A global FSHD registry framework

Location: Heemskerk

This workshop was co-sponsored by:

      

Consensus reached on a global FSHD registry. Global FSHD consortium created

Lay Summary

If you are an individual with FSHD, or a family member, you may have been asked to join a patient registry. Perhaps you are wondering what a registry is?

Disease registries are an essential tool for advancing research to understand a disease, improve patient care, and develop treatments. Typically, registries collect patient contact information, and demographic and diagnosis data. In addition, registries may collect varying amounts of data about your health and symptoms. The data will be anonymized and accessible only by authorized individuals, to protect the privacy of patients and families who participate.

In the FSHD field, there are patient registries in at least 13 countries. On the one hand, that’s great news. On the other hand, having data on this rare disease scattered across so many registries that work in isolation is a cause for concern. Ideally, FSHD patient data from around the world should be collected in a single global registry or a federation of national registries that could talk to one another, so that we have data from as many patients as possible, gathered in a uniform way using the latest standards for diagnosing and describing the condition.

A group of registry curators worked with the FSHD Champions, an international alliance of FSHD patient advocacy organizations, to organize an international workshop to discuss how to move toward this vision of a global FSHD registry. We all agreed that the key goals for this registry are to:

  1. Accelerate research to understand and treat FSHD;
  2. Empower patients to gain insights from the data about their condition and improve their health and quality of life.

This second point is very important. Traditionally, registries have not given information back to patients. Doing so takes considerable thought and work, but we all feel strongly that providing this information to patients and families is an obligation we owe to the patient community.

Over the three-day workshop (November 18-20, 2016) supported by the European Neuromuscular Center (ENMC), 23 individuals from the U.S., Canada, U.K., France, Italy, Spain, the Netherlands, Czech Republic, Australia, New Zealand, representing academia, industry, and patient advocacy groups, gathered to review current FSHD registries.

The participants of the 225th ENMC workshop on “A global FSHD Registry Framework”

We discussed issues in clinical and genetic diagnosis, and ideas for how to evolve from the current 13 registries toward a global network with a way to aggregate data from multiple registries. There was a powerful desire among the participants to collaborate and arrive at a consensus on a number of essential topics. We are happy to report that we delivered on our aims, and more.

The workshop attendees agreed on an updated list of “core data elements” (information that are considered fundamental for the description of disease in each subject) that all registries should collect, and drafted a set of questions that will enable patients to supply this data to registries. We plan to publish the new core data elements in the Neuromuscular Disorders journal and distribute them to all FSHD registry curators.

Very importantly, while FSHD patients show a very wide range of symptoms and severity, the new core data elements focus on a small subset of signs that are mostly likely present in an FSHD patient. This ensures that the registry will not exclude any FSHD patient, while limiting the number of questions that patients would need to answer about their clinical status.

We also agreed on a genetic definition of FSHD that reflects our latest knowledge of FSHD genetics. This allows for “non-penetrant” and “asymptomatic” individuals to be defined as carriers of FSHD based on their genetics, but who have no symptoms or have such mild symptoms that the individual does not notice them. This is important to isolate elements (genetic or environmental) that can interfere with the appearance of disease symptoms. It also excludes patients who appear to have FSHD but lack of what it is now considered the essential genetic basis for FSHD.

In addition, we agreed that FSHD registries should serve as a platform for research. By time-stamping patients’ updated information (rather than overwriting old information with new), a registry can track changes in patients’ health and symptoms over time. Researchers can send surveys to registry participants to gain insight into a wide range of topics, from pain management, the effects of exercise, diet, and medications, the impact of pregnancy and menopause, and so on. We agreed that such research surveys should be shared among the registries so that they can be used in different populations.

Buoyed by this success, we went even further. Dr. George Padberg proposed that an international consortium be formed to continue the work. Workshop organizers Rossella Tupler (Italy), Baziel van Engelen (The Netherlands), Hanns Lochmuller (UK), and June Kinoshita (USA, patient advocacy representative) were asked lead the new consortium, joined by Drs. Rabi Tawil (USA).

The new organization will be called the FSHD Consortium. The name leaves open the possibility of expanding beyond registries to drive international collaboration on a variety of future research studies and initiatives.

