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Logo of neurologyNeurologyAmerican Academy of Neurology
 
Neurology. 2012 November 20; 79(21): 2115–2121.
PMCID: PMC3511930

PRRT2 gene mutations

From paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine
Alice R. Gardiner, MSc,

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. (1) The Muscular Dystrophy Campaign

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
Kailash P. Bhatia, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. Funding for travel: (1) GlaxoSmithKline, (2) Orion Corporation, (3) Ipsen, (4) Merz Pharmaceuticals, LLC.Speaker honoraria: (1) GlaxoSmithKline, (2) Ipsen, (3) Merz Pharmaceuticals, LLC, (4) Sun Pharmaceutical Industries Ltd.

Editorial Boards:

  1. (1) Movement Disorders, Editorial Board, (2) Therapeutic Advances in Neurological Disorders, Editorial Board

Patents:

  1. NONE

Publishing Royalties:

  1. (1) Oxford Specialist Handbook of Parkinson's Disease and Other Movement Disorders, Oxford University Press, 2008

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. (1) Ipsen

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. (1) Halley Stewart Trust through Dystonia Society UK, (2) the Wellcome Trust MRC strategic neurodegenerative disease initiative award (WT089698), (3) Parkinson's UK

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
Maria Stamelou, MD,

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. European Federation of Neurological Societies (EFNS), Scientific Grant 2010

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
Russell C. Dale, MD,

Scientific Advisory Boards:

  1. Queensland Children's Medical Institute Research advisory committee. Not for profit.

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Editorial advisory borad member of MSARD

Patents:

  1. NONE

Publishing Royalties:

  1. Biogen Idec 1000 dollar honoria in 2008

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. NHMRC national grant in 2010 national grant for encephalitis study

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
Manju A. Kurian, MD,

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. (1) Action Medical Research

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
Susanne A. Schneider, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. editorial board member of Movement Disorders Journal (no financial compensation)

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
G.M. Wali, MD,

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
Tim Counihan, MD,

Scientific Advisory Boards:

  1. Member of an ad hoc advisory board for Eisai Pharmaceuticals

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
Anthony H. Schapira, MD,

Scientific Advisory Boards:

  1. Consultancy/advisory board: Boehringer Ingelheim, Orion-Novartis, GlaxoSmithKline, UCB, EMD Serono, and Teva-Lundbeck, Merck

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. Consultancy/honoraria: Merck-Serono, Orion-Novartis, GlaxoSmithKline, Boehringer Ingelheim, UCB, and Teva-Lundbeck.

Editorial Boards:

  1. Co-Editor-in-Chief for the European Journal of Neurology.

Patents:

  1. NONE

Publishing Royalties:

  1. Neurology & Clinical Neuroscience Elsevier, 2006 Parkinson's disease, Wiley 2008

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Consultancy/advisory board: Boehringer Ingelheim, Orion-Novartis, GlaxoSmithKline, UCB, EMD Serono, and Teva-Lundbeck, Merck

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Research grants (administered through University College London): Boehringer Ingelheim.

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. Medico-legal expert testimony
Sian D. Spacey, MD,

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
Enza-Maria Valente, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Pediatric Research, associate editor, 2011; BMC Neurology, associate editor, 2010-2011

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. Italian Ministry of Health, rare disease grants, PI, 2011-2012, Italian Ministry of Health, grants giovani ricercatori, PI, 2011-2013, European Community FP7 Program, MEFOPA project, clinical partner, 2009-2013, European Research Council, Starting Grant, PI, 2011-2016Italian Ministry of University and Research,

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Italian Telethon Foundation (Grant# GGP10140)

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
Laura Silveira-Moriyama, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. Received funding for a trip from Teva-Lundbeck for one trip in 2010, and funding from UCB Pharma for trips in 2010 and 2011. Received speaker honoraria from Teva-Lundbeck.

