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

Lead Research Organisation: Newcastle University
Department Name: Institute for Ageing and Health

Abstract

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.

Technical Summary

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.

Publications


10 25 50
Ahmed M (2016) Targeting protein homeostasis in sporadic inclusion body myositis. in Science translational medicine
Alston CL (2011) Maternally inherited mitochondrial DNA disease in consanguineous families. in European journal of human genetics : EJHG
 
Description Cardiac manifestations of mitochondrial disease - incidence, mechanisms and treatment
Amount £242,206 (GBP)
Organisation British Psychological Society (BPS) 
Sector Learned Society
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2010 
End 03/2013
 
Description Clinical training fellowship
Amount £244,514 (GBP)
Organisation Royal College of Psychiatrists 
Sector Learned Society
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start  
 
Description Fight Alpers/The Ryan Stanford Appeal
Amount £24,000 (GBP)
Organisation Ryan Stanford Appeal 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2010 
End 09/2013
 
Description Fondazione IRCCS Istituto Neurologico Carlo Besta - Fight MERFF Y1/Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Amount £83,787 (GBP)
Organisation Carlo Besta Neurological Institute 
Sector Public
Country Italy, Italian Republic
Start  
 
Description In situ characterisation of stem cells and their fate in the human prostate (co-applicant)
Amount £73,430 (GBP)
Organisation Cancer Research UK (CRUK) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2011 
End 12/2014
 
Description Keystone Scholarship/National Institutes of Health, National Institute on Aging Grant #1R13AG034755-01.
Amount £625 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States of America
Start  
 
Description MRC Centre for Neuromuscular Diseases
Amount £957,958 (GBP)
Funding ID K000608 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2013 
End 01/2018
 
Description MRC Exercise Lab
Amount £759,103 (GBP)
Funding ID G0802536 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2009 
End 12/2013
 
Description Mitochondrial Disease Patient Cohort (UK)
Amount £724,428 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2009 
End 08/2015
 
Description NIHR Senior Investigator
Amount £60,000 (GBP)
Organisation University College London Hospitals Charity (UCLH) 
Department National Institute for Health Research (NIHR)
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2009 
End 04/2012
 
Description RCF - salary funding for backfill post
Amount £200,010 (GBP)
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2014 
End 03/2016
 
Description Wellcome Trust Centre for Mitochondrial Research
Amount £4,500,000 (GBP)
Funding ID 096919 
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 05/2012 
End 04/2017
 
Title Mitochondrial Disease Cohort 
Description The funding is to develop a mitochondrial disease cohort. We have collected 240 patients in first year with funding to develop the cohort over the next 2 years 
Type Of Material Biological samples 
Provided To Others? No  
Impact Collecting cohort only at this stage 
 
Title Quality of Life questionnaire 
Description A questionnaire that is honed to pick up quality of life measurements in this particular patient group. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact This evaluation will allow us to better measure quality of life in patients, and design future studies and interventions around this. We aim to develop this further before disseminating to other research and clinical settings. 
 
Description Collaboration with Harvard University 
Organisation Harvard University
Department Harvard Medical School
Country United States of America 
Sector Academic/University 
PI Contribution Analysis of single cells, laser microdissection
Collaborator Contribution Expertise in single molecule PCR
Impact Greaves LC, Beadle NE, Taylor GA, Commane D, Mathers JC, Khrapko K, Turnbull DM. Quantification of mitochondrial DNA mutation load. Aging Cell 2009a; 8: 566-72. Multidisciplinary involving molecular genetics, cell biology
Start Year 2008
 
Description Collaboration with Mitochondrial Biology Unit 
Organisation Medical Research Council (MRC)
Department MRC Mitochondrial Biology Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
PI Contribution I provide him with ideas and patient materials.
Collaborator Contribution Ian has provided reagents advice and expertise for many years
Impact We co-chaired an international workshop (163rd ENMC International Workshop: Nucleoid and nucleotide biology in syndromes of mitochondrial DNA depletion myopathy. 12-14 December 2008, Naarden, The Netherlands) resulting in 2 publications. Cross-ferlisation of ideas result in a PLOS-genetics paper in 2010 and a Nucleic Acids Research paper in 2009.
 