Establishment of the global registry and FSHD Consortium will enable us to achieve greater clarity on the nature of FSHD and on factors that can make a difference to patients’ health and quality of life.

Acknowledgements: We thank the European Neuromuscular Center for a generous grant to support the workshop. The FSH Society, FSHD Stichting, and Friends of FSH Research provided additional support.

A full report of this workshop is published in Neuromuscular Disorders (pdf)

List of FSHD Champions members:

FSHD Champions members Country
Amis FSHD France
Chris Carrino Foundation USA
Friends of FSH Research USA
FSH Society USA
FSHD Canada Foundation Canada
FSHD Europe EU
FSHD Global Research Foundation Australia
FSHD Stichting The Netherlands
FSHD Champions Allies Country
AFM Telethon France
Muscular Dystrophy Association USA
Muscular Dystorphy Campaign UK
MD Canada Canada
National Institutes of Health USA
Prinses Beatrix Spierfonds The Netherlands
Spieren voor Spieren The Netherlands

Clinicopathological classification of Immune-mediated necrotizing myopathies

Location: Zandvoort, The Netherlands

Translation of this report:
German Translation
French Translation

Organizers: Prof. W. Stenzel (Germany), Prof. O. Benveniste (France), Dr. Y. Allenbach (France) and Dr. A. Mammen (U.S.A.)

A multidisciplinary group of 20 participants from eight different countries attended this workshop in Zandvoort, The Netherlands, including clinical and basic researchers and one patient representative.

Participants: Dr. Y. Allenbach (internist, France), Dr. A.  Amato (neurologist, USA), Dr. A. Aussy (PhD student, France), Prof. O. Benveniste (internist, France), Prof. J. de Bleecker (neurologist, Belgium), Dr. A. Corse (pathologist, USA), Mrs. I. de Groot (patient representative, The Netherlands), Mrs. N. Fischer (medical PhD student, Germany), Prof. H. Goebel (neuropathologist, Germany), Dr. D. Hilton-Jones (neurologist, UK), Dr. J. Lamb (geneticist, UK), Prof. I. Lundberg (rheumatologist, Sweden), Dr. A. Mammen (neurologist, USA), Prof. T. Mozaffar (neurologist, USA), Dr. I. Nishino (pathologist, Japan), Dr. A. Pestronk (pathologist, USA), Prof. U. Schara (paediatric neurologist, Germany), Prof. W. Stenzel (neuropathologist, Germany), Prof. M. de Visser (neurologist, The Netherlands)

Summary of the workshop from a patient´s perspective:

Aim of the workshop: to reach international consensus on the pathological and clinical criteria of IMNM and its possible subtypes. Another aim was to agree on guidelines for diagnosis and treatment schemes.

As a patient representative I was invited to participate in the previous ENMC workshop in 2015, which was dealt with the outcome measures and clinical trial readiness in Idiopathic Inflammatory Myopathies (IIM). The timing for this 2016 workshop solely on IMNM was perfectly planned, since clinicians and researchers recently have discovered more and more about these rare subtypes of myositis. On the other hand there also appears to be a lack of evidence-based guidelines for treating myositis patients. What is needed now is a consensus on diagnostic criteria and preferably also on guidelines for therapeutic options, which can be disseminated  to every doctor concerned. This is very important since IMNM can show a very severe course of disease.

In two days all attendants presented new data and findings from trials and research in their respective countries, followed by lively discussions. A lot of hard work was done by dedicated myositis experts. We focussed on pathological and clinical criteria of IMNM, on serology (= detection of auto-antibodies in blood samples), genetics (= science on heredity), pathology (science of microscopic features in tissue) and also on treatment strategies.

My contribution as a patient was sharing my story of living with this chronic and rare disease: its impact on every aspect of my life and the challenges and limitations that come with myositis. During the following sessions I was invited several times to express my opinion on things (e.g. on muscle biopsies and on the importance of physiotherapy and exercise) and join the discussions.