Editorial Boards:

  1. Editorial board of the journal Arquivos de Neuropsiquiatria (2011)

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. Parkinson's UK

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
Hélio A.G. Teive, MD, PhD,

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
Salmo Raskin, MD,

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
Josemir W. Sander, MD,

Scientific Advisory Boards:

  1. 1) GSK Pharma - membership of Advisory Board, 2) Viropharma - membership of Advisory Board, 3) UCB Pharma - membership of Advisory Board

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. 1) UCB Pharma - travel grant, 2) Janssen Cilag - travel grant

Editorial Boards:

  1. 1) Lancet Neurology - member of Editorial Board, 2) Epilepsia - member of Editorial Board, 3) Epileptic Disorders - member of Editorial Board

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. 1) UCB Pharma - membership of Speakers' Bureau, 2) GSK Pharma - Membership of Speakers' Bureau

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. 1) UCB Pharma - research grant to my department, 2) GSK - research grant to my department

Research Support, Government Entities:

  1. 1) NIH Grant number 1R21NS069223-01. PI, 2010 - 2012, 2) CBRC Project Grant ID: 6BFP/06. PI, 2008-2012, 3) European Union Seventh Framework Programme. Large-scale-collaborative project 20138. Associate PI,2008 - 2011

Research Support, Academic Entities:

  1. 1) Wellcome Trust. Grant number: 084730. PI 2008 - 2011

Research Support, Foundations and Societies:

  1. 1) Nationaal Epilepsie Fonds Nederland Projectnumber:10-07. PI, 2010 - 2013, 2) The Brain Research Trust Project Grant 01-81/09. PI,2009 - 2010

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
Andrew Lees, MD,

Scientific Advisory Boards:

  1. Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion, BIAL, Noscira, Roche

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion, BIAL, Noscira, Roche

Editorial Boards:

  1. 2006 Archivas de Nevropsiquiatria (Brazil), 1995-03 Co-Editor in Chief, Movement Disorders Journal and Historical Section Editor, 1994-98 Founder Editor, Behavioural Neurology, 1994-Neurologia Espana, 1994-00 Revista Neurologica, Argentina, 1994-95 European Journal of Neurology, 1993- Revue Neurologique, 1993-03 Brain, 1991-95 Journal Neurology, Neurosurgery & Psychiatry, 1989-95 Journal of Neurology, 1988-95 Journal of Neural Transmission

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. UCLH, Institute of Neurology, UCL

Consultancies:

  1. Genus

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. PSP Association, Weston Trust - The Reta Lila Howard Foundation

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
Tom Warner, MD,

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. Brain Research Trust PI 2 years, CHDI PI 3yrs

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
Dimitri M. Kullmann, MD,

Scientific Advisory Boards:

  1. Glaxo Smith-Kline, Ad-hoc scientific advisory panels on epilepsy and on synaptic plasticity, 2007, 2008

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Brain, Associate Editor, since 2004, Neuron, Editorial Board member, since 1997, The Neuroscientist, Editorial Board member, since 2001, Synapse, Editorial Board member, since 2011

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. Guarantors of

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
Nicholas W. Wood, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Ed board member, Neurogenetics 2005-Journal of PD associate ed 2010-Journal of neurodegenerative disease 2010-Progress in Neurology and Psychiatry 2002-

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. MRC- UK

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Wellcome trust, Parkinson's UK

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 Hanna, MD,

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. 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
and Henry Houlden, MDcorresponding author

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

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ABSTRACT

Objective:

The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM).

Methods:

The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls.

Results:

PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone.

Conclusions:

This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders.

Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesia. The disorder was first reported in 1892 by Shuzo Kure1 in a 23-year-old Japanese man who had frequent movement-induced paroxysmal attacks, typical of PKD, starting from age 10 years. In 1901, Gowers2 described a similar child, and in 1967, Kertesz3 and Weber4 described families with this condition. Idiopathic or familial attacks often occur in childhood induced by sudden movements, accelerating from walking to running, or infrequently other stimuli such as sound, stress, or hyperventilation. There is often a warning of an impending attack such as numbness or paraesthesia in the affected limb or face, which then develops into pure or mixed dystonic, choreic, ballistic, or athetotic manifestations. In most patients up to 20 attacks per day occur, lasting between 30 seconds and 2 minutes.57

