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12th International Conference on Myasthenia Gravis and Related Disorders

12th International Conference on Myasthenia Gravis and Related Disorders

Monday, May 21, 2012 - Wednesday, May 23, 2012

The New York Academy of Sciences

Presented By

Presented by the New York Academy of Sciences and the Myasthenia Gravis Foundation of America, Inc.

 

Myasthenia gravis (MG) is a rare, acquired autoimmune syndrome in which pathogenic auto-antibodies attack key proteins at the neuromuscular junction—most often, the muscle nicotinic acetylcholine receptor—disrupting synaptic transmission. Often, the result is severe muscle weakness, fatigability, and disability in patients, which may be life threatening. In the last 30 – 40 years, significant advances in diagnosis and treatment of MG have reduced the burden of high mortality and severe disability, and more recently research has produced novel potential therapeutic targets, clearer definitions of MG clinical subtypes, and new clinical trials to improve treatment options. Yet, diagnosis remains problematic because of nonspecific and fluctuating symptoms, and available therapeutics primarily treat symptoms or involve global suppression of the immune system.

The Myasthenia Gravis Foundation of America and the New York Academy of Sciences present this 12th international conference to galvanize efforts among researchers studying autoimmune and neuromuscular junction disease and to encourage continued progress in the diagnosis and treatment of MG that will help to improve patient outcomes and quality of life. This 3-day international conference will feature topics that span basic, translational, and clinical neuroscience and immunology related to MG and other autoimmune and neuromuscular junction disorders.

Organizers

Emma Ciafaloni, MD

University of Rochester

Matthew N. Meriggioli, MD, FAAN

University of Illinois College of Medicine

Robert L. Ruff, MD, PhD

Louis Stokes Cleveland Department of Veterans Affairs Medical Center and Case Western Reserve University

Gil I. Wolfe, MD

University at Buffalo School of Medicine and Biomedical Sciences

Young Investigator Travel Fellowships

On behalf of the Myasthenia Gravis Foundation of America, we are pleased to announce the following travel fellowship winners. Winners were chosen based on their application materials and outstanding abstract submissions. Each winner will receive waived conference registration and $1000 towards their travel and accommodation expenses to attend the conference.

Revital Aricha, PhD, The Weizmann Institute of Science
Eyal Ben-Ami, MSc, Technion-Israel Institute of Technology
Alejandro M. Gomez, MSc Maastricht University
Maartje G. Huijbers, MSc, Leiden University Medical Centre
Paraskevi Zisimopoulou, PhD, Hellenic Pasteur Institute

Registration Pricing

By 4/13/2012After 4/13/2012Onsite: 5/20/2012
Member$550$600$650
Student / Postdoc / Fellow Member$350$375$400
Nonmember Academic$700$750$800
Nonmember Corporate$850$900$950
Nonmember Not for Profit$700$750$800
Student / Postdoc / Fellow Nonmember$350$375$400

Myasthenia Gravis and other neuromuscular junction disease patients are eligible to register at NYAS member rates. For more information, please contact Ms. Melanie Koundourou at mkoundourou@nyas.org or 212.298.8681.

Presented by

    • The New York Academy of Sciences
  • Myasthenia Gravis Foundation of America

Silver Sponsor

  • CSL Behring

Grant Support

This project is supported by Grant Number R13NS077665 from the National Institute of Neurological Disorders and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and the Office of Rare Diseases (ORD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NCATS, ORD, or the National Institutes of Health.

For a full list of sponsors, please view the Sponsors tab.

Agenda

* Presentation times are subject to change.


Day One — Monday, May 21, 2012

7:45 AM

Registration & Continental Breakfast

8:30 AM

Opening Remarks
Brooke Grindlinger, PhD, The New York Academy of Sciences
Samuel Schulhof, Myasthenia Gravis Foundation of America, Inc.

Session I: Structure and Function of the Neuromuscular Junction: Recent Advances

Session Chair: Henry J. Kaminski, MD, George Washington University

8:50 AM

Structure of the Neuromuscular Junction: Function and Cooperative Mechanisms in the Synapse
Masaharu Takamori, MD, Kanazawa-Nishi Hospital and Kanazawa University

9:10 AM

Presynaptic Organization of the Neuromuscular Junction
Hiroshi Nishimune, PhD, University of Kansas Medical School

9:30 AM

Dok7, MuSK and the Development of Neuromuscular Junction
Yuji Yamanashi, PhD, The University of Tokyo

9:50 AM

Myasthenogenicity of the Main Immunogenic Region
Jon M. Lindstrom, PhD, University of Pennsylvania School of Medicine

10:10 AM

Networking Break

Session II: Advances in Immunology and their Relationship to Myasthenia Gravis

Session Chair: Angela Vincent, FRCP, FRS, University of Oxford

10:40 AM

Etiology of Autoimmune Diseases
Jean-François Bach, MD, DSc, Necker Hospital

11:00 AM

Defects of Immunoregulatory Mechanisms in MG
Sonia Berrih-Aknin, DSc, University Pierre et Marie Curie & Institut National de la Santé et de la Recherche Médicale

11:20 AM

A Journey from the Thymus to the Endplate
Marc De Baets, MD, PhD, Maastricht University

11:40 AM

Functional Defect in Regulatory T Cells in Autoimmune Myasthenia Gravis
Matthew N.Meriggioli, MD, FAAN, University of Illinois College of Medicine; Chair, Medical Scientific Advisory Board, Myasthenia Gravis Foundation of America

12:00 PM

Neuronal Acetylcholine Receptor Autoimmunity
Steven Vernino, MD, PhD, University of Texas Southwestern Medical Center

12:20 PM

The Role of B Cell Activating Factor in Autoimmune Myasthenia Gravis
Robert P. Lisak, MD, Wayne State University School of Medicine