Outcomes of the workshop:

  • Consensus on clinical definition of IMNM
  • Agreement on subdivision of IMNM types
  • Agreement on clinical and pathologic diagnostic criteria
  • Consensus on therapeutic guidelines

I was impressed how studies done by all these myositis experts in different parts of the world led to similar findings. In the course of the workshop it appeared that this knowledge led them to believe that the time was ripe to reach agreement on subdividing the IMNM on the basis of specific auto-antibodies (anti-SRP and anti-HMGCR). And subsequently also to agree on clinical and pathological diagnosis criteria and propose treatment options for each subtype. What a beautiful and promising outcome of this unique workshop!

Ingrid de Groot, patient representative, The Netherlands

Norina Fischer, medical PhD student, Germany

A full report is published in Neuromuscular Disorders (pdf).

AAV Microdystrophin gene therapy for DMD

Location: Naarden

Translation of this report:
French

This workshop was co-sponsored by:

  

Organizers:

Diana Ribeiro (London, UK), Caroline Le Guiner (Nantes, France), Fulvio Mavilio (Evry, France), George Dickson (London, UK).

Workshop Description:

The 223rd ENMC workshop entitled “AAV (Adeno-Associated Virus) Microdystrophin Gene therapy: Trial Ready for Duchenne Muscular Dystrophy (DMD)” took place from the September 16th to 18th September 2016 in Naarden, The Netherlands. A multidisciplinary group of 23 persons from 7 countries (UK, USA, Germany, France, Netherlands, Belgium, Iceland and Ireland) attended the workshop, including 14 clinical and basic science researchers, 3 industry participants, 2 patients, and 4 representatives from the following DMD patient organisations: AFM, MDUK, Action Duchenne, Join our Boys and Living with Duchenne. It is unique, since an ENMC workshop on gene therapy for DMD has never been organized before. The discussions were divided in 4 sessions, encompassing the following topics: background and other examples of AAV gene therapy; preclinical development of microdystrophin AAV vectors; AAV vector GMP production, toxicology and immuno-toxicology; DMD gene therapy clinical trial design and execution. The aim of the workshop was to share, receive, collate and report on the expert opinions in the field on: (i) current ongoing or near-horizon AAV gene therapy trials, (ii) development of AAV microdystrophin vectors, (iii) production and toxicology of AAV vectors, (iv) immunogenicity of AAV vectors and transgenes, and (v) DMD Gene therapy clinical trial design and execution.

Workshop Outcomes:

Virus-mediated gene therapy applications to restore dystrophin expression are widely considered as a promising treatment avenue to directly address the underlying genetic cause of DMD. Many different viral vectors exist, each with specific properties. Adeno-associated virus (AAV) is non-pathogenic and has been well characterised in pre-clinical studies and in recent clinical gene therapy trials, for example for spinal muscular atrophy and haemophilia. There are various challenges involving AAV gene therapy both in general and for the DMD gene. Lab-based genes encoding the full-sized dystrophin protein are generally too large to be accommodated into AAV gene therapy vectors. For this reason, there have been a range of so-called microdystrophin genes artificially designed, which are small enough to fit into an AAV vector, and yet retain much if not all of the functionality of the normal sized dystrophin can be discarded without losing much of its function. These approaches were discussed in detail. The distribution of viral vectors to the skeletal muscle, diaphragm and heart to deliver the treatment and expression of microdystrophin was also discussed in detail. Two types of AAV vectors or serotypes (AAV8 and AAV9) were described for microdystrophin delivery and seem to be currently best suited and practical for DMD gene therapy. These variant vectors and microdystrophins have been studied in the mouse, rat and dog animal models of DMD with significant positive results, in terms of reduced degeneration of muscle tissue, scar tissue, and improved muscle functionality and stability, and improved clinical parameters (movement, gait and breathing). Duration of microdystrophin expression and clinical improvements were observed for at least 2 years after a single administration of an AAV gene therapy vector. Effective gene therapy targeting widespread muscles has been shown to require relatively large doses of AAV vectors to be administered which challenges production methods and may limit the number of people that can be recruited into clinical trials. Scaling up of AAV vector production from lab-based levels to semi-industrial pharmaceutical grade production takes significant investment to meet the stringent standards related to purity, potency and safety that are required for human clinical trials. Different methodologies to generate the required amount of purified product for DMD trials are currently being evaluated were discussed in terms of efficiency and practicalities of production. The safety of, and immune response to, AAV gene therapy vectors and microdystrophin products were extensively discussed. While no adverse immunological responses are observed generally in animal studies, prior and ongoing clinical trials in humans have shown that low-level and transient elevations in serum liver enzymes may occur most likely due to immune system reactions to AAV surface protein (called the capsid). Such responses in human subjects have been below the level to generate serious clinical concerns, but have nevertheless been managed by transient mild immunosuppression using steroid drugs (glucocorticoids). It was discussed that any DMD patients recruited into AAV-microdystrophin gene therapy trials will likely be already receiving steroid treatments and that this was considered an advantageous situation although steroid dose levels might have to be adjusted temporarily. It was also discussed that either due to pre-existing exposure to AAV in individuals prior to gene therapy, or following an initial gene therapy treatment, the presence of antibodies to AAV in patients would present a barrier to efficient re-administration of second and subsequent doses. It was noted that approaches to prevent and/ or circumvent this effect were under development but would likely prove difficult. Discussion of trial designs indicated that they would follow a standard approach in the field with initial small scale safety and dose-escalation studies (Phase I and Phase II), with primary outcomes of safety and tolerability, and secondary outcomes monitoring microdystrophin expression, immune parameters, MRI scans and clinical tests of muscle function. Due to the unusual circumstances in AAV gene therapy trials where a first treatment may preclude secondary higher dose treatments, it was noted and discussed that in dose-escalation safety studies, careful consideration of the initiating dose, and patient recruitment and ethical consent would be required. A full report of this ENMC workshop will be published in Neuromuscular Disorders in the first half of 2017.

