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NCT04734626
The purpose of this study is to perform a "muscle phenotyping" magnetic resonance imaging (MRI) assessment in patients receiving clinical care at the Children's Hospital of Philadelphia (CHOP) for mitochondrial disease that is either suspected (based on clinical presentation) or has a definite genetic diagnosis. The MRI assessment quantifies skeletal muscle oxidative phosphorylation (OXPHOS) capacity. Investigators hope that this study will contribute to our current knowledge of mitochondrial diseases and this study will help create a new diagnostic tool for use in both clinical care and in clinical trials.
NCT01148550
The specific aims of this study are (1) to determine the clinical phenotypes and natural history of hepatic RC and FAO disorders, (2) to determine the correlation between genotype and phenotype, (3) to determine if circulating biomarkers reflect diagnosis and predict liver disease progression and survival with the native liver, (4) to determine the clinical outcome of these disorders following liver transplantation, and (5) to develop a repository of serum, plasma, urine, tissue and DNA specimens that will be used in ancillary studies. To accomplish these aims, the ChiLDReN investigators at clinical sites (currently 9 sites) will prospectively collect defined data and specimens in a uniform fashion at fixed intervals in a relatively large number of subjects. Clinical information collected from subjects and their parents will enhance the potential for meaningful research in these disorders. A biobank of previously collected subject specimens and DNA samples will be established for use in ancillary studies to be performed in addition to this study.
NCT04548843
The study objectives are to evaluate the safety of a single intravenous (IV) infusion of autologous CD34+ cells enriched with placenta-derived allogeneic mitochondria in participant with primary mitochondrial disease associated with mitochondrial DNA mutations or deletions. 6 participants aged from 4 to 18 years old on the day of screening visit with primary mitochondrial disease associated with mitochondrial DNA mutations or deletions will be enrolled.
NCT06080594
The overarching aim of this intervention study is to interrogate the interconnection between the muscle mitochondrial adaptations and the changes in muscle insulin sensitivity elicited by exercise training in individuals harbouring pathogenic mitochondrial DNA mutations associated with an insulin-resistant phenotype. In a within-subject parallel-group longitudinal design, participants will undergo an exercise training intervention with one leg, while the contralateral leg will serve as an inactive control. After the exercise intervention, patients will attend an experimental trial including: * A hyperinsulinemic-euglycemic clamp combined with measurements of femoral artery blood flow and arteriovenous difference of glucose * Muscle biopsy samples
NCT05554835
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.
NCT04802707
Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis. MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. No treatment for MDS. Clinical trials studies and in vitro/in vivo research studies showed that the enhancement of the salvage pathway by increasing the availability of deoxyribonucleosides needed for each specific genetic defect prevents mtDNA depletion. Early recognition and immediate therapy to restore mitochondrial function could potentially improve clinical course. Confirming the benefit of deoxynucleosides as a safe and potentially efficacious therapy, will lead to the availability of the first specific and effective treatment for Mitochondria Depletion Disorders. In this phase II Trial a mix of Deoxynucleosides Pyrimidine (Deoxycytidine dC and Deoxythymidine dT) will be used as early treatment of MDS. The dose used has been already used in other clinical trials, and appears to effective and well-tolerated. The subjects included are children (0-18Y), with positive MDS diagnosis and express mutations in one of the following genes: POLG, POLG2, C10orf2, RRM2B, MPV17, SUCLA2, SUCLG1, FBXL4, DTYMK. Subjects with MDS expressing neurological phenotypes dysfunction.
NCT06573866
Work participation is essential for quality of life, providing purpose, social interaction, financial security, and shaping social status. Work participation is increasingly compromised in people with slowly progressive chronic disorders (hereafter referred to as progressive disorders). This negatively impacts their quality of life. Early work-related support, focused on sustainable work-retention, has the potential to enhance work participation in people with progressive disorders. Therefore, this study investigates the (cost)effectiveness of the Preventive Participatory Workplace Intervention (PPWI), a personalized work intervention to enhance sustainable work participation. The investigators perform an 18-month randomized controlled trial (RCT). In addition, the investigators perform a process evaluation and an economic evaluation alongside the RCT. 124 Dutch working persons with three types of movement disorders will be included: Parkinson's Disease (PD), cerebellar ataxia (CA) and hereditary spastic paraparesis (HSP) and with slowly progressive neuromuscular and mitochondrial disorders.