PKD is often associated with infantile convulsions (IC) or convulsions with choreoathetosis (ICCA). Attacks respond well to anticonvulsant therapy, indicating an overlap in the pathologic mechanisms that underlie these episodic disorders.6,7 In 1997, genetic linkage analysis identified a locus for IC or ICCA on chromosome 16p12-q12.8 A number of family members later developed attacks typical of PKD. Subsequently, multiple families with either PKD or ICCA syndrome from multiple populations were linked to chromosome 16, within or near the original ICCA linkage, suggesting that these disorders are allelic with variable expression, although other studies have demonstrated heterogeneity.817

Over the last 15 years, a considerable amount of work has been expended on the identification of the PKD/IC gene1720 until recently, when mutations in the PRRT2 gene were identified as an important cause using exome sequencing.2125 This is consistent with a recent report of PKD in 2 cases associated with a microdeletion of this region.26 These were mainly heterozygous loss-of-function mutations. In the homozygous state one case has been reported to cause nonsyndromic intellectual disability.27 In addition, missense PRRT2 mutations were also reported that could also be loss-of-function or consistent with a dominant-negative effect.22,23 The PRRT2 gene encodes a proline-rich transmembrane protein that is highly expressed in the CNS. Using yeast 2-hybrid screening, the PRRT2 protein has been shown to interact with the synaptosomal-associated protein 25 (SNAP25), suggesting a role in the fusion of synaptic vesicles to the plasma membrane.28

To assess the PRRT2 mutation frequency, spectrum, and associated phenotype, we analyzed this gene in 3 series of episodic neurologic disorders identifying mutations in 28 out of 58 PKD/IC, 1 out of 182 episodic ataxia (EA), and 1 out of 128 probands or sporadic cases with hemiplegic migraine (HM). There were 27 loss-of-function and 3 missense mutations identified; they were in males more frequently than females (male to female ratio 52:32). A number of families with PRRT2 mutations and PKD had associated migraine or HM, 1 family had EA with HM, and another large family had HM alone in several individuals, extending the phenotype of this disorder to involve other types of episodic neurologic conditions such as EA, migraine, and HM.

METHODS

Standard protocol approvals, registrations, and patient consents

We have ethical approval for this research and patients and unaffected family members were recruited with informed consent (NHNN studies 06/N076 and 07/Q0512/26). The diagnosis of PKD or IC/ICC, migraine/HM, and EA was made using recognized criteria5,16,2932 by the clinicians who are authors on this publication (tables 1 and 2). The EA cases are part of the channel gene UK service and had already been screened as negative for the KCNA1 and CACNA1A gene by Sanger sequencing and MLPA. The PRRT2-positive cases were also negative for these 2 genes.

Table 1
Mutations identified in the PRRT2 gene
Table 2
Age at onset, family history, and phenotype details of cases/families with PRRK2 mutations

Genetic analysis

DNA was extracted by a standard phenol chloroform method from blood in affected and unaffected patients. PCR was employed to analyze the coding exons of the PRRT2 gene. The longest PRRT2 transcript was used for primers design and sequencing, Genbank NM_145239, Ensemble (PRRT2 ENSG00000167371) transcript PRRT2-001–ENST00000358758. Primers were designed to exons and flanking introns of the coding exons 2 and 3 of the PRRT2 gene. Synthesized primers were from Sigma Genesis (Sigma-Aldrich Co. LLC, USA) (Prrt2_2f CCTATCTCCTCCTCTTCCAG, Prrt2_2r CTCCAGAGGCTCTATTGCAG, Prrt2_3f CTTACCCGCCATCTATGG, Prrt2_3r AGGCTCCCTTGGTCCTTAGG). PCR analysis was performed using 10 pmol of both forward and reverse genomic primers and FastStart Taq DNA polymerase (www.roche-applied-science.com). Then each purified product was sequenced using forward or reverse primers, as well as sequencing primers to sequence the middle part of exon 2 (Prrt2_2fmid AAGAGGCCACTGCAGACCAG and Prrt2_2rmid TGGTTGAAGGGCTGGCTTG) with Applied Biosystems BigDye terminator v3.3 sequencing chemistry as per the manufacturer's instructions.33 The resulting reactions were resolved on a ABI3730XL genetic analyser (Applied Biosystems, Foster City, CA) and analyzed with SeqScape v2.5 software (Gene Codes, VA). Mutations were verified in both directions, repeat sequencing carried out for specific exons in the proband and other family members to confirm and verify segregation. Mutation position was labeled from the start ATG of the PRRT2 gene according to the standard nomenclature,34,35 Genbank accession number NM_145239, Ensemble transcript PRRT2-001–ENST00000358758. None of these mutations were present on sequencing the PRRT2 gene in 475UK and 96 Asian controls. Several reported SNPs were identified and these include P75P, P138A, P216L, and C276C.