12:40 PM

Panel Discussion

1:00 PM

Networking Lunch

Session III: Myasthenia Gravis: Clinical and Laboratory Developments

Session Chair: Richard J.Barohn, MD, University of Kansas Medical Center

2:30 PM

Population Differences in the Clinical Presentation and Serology of MG
Janice M. Massey, MD, Duke University Medical Center

2:50 PM

Cell-Based Assays in Myasthenia Gravis
Angela Vincent, FRCP, FRS, University of Oxford

3:10 PM

Concentric Needle Jitter Studies
Erik Stålberg, MD, PhD, Pro.em, Uppsala University Hospital

3:30 PM

Management Challenges in Muscle-Specific Tyrosine Kinase MG
Amelia Evoli, MD, Catholic University - Roma

3:50 PM

Genome-Wide Association Study of Myasthenia Gravis
Daniel B. Drachman, MD, Johns Hopkins School of Medicine

4:10 PM

Networking Break

Session IV: Myasthenia Gravis: Outcome Measurements and Clinical Trial Development

Session Chair: Ted M. Burns, MD, University of Virginia

4:40 PM

MG Activities of Daily Living (ADL) Profile
Srikanth Muppidi, MD, University of Texas Southwestern Medical Center

5:00 PM

Quality of Life in Myasthenia; Why and How to Measure It
Michael Rose, MD, FRCP, King's College Hospital

5:20 PM

The MG Composite 
Ted M. Burns, MD, University of Virginia

5:40 PM

Patient Registries: Useful Tools for Clinical Research in Myasthenia Gravis
Fulvio Baggi, PhD, Neurological Institute "Carlo Besta"

6:00 PM

Panel Discussion

Poster Session Short Talks

6:20 PM

Identification of a New Gene Causing Congenital Myasthenic Syndrome
Katsiaryna Belaya, PhD, University of Oxford

6:30 PM

Proteasome Inhibition with Bortezomib Eliminates Plasma Cells in Cultured Thymic  Cells from Myasthenia Gravis Patients
Alejandro M. Gomez, MSc, Maastricht University

6:40 PM

LRP4 (Low-Denslty Lipoprotein Receptor-Related Protein 4) Is a Novel Autoimmune Target in Patients with Seronegative Myasthenia Gravis
Arthur Melms, MD, Tubingen University Medical Center

6:50 – 8:50 PM

Welcome Reception and Poster Session I

Day Two — Tuesday, May 22, 2012

7:45 AM

Registration & Continental Breakfast

8:30 AM

Keynote Address

Biologics and Other Novel Approaches in Autoimmune Neuromuscular Disorders as Applicable in Myasthenia Gravis
Marinos C. Dalakas, MD, FAAN, National University of Athens Medical School

Session V: Animal Models of Neuromuscular Junction Disease

Session Chair: Matthew N. Meriggioli, MD, FAAN, University of Illinois College of Medicine; Chair, Medical Scientific Advisory Board, Myasthenia Gravis Foundation of America

9:20 AM

The Role of Complement in Experimental Autoimmune MG
Linda L. Kusner, PhD, George Washington University

9:40 AM

Acute Severe Model of Anti-Muscle Specific Kinase Myasthenia
David P. Richman, MD, University of California – Davis

10:00 AM

Animal Models of AChR-Related MG
Premkumar Christadoss, MD, MBBS, University of Texas Medical Branch

10:20 AM

Regulatory T Cells in Experimental Autoimmune MG
Miriam C. Souroujon, PhD, Open University of Israel and Weizmann Institute of Science

10:40 AM

Networking Break

Session VI: Myasthenia Gravis — Treatment Update and What Lies Ahead

Session Chair: Emma Ciafaloni, MD, University of Rochester

11:10 AM

Update on Mycophenolate Mofetil Treatment of MG
Zaeem A. Siddiqi, MD, PhD, University of Alberta

11:30 AM

Efficacy of Prednisone in the Treatment of Ocular Myasthenia - Epitome
Michael Benatar, MBChB, Dphil, University of Miami

11:50 AM

Intravenous Immunoglobulin versus Plasma Exchange for MG Exacerbations
Vera Bril, MD, FRCPC, University Health Network & University of Toronto

12:10 PM

Panel Discussion

12:30 PM

Networking Lunch

Session VI: (CONT.) Myasthenia Gravis — Treatment Update and What Lies Ahead

Session Chair: Emma Ciafaloni, MD, University of Rochester

2:00 PM

Randomized, Double-Blind, Placebo-controlled, Crossover, Multicenter, Phase II Study of Eculizumab in Patients with Refractory Generalized Myasthenia Gravis (GMG)
James F. Howard Jr., MD, The University of North Carolina at Chapel Hill

2:20 PM

Further Developments with Antisense Treatment for Myasthenia Gravis
Jon D. Sussman, MBChB, PhD, FRCP, Greater Manchester Neuroscience Centre

2:40 PM

Phase II Trial of Methotrexate in Myasthenia Gravis
Richard J. Barohn, MD, University of Kansas Medical Center

3:00 PM

Rituximab in Myasthenia Gravis
Rup Tandan, MD, FRCP, University of Vermont College of Medicine

3:20 PM

Networking Break

3:50 PM

Antigen-Specific Apheresis of Autoantibodies in MG
Socrates Tzartos, PhD, Hellenic Pasteur Institute and University of Patras

4:10 PM

Issues in Clinical Trial Design for Myasthenia Gravis
Donald B. Sanders, MD, Duke University Medical Center

4:30 PM

Panel Discussion

Poster Session Short Talks

4:50 PM

Epitope Mapping of Anti-Musk Autoantibodies in Myasthenia Gravis
Maartje G. Huijbers, MSc, Leiden University Medical Centre

5:00 PM

Experimental MG in Aire KO Mice—A Link Between Aire and Treg Cells
Revital Aricha, PhD, Weitzmann Institute of Science

5:10 PM

Novel Calcium Channel Agonists as Potential Therapeutics in LEMS and Other Neuromuscular Diseases
Stephen D. Meriney, PhD, University of Pittsburgh