Participants:

Eduard Ayuso (Nantes, France), Anna Buj-Bello (Evry, France), Serge Braun (Paris, France), Jeff Chamberlain (Seattle, USA), Marinee Chuah (Brussels, Belgium), George Dickson (London, UK), Dongsheng Duan (Missouri, USA), Ward Greve (The Netherlands), Caroline Le Guiner (Nantes, France), Michael Linden (London, UK), Fulvio Mavilio (Evry, France), Anna Mayhew (Newcastle, UK), Francesco Muntoni (London, UK), Paula Naughton (Dublin, Ireland), Guðjón Reykdal Óskarsson (Iceland), Diana Ribeiro (London, UK), Jude Samulski (Florida, USA), Laurent Servais (Paris, France), Volker Straub (Newcastle, UK), Thierry VandenDriessche (Brussels, Belgium), Jenny Versnel (London, UK), Jim Wilson (Philadelphia, USA).

A full report will be published in Neuromuscular Disorders.

Myotonic Dystrophy – Developing a European Consortium for Care and Therapy

Organizers: Hanns Lochmüller, Baziel van Engelen, Benedikt Schoser, Guillaume Bassez

Description of the workshop

Myotonic dystrophy is a rare disorder, characterised by enormous genetic and clinical variability. This makes clinical testing of therapeutic approaches more challenging and warrants close international collaboration between expert centres in Europe. To ensure clinical trials to be conducted, sharing of existing, partly unpublished natural history data, refinement of suitable outcome measures, identification of patient populations, and qualification of trial sites is required. Moreover, networking of the existing knowledge, infrastructure and personnel will facilitate appropriate inclusion and communication of patients and patient organisation, the interaction with commercial as well as academic trial sponsors, and the involvement of regulators and payers along the translational pathway.

The aim of the workshop

  • Found a European DM Consortium
  • Increase collaboration
  • Build upon work already carried out by others, e.g. share natural history data
  • Harmonise procedures (e.g. outcomes, registries)
  • Create a trial network and define rules of engagement.

Participants shared their expertise in research on a range of clinically meaningful endpoints.  The limited knowledge of endpoints that can be used to make decisions in clinical trials is one of the most significant barriers to drug discovery and development in Myotonic Dystrophy type1. The workshop was dedicated to address this key gap by taking advantage of expertise from patient representatives, academic scientists, company drug developers, and European regulatory authorities.

