Natural History in Primary Mitochondrial Myopathies

Mitochondrial Diseases (MD) are among the most frequent inherited metabolic diseases. Despite their high impact on patients, there are still no authorized drugs capable of modifying their clinical course. MD are clinically and genetically heterogeneous disorders, with muscular symptoms being one of their main manifestations. When muscular symptoms predominate, the disorder is classified as a Primary Mitochondrial Myopathy. In recent years, there have been significant advances in developing potential new treatments in this field. However, the absence of natural history studies makes the design and interpretation of clinical trials difficult and leads to long delays or even failures in the development of new treatments. The investigators propose to characterize in-depth a cohort of patients with Primary Mitochondrial Disorders due to mutations in the mitochondrial DNA (mtDNA) or in genes located in the nuclear genome (nDNA), from a clinical perspective but also a radiological, biochemical, and molecular point of view, and carry out a longitudinal follow-up of these parameters to identify those that are better correlated with severity and that allow measuring changes in the patient's clinical situation. With this objective, the investigators will analyze clinical variables (evaluation of motor function through manual force exploration, functional scales, and timed test, quality of life scales, serum biomarkers (growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21)), levels of heteroplasmy for cases harboring mtDNA mutations and mtDNA copy-number, and muscle magnetic resonance image of the lower extremities with quantification of fat replacement. All parameters will be evaluated at the beginning of the study and then annually during two years of follow-up.

Inclusion criteria

• Muscle symptoms: exercise intolerance and fatigue, myalgia, recurrent rhabdomyolysis, chronic progressive external ophthalmoplegia and/or muscular weakness
• Primary mtDNA mutation or pathogenic mutations in nDNA, especially in genes related to mtDNA maintenance such as TK2, POLG, TWNK and RRM2B, among others.

Exclusion criteria

• None