5:20 – 7:20 PM

Poster Session II

Day Three — Wednesday, May 23, 2012

7:45 AM

Registration & Continental Breakfast

Session VII: Congenital Myasthenic Syndromes

Session Chair: Andrew G. Engel, MD, Mayo Clinic

8:30 AM

Synaptic Basal Lamina - Associated Congenital Myasthenic Syndromes
Ricardo A. Maselli, MD, University of California – Davis

8:50 AM

DOK7 Mutations Underlie Neuromuscular Junction Synaptopathy
Jacqueline Palace, DM, FRCP, Oxford University Hospital

9:10 AM

Synaptic Dysfunction in Congenital Myasthenic Syndromes
David Beeson, PhD, University of Oxford

9:30 AM

Congenital Myasthenic Syndromes (CMS) in 2012
Andrew G. Engel, MD, Mayo Clinic

9:50 AM

Clinical and Electrodiagnostic Observations in Congenital Myasthenic Syndromes
Charles (Mike) Harper, MD, Mayo Clinic

10:10 AM

Networking Break

Session VIII: Lambert-Eaton Myasthenic Syndrome

Session Chair: Donald B. Sanders, MD, Duke University Medical Center

10:40 AM

Treatment in Lambert-Eaton Myasthenic Syndrome
Paul Maddison, MD, FRCP, Queen's Medical Centre

11:00 AM

SOX1 in Lambert-Eaton Myasthenic Syndrome and Screening for Small Cell Lung Cancer
Maarten J. Titulaer, MD, PhD, University of Pennsylvania and Leiden University Medical Centre

11:20 AM

Panel Discussion

Session IX: Thymus, Thymectomy, and the MGTX Trial

Session Chairs: Gil I. Wolfe, MD, University at Buffalo School of Medicine and Biomedical Sciences

11:40 AM

MGTX: Update on the Thymectomy Trial in Non-Thymomatous Myasthenia Gravis
Gil I. Wolfe, MD, University at Buffalo School of Medicine and Biomedical Sciences
Gary R. Cutter, MS, PhD, University of Alabama School of Public Health

12:00 PM

Biomarker Development for Myasthenia Gravis
Henry J. Kaminski, MD, George Washington University

12:20 PM

Networking Lunch

Session IX: (CONT.) Thymus, Thymectomy, and the MGTX Trial

1:50 PM

Thymus Pathology Observed in the MGTX Trial
Alexander Marx, MD, University of Heidelberg

2:10 PM

Minimally Invasive Thymectomy: An Update
Dan M. Meyer, MD, University of Texas Southwestern Medical Center

2:30 PM

Thymectomy for Myasthenia Gravis Patients- The Robotic Approach
Pier C. Giulianotti, MD, FACS, University of Illinois at Chicago

2:50 PM

The MGTX International Trial: Methods for Management and Lessons Learned
Greg Minisman, MA, University of Alabama School of Public Health   Inmaculada B. Aban, PhD, University of Alabama School of Public Health

3:10 PM

Panel Discussion

3:30 PM

Networking Break

Session X: Hot Topics Selected from Submitted Abstracts

Session Chair: Robert L. Ruff, MD, PhD, Louis Stokes Cleveland Department of Veterans Affairs Medical Center and Case Western Reserve University

4:00 PM

The search for New Antigenic Targets in Myasthenia Gravis
Judith Cossins, Dphil, University of Oxford

4:20 PM

IgG4 Subclass Autoantibodies from MuSK Myasthenia Gravis Patients Cause Defective Neuromuscular Synaptic Transmission in Mice
Jaap J. Plomp, PhD, Leiden University Medical Centre

4:40 PM

Molecular Recognition of Nicotinic Acetylcholine Receptors by Agonist and a-Neurotoxins: Structural and Mechanistic Insights
Steven M. Sine, PhD, Mayo Clinic

5:00 PM

Failure of Neuromuscular Transmission in Myasthenia Gravis: Decline in Safety Factor and Susceptibility of Extraocular Muscles
Alessandro Serra, MD, PhD, Veterans Affairs Medical Center and Case Medical Center

5:20 PM

Mesenchymal Stem Cells-Mediated Immunomodulation of Myasthenia Gravis Patients' Lymphocytes
Eyal Ben-Ami, MSc, Technion-Israel Institute of Technology

5:40 – 6:00 PM

Closing Remarks
Matthew N. Meriggioli, MD, FAAN, University of Illinois College of Medicine; Chair, Medical Scientific Advisory Board, Myasthenia Gravis Foundation of America
Robert L. Ruff, MD, PhD, Cleveland VA Medical Center and Case Western Reserve University
Gil I. Wolfe, MD, University at Buffalo School of Medicine and Biomedical Sciences
Emma Ciafaloni, MD, University of Rochester

Speakers

Inmaculada B. Aban

University of Alabama School of Public Health

Revital Aricha, PhD

Weitzmann Institute of Science

Jean-François Bach

Necker Hospital

Fulvio Baggi

Neurological Institute "Carlo Besta"

Richard Barohn

University of Kansas Medical Center

David Beeson

University of Oxford

Katsiaryna Belaya, PhD

University of Oxford

Eyal Ben-Ami, MSc

Technion-Israel Institute of Technology

Michael Benatar

University of Miami

Sonia Berrih-Aknin

University Pierre et Marie Curie & Institut National de la Santé et de la Recherche Médicale

Vera Bril

University Health Network & University of Toronto

Ted M. Burns

University of Virginia

Premkumar Christadoss

University of Texas Medical Branch

Emma Ciafaloni

University of Rochester

Judith Cossins, DPhil

University of Oxford

Gary Cutter

University of Alabama School of Public Health

Marinos C. Dalakas

Imperial College London

Marc De Baets

Maastricht University

Daniel B. Drachman

Johns Hopkins School of Medicine

Andrew G. Engel

Mayo Clinic

Amelia Evoli

Catholic University – Roma

Pier Cristoforo Giulianotti

University of Illinois at Chicago

Alejandro M. Gomez, MSc

Maastricht University

Charles (Mike) Harper

Mayo Clinic College of Medicine

James F. Howard, Jr.

