our multivariate analysis primarily focused on clinical variables and biochemical markers, without thoroughly investigating the relationships between clinical phenotypes, mtDNA heteroplasmy, or emerging biomarkers such as fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) (25), both of which have been linked to mitochondrial disease severity (26). This evidence concerns the gene GDF15 and mitochondrial disease.