Growth Differentiation Factor 15 Is A Novel Biomarker Of Mitochondrial Disease

BACKGROUNDMitochondrial diseases are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain due to both nuclear and mitochondrial DNA mutations. The estimated prevalence of the mitochondrial disorders in world is at least one per 5000 of the general population. Mitochondrial diseases are multisystem disorders with onset at any age[1-3]. Clinical features vary from an acute life-threatening metabolic derangement to intermittent or episodic crises with partial recovery to a more gradual progressive neurodevelopmental decline or regression. Given the variable and often nonspecific presentation of these disorders and the absence of a reliable biomarker, the diagnosis of mitochondrial disease represents a challenge to clinicians.Growth and differentiation factorl5 (GDF15), also known as macrophageinhibitory cytokine-1 (MIC-1), is a member of the transforming growth factor beta (TGF-β) superfamily. GDF-15 is released from various tissues, including heart and liver, in response to inflammation, oxidative stress and hypoxia. Recently, it is emerging as a nonspecific biomarker for patients with cancer, cardiac, pulmonary, renal, as well as gynecological disease. Interestingly, Kalko and Saskia Koene etal found that GDF-15 may represent a potential novel biomarker for mitochondrial dysfunction and is correlate to mitochondrial disease severity in adult m.3243A>G CarriersOBJECTIVE:The aim of this study was to investigate whether serum GDF15 concentrations is a feasible biomarker and its sensitivity and diagnostic reliability as a biomarker of mitochondrial disease in china.METHODS:We recruited patients with muscle-manifesting mitochondrial disease, non-mitochondrial neuromuscular disease (disease controls) and healthy volunteers (healthy controls) from the same center.GDF15 serum levels were measured by ELISA. We compared serum GDF15 levels to serum FGF21, lactate, and creatine kinase and determined the sensitivity, specificity,odds ratio(OR), and overall reliability of GDF15 as a marker of mitochondrial disease using statistical analyses.RESULTSMean serum GDF15 was significantly increased in 42 patients(31 adult andll children)with mitochondrial disease as compared with 20 patients(17 adult and 3 children) in disease control group and 50 subjects in healthy control group.GDF15 showed an obviously higher diagnostic OR (546 [95% CI(62-4839), p＜0.001]) than other biomarkers. GDF15 was significantly correlated with MD severity and the proportion of RRFs identified in the biopsied muscles. For the identification of mitochondrial disease, the sensitivity was 97.7% (95%C186.20-99.87%) and specificity was 92.86% (95%C183.43-97.34%). The positive and negative predictive values for GDF15 were 89.36%(95%C1 76.11-96.01) and 98.48%(95%C190.73-99.92).The accuracy of GDF15 to correctly identify muscle-manifesting mitochondrial disease was the best when compared with other conventional serum biomarkers. The area under the curve (AUC) of GDF15 for the diagnosis of muscle-manifesting mitochondrial disease was 0-998 (95%C10.956 to 1.000); by comparison, the values for other biomarkers were 0.928 for FGF21 (p=0.0043),0.878 for lactate (p=0.0014), and 0.553 for creatine kinase (p＜0.001).CONCLUSIONCirculating GDF15 can be developed into a non-invasive and first-line diagnostic test for the prediction of susceptible individuals with mitochondrial disease and then reduce the need for muscle biopsy.