University of North Carolina at Chapel Hill

Maartje G. Huijbers, MSc

Leiden University Medical Centre

Henry J. Kaminski

George Washington University

Linda L. Kusner

George Washington University

Jon Martin Lindstrom

Medical School of the University of Pennsylvania

Robert P. Lisak

Wayne State University

Paul Maddison

Nottingham University Hospitals – Queen's Medical Centre

Alexander Marx

University of Heidelberg

Ricardo A. Maselli

University of California – Davis

Janice Massey

Duke University Medical Center

Arthur Melms, MD

Tübingen University Medical Center

Matthew Meriggioli

University of Illinois College of Medicine; Chair, Medical Scientific Advisory Board, Myasthenia Gravis Foundation of America

Stephen D. Meriney, PhD

University of Pittsburgh

Dan M. Meyer

University of Texas Southwestern Medical Center

Greg Minisman

University of Alabama School of Public Health

Srikanth Muppidi

University of Texas Southwestern Medical Center

Hiroshi Nishimune

University of Kansas Medical School

Jacqueline Palace

Oxford University Hospital

Jaap J. Plomp, PhD

Leiden University Medical Centre

David P. Richman

University of California – Davis

Michael Rose

King's College Hospital

Robert Ruff

Louis Stokes Cleveland Department of Veterans Affairs Medical Center and Case Western Reserve University

Donald B. Sanders

Duke University Medical Center

Alessandro Serra, MD, PhD

Veterans Affairs Medical Center and Case Medical Center

Zaeem Siddiqi

University of Alberta

Steven M. Sine, PhD

Mayo Clinic

Miriam C. Souroujon

Open University of Israel and Weizmann Institute of Science

Erik Stålberg

University Hospital Uppsala

Jon D. Sussman

Greater Manchester Neuroscience Centre

Masaharu Takamori

Kanazawa University

Rup Tandan

University of Vermont (UVM) Fletcher Allen Health Care

Maarten J. Titulaer

University of Pennsylvania

Socrates Tzartos

Hellenic Pasteur Institute and University of Patras

Steven Vernino

University of Texas Southwestern Medical Center

Angela Vincent

University of Oxford

Gil I. Wolfe

University at Buffalo School of Medicine and Biomedical Sciences

Yuji Yamanashi

The University of Tokyo

Sponsors

For sponsorship opportunities, please contact Melinda Miller at mmiller@nyas.org or 212.298.8648.

Presented by

    • The New York Academy of Sciences

  • Myasthenia Gravis Foundation of America

Silver Sponsor

  • CSL Behring

Academy Friend

Athena Diagnostics, Inc.

IBL International Corp.

KRONUS Inc.

Terumo BCT

Promotional Partners

American Association of Immunologists

American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM)

American Autonomic Society

American Neurological Association

A.I.M. Associazione Italiana Miastenia e Malattie Immunodegenerative — Amici del Besta Onlus

The Dana Foundation

Nature Reviews Neurology

The New York Academy of Medicine

OrphaNews Europe

TREAT-NMD

World Federation of Neurology

Grant Support

This project is supported by Grant Number R13NS077665 from the National Institute of Neurological Disorders and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and the Office of Rare Diseases (ORD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NCATS, ORD, or the National Institutes of Health.

Supported by a grant from BioMarin Pharmaceutical Inc.

Supported by an unrestricted educational grant from Alexion Pharmaceuticals

Abstracts

Day 1: Monday, May 21, 2012


Session I: Structure and Function of the Neuromuscular Junction: Recent Advances

Structure of the Neuromuscular Junction: Function and Cooperative Mechanisms in Synapse
Masaharu Takamori, MD, Kanazawa-Nishi Hospital and Kanazawa University

Acetylcholine (ACh)-mediated signal transmission in the neuromuscular junction depends on coordinated interaction between the presynaptic active zone where synaptic vesicles fuse and the postsynaptic differentiation where ACh receptors (AChRs) are clustered. As cooperative mechanisms in the presynapse, the activation of G protein-coupled receptor (M1 muscarinic AChR) and tyrosine kinase B receptor helps on the Ca2+ influx mediated by voltage-gated Ca2+ channel (P/Q-type) and non-voltage-gated Ca2+ channel (Transient receptor potential canonical, TRPCs 3, 6 and 7). These signals are mediated through phospholipase C activation and lead to the Ca2+-triggered exocytosis and also the fast-mode of endocytosis which requires larger influx of external Ca2+. The synaptic vesicle recycling is thus promoted and potentially compensates synaptic fatigue. In the postsynapse, the Dok7-stimulated MuSK contributes to AChR clustering via its interacting sites for the signals including agrin/Lrp4 (via MuSK Ig1/2 domains), Wnts/Dishevelled (via MuSK Frizzled-like cysteine-rich domain), Tid1s (helps rapsyn stabilization via Hsps 70 and 90β), neuregulin/ErbB, and collagen Q (C-terminus). In the muscle contraction, the TRPC3 collaborates with ryanodine receptor-1 for sarcoplasmic Ca2+ release, refilling Ca2+ after the store depletion in cooperation with Orai1 (Ca2+ influx channel) and STIM1 (Ca2+ sensor). The IP3-dependent dissociation of the TRPC-Homer1-IP3R complex allows STIM1 access to TRPC. The various sites in these structures are immunologically targeted in Lambert-Eaton myasthenic syndrome and myasthenia gravis.

