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Clinical Measures, Gait and Exercise in Mitochondrial Disease Jane Newman

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Clinical Measures, Gait and Exercise in Mitochondrial Disease Jane Newman Clinical Measures, Gait and Exercise in Mitochondrial Disease Jane Newman Institute of Cellular Medicine Newcastle University This thesis is submitted for admission to the degree of Doctor of Philosophy at Newcastle University, UK May 2015 i Abstract Mitochondrial diseases are one of the most common forms of inherited neuromuscular disease. The presentations of these diseases are highly variable with both neurological and systemic involvement . Despite progress in identifying mitochondrial DNA mutations that result in disease, the natural history of mitochondrial diseases still remains unclear and no effective treatments are currently available (Pfeffer et al., 2012). The use of numerous primary outcomes in studies has made comparisons between studies difficult. A recent Cochrane review recommended the use of measures that were more relevant to patients in studies. This thesis aims to explore the use physiological measures alongside functional measures and gait in mitochondrial disease. The studies demonstrated that all functional outcome measures were able to discriminate between participants with mitochondrial disease and control subjects. However, gait characteristics were also able to discriminate between the two different mitochondrial genotypes. An aerobic exercise intervention resulted in an improvement in exercise capacity. However, disease severity, functional ability and gait measures remained unchanged. The main findings from this thesis are that: Clinical functional measures and gait are relevant for use in the research and clinical management of mitochondrial disease to monitor disease burden. The improvement in exercise capacity following a cycling intervention was unable to be translated into an improvement in function or gait. Therefore further research into other types of interventions, which may improve activities relevant to patients, is required. ii The outcome of any serious research can only be to make two questions grow where only one grew before. Thorstein Veblen iii Acknowledgements I would like to thank my supervisors Professor Douglass Turnbull, Professor Mike Trenell and Professor Lynn Rochester who have guided me along the steep learning curve from aged clinician to early year’s researcher. Alongside my official supervisors a massive thank you must go to Dr Grainne Gorman. Her constant reassurance, advice and drive have been invaluable. Many thanks also have to go to the whole Movelab team for their moral support and for keeping the old girl smiling. Special thanks also to Kate Hallsworth and Sarah Moore, my fellow Physiotherapists, who started on this academic journey at the same time. My thanks also has to go to Brook Galna, who was my ray of sunshine with his Aussie banter and made my introduction into gait assessment a joy with his unflustered approach and extensive knowledge of gait assessment equipment. Thank you to my children; for putting up with me monopolizing the home computer over this lengthy time period. Thanks also to my husband for proof reading the final document and paying the bills. Finally thank you to all the participants for all their hard work, continued support and interest in what I am doing. They constantly keep me reflecting on what I do and how I can improve the management of mitochondrial disease. iv Author contribution Funding for the projects included in this thesis was obtained from awards to my supervisors and the UK National Institute for Health Research Biomedical Research Centre for Ageing and Age-related Diseases award to Newcastle upon Tyne Hospitals NHS Trust. Project proposals and design were written by the author, Professor Michael Trenell and Professor Lynn Rochester. The author applied for ethical approval for the projects with the assistance Geoff Bell and Professor Michael Trenell. Participants were recruited and consented by the author and Dr Matthew Bates. The author oversaw the running of the studies and completed the majority of participant visits. Exercise testing was completed with the assistance of Dr Djordje Jakovljevic and Dr Matthew Bates. The author performed all gait assessments with the assistance of Dr Brook Galna. Data from gait assessments was retrieved by Dr Brook Galna. Supervision of the exercise intervention was performed by the author. Project supervisors, Kim Pearce and Dr Brook Galna provided assistance with statistics. Graph templates were produced with the assistance of Dr Brook Galna. v Publications and presentations Publications First name publications Bates MG*, Newman JH*, Jakovljevic DG, Hollingsworth KG, Alston CL, Zalewski P, Klawe JJ, Blamire AM, Macgowan GA, Keavney BD, Bourke JP, Schaefer A, McFarland R, Newton JL, Turnbull DM, Taylor RW, Trenell MI, Gorman GS. Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G related mitochondrial disease. International Journal of Cardiology 2013, 168 (4), 3599-3608. Galna B*, Newman JH*, Jakovljevic DG, Bates MG, Schaefer AM, McFarland R, Turnbull DM, Trenell MI, Gorman GS, Rochester L. Discrete gait characteristics are associated with m.3243A > G and m.8344A > G variants of mitochondrial disease and its pathological consequences. Journal of Neurology 2014, 261 (1), 73-82. Newman JH*, Galna B*, Jakovljevic DG, Bates MG, Schaefer AM, McFarland R, Turnbull DM, Trenell MI, Taylor RW, Rochester L, Gorman GS. Preliminary Evaluation of Clinician Rated Outcome Measures in Mitochondrial Disease. Journal of Neuromuscular Diseases 2015, (epub ahead of print) (*Joint contributions) Other publications Spendiff S, Reza M, Murphy JL, Gorman G, Blakely EL, Taylor RW, Horvath R, Campbell G, Newman J, Lochmüller H, Turnbull DM. Mitochondrial DNA vi deletions in muscle satellite cells: implications for therapies. Human Molecular Genetics 2013, 22 (23), 4739-4747. Bates MG, Hollingsworth KG, Newman J, Jakovljevic DG, Blamire AM, MacGowan GA, Keavney BD, Chinnery PF, Turnbull DM, Taylor RW, Trenell MI, Gorman GS. Concentric hypertrophic remodeling and subendocardial dysfunction in mitochondrial DNA point mutation carriers. European Heart Journal - Cardiovascular Imaging 2013, 14, (7), 650-658. Muscular Dystrophy Campaign, Exercise advice for adults with muscle wasting conditions. Adult Neuromuscular Physiotherapy Special Interest Group. Nov 2014 Gorman GS, Blakely EL, Hornig‑Do H, Tuppen H, Greaves LC, Langping He, Baker A, Falkous G, Newman J, Trenell M, Lecky B, Petty R, Turnbull D, McFarland R, Taylor RW. Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression. Clin. Sci. (2015) 128 (895-904). Presentations Conference presentations Newman J, Jakovljevic D, Galna B, Bates M, Turnbull D, Trenell M, Gorman G. Improving clinical trials evaluation: physiological and functional correlates in mitochondrial disease. Poster Presentation. Fifth UK Neuromuscular Translational Research Conference. March 2012. Newman J, Galna B, Jakovljevic D, Bates M, Schaefer A, McFarland R, Turnbull D, Trenell M, Taylor R, Rochester L, Gorman G. Evaluation of functional outcome measures as a surrogate marker of disease severity in vii patients with mitochondrial disease. Poster presentation. ABN, RCP joint meeting. Journal of neurology, neurosurgery, and psychiatry, 11/2013; 84(11). Newman J, Galna B, Turnbull DM, Trenell MI, Gorman G, Rochester L. Can discrete gait characteristics serve as a surrogate marker of mitochondrial disease? Poster presentation. Third annual showcase meeting held by the cross-council Lifelong Health and Wellbeing (LLHW) programme. Nov 2013. Prize Winner. Newman J, Galna B, Jakovljevic D, Bates M, Schaefer A, McFarland R, Turnbull D, Trenell M, Taylor R, Rochester L, Gorman G. Can aerobic exercise improve function in patients with mitochondrial disease? Poster presentation. UK Neuromuscular Translational Research Conference. March 2014. London. Neuromuscular Disorders 03/2014; 24:S13-S14. Newman J, Galna B, Turnbull DM, Trenell MI, Rochester L, Gorman G. Gait analysis in patients with mitochondrial disease. UK Neuromuscular Translational Research Conference. March 2015. Newman J, Galna B, Turnbull DM, Trenell MI, Rochester L, Gorman G. Gait analysis: Accuracy as a clinician reported measure in mitochondrial disease. UK Neuromuscular Translational Research Conference. March 2015. Lay presentations Newman, J. “Physiotherapy in Mitochondrial Disease”, Patient Information Day, SAGE, Gateshead. March 2011. Newman, J. “Use it or Lose it”, Keeping Active Matters, Newcastle Biomedical Research Centre, May 2014. viii Newman, J. “How to move and exercise safely?” NMD Patient conference, Centre for Life, March 2015. ix Abbreviations 10MTW 10 metre timed walk 31PMRS 31 Phosphorus Magnetic Resonance Spectroscopy 5XSTS 5 times sit to stand 6MWD 6 minute walk distance a-vO2 diff Arterio venous oxygen difference ACE-R Addenbrooks Cognitive Examination –revised ACSM American College of Sports Medicine ADP Adenosine Diphosphate AT Anaerobic Threshold ATP Adenosine Triphosphate AUC Area under the curve BMI Body mass Index BP Blood Pressure CO Cardiac output CO2 Carbon Dioxide CoA Co enzyme A COX Cytochrome oxidase CPOE Chronic Progressive Opthalmoplegia DNA Deoxyribonucleic acid ECG Electrocardiogram ETC Electron transport chain FADH2 Flavin adenine dinucleotide FOM Functional Outcome Measure GP General Practitioner H2O Water HR Heart Rate IPAQ International Physical Activity Questionnaire MD Mitochondrial Disease Mitochondrial myopathy, encephalopathy, lactic acidosis and MELAS stroke like episodes MERRF Myoclonic
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