Description Collaboration with UCL 
Organisation University College London (UCL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Expertise in muscle disease and sarcopenia. This is close working between two MRC Centres. Professor Hanna directs the MRC Translational Centre for Neuromuscular Disorders
Collaborator Contribution Expertise in muscle disease
Impact Joint conference on Neuromuscular diseases
Start Year 2008
 
Description Collaboration with University of Edinburgh 
Organisation University of Edinburgh
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Expertise in mitochondrial genetics
Collaborator Contribution Expertise in genetics
Impact Wright AF, Murphy MP, Turnbull DM. Do organellar genomes function as long-term redox damage sensors? Trends Genet 2009; 25: 253-61
Start Year 2008
 
Description Collaboration with University of Edinburgh - Mouse Model 
Organisation University of Edinburgh
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution This collaboration is with Dr K Horsburgh of the Centre for Cognitive Ageing and Cognitive Epidemiology. Expertise in characterisation of the neuropathological changes in a mouse model of cerebral hypoperfusion. The collaboration is expected to lead to the development of another mouse model on site within the CBAV.
Collaborator Contribution Characterisation of mouse models of brain hypoperfusion
Impact Coltman R et al. Selective white matter pathology induces a specific impairment in spatial working memory. Neurobiol Aging, in press.
Start Year 2008
 
Description Collaboration with University of Texas 
Organisation University of Texas
Country United States of America 
Sector Academic/University 
PI Contribution Analysis of muscle biopsies from patients undergoing exercise regimes
Collaborator Contribution Exercise physiology
Impact Murphy JL, Blakely EL, Schaefer AM, He L, Wyrick P, Haller RG, Taylor RW, Turnbull DM, Taivassalo T. Resistance training in patients with single, large-scale deletions of mitochondrial DNA. Brain 2008a; 131: 2832-40. Multidisciplinary involving exercise phsyiology, clinical and molecular genetics
Start Year 2007
 
Description BPNA 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary talk

Increased patient referrals
Year(s) Of Engagement Activity 2007,2012
 
Description CLIMB Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact JP invited to give an illustrated talk to families of mitochondrial patients for 40 minutes

Personal feedback from grateful families and commendation by chief exec of CLIMB as well as chairperson. Report to appear in organisation literature.
Year(s) Of Engagement Activity 2008
 
Description DMT Max Planck Cologne 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote speech at the Max Planck Institute Symposium in Cologne. Talk generated a lot of questions and discussion.

continued collaboration with researchers at the Max Planck Institute
Year(s) Of Engagement Activity 2014
 
Description Elders Council Radio interview 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Dr Gorman was interviewed for the Elders Council radio programme on a local Newcastle radio station about why an active lifestyle and its relationship to older people's quality of life, with particular reference to the effect of physical activity on cognitive ability.

not known
Year(s) Of Engagement Activity 2010
 
Description Fit as a Falcon 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact An activity day attended by over 100 school children showcasing the four themes of the Centre. The day was organised in collaboration with Newcastle Falcons Community Foundation and built on work they were already doing with schools in the area. The activities were designed to show how a healthy lifestyle when we are younger affects the way we age, focusing on exercise and nutrition.
Feedback from the children, teachers and students and scientists involved in the event was very positive. It also worked well from the Falcons perspective and they have asked us to make this an annual event. There will also be opportunities to be involved with other engagement programmes that the Falcons Community foundation are running.
Year(s) Of Engagement Activity 2016
 
Description Natural History Museum display 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We mounted a very successful exhibition as part of the Science Uncovered event at the Natural History Museum in London. We put together a portable display which included many interactive stations. The display can be re-assembled and used at future events.

The display was very popular with both children and adults who visited the exhibition and led to some interesting and thought provoking discussions with members of the public. Feedback (via brief questionnaires on the evening) was very positive.
Year(s) Of Engagement Activity 2014
URL http://conscicom.org/2014/09/10/science-uncovered-at-the-natural-history-museum-friday-26th-septembe...
 
Description Newcastle Science Festival 2010 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presented a poster entitled, "Should you put all your eggs in one basket? Fitting another piece to the Parkinson's disease puzzle." Attendees asked questions and discussed the findings.

not known
Year(s) Of Engagement Activity 2010
 
Description Newcastle University engagement activities 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The Centre continues to provide funding towards the salary of Newcastle University's Public Engagement Team. The University has a broad programme of engagement activities. Over the last 12 months there have been over 15 events aimed at disseminating the University's research and activity to the general public. They communicate the activities of CBAV on a monthly basis through Voice North (the Regional Engagement Panel made up of a group of over 700 people reflecting the ag- structure and geographical and socioeconomic make-up of the North East) communications and events and through Years Ahead, the North East Regional Forum on Ageing.

The activities of the public engagement team raise awareness of the research being undertaken by the Centre and the University as a whole. Voice North provides focus groups which contribute to the development of research projects and provide participants for research projects.
Year(s) Of Engagement Activity 2008,2009,2010,2011
 
Description Nuffield students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact 3 students, who were interested in following science as a career, had successfully applied to the Nuffield Foundation for work placements. At the request of the Nuffield Foundation, we were very happy to welcome them into our labs. They spent several weeks in the lab gaining hands-on experience of research.