Presynaptic Organization of Neuromuscular Junction
Hiroshi Nishimune, PhD, University of Kansas Medical School

Presynaptic active zones play essential roles for the function and pathology of neuromuscular junctions (NMJs) because they are synaptic vesicle release sites. We recently reported that the number of active zones increases as the size of mouse NMJs increases 3-fold during postnatal development, however, the density of active zones remains constant from postnatal day 0 to 54. Interestingly, the active zone density decreases at the NMJs of aged mice. These results suggest that NMJs maintain the density of synaptic vesicle release sites while they mature, but this density becomes impaired during aging. What is the molecular mechanism for organizing active zones? Recent findings in the central and peripheral nervous systems demonstrate that synaptic channel proteins are involved in the formation and maintenance of synapses by interacting directly with synapse organizers. We identified recently that presynaptic voltage-dependent calcium channels (VDCC) of NMJs interact extracellularly with the muscle-derived synapse organizer laminin β2 and intracellularly with active zone proteins, Bassoon, CAST/Erc2, and ELKS. These results suggest that VDCCs function as a scaffolding protein to organize the active zones. Consistent with this model, double knock out mice for P/Q- and N-type VDCCs has a significantly reduced number of active zones at NMJs and features an attenuation of the active-zone proteins. These molecular mechanisms of active zone organization and the loss of active zones in VDCC knock out mice are consistent with the pathological conditions observed in Lambert-Eaton myasthenic syndrome cause by autoantibodies against VDCCs and Pierson syndrome caused by laminin β2 mutation.

Dok7, MuSK and the Development of Neuromuscular Junction
Yuji Yamanashi, PhD, The University of Tokyo

Skeletal muscle contraction is controlled by motor neurons, which contact the muscle at the neuromuscular junction (NMJ). Defective neuromuscular transmission at NMJs gives rise to the fatigable muscle weakness known as myasthenia. The formation of the NMJ is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural agrin, which can activate MuSK via the coreceptor Lrp4. Previously, we demonstrated that the muscle protein Dok-7 is essential for neuromuscular synaptogenesis, and also demonstrated in collaboration with David Beeson and his colleagues that mutations in DOK7 underlie a limb-girdle type of congenital myasthenic syndrome, DOK7 myasthenia, which is associated with abnormally small and simplified NMJs. In addition, we showed that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural agrin requires Dok-7 in order to activate MuSK in myotubes. In vivo overexpression of exogenous Dok-7 indeed increased MuSK activation and promoted NMJ formation in mice, which did not exhibit defects in motor function. Interestingly, the overexpression of Dok-7 promoted NMJ formation in the appropriate location, namely, the central region of the skeletal muscle. These observations indicate that Dok-7 positively regulates the development of NMJs by controlling MuSK activity and its responsiveness to neural agrin, identifying the Dok-7-MuSK signaling pathway as a new therapeutic target not only for DOK7 myasthenia but also other NMJ synaptopathies.

Myasthenogenicity of the Main Immunogenic Region
Jon Martin Lindstrom, PhD, Medical School of the University of Pennsylvania

In myasthenia gravis (MG) and experimental autoimmune MG (EAMG), many pathologically significant autoantibodies are directed at the main immunogenic region (MIR), a conformation-dependent region at the extracellular tip of α1 subunits of muscle nicotinic acetylcholine receptors (AChRs). Human muscle AChR α1 MIR sequences were integrated into Aplesia ACh-binding protein (AChBP). The chimera was potent at inducing both acute and chronic EAMG, though less potent than Torpedo electric organ AChR. Wild-type AChBP also induced EAMG but was even less potent, and weakness developed slowly without an acute phase. AChBP is more closely related in sequence to neuronal α7 AChR, however, autoimmune responses were induced to muscle AChR, but not to neuronal AChR subtypes. The greater accessibility of muscle AChRs to antibodies, compared to neuronal AChRs, may allow muscle AChRs to induce self-sustaining autoimmune responses. The human α1 subunit MIR is a potent immunogen for producing pathologically significant autoantibodies. Additional epitopes in this region or other parts of the AChR extracellular domain contribute significantly to myasthenogenicity. We show that an AChR-related protein can induce EAMG. Thus, in principle, an AChR-related protein could induce MG. AChBP is a water-soluble protein resembling the extracellular domain of AChRs, yet rats immunized with chimeras developed autoantibodies to both extracellular and cytoplasmic domains of muscle AChRs. We propose that an initial autoimmune response directed at the MIR on the extracellular surface leads to an autoimmune response sustained by muscle AChRs. Autoimmune stimulation sustained by endogenous muscle AChR may be a target for specific immunosuppression.

Session II: Advances in Immunology and their Relationship to Myasthenia Gravis

Etiology of Autoimmune Diseases
Jean-François Bach, MD, DSc, Necker Hospital

There is not a single cause for autoimmune diseases but a combination of genetic and acquired predisposing factors. Genetic determinism is complex involving many genes. A growing number of genes or more often genetic regions have been identified but their pertinence to the disease etiology is made uncertain by the low or very low relative risk associated with a given gene polymorphisms. The only exception is that of HLA genes whose involvement in disease pathogenesis is, however, not as clearly understood as generally assumed. Environmental factors are very diverse. Some are clearly identified: specific virus or bacteria in a small number of autoimmune diseases. Several candidate infectious agents, notably viruses, have been incriminated as in the case of multiple sclerosis (EBV) or of Type 1 diabetes (T1D) (Coxsackie virus) without any definite evidence perhaps due to the long time elapsed between viral infection and disease onset (hit and run hypothesis). Other factors have been considered such as defective vitamin D exposure, chemical modification of auto-antigenes or polyclonal B or T cell stimulation as in the case of some drug induce auto-immunity. The problem is complicated by the fact that the environment often has a protective rather than a triggering role. A correlation has been observed, over the last decades, between the decline of certain infectious diseases and the increase in autoimmune diseases. The causal relationship between these two observations has been directly demonstrated in animal models and indirectly in man. The mechanisms underlying the protective effect of infections are becoming better known with, in particular, the involvement of homeostatic competition regulatory T cells and Toll-like receptors with a possible influence of microbiota.