The consensus from the workshop was to meet this need through the establishment of a European Consortium that would share the diversity of expertise and patient data to inform clinical trial design and patient treatment paradigms through a standardised core data set.

The following key deliverables were achieved: 

  1. Establishment of standardised operating procedures for endpoint measures that are critical to natural history studies and clinical trials.
  2. Harmonisation of disease classification.
  3. Commitment to more open sharing of data and samples together with lessons learned across the Myotonic Dystrophy type 1 community
  4. Agreement on a mechanism for members to come together into an effective consortium to address these key issues in Myotonic Dystrophy type 1
  5. Agreement to work in partnership with the USA and Canada

Road map for the future

Findings from the Optimistic trial will be published during 2017 and this will provide not only extensive natural history information but also a proven framework for future trials. The nature and findings from the trial in addition to being a study in its own right can be used as building blocks to design and input into future trials together with aiding interpretation of results. The Community is now significantly better prepared to enter into and interpret clinical trials and there is an impetus to further develop along these lines.

The members of the Steering Group for the Consortium have been appointed and progress will be reviewed within six months of this meeting. A full report is published in Neuromuscular Disorders (pdf).

Participants:

Baziel van Engelen, (Radboud University Medical Centre, The Netherlands), Hanns Lochmüller (University of Newcastle, UK), Benedikt Schoser (Ludwig/Maximilians University, Germany), Guillaume Bassez (Créteil University Hospital, France), Jeannette Charlton (representative of Muscular Dystrophy, UK), Alain Geille (AFM Telethon representative, France), Shaun Treweek (University of Aberdeen, UK), Antonio Atalaia (University of Newcastle, UK), Libby Wood (University of Newcastle, UK), Rachel Thompson (University of Newcastle, UK), Giovanni Meola (University of Milan, Italy), Christopher Lindberg (Sahlgrenska University Hospital, Sweden), Vidosava Stojanović (Clinical Center of Serbia, Serbia), Marie Kierkegaard (Karolinska University Hospital, Sweden), Cornelia Kornblum (University Hospital Bonn, Germany), Darren Monckton (University of Glasgow, UK), Cynthia Gagnon (Clinique des Malades neuromusculaires, Canada), Chad Heatwole (University of Rochester, USA), Valeria Sansone (University of Milan, Italy), Matthias Boentert (University Hospital Munster, Germany), John Vissing (Rigshospitalet, Denmark), Arend Heerschap (Radboud University Medical Centre,The Netherlands), John Porter (MDF representative, USA), Pavel Balabanov (EMA representative, UK), Laury Mignon (IONIS Pharmaceuticals, USA).

Foot surgery in Charcot-Marie-Tooth disease

Location:Naarden, The Netherlands

Organizers: M. M. Reilly (UK), D. Pareyson (Italy), J. Burns (Australia), D. Singh (UK).

Participants: Mary M Reilly (London, UK); Davide Pareyson (Milan, Italy); Dishan Singh (Stanmore, UK); Joshua Burns (Sydney, Australia); Michael Shy (Iowa City, US); Matilde Laurá (London, UK); Jonathan Baets (Antwerp, Belgium); Gita Ramdharry (London, UK); Adnan Manzur (London, UK); Isabella Moroni (Milan, Italy); Luca Gaiani (Imola, Italy); Paul Gibbons (Sydney, Australia); Glenn Pfeffer (Cedars Sinai, US); Wolfram Wenz (Heidelberg, Germany); Jan Willem Louwerens (Nijmegen, the Netherlands); Per Henrik Agren (Stockholm, Sweden); Viola Altmann (Nijmegen, the Netherlands); Peter Briggs (Newcastle upon Tyne, UK); Nicolò Martinelli (Milan, Italy) who was able to attend with the Young Scientist Award, made possible by the ENMC Company Forum (see www.enmc.org); Karen Butcher (Christchurch, UK); Fillippo Genovese (Modena, Italy); Marco van der Linden (Eindhoven, the Netherlands).