RESULTS

The PRRT2 gene was sequenced in 58 PKD/IC, 182 EA, and 128 HM family probands or sporadic cases (tables 1 and 2). The majority of families and sporadic individuals were of English origin but mutations were also identified in families from Malaysia, India, Wales, Somalia, Pakistan, Kenya, Poland, Malta, Austria, Philippines, Ireland, Scotland, and Australia (table 1). Families 6, 11, and 20 were used in the initial identification of the PRRT2 gene.24 Few patients had associated IC or ICC, reflecting a bias toward adult movement disorders in our department. The p.R217Pfs*8 mutation was by far the most common change, identified in 24 cases/probands from multiple ethnic origins (table 1) as previously reported.2124 Fifteen of these were in families where the mutation segregated with the disease and was also present in 2 clinically unaffected members, suggesting incomplete penetrance. Males were more often affected with PRRT2 mutations compared to females (ratio 52:32). Additional loss-of-function heterozygous mutations were identified in one PKD family with a heterozygous p.C332insGAC, one sporadic PKD patient had a p.L171Lfs*3 mutation, and an additional family with PKD had an exon 3 mutation, c.1011C>T, that results in abnormal splicing. Three missense mutations were identified, a P215R and a P216H mutation in different sporadic PKD cases and a G305W mutation in a child with early onset PKD very responsive to carbamazepine. Although all 3 were predicted to be damaging using SIFT and Polyphen,36 these families were not large enough for segregation and the PRRT2 mutations should be considered as variants of unknown significance on this basis until further proof is obtained. None of these mutations were present on sequencing the PRRT2 gene in 475 UK and 96 Asian control individuals.

The majority of patients with PRRT2 mutations had typical PKD, but we observed a number of cases/families with associated migraine. Two PKD cases with HM were observed in the same family (table 2), a mother and child had severe migraine headaches with PKD and ipsilateral hemimotor and sensory features associated with the p.R217Pfs*8 mutation. Two cases with EA and migraine or HM were also identified. The proband with EA and HM (tables 1 and 2, F18) had the p.R217Pfs*8 mutation with episodic balance difficulties starting at the age of 18 years with unilateral headaches and hemiplegic episodes. She had frequent attacks every day of involuntary movement and balance problems, and cerebellar ataxia on examination but normal imaging. The mother had a past history of epilepsy and severe headaches, and one of her daughters had HM.

An additional family (tables 1 and 2, F30) had HM in a number of individuals in association with infantile convulsions in the proband (tables 1 and 2; figure, B) and we also identified a child with PKD, Asperger syndrome, and attention-deficit/hyperactivity disorder (ADHD), associated with the p.R217Pfs*8 mutation.