Defects of Immunoregulatory Mechanisms in MG
Sonia Berrih-Aknin, PhD, University Pierre et Marie Curie & Institut National de la Santé et de la Recherche Médicale

Regulatory CD4+CD25+ T cells prevent the activation of auto-reactive T cells and play a key role in the induction of peripheral tolerance. Using purified CD4+CD25+ (Treg) and CD4+CD25- (Tconv) cells from Myasthenia Gravis (MG) thymus, we previously showed a severe defect in the autologous suppression assay compared to control cells. Cross-experiments (using MG Treg cells and healthy T conv, and conversely) showed that not only MG Treg cells were defective in suppressing healthy Tconv cell proliferation, but also that MG Tconv cells were resistant to suppression by healthy Treg cells. The resistance of MG Tconv cells to suppression was not due to their over-proliferation. However, after activation, MG Tconv cells expressed a lower expression of FoxP3 compared to CTRL cells, and secreted higher levels of IL-6 and IL-17, two cytokines implicated in Treg regulation and auto-immunity. These results were corroborated by the transcriptomic analysis of Treg and Tconv subsets, which pointed out a dysregulation of TH17 related genes (IL17A, IL17F, IL17RA, IL21, IL22, IL23R) in MG cells compared to controls.
 
Altogether, our results demonstrate that the defects of immunoregulation observed in MG patients are due to both Treg and Tconv cells, and that IL-17 and related cytokines could play an important role in this defect. This work was supported by FP7 FIGHT-MG project.

A Journey from the Thymus to the Endplate
Marc De Baets, MD, PhD, Maastricht University
Abstract pending

Functional Defect in Regulatory T Cells in Autoimmune Myasthenia Gravis
Matthew N.Meriggioli, MD, FAAN, University of Illinois College of Medicine

Published studies examining the role of regulatory T cells (Tregs) in the pathogenesis of myasthenia gravis (MG) have reported conflicting results. In these investigations, isolation of Tregs was achieved based on expression of CD25 alone, likely resulting in the isolation of impure and/or heterogenous human "Treg" populations. In this study, we used surface CD4, CD25high, and CD127low expression to isolate a relatively pure population of Tregs, and then investigated whether there was a deficiency and/or a functional defect in these cells in the peripheral blood of MG patients.
 
We collected blood samples from 24 MG patients and 22 age-matched healthy control subjects. Peripheral blood mononuclear cells (PBMCs) were isolated, and the expression of surface CD4, CD25, and CD127, and intracellular FOXP3 was analyzed by flow cytometry, and the function of Tregs (CD4+CD25highCD127low/- cells) was assessed by co-culture experiments with CD25-negative autologous responder T cells (Tresp). Expression of intracellular FOXP3 was assessed by flow cytometry and RT-PCR, and cytokine profiles from T cell co-culture supernatants were analyzed.
 
No alteration in the relative numbers of Tregs within the peripheral CD4+ T cell pool was seen in MG patients. In vitro proliferation assays demonstrated that Treg-mediated suppression of responder T cells (Tresp) was impaired, both for polyclonal activation (anti-CD3 Abs) and activation with specific antigen (acetylcholine receptor peptides). This defect was associated with a reduced cellular expression of FOXP3 at both the protein and mRNA level. Both polyclonal and AChR-activated Tresp cells from MG patients could be effectively suppressed using Tregs isolated from healthy controls, while polyclonal-activated Tresp cells from controls were not suppressed using Tregs isolated from MG patients. Cytokine profiles revealed altered levels of IL-6, IL-17, IFN-?, and IL-10 in MG patients.
 
Our findings indicate a clinically relevant Treg-intrinsic defect in immune regulation in MG that may reveal a novel therapeutic target. Study supported by: This work was supported by the NIH (National Institute of Neurologic Disorders and Stroke, K08NS058800, and the Muscular Dystrophy Association (MDA); and National Institute of Allergy and Infectious Diseases, RO1 AI 058190, BSP.

Neuronal Acetylcholine Receptor Autoimmunity
Steven Vernino, MD, PhD, University of Texas Southwestern Medical Center

Autoimmunity against acetylcholine receptors (AChR) at the neuromuscular junction is the usual cause of myasthenia gravis. Neuronal nicotinic AChRs that are highly homologous to the neuromuscular AChR are found throughout the nervous system. The ganglionic neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic and enteric autonomic ganglia. Impaired ganglionic synaptic transmission is one important cause of autonomic failure.
 
Ganglionic AChR antibodies are found in many patients with autoimmune autonomic ganglionopathy (AAG). Patients with high levels of ganglionic AChR antibodies typically present with rapid onset of severe autonomic failure, with orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction and sicca symptoms. A characteristic impairment of the pupillary light reflex is often seen. Lower levels of ganglionic AChR antibodies may be found in patients with other disorders including those with malignancy. However, AAG is only rarely associated with malignancy such as thymoma, lung cancer or lymphoma.
 
Like myasthenia gravis, AAG is an antibody-mediated neurological disorder. Antibodies from patients with AAG inhibit synaptic transmission in autonomic ganglia. Animal models of AAG provide additional evidence that AAG is an antibody-mediated disorder caused by impairment of synaptic transmission in autonomic ganglia. AAG patients improve clinically when treated with therapies to reduce antibody levels (such as plasma exchange, IVIG, corticosteroids, or immunsuppression). Although symptoms improve, most patients continue to have objective evidence of severe autonomic failure.
 
Autoimmunity against other neuronal nicotinic or muscarinic AChR subtypes may also be important, and studies are ongoing in this area.