This workshop was co-sponsored by the CMT UK and INC

 

Description of the workshop

The 221st ENMC workshop entitled “Foot surgery in Charcot-Marie-Tooth disease (CMT)” took place from  the 10th of June to the 12th of June 2016 in Naarden, The Netherlands. A multidisciplinary group of 22 participants from 8 countries (UK, Italy, Germany, Belgium, Australia, USA, Sweden and the Netherlands) attended the workshop, including clinical researchers, orthopaedic surgeons (expert in foot and ankle surgery), physiotherapists and three patient representatives from CMT UK, ACMT-RETE and Dutch Neuromuscular Disease Association. They shared ideas and experiences related to surgery in CMT and identified new research areas for the future. It was unique, since a meeting on surgery and CMT with neurologists, orthopaedic surgeons and patient representatives has never been organized before.

Background

Foot deformities in CMT patients are common.  A cavo-varus deformity (the typical high arched foot seen in CMT), which represents the most frequent deformity, may increase the level of disability of these patients due to instability and foot pain. Over the years many surgical procedures have beenadvocated for the treatment of foot deformities in CMT. However, the lack of well-documented clinical indications and proven results mean we do not know the optimal surgical treatment of such deformities.

Furthermore, in the orthopaedic literature most of the studies reporting the clinical outcomes after different techniques for treatment of CMT foot deformities use a broad set of clinical scores and are relatively short term, leading to difficulties in comparing studies on the same condition.

Aims

The purpose of this workshop was to provide physicians and orthopaedic surgeons involved in the management of CMT foot deformities with an opportunity to review the surgical interventional techniques from an evidence-based and expert perspective and to promote collaborative multidisciplinary research that produces high-quality studies. Therefore, one of the primary goals of this workshop was to agree some basic principles for foot surgery in CMT patients, including types of procedures, indications and outcomes as well as identify areas for future research.

Discussions and achievements

The first part of the workshop was dedicated to a review of the international contemporary practices in CMT treatment by different participants and a comprehensive review of the literature. This part included an introductory presentation by Dr. Singh focusing on the most frequent surgical approaches to treat foot deformities in CMT patients.

In the second and main part, leading experts gave presentations on foot surgery techniques for CMT patients and a discussion was held regarding all approaches.

In the final day the discussion focused on the timing of surgery, the optimum follow up protocol and the identification of the main research questions going forward.

The following key points were achieved

  1. Decision on timing and type of surgery should be taken in a multidisciplinary team, including the neurologist and the orthopaedic surgeon.
  2. The main broad aim of surgery is to achieve a stable well-balanced foot.
  3. A follow-up protocol is being developed to adopt in the clinical setting and which will be  suitable for future research purposes.
  4. The critical research question going forward is to standardize a follow up protocol in an international setting to allow proper comparison of surgical techniques and to allow proper long term follow of outcomes.
  5. A working group was formed to take the actions identified forward

The participants of the 221st ENMC workshop on foot surgery in CMT

A full report is published in Neuromuscular Disorders (pdf)

 

The 2nd ENMC workshop on Dystroglycan and the Dystroglycanopathies

Location: Naarden

Organisers

Prof Steve Winder (Sheffield UK) and Dr Sue Brown (London, UK)

We are grateful to the LGMD2i Fund for contributing to travel expenses for speakers from non-ENMC member countries.

Description

The 220th ENMC Workshop entitled ‘Dystroglycan and the dystroglycanopathies’ and the second such workshop on the same subject, took place from the 27th – 29th May 2016 in Naarden, The Netherlands. The 18 participants were a multidisciplinary group comprising clinical and basic scientists from seven different countries (France, Germany, Mexico, Sweden, The Netherlands, UK and USA) including a patient and carer and a representative from a patient organisation.

Background

Dystroglycan is a core and essential component of the protective layer that surrounds each individual muscle fibre and the developing brain. It is also present in many other tissues where it performs a wide variety of functions. Dystroglycan along with other proteins maintains vital links between the inside of the cell and the outside which serves to protect the delicate cell membrane. Perturbations in the ability of dystroglycan to interact with components, particularly on the outside of the cell, have severe implications for human disease. These diseases are collectively termed the dystroglycanopathies.

In a few isolated instances worldwide they involve mutations of the dystroglycan gene itself, but more frequently are associated with mutations in other genes involved in modification of the dystroglycan