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Abstract

Objective:

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).

Methods:

A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function.

Results:

Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme.

Conclusions:

We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.

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AUTHOR AFFILIATIONS

From the MRC Centre for Neuromuscular Diseases (R.D.S.P., S.M.M., E.C., J.L.H., M.P.L., S.R., M.M.R., M.G.H.) and Department of Clinical Neurophysiology (J.B.), UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK; Neurometabolic Unit (A.C., I.H., S.H., J.L.) and Neurogenetics Unit (M.G.S., C.W., E.E.M.), National Hospital for Neurology and Neurosurgery, London, UK; Department of Molecular Neuroscience (J.L.H., H.H., M.P.L., M.M.R., M.G.H.), UCL Institute of Neurology, London, UK; Department of Clinical Neurophysiology (J.B.), Norfolk and Norwich University Hospital, Norwich, UK; Department of Inherited Metabolic Disease (M.C.), Evelina Children's Hospital, St Thomas' Hospital, London, UK; Clinical Genetics Department (F.F.), Guy's & St Thomas' NHS Foundation Trust, London, UK; Dubowitz Neuromuscular Centre (S.A.R.), UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, UK; Dorset Epilepsy Service (R.P.), Poole Hospital NHS Foundation Trust, Poole, Dorset, UK; Department of Neurology (M.R.), King's College Hospital NHS Foundation Trust, London, UK; Department of Clinical Neurology (J.P.), University of Oxford, John Radcliffe Hospital, Oxford, UK; Division of Clinical Genetics (C.C.), MetroHealth Medical Center, Cleveland, OH; Ferguson Smith Centre for Clinical Genetics (C.L.), Yorkhill Hospital, Glasgow, UK; and Mitochondrial Research Group (S.R.), Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK.

STUDY FUNDING

Supported by the NIHR UCLH/UCL Comprehensive Biomedical Research Centre and undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme.

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Information & Authors

Information

Published In

Neurology®
Volume 79Number 11September 11, 2012
Pages: 1145-1154
PubMed: 22933740

Publication History

Received: February 16, 2012
Accepted: April 19, 2012
Published online: August 29, 2012
Published in print: September 11, 2012

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Disclosure

R.D.S. Pitceathly is funded by MRC grant G0800674. S.M. Murphy is supported by NINDS/ORD (1U54NS065712–01). E. Cottenie is funded by MRC Centre grant G0601943. A. Chalasani, M.G. Sweeney, C. Woodward, E.E. Mudanohwo, I. Hargreaves, S. Heales, and J. Land work at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. J.L. Holton is supported by The Myositis Support Group and the Reta Lila Weston Institute for Neurological Studies. H. Houlden is supported by the MRC and Wellcome Trust. J. Blake, M. Champion, F. Flinter, S. Robb, R. Page, M. Rose, J. Palace, C. Crowe, and C. Longman report no disclosures. M. P. Lunn is supported by MRC Centre grant G0601943. S. Rahman is supported by Great Ormond Street Hospital Children's Charity. M.M. Reilly is supported by MRC Centre grant G0601943, the Muscular Dystrophy Campaign, and NINDS/ORD (1U54NS065712–01). M.G. Hanna is supported by an MRC Centre grant G0601943 and by The Myositis Support Group. Go to Neurology.org for full disclosures.