The Role of B Cell Activating Factor in Autoimmune Myasthenia Gravis
Robert P. Lisak, MD, Wayne State University

Autoimmune myasthenia gravis (MG) is a disease mediated by antibodies directed against molecules of the post-synaptic portion of the neuromuscular junction (NMJ), most often skeletal muscle nicotinic acetylcholine receptor (AChR). In addition, many patients with MG also have increased incidence of other organ specific and non-organ specific autoantibodies as well as other autoimmune diseases. This supports the hypothesis that MG patients have increased activity of B cells and their progeny, plasmablasts and plasma cells. B cell activating factor (BAFF) is a member of the tumor necrosis factor superfamily and is an important factor in B cell development, activation, and survival. Increased serum levels of BAFF have been reported by several groups in MG as well as in some other autoimmune diseases. BAFF is found in germinal follicles at sites of inflammation along with the chemokine CXCL13, a major chemotactic factor for B cells. Thus it is not surprising that BAFF has been found in germinal follicles within the hyperplastic thymus of patients with MG along with increased expression of CXCL13. Production of anti-AChR as well as antibodies to other antigens by cells from the thymus of patients with MG has also been reported. Several BAFF antagonists exist and treatment of patients with these might offer an additional approach to treatment of patients with MG.

Session III: Myasthenia Gravis: Clinical and Laboratory Developments

Population Differences in the Clinical Presentation and Serology of MG
Janice M. Massey, MD, Duke University Medical Center

Clinical classification of MG, epidemiologic data and serologic status define various subsets of MG. Previous studies showed 16% of patients persist with restricted ocular disease but 25% of untreated patients with generalized weakness died. Thymoma is found in 15% of patients. MG has an incidence of 14-20/100,000 and appears to be increasing in part due to better diagnosis in an aging population. While women predominate in younger and men in older populations, each increase with age, as does the incidence of MG. AChR antibodies are present in 50-80% of patients with a higher sensitivity in more severe patients. of seronegative patients, 20-40% have antibodies to MuSK. Patients with MuSK MG (MMG) are often female and may have distinct clinical and electrophysiologic patterns. While some MMG patients are indistinguishable from AChR+ MG, others show facial and bulbar weakness with marked muscle atrophy while another group has prominent neck extensor, shoulder or trunk weakness and frequent crisis. Furthermore, there are differences in response to certain treatments. Cholinesterase inhibitors may produce worsening, while a sustained improvement may occur with rituximab. The recognition of these clinical patterns among patients with MG is evolving. Further delineation by serotyping or genotyping may allow for targeting phenotypes for specific or novel therapies and provide further insights in questions of basic pathophysiology of MG.

Cell-Based Assays in Myasthenia Gravis
Angela Vincent, FRS, University of Oxford

The increasing number of antibody-mediated diseases, and the diversity of target antigens now known, make it imperative to establish diagnostic antibody assays that are sensitive, informative and distinguish between different forms of a disease or syndrome. In myasthenia gravis, antibodies to the AChR are still measured mainly by radioimmunoprecipitation as first reported by Lindstrom et al in 1976. This assay, although sensitive and specific, does not usually distinguish between antibodies to the fetal and adult forms of the AChR which can be relevant to fetal or neonatal disorders. Moreover, a proportion of those that are negative for AChR antibodies have antibodies to MuSK and a few to LRP4, so these also need to be measured separately in many cases. And there are other potential antigens at the neuromuscular junction that need to be explored.
 
We have performed cell-based assays for each of these antibodies. These involve expressing the antigen on the surface of live human embryonic kidney (HEK) cells by DNA transfection, and measurement of antibody binding by indirect immunofluorescence. By clustering the AChRs using co-transfection with rapsyn, we have improved the sensitivity for AChR antibodies in both generalized (Leite et al 2008) and ocular MG and shown that these antibodies are pathogenic (Jacob, et al 2012). We have also used the same approach to look for antibodies to other neuromuscular junction proteins in cohorts of patients previously negative for AChR or MuSK antibodies.
 
The cell-based approach offers not only increased sensitivity but also the knowledge that the antibodies are binding to the extracellular domain of the antigen and are therefore potentially pathogenic; antibodies that bind to intracellular epitopes will not be detected on the unpermeabilised live cells. In addition, they have the potential to be used for multiple antigen (multiplex) testing; mosaics of fixed HEK cells expressing different antigens can be placed together for testing each serum (as already being done for some of the CNS antigens by Euroimmun AG, Luebeck, Germany). In this manner it should be possible in the future to provide simultaneous sensitive assays for antibodies to fetal and adult AChRs, MuSK, LRP4 and other antigens in a single test.

Concentric Needle Jitter Studies
Erik Stålberg, MD, PhD, Pro.em, University Hospital Uppsala

The presence of abnormal neuromuscular jitter is the most sensitive electrophysiologic evidence of disturbed neuromuscular transmission. Jitter has usually been measured using SFEMG needle electrodes (SFE). Recently, many countries do not allow reusable electrodes, thus an alternative to the SFE must be found. The best surrogate at the moment is the smallest available concentric electrode (CNE), a so-called facial electrode. It has a recording surface area three times that of the SFE, and thus usually records from more than one muscle fiber. There is a significant risk of obtaining a summation signal from more than one muscle fiber in a motor unit. It is however possible to obtain reasonable signals mainly representing single fiber action potentials, called "apparent single muscle fiber action potentials "(ASFAP), which can be used for jitter analysis.
 
This method is more difficult than SFEMG in muscles with large or dense motor units, e.g. large limb muscles, and in reinnervation. In facial muscles it is easier to obtain acceptable signals.
 
Reference CNE jitter values have been obtained in extensor digitorumn, orbicularis and frontalis muscles. The CNE reference limits are somewhat lower than with the SFEMG electrode. The diagnostic sensitivity of CNE in MG is similar to that of SFEMG, thus very high.
 
The CNE can be used for jitter studies. Until more reference values have been obtained using standardized equipment, signal and measurement criteria, borderline findings should be interpreted with caution.