At the end of their time in the lab, both the students and ourselves produced a report on the experience which was submitted to Nuffield.
Year(s) Of Engagement Activity 2014
URL http://www.nuffieldfoundation.org/nuffield-research-placements
 
Description OK to ask campaign 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact The NIHR 'Ok to ask' campaign aims to encourage patients or carers to ask about research opportunities that could be available to them or their families. We took part in this campaign by holding a stall outside of the Medicinema within the The Great North Children's Hospital. It gave members of the public an informal opportunity to chat to some of our researchers and ask questions about our research.
Year(s) Of Engagement Activity 2016
URL http://www.newcastle-mitochondria.com/ok-to-ask-campaign-2/
 
Description Patient Information Day - London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact A Patient Information Day was held in London for local patients, carers and relatives. The day included discussion about the cohort and how patients could get involved.

A number of patients were recruited to the study as a result of the information day, and awareness of the cohort study in general was increased.
Year(s) Of Engagement Activity 2009
 
Description Patient Information Day - Newcastle 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact A patient information day for patients, carers and relatives. This gave information on a range of subjects related to mitochondrial disease, with a specific section of the day devoted to providing information about this cohort.

We were able to recruit a number of patients as a result of the information provided, and raised awareness of the cohort in the patient gorup.
Year(s) Of Engagement Activity 2009
 
Description Patient Information Evening 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact I organised and obtained finance for an information day for patients with mitochondrial DNA diseases. As well as chairing the meeting I gave a 30 minute talk to a lay audience

High patient satisfaction score on subsequent questionaire and complements from professionals who attended
Year(s) Of Engagement Activity 2009
 
Description Patient Information Event Gateshead 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact One of the Principal Investigators on the project participated at a Patient Information Event held in Gateshead in June 2010/

not known
Year(s) Of Engagement Activity 2010
 
Description Patient information day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 84 patients and their families atended an information day covering research and clincial needs. The Cohort study was mentioned and patients were invited to join the cohort.
The session was recorded and placed on YouTube

Questionnaires at end of session showed great support for such a day
Year(s) Of Engagement Activity 2010
 
Description Pronuclear paper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The publication of this paper in April 2010 generated a huge amount of media interest both nationally and inernationally.
Articles appeared in the following newspapers: The Times - page 15 http://tinyurl.com/y625ewj; Daily Mail - page 4 http://tinyurl.com/y5wr6x8; The Telegraph - page 1 http://tinyurl.com/y62t89o; The Guardian - page 1 http://tinyurl.com/y3u4g3m; The Express - page 7 http://tinyurl.com/yyanlh6; Financial Times - page 4 http://tinyurl.com/y6kw2qo; The Sun - page 4 http://tinyurl.com/y6f96cu (The Mirror - page 22 http://tinyurl.com/y6mm3fa

There was also extensive coverage on radio and television, most notably: The story led the Six O'clock news with a 5-minute slot; Sky News ran the story all night; Channel Four did a nice piece and a mention on the ITV news. There were slots on Radio 5 Live and the Today programme and mentions on
most BBC regional stations.

The story was also reported by the following international organisations: ABC News
CBC (Canada)
Globe and Mail (Canada)
MSNBC/ NBC
San Francisco Chronicle
BBC News
Daily Mail
Daily Telegraph
Financial Times
Guardian
Herald
Independent
Sun
Times
AFP (France)
Bloomberg
EFE (Spain)
Reuters
UPI
Xinhua (China)
ABC (Australia)
The Australian
Sydney Morning Herald
China Daily
People's Daily (China)
Spiegel (Germany)
Corriere della Sera (Italy)
La Repubblica (Italy)
Times of India



HFEA launched a public consultation into the ethics of pronuclear research in 2012.
Year(s) Of Engagement Activity 2010
 
Description Response to Science comment article on mitochondrial transfer 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The article on the mitochondrial transfer technique sparked a media frenzy with articles appearing in many newspapers and magazines worldwide as well as extensive coverage on TV, radio and the internet. Below is a selection of items.
http://www.sciencemediacentre.org/tag/mitochondrialdna/
http://theconversation.com/viewpoints-the-promise-and-perils-of-three-parent-ivf-18402
http://www.bbc.co.uk/news/health-24158049
BBC News (quotes Robin LovellBadge and Doug Turnbull)
http://www.bbc.co.u

The extensive media coverage has increased awareness of mitochondrial disease and we have received an increased number of enquiries and hits on our website.
Year(s) Of Engagement Activity 2014
 
Description Website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact A website (http://www.mitochondrialncg.nhs.uk) for both patient and health professional use. This is to increase awareness and knowledge of the disease and disseminate good practice.

This website is providing information for clinicians about referral and diagnostic options for patients not currently seen at a specialist centre. Likewise, patients are also able to find out about options, and also to gain knowledge and information about their condition.
Year(s) Of Engagement Activity 2009