Authors

Affiliations & Disclosures

Robert D.S. Pitceathly, MRCP
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Sinéad M. Murphy, MRCP
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Irish Health Service Executive Scholarship 2009-2010 Fellowship NINDS/ORD (1U54NS065712-01) 2010-2011
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Ellen Cottenie, MSc
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Annapurna Chalasani, PhD
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Mary G. Sweeney, BSc
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Cathy Woodward, BSc
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Ese E. Mudanohwo, BSc
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Iain Hargreaves, PhD
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Simon Heales, PhD
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John Land, PhD
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Annals of Clinical Biochemistry. Associate Editor 2005- 2012
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Janice L. Holton, PhD
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Member of the editorial board Neuropathology Applied Neurobiology 2007- present Executive Editor Neuropathology Applied Neurobiology 2012- present
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Alzheimer's Research Trust. January 2008 – December 2010 The Margaret Watson Memorial Trust Grant from The Sarah Matheson Trust. January 2008 – December 2008 Action Medical Research November 2007 – October 2009 Brain Net Europe: Support for the Queen Square Brain Bank for Neurological Disorders July 2007 – June 2009 The Sarah Matheson Trust. January 2009 – December 2011 Myositis Support Group June 2009 – May 2010 The Multiple System Atrophy Trust. August 2012 – July 2014 Michael J Fox Foundation for Parkinson's Research December 2010 – November 2011 Alzheimer's Research UK March 2012 - February 2013
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Henry Houlden, PhD
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My laboratory is funded by: The Medical Research Council (MRC) and the National Institute for Health Research (NIHR) UCLH/UCL Comprehensive Biomedical Research Centre.
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Julian Blake, MRCP
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Michael Champion, FRCPCH
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Essential Revision Notes in Paediatrics for the MRCPCH 2nd edition,eds Beattie m & Champion M, Pastest 2006
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Frances Flinter, PhD
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Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Stephanie A. Robb, FRCPCH
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Rupert Page, FRCP
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Michael Rose, FRCP
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Cochrane Collaboration, co-editor, on-going since 1998
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
European Union, Framework 6 grant, Work package leader, 5 years to December 2011
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Association Francais contre Myologie (AFM) Principle Investigator One year to June 2012
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Jacqueline Palace, FRCP
Disclosure
Scientific Advisory Boards:
1.
UK advisory board participant:; Merck Serono; Bayer Schering Pharma; Biogen Idec; Teva Pharmaceutical Industries Ltd.; Novartis Pharmaceuticals UK Ltd; Sanofi-Aventis
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Support for attending ECTRIMS Serono 2008 and 2009
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Department of Health Risk Sharing Scheme, Clinical Coordinator since 2002
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
MS Society
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Carol Crowe, MD
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Cheryl Longman, FRCP
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Michael P. Lunn, FRCP
Disclosure
Scientific Advisory Boards:
1.
Baxter pharmaceuticals Scientific Advisory Board
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Cochrane Collaboration Neuromuscular Disease Group. Co- ordinating Editor 2009-present
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Shamima Rahman, PhD
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Journal of Inherited Metabolic Diseases, Communicating Editor, 2008-present
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Vitaflo, funding for PhD studentship unrelated to this manuscript, 2011-present
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Funding from charities not related to the present study:; Children's Liver Disease Foundation, 2010-2011; Climb, 2011-2012; Great Ormond Street Hospital Children's Charity, 2012-present; Muscular Dystrophy Campaign, 2012-present
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Mary M. Reilly, FRCP
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Brain, Editorial Board, appointed 2008; Neuromuscular Disorders, Editorial Board, appointed 2005; Journal of the Peripheral Nervous System, Editorial Board, appointed 2005
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NIH grant U54NS065712 MRC centre grant
Research Support, Academic Entities:
1.
•CLRN grant to support NIH RDCRC natural history study (PI) (2011-2012) •MRC - Using Next Generation Sequencing to investigate neuromuscular disorders. Project grant (CO- PI) (2011-2014) •Wellcome Trust – A next generation sequencer for the Institute of Neurology. Equipment Grant" (CO-PI) (2011 – 2016) •UCL CBRC – A next generation sequencer for the Institute of Neurology. Capital bid (CO-PI) (2011-2016) •Ipsen training grant for Dr. Alex Rossor (2010-2011). •NIHR Doctoral Research Training Fellowship for Dr. Taibish Saifee "The clinical spectrum and pathophysiology of tremor in peripheral neuropathy" (Supervisor) (2010-2013) •Muscular Dystrophy Association (US) grant "Genetic Modifiers of the CMT1A phenotype" (Mentor on development grant for Henry Houlden) (2009-2012) •Muscular dystrophy campaign grant "Strengthening Hip Flexors to improve walking distance in people with Charcot-Marie-Tooth disease" (PI) (2008-2010) •UCLH / UCL Comprehensive Biomedical Research Centre "Investigation of the genes responsible for Charcot Marie tooth disease and related disorders in a UK population and development/implementation of diagnostic guidelines and genetic testing" (PI) (2008-2010) •CRDC project grant "Pathomechanism and possible treatment strategies for distal hereditary neuropathies secondary to HSP27 mutations (CO-PI) (2008-2010) •Muscular Dystrophy campaign centre grant "Combined Dubowitz and Institute of Neurology neuromuscular centre grant (CO-PI) (2008-2011)
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Michael G. Hanna, FRCP
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Journal of Neurology, Neurosurgery & Psychiatry, deputy editor, 2012
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
I am funded by an MRC Centre grant (G0601943) and by The Myositis Support Group.
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence & reprint requests to Professor M.G. Hanna: [email protected]

Author Contributions

Robert D.S. Pitceathly: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, acquisition of data. Sinéad M. Murphy: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, acquisition of data. Ellen Cottenie: analysis or interpretation of data, acquisition of data. Annapurna Chalasani: analysis or interpretation of data, acquisition of data. Mary G. Sweeney: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data. Cathy Woodward: analysis or interpretation of data, acquisition of data. Ese E. Mudanohwo: analysis or interpretation of data, acquisition of data. Iain Hargreaves: drafting/revising manuscript for content, including medical writing for content, analysis or interpretation of data, acquisition of data. Simon Heales: drafting/revising manuscript for content, including medical writing for content, analysis or interpretation of data. John Land: drafting/revising manuscript for content, including medical writing for content, analysis or interpretation of data. Janice L. Holton: analysis or interpretation of data, acquisition of data. Henry Houlden: drafting/revising manuscript for content, including medical writing for content, analysis or interpretation of data, study supervision or coordination. Julian Blake: analysis or interpretation of data, acquisition of data. Michael Champion: analysis or interpretation of data, acquisition of data. Frances Flinter: analysis or interpretation of data, acquisition of data. Stephanie Robb: analysis or interpretation of data, acquisition of data. Rupert Page: analysis or interpretation of data, acquisition of data. Michael Rose: analysis or interpretation of data, acquisition of data. Jacqueline Palace: analysis or interpretation of data, acquisition of data. Carol Crowe: analysis or interpretation of data, acquisition of data. Cheryl Longman: analysis or interpretation of data, acquisition of data. Michael P. Lunn: drafting/revising manuscript for content, including medical writing for content, acquisition of data. Shamima Rahman: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, study supervision or coordination. Mary M. Reilly: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, study supervision or coordination. Michael G. Hanna: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, study supervision or coordination.

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