Management Challenges in Muscle-Specific Tyrosyne Kinase MG
Amelia Evoli, MD, Catholic University, Roma

Myasthenia gravis with antibodies to muscle-specific tyrosine kinase (MuSK-MG) is generally considered a severe disease on account of weakness distribution with prevalent involvement of bulbar muscles and a rapidly progressive course with early respiratory crises. Its treatment can be unrewarding owing to poor response to acetyl-cholinesterase inhibitors in most patients, disease relapses in spite of high-dose immunosuppression and development of permanent bulbar weakness. In a population of 75 MuSK-MG patients treated in our Institution for at least 2 years (follow-up ranging 2-35 years), the maximum MGFA clinical class was IIIb or greater in 89%, with 32% rate of respiratory crises. High-dose prednisone plus plasma-exchange, as in other forms of MG, is the recommended approach in treating rapidly progressive bulbar weakness. Maximum disease severity did not predict the disease course. Twenty patients (26.6%) suffered from two or more disease relapses while under combined immunosuppressive therapy, and 15 (20%) developed fixed facial and oro-pharyngeal weakness (most patients who developed permanent weakness also had relapsing disease). In the management of these patients, oral steroids proved effective through the whole disease course, and repeated plasma-exchange produced clear albeit short-term improvement, while conventional immunosuppressants resulted comparatively less effective. Rituximab is a very promising treatment for refractory MuSK-MG, as all treated patients, reported so far, achieved significant improvement with substantial decrease of medication. It is yet to be clarified whether the early use of rituximab could prevent the permanent oro-pharyngeal weakness which constitutes a relevant disability in these patients.

Daniel B. Drachman, MD, Johns Hopkins School of Medicine
Abstract pending

Session IV: Myasthenia Gravis: Outcome Measurements and Clinical Trial Development

MG Activities of Daily Living (ADL) Profile
Srikanth Muppidi, MD, University of Texas Southwestern Medical Center

The MG-specific Activities of Daily Living scale (MG-ADL) was developed to assess the status of symptoms and activities in MG. MG-ADL is an eight-item patient-reported questionnaire that can be completed in a few minutes without need for equipment or training. Previously in 254 MG patients, MG-ADL score was compared to quantitative MG score (QMG). MG-ADL correlates well with Quantitative MG score (r= 0.583, P < 0.001). Recently, we analyzed the performance of MG-ADL during a multicenter, prospective scale validation study. Eighty-seven patients completed the MG-ADL, MG Composite and MG-QOL15 on the first visit and 76 returned for the second visit. The mean initial MG-ADL score was 4.89 (±3.54) and improved to 3.59 (±3.3) at the second visit. At the first visit, there was a strong positive correlation between the MG-ADL and MGC (r=0.85, P < 0.0001) and the MG-QOL15 (r=0.76, P<0.0001). Correlation of the change in MG-ADL score and physician impression of change between the two visits was also strong (r= 0.70, P < 0.0001). Test-retest analysis demonstrated a high reliability coefficient. Sensitivity/specificity analysis revealed that a 2-point improvement in the MG-ADL best predicted clinical improvement. The MG-ADL correlates strongly with QMG, other newer validated MG outcome measures and a 2-point improvement in MG-ADL indicates clinical improvement. The MG-ADL is useful as a secondary outcome measure in MG treatment trials and was responsive to change MG status in recent MG treatment trials. Because of the simplicity and ease of use, MG-ADL can also be used in routine clinical management.

Michael Rose, MD, FRCP, King's College Hospital
Abstract pending

The MG Composite
Ted M. Burns, MD, University of Virginia

The "MG Composite" (MGC) scale consists of test items that measure symptoms and signs of MG, with weighted response options. The individual test items of the MGC were selected from existing MG-specific scales based on their performance during two randomized, controlled clinical trials of mycophenolate. Test items were selected so as to be meaningful to both the physician and the patient, frequently abnormal in patients with active disease, responsive to clinical change and appropriately weighted. The MGC was validated in a 175-subject study (11 sites). Total MGC scores showed excellent concurrent validity with other scales. Analyses of sensitivities and specificities of the MGC for identifying clinical improvement revealed that a 3-point improvement in MGC score was optimal for signifying clinical improvement. A 3-point improvement in the MGC appeared to be meaningful to the patient, as indicated by improved MG-QOL15 scores. The test-retest reliability coefficient was 98%, indicating excellent test-retest reliability. Rasch analysis of the MGC was also performed to investigate additional properties, including its unidimensionality and the appropriateness of the weights assigned to the response categories for the MGC items. The fit statistics indicated that the items belong together and can be summated for a total score. There was an overall absence of item order distortion between response categories. The Rasch model expected category response values were compatible with item weights previously assigned. Our Rasch analysis suggested that: 1) the score can be summated to estimate an overall disease severity score; 2) the response options of the ten items are not significantly distorted; and, 3) the assigned weights of the response options are appropriate.

Patient Registries: Useful Tools for Clinical Research in Myasthenia Gravis
Fulvio Baggi, PhD, Neurological Institute "Carlo Besta"

Clinical trials in MG are challenging, not least because of the numerous disease subcategories that must be considered: AChR-MG, MuSK-MG, Double Negative-MG, Ocular-MG, Generalized-MG, Childhood-MG, Early-and Late-Onset MG, and Thymoma-MG. MG Registries can facilitate clinical trials in several ways, including as a source of clinical, biological and immunological data on large numbers of patients, and as a source of referrals.
 
A European-MG database (European MG Network, Grant EU-2005105, DG SANCO) has been developed, and the Myasthenia Gravis Foundation of America is developing a patient-driven registry, to be used in support of research, advocacy and public awareness.
 
Physician-derived registries have the advantage of incorporating diagnostic and treatment data that may allow comparison of outcomes from different therapeutic approaches, which can be supplemented with patient self-reported data. By analyzing data on disease progression and responses to different disease management strategies, registries may help to improve disease outcomes.
 
We present an ongoing collaborative project involving two large physician-derived registries, the Duke MG Patient Registry (US) and the INNCB MG Registry (Italy), and our efforts to develop and implement a common platform with a core of Common Data Elements (CDE) that are concordant with an ongoing NINDS project to establish MG-specific CDEs. Registries have inherent ethical issues about privacy and data use that must be clearly discussed and presented to patients via informed consent. MG Patient Associations should play a pivotal role in disseminating information about registries and encouraging patient participation.

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