Mitochondrial Myopathies

The main goal of the project is provision of a global registry for mitochondrial disorders to harmonize previous national registries, enable world-wide participation and facilitate natural history studies, definition of outcome measures and conduction of clinical trials.

Positive effect of physical activity on health arouses a strong interest at international level and is developped within the scope of national programs. Recommandations exist but must be designed for patients with functional limitations of activities. Patients with mitochondrial diseases have exercice intolerance with an increase of muscular weakness and fatigue after low exercice volume. Theses patients have functional limitations of activities. In order to establish an appropriate training programme, it will be important to define and consider the physical condition. The Society of Mitochondrial Medecine published recommandations for management of theses patients,However, theses recommandations do not allow them to propose a training program of what can be done. For these vulnerable patients, therapists are responsible fo advising a training programm without guidelines to establish its terms and conditions. In addition, some exercices do not appear to have been the subject of complete assessmeents. Regarding training programs (aerobic training, muscle reinforcement, miwed training), scientific literature shows a significant genetic and clinical variabilities, as well as a lack of data on clinical severity of included patients. In addition, the lack of informations regarding training effects of heteroplamy level limits our comprehension of mechanisms involved in adaptation of mitochondrial pool during training. Therefore, further reserchs on this subject are essential. It is necessary to offer these patients a follow-up and personalized training program, which are in adequation with daily life. Some publications call on specifics concepts which are not compatible with day-to-day life. The investigators think it will be useful to investigate training effects in order to have practival conclusions, easily reproducible at home by patients with simple and inexpensive equipment. In this context, video consultation could allow the close follow-up of these patients. The investigators hypothesize that a mixed training (endurance and muscle reinforcement), personalized, at home and followed by video consultation have positive effects on some physical criteria (such as musclar strength, tolerance to effort, functional abilities) without increasing heteroplasmy and creatine phosphokinase levels.

Past mitochondrial disease treatment studies have been unsuccessful in determining treatment efficacy, and a major factor has been the lack of validated biomarkers in mitochondrial myopathy (MM). There is currently a growing number of potential new treatments to be tested through MM clinical intervention trials, which has created a pressing need for quantitative biomarkers that reliably reflect MM disease severity, progression, and therapeutic response. The purpose of the study is to measure the efficacy of an electrochemical oxygen nanosensor to measure in vivo mitochondrial function in human muscle tissue, and its ability to discriminate MM patients from healthy volunteers. The data and results from this nanosensor study may contribute to current and future research, including improved diagnostic and therapeutic approaches for patients with mitochondrial disease.

Past mitochondrial disease treatment studies have been unsuccessful in determining treatment efficacy, and a major factor has been the lack of validated biomarkers in mitochondrial myopathy (MM). There is currently a growing number of potential new treatments to be tested through MM clinical intervention trials, which has created a pressing need for quantitative biomarkers that reliably reflect MM disease severity, progression, and therapeutic response. The purpose of the study is to measure the efficacy of an electrochemical oxygen nanosensor to measure in vivo mitochondrial function in human muscle tissue, and its ability to discriminate MM patients from healthy volunteers. The data and results from this nanosensor study may contribute to current and future research, including improved diagnostic and therapeutic approaches for patients with mitochondrial disease.

This is a multi-aim study, studying the effects of conventional exercise (measured through Cardiopulomary Exercises Testing or an in-bed pedal exercise) and passive exercise through periodic acceleration (pGz). Aim 1 will focus on the differences between primary mitochondrial disease (PMD) patients and healthy volunteers. Aim 2 is an exploratory aim, which will be studying the effects in patients admitted to the Children's Hospital of Philadelphia Pediatric Intensive Care Unit (PICU).

The purpose of this clinical trial is to evaluate the efficacy and safety of Doxecitin and Doxribtimine (dC+dT) in adult participants with thymidine kinase 2 (TK2) deficiency attended in the Neuromuscular Unit of '12 de Octubre' Hospital. The main questions it aims to answer are: * Is dT+dC effective in the treatment of the adult participants with TK2 deficiency? * Is dT+dC safe in the treatment of adult participants with TK2 deficiency? Researchers will evaluate the effectiveness of the treatment doxecitin and doxribthymine in adult participants with TK2 deficiency. In addition, the mitochondrial DNA levels before and after treatment (extracted from the muscle and from uroepithelial cells) of these participants will be also studied.

The main goal of the project is provision of a global registry for mitochondrial disorders to harmonize previous national registries, enable world-wide participation and facilitate natural history studies, definition of outcome measures and conduction of clinical trials.

Mitochondrial diseases caused by defects in oxidative phosphorylation (OXPHOS) due to heteroplasmic mitochondrial DNA (mtDNA) mutations are rare (frequency 1/5,000), but severe multi-system disorders. Clinical manifestations are highly variable, but predominantly affect energy demanding tissues, like brain and muscle. Myopathy is a common feature of mtDNA disorders, being present in more than 50% of the mtDNA mutation carriers, and seriously affects patients' general well-being and quality of life. Currently, no treatment is available for these patients, although the induction of muscle regeneration by exercise treatment has been shown to alleviate their myopathy. This implies that these patients can produce muscle fibres that perform better, most likely because the mutation load is lower. Mesoangioblasts (MABs) are myogenic precursors that have been recognized as a source for development of a systemic myogenic stem-cell therapy. Autologous MABs may be feasible for half of the mtDNA mutation carriers of 6 different mtDNA mutations, as their mtDNA mutation load in mesoangioblasts was (nearly) absent (\<10%). However, there are many more mtDNA mutations in the 16.5kb mtDNA and the aim of this study is to determine the mtDNA mutation load in mesoangioblasts of other mtDNA mutation carriers and identify the patients or mutations for which this is a feasible approach.