF15 had a significant negative correlation with GSH/GSSG ratio (r=–0.256; P = 0.038 and r=–0.367; P = 0.005, respectively); however, only GDF15 had a negative correlation with both total and reduced glutathione (r=–0.443; P < 0.001 and r=–0.459; P < 0.001, respectively). GDF15 had a better performance in the ROC curve analysis; AUC = 0.805 vs. 0.668 for FGF21, while FGF21 was a significant predictor of eGFR in the linear regression analysis. FGF21 and GDF15 were both significantly increased in the studied MMA pediatric patients and had strong correlations with established oxidative stress biomarkers. Since both are more stable during storage and easier to assay than glutathione based indicators, their use as candidate biomarkers for oxidative stress in MMA children can be considered.