Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to
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ORIGINAL ARTICLE
Fibroblast growth factor 21 and grow differentiation factor 15 are sensitive biomarkers of mitochondrial diseases due to mitochondrial transfer-RNA mutations and mitochondrial DNA deletions Patrizia Formichi 1,2 & Nastasia Cardone 2,3 & Ilaria Taglia 2 & Elena Cardaioli 2 & Simona Salvatore 2 & Annalisa Lo Gerfo 4 & Costanza Simoncini 4 & Vincenzo Montano 4 & Gabriele Siciliano 4 & Michelangelo Mancuso 4 & Alessandro Malandrini 1,2 & Antonio Federico 1,2 & Maria Teresa Dotti 1,2 Received: 2 December 2019 / Accepted: 13 April 2020 # Fondazione Società Italiana di Neurologia 2020
Abstract Background Diagnosis of mitochondrial diseases (MDs) is challenging, since they are multisystemic disorders, characterized by a heterogeneous symptomatology. Recently, an increase in serum levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has been found in the majority of patients with MDs compared with healthy controls. On the other hand, the finding of low FGF21 and GDF15 levels in some patients with MDs suggests that different types of respiratory chain defects may lead to different profiles of these two proteins. Objective In this study, we aimed to validate the diagnostic reliability of FGF21 and GDF15 assays in MDs and to evaluate a possible correlation between serum levels of the two biomarkers with genotype of MD patients. Serum FGF21 and GDF15 levels were measured by a quantitative ELISA. Results Our results showed increased serum FGF21 and GDF15 levels in MD patients; however, GDF15 measurement seems to be more sensitive and specific for screening tests for MD than FGF21. Moreover, we showed a positive correlation with both FGF21 and GDF15 levels and the number of COX-negative fibers. Conclusion Finally, we also demonstrated that the increase of FGF21 and GDF15 was related to MDs caused by mitochondrial translation defects, and multiple and single mtDNA deletions, but not to MDs due to mutations in the respiratory chain subunits. Keywords FGF21 . GDF15 . Mitochondrial diseases . Biomarkers
Introduction
* Patrizia Formichi [email protected]; [email protected] 1
UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
2
Department of Medicine, Surgery and Neurosciences, University of Siena, V.le Bracci, 2, 53100 Siena, Italy
3
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
4
Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy
Mitochondrial disorders (MDs) are the most common form of inherited metabolic diseases with an estimated prevalence of 1:5000 [1]. MDs are associated with dysfunctions of oxidative phosphorylation and mutations in the mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). In MDs, different organs and tissues can be affected, mostly those with the greatest energy demand, such as muscles and brain. Clinical diagnosis is often difficult to establish for the multisys
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