Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease

Abstract

The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy taken <12 months apart, a mitochondrial disorder would have been identified in 70% with analysis of FGF21 and GDF15 compared to 50% of patients whom could have been identified with muscle biopsy alone. Muscle findings were nondiagnostic in 72% (children) and 45% (adults). Induction of FGF21 and GDF15 suggest a mitochondrial

Plasma GDF-15 concentration is not elevated in open-angle glaucoma

“…However, most of the mitochondrial disease patients with abnormal GDF-15 levels had a myopathy i.e. mitochondrial dysfunction in muscle cells [ 24 ]. It is known that GDF-15 in the blood originates from visceral organs such as the liver and that these organs can strongly increase expression of GDF-15 in response to signaling molecules from muscle cells affected by mitochondrial dysfunction as a result of mtDNA translational defects or mtDNA deletions [ 49 , 50 ].…”

“…Alternatively, an explanation could be that GDF-15 is not a suitable biomarker. Plasma GDF-15 is currently one of the most sensitive biomarkers to detect mitochondrial dysfunction, with an average sensitivity vs specificity of 89.7% to identify mitochondrial disease patients [17][18][19][20][21][22][23][24]. However, most of the mitochondrial disease patients with abnormal GDF-15 levels had a myopathy i.e.…”

“…blood, since obtaining a retinal biopsy is not possible. Recently, blood levels of growth differentiation factor-15 (GDF-15) have been described as a biomarker to diagnose mitochondrial dysfunction, with an estimated average sensitivity vs. specificity of 89.7% to identify primary mitochondrial disease patients [17][18][19][20][21][22][23][24].…”

Skeletal Muscle and Bone – Emerging Targets of Fibroblast Growth Factor-21

“…In humans, serum FGF21 levels are significantly increased in patients with primary muscle-manifesting respiratory chain deficiencies, particularly those caused by pathogenic mutations in mitochondrial DNA (Suomalainen et al, 2011;Crooks et al, 2014) with the muscle believed to be the primary contributory organ to circulating levels (Crooks et al, 2014). Thus, FGF21 has recently gained attention as a potential biomarker of mitochondrial diseases (Tyynismaa et al, 2010;Suomalainen et al, 2011;Lehtonen et al, 2016Lehtonen et al, , 2020 and could represent a potential target for the treatment of mitochondrial myopathies and muscle mitochondria dysfunction.…”

Plasma Gelsolin Reinforces the Diagnostic Value of FGF-21 and GDF-15 for Mitochondrial Disorders

“…Alternatively, GDF-15 is a member of the transforming growth factor beta superfamily, which is highly expressed in placenta [20]. Increased serum GDF-15 levels have been associated with MD originated by different mutations and clinical conditions [21][22][23][24]. In different cohorts of MD patients, GDF-15 positively correlated with FGF-21, but usually showing a higher sensitivity for MD diagnosis than the latter [23,[25][26][27].…”