The MRC Centre for Translational Research in Neuromuscular Disease Mitochondrial Disease Patient Cohort (UK)

Mitochondria are found in every cell in the body and function like tiny batteries, converting energy locked in foodstuffs into a form that can be used easily by the cell. These tiny batteries contain their own genetic information (mtDNA) that is passed from mother to child. This genetic information is a blueprint for parts of the enzymes crucial for the energy conversion process. Genes stored in the nucleus are also important for normal mitochondrial function and disruption (misspelling or omissions in the genetic code) of either mtDNA or nuclear DNA (nDNA) can cause the batteries to fail, resulting in mitochondrial disease. This problem appears to affect at least 1 in 6500 people in the UK and commonly leads to symptoms of fatigue, weakness, unsteadiness, swallowing difficulties, stroke-like episodes, seizures, acidosis and heart disease. Recognition of mitochondrial disease as a significant clinical problem is relatively recent and many of the different forms of the disease (virtually any body organ can be affected) are still being characterized. At present no cure is available and patients? symptoms are treated with conventional medicines that have not been assessed in patients with mitochondrial disease.
We plan to define a cohort of 1500 patients, (adults and children), in whom mitochondrial disease has been identified on both clinical and genetic grounds. Our aims in developing this cohort are to translate improvements in our understanding of the science of mitochondrial disease into direct health benefits for patients. We also want to further our understanding of mitochondrial disease mechanisms and transmission and to evaluate (and optimise) the treatment of complications such as stroke, seizures, diabetes, poor growth and heart disease in patients with mitochondrial disease. The cohort will also be a rapidly accessible resource for assessing novel clinical interventions such as drugs targeted to mitochondria and exercise therapy. The cohort will be managed through The MRC Centre for Translational Research in Neuromuscular Disease and transferred to the NHS at the end of the period of funding. Data collected will be managed and stored responsibly and patient care will be unaffected by their decision to enrol in the cohort or not.

Mitochondrial disease is a severely debilitating and often life-threatening condition with a minimum prevalence of 9.2/100000 and a further 16.5/100000 at risk of developing the disease. Neuromuscular symptoms are common and developing new treatments is a key component of the recently established MRC Centre for Translational Research in Neuromuscular Disease. The clinical phenotype is extremely variable and descriptions of the natural history are largely anecdotal with no systematic attempts to study mitochondrial disease progression in a tightly defined patient cohort. The development of both retrospective and prospective assessment tools, by the Newcastle Mitochondrial Research Group, will permit acquisition of accurate objective data on mitochondrial disease progression in both children and adults from the proposed cohort. This data will be crucial in terms of providing evidence based prognostic advice to patients and is a prerequisite for assessing efficacy of clinical interventions. Trials of potential treatments for mitochondrial disease have been confined to very small groups of patients and conclusions underpowered and virtually meaningless. The development of this cohort by the MRC Centre for Translational Research in Neuromuscular Disease will facilitate large-scale interventional trials of drugs and novel treatments such as sequential resistance-endurance exercise. Strategies to prevent the complications of mitochondrial disease have been empiric with no direct evidence base. This cohort will also provide the opportunity to assess various prevention strategies including those for cardiomyopathy, stroke-like episodes, migraine and epilepsy. The unprecedented access to family data including genotyping will also permit definitive studies on the transmission of mitochondrial DNA (mtDNA) mutations and related to this, the effects of mitochondrial disease on female fertility and pregnancy. The timing of this call coincides perfectly with the recent awarding to the applicant centres in Newcastle and London of National Commissioning Group (NHS) funding for Rare Mitochondrial Diseases and MRC funding for Centre for Translational Research in Neuromuscular Disease. The cohort will provide real added value to these initiatives and benefit from the close working relationships already established.