Figure
The structure of the PRRT2 gene and the position of the mutations identified (A) and larger families identified with PRRT2 gene mutations (B)

DISCUSSION

The frequency of PRRT2 mutations in ethnically diverse PKD families and sporadic cases was 28 out of 58 (48%), similar to the previous report of 50.4%.24 The PRRT2 mutation frequency in EA (1/182) and in the HM (1/128) series was low, with less than 1% of patients screened in each group. It is still possible that PRRT2 defects exist in the other 30 PKD cases, as whole gene26 or exon deletions or as deep intronic or regulating mutations in the untranslated promoter regions of the gene. No large PKD/IC families remain in our series that are negative for PRRT2.15 The previously reported Indian PKD family, linked to a different region of chromosome 16 than the PKD/IC kindreds, was found to have the p.R217Pfs*8 mutation.14

The p.R217Pfs*8 mutation was identified in a large number of cases from many different ethnic backgrounds. We identified a number of other novel loss-of-function mutations as well as missense amino acid changing mutations in the PRRT2 gene. These additional mutations were consistent with the previous reports where other types of indel and nonsense loss-of-function changes were seen, as well as damaging missense mutations. These data suggest that a mechanism of PRRT2 haploinsufficiency as well as a possible dominant-negative mutational effect is associated with PKD.

The majority of patients with PRRT2 mutations identified here and before had typical PKD (tables 1 and 2). However, in addition to infantile convulsions, the phenotype is frequently complicated by other episodic neurologic disorders such as epilepsy, migraine, or HM. In total, 12 out of 30 probands/cases had migraine type headaches; 3 of these families had HM. It is possible that these associations are coincidence, given the high incidence of migraine in the general population, although the frequency is high in these cases and migraine associated with hemiplegia is very rare. The association is not surprising as the coexistence of movement disorders, migraine, and epilepsy is often described in the neurologic channelopathies,37 indicating an overlap in etiologic pathways as well as clinical features.38

The function of PRRT2 is poorly understood. The gene is known to interact with the SNAP25 and both are highly expressed in the basal ganglia. SNAP25 is a presynaptic protein involved in synaptic vesicle release playing an important role in calcium triggered exocytosis.28 The interaction with SNAP25 and the possible disruption of neurotransmitter release associated with PRRT2 mutations is consistent with the pathogenic pathways involved in other paroxysmal movement disorders. In paroxysmal nonkinesigenic dyskinesia (PNKD), mutations in the PNKD gene are associated with disruption of synaptic protein regulated exocytosis39 and SNAP25 has also been shown to be associated with ADHD,40 which was seen in one of our PKD cases with the p.R217Pfs*8 mutation. Although further work is required, the genetic data and extension of the clinical phenotypes associated with the PRRT2 genes indicates an overlap in the pathways with other similar disorder of channel or synapse dysfunction such as epilepsy, migraine, and PNKD.

Supplementary Material

Accompanying Editorial:

ACKNOWLEDGMENT

The authors thank the patients and controls for their participation in this study.

Glossary

ADHD
attention-deficit/hyperactivity disorder
EA
episodic ataxia
HM
hemiplegic migraine
IC
infantile convulsions
ICCA
infantile convulsions with choreoathetosis
PKD
paroxysmal kinesigenic dyskinesia
PNKD
paroxysmal nonkinesigenic dyskinesia

Footnotes

See pages 2097, 2104, 2109, 2122, and 2154

Editorial, page 2086

AUTHOR CONTRIBUTIONS

This study was designed and funding obtained by HH, KB, NWW, MGH. KB, MS, RCD, MAK, SAS, GMW, TC, SDS, EMV, LSM, AHS, HAT, SR, JWS, AL, TW, DK, NWW, MH, HH collected samples and assessed patients clinically. AG and HH conducted experiments and performed data analysis. The manuscript was written by HH with input and revision from KB, MS, RCD, MAK, TC, SDS, LSM, JWS, DK, NWW and MH.

STUDY FUNDING

Supported by grants from The Medical Research Council (MRC), The Wellcome Trust, The Muscular Dystrophy Campaign, Action Medical Research, The Dystonia Medical Research Foundation (DMRF), National Organisation for Rare Disorders (NORD), The Brain Research Trust (BRT), and the Italian Ministry of Health. L.S.M. was supported by a Reta Lila Weston Fellowship. S.A.S. is supported by a Robert Bosch Fellowship. This study was also supported by the National Institute for Health Research (NIHR) UCLH/UCL Comprehensive Biomedical Research Centre.

DISCLOSURE

The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

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