NCT04831424
The MiSBIE study collects biological, behavioral, psychosocial, neuropsychological, and brain imaging data in participants with either: normal mitochondrial function, individuals with the m.3243A\>G mitochondrial DNA (mtDNA) mutation, and individuals a single large-scale mtDNA deletion. These defects induce mitochondrial allostatic load (MAL). The 2-day protocol, plus home-based data collection, will provide a comprehensive assessment of the multi-systemic dysregulation associated with MAL or mitochondrial dysfunction, and the link to physical and mental health-related symptoms. Aim 1: Determine the influence of MAL on systemic AL biomarkers. Aim 2: Establish the influence of MAL on stress reactivity profiles. Aim 3. Examine the association between MAL and psychological functioning.
NCT06621732
Next-generation sequencing (NGS), and in particular whole exome sequencing (WES) or genome sequencing (WGS), has enabled a significant technical advance that has considerably improved genetic diagnostics. However, around 50% of patients still remain undiagnosed and are in diagnostic limbo. One of the causes of this is pathogenic variants that modify transcript expression and/or RNA splicing. These variants may be located in deep intronic or intergenic regions, or in the coding sequence, synonymous or missense variants, also having pathogenic consequences on splicing or gene expression. It is very often difficult to interpret the pathogenicity of these variants, which often remain variants of uncertain significance (VSI). The usefulness of transcriptome sequencing (RNA-seq) in the genetic diagnosis of MM has been demonstrated in recent years by several teams with diagnostic yields of 10% to 35%. These studies are ideally performed using muscle tissue, as MMs are most often expressed in tissues with high energy metabolism such as muscle, heart, brain or liver. However, as biopsies of these tissues are difficult to obtain, most transcript studies are performed using fibroblasts obtained from skin biopsies. Indeed, extreme regulatory defects such as loss of expression or aberrant splicing can be detected in fibroblasts, even though the physiological consequence on fibroblasts may be negligible. However, some patients also refuse these biopsies and may remain in diagnostic limbo in the absence of functional analysis to confirm the pathogenicity of the variants identified. RNA studies can also be performed using RNA extracted from blood cells on PAXGene tubes. The quantity of RNA extracted is lower than that extracted from fibroblasts, but this type of analysis avoids a more invasive procedure, saves technical time by avoiding the manips associated with cell culture, and saves time for the patient by enabling immediate extraction from the blood tube without waiting for cell culture. Frésard et al showed in patients with 16 different Mendelian pathologies that RNA-seq on blood cells identified a diagnosis in 7.5% of patients tested. Their approach revealed both expression variations and splicing anomalies. The investigators therefore propose to carry out a transcript study using high-throughput RNA sequencing (RNA-Seq), in parallel on RNA extracted from fibroblasts and on RNA extracted from blood cells, on 10 patients with suspected mitochondrial disease in whom variants of uncertain significance in candidate genes (VSI+) have been identified. The investigators chose to target our study on patients with VSI+, previously identified by NGS, to facilitate interpretation of the RNA-Seq data within the framework of a "pilot" study. In these patients, who carry variants in candidate genes, the investigators will focus our bioinformatics analysis on these genes. For the interpretation of VSI+, a targeted approach using Sanger sequencing based on RT-PCR, or quantification of gene expression using quantitative PCR, is also feasible, but requires custom development for each variant, which is very time-consuming and not insignificantly expensive. The advantage of an RNA-seq approach is that it homogenizes the diagnostic strategy for patients, saves analysis time and therefore reduces the time spent in diagnostic wandering. Finally, the drastic reduction in the cost of NGS sequencing means that this technique could be used routinely as a complement to exome/genome sequencing. It could therefore eventually be applied not only to patients with VSI+ but also, in the absence of evidence of potentially pathogenic variants, as an aid to filtering variants identified by WES/WGS.
NCT04920812
MITOMICS aims to determine which RNA-Seq results (from muscle or fibroblasts) are the most informative for the interpretation of VUS identified by WES for patients suspected of mitochondrial myopathy. Analysis of RNA-Seq and WES results will performed with a computational approach using an autoencoder-based method
NCT04689360
Choosing to participate in an expanded access program is an important personal decision. Talk with your doctor to learn more about this program. The treating physician must contact StealthBiotherapeutics using the Expanded Access Program Contacts provided. Elamipretide will only be made available after careful review of an individual request submitted by the treating physician. The initiation and conduct of the treatment with elamipretide for an individual patient, and compliance with this treatment guideline, will be under the full and sole responsibility of the treating physician.
NCT06051448
The goal of this study is to find the best way to help people with primary mitochondrial disease deal with the stress of their condition, and to help these people be better able to "bounce back," or be resilient. In order to do this, the investigators are going to test two interventions (an intervention means that it aims to change something): Promoting Resilience in Stress Management (PRISM) and clinical-focused narrative (CFN) intervention.
NCT06504433
The Natural History of Mitochondrial (MITO) Diseases (a longitudinal study observing the natural history of mitochondrial diseases) The goal of this observational study (non-randomised retrospective and prospective) is to fully characterise primary MITO disease; that includes both sexes/genders, over 18 years of age and healthy volunteers\]. The main question\[s\] it aims to answer is to: • better characterise MITO phenotypes (organ involvement, severity, progression) and collect biospecimens to create a biobank that can be used for future biomarker discovery to improve early diagnosis, prognostication and management of mitochondrial disease. The study will be a longitudinal, retrospective, prospective, observational study of participants (400) with confirmed MITO and relevant controls followed for up to 10 years. Data will be collected at regularly scheduled standard-of-care (SOC), 6 to 12 monthly appointments. The 100 control participants will therefore be comprised of (i) unaffected asymptomatic family members of MITO participants with no genetic risk; (ii) participants with non-MITO movement disorders that are not classified as MITO by their clinical presentation and genetic tests (for example Parkinson's disease) and/or (iii) age-matched healthy controls recruited from the NeuRA database of volunteers. Demographic data, medical history, biochemical, histological, genetic, social and other clinical SOC data will be collected. Additionally, seizure and migraine frequency in participants who experience these, will be collected and a quality-of-life questionnaire (SF-12v2), as part of the validated neurological assessment using the Newcastle Mitochondrial Disease Adult Scale (NMDAS).
NCT05012358
This study is an observational longitudinal study involving the use of MRIs and video recordings taken at home of patients completing basic tasks. Once consent is obtained, subjects will be asked to schedule an appointment with radiology to undergo the listed MRIs of the heart and/or muscle. Subjects will also be given instructions on how to use the video recording app on their personal devices, or study provided device. The subjects will be followed regularly over the course of two years, submitting video recordings of their movements and reporting to Mayo Clinic for MRIs as scheduled.
NCT04604548
This is an open-label, multi-centre study in subjects with a genetically confirmed mitochondrial deoxyribonucleic acid (DNA) transfer ribonucleic acid (tRNA)Leu(UUR) m.3243A\>G mutation who completed study KH176-202. In the KH176-203 study subjects will be receiving KH176 100 mg BID or KH176 50 mg bid in die (BID) (as determined by the investigator based on safety / tolerability considerations) for a year, thereby ensuring continued treatment with KH176 after study KH176-202. A final follow-up visit is scheduled 4 weeks after the intake of the last dose of study medication for patients not rolling over into the compassionate use program. Primary safety data and secondary efficacy (endpoint) data will be monitored and reviewed every three months by an independent Data Safety Monitoring Board (DSMB) to evaluate potential risks and benefits.
NCT01370447
This study will evaluate the safety and efficacy of EPI-743 in participants with severe mitochondrial respiratory chain diseases who are considered to be within 90 days of end-of-life care.
NCT04226820
Oxygen is required for an optimal muscle function. In patients with diabetes mellitus, hyperglycemia can cause vascular complications. The endothelium (inter layer of the blood vessels) can be damaged leading to a reduced oxygen flow towards the muscle cells. Besides, it is possible that mitochondrial dysfunction is occuring leading to reduced extraction of oxygen. Both conditions will lead to a reduced flow of oxygen towards the muscle and this can have impact on the production of energy necessary for optimal functioning. In this study, the investigators will examine the functionality of the blood vessels (1) and the uptake of oxygen into the muscles (2) in patients with diabetes mellitus type 1 and type 2 (with and without vascular complications) compared to healthy persons.
NCT03432871
Mitochondria are important parts of the cell that are responsible for producing energy. The amount of energy they produce depends on how much energy the body needs to function and this energy production can be severely impaired in people with mitochondrial disease. Symptoms of mitochondrial disease vary widely but usually involve the brain, nerves and muscles, as these are tissues that need a lot of energy. Mitochondrial disorders affect 1 in 5000 of the UK population and there is currently no cure. Some scientists think that increasing the number of mitochondria in the body (mitochondrial biogenesis) might be an effective treatment for the symptoms of mitochondrial disease. Studies carried out in mice have shown that a type of B-vitamin called Nicotinamide Riboside (NR) is able to increase the number of mitochondria, leading to increased energy and a reduction in the symptoms of mitochondrial disease. The aim of this study is to investigate if the same B vitamin, Nicotinamide Riboside, can increase energy production and reduce symptoms in humans with mitochondrial disease. The study will consist of two parts: Part 1: Participants will be given a single oral dose of Nicotinamide Riboside and the levels of NR in their bloodstream will be measured at regular intervals. This will involve a single overnight stay and simple blood tests. Part 2: This requires 6 separate visits from each participant. Each participant will undergo a series of standard tests including a muscle biopsy and an MRI scan, then they will take a course of Nicotinamide Riboside (twice daily for 4 weeks). After 4 weeks of treatment, the participants will undergo the same tests again to see if there have been any changes in response to the treatment.
NCT03888716
This will be a double blind, randomised, placebo controlled, single and multiple oral dose study conducted in 3 parts: Part A, Part B and Part C. Part A and Part B include healthy volunteers only and will be completed before Part C including patients with primary mitochondrial disease will be initiated. The starting dose in the first cohort of Part A will be 25 mg. The dose level in the additional cohorts will be decided following review of data of the previous cohorts.
NCT03213067
Gastrointestinal (GI) dysmotility in patients with mitochondrial disease are increasingly recognized and often include dysphagia, abdominal pain, abdominal distention, bacterial overgrowth, constipation, and in severe cases surgery. Although the proposed pathological mechanisms underlying the development of GI dysmotility remain diverse, potential mechanisms include mitochondrial dysfunction of smooth muscle within the GI tract and visceral myopathy. Moreover, bacteria within the GI tract, termed 'gut microbiota' has also been identified as a key contributor towards GI dysmotility. Aim: The aim of this study is to assess the role that the gut microbiota has on clinical disease expression in patients with mitochondrial disease. Objectives: This is a feasibility study to assess: 1. How does clinical disease severity impact upon the gut microbiota in mitochondrial patients compared to healthy controls. 2. How diagnostic and therapeutic approaches for mitochondrial disease be improved. Methods: This is a pilot study and is part of the Newcastle Mitochondrial Research Biobank. Stool samples will be collected from patients with a Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episodes (MELAS) phenotype carrier of the m.3243 A\>G mutation (N=20) from the United Kingdom Medical Research Council (MRC) Centre for Mitochondrial Disease Patient Cohort (RES/0211/7552, the largest cohort of mitochondrial patients in the world) and the mitochondrial clinic and age and gender matched healthy controls (N=20). DNA will be extracted from stool samples and the 16S rRNA gene (V4 region) will be sequenced. This data will be analysed using bioinformatics pipelines and computational biology. Long Term Goal: To generate novel information relating to how the gut microbiota impacts upon clinical disease expression. This information could then be used to build a predictive model designed to optimise diagnosis and therapeutic treatments. This method also holds potential for use as a model for ageing and diseases associated with mitochondria not working properly, such as diabetes, cancer and Parkinson's disease. This research has the potential to reduce costs to the NHS and improve patient care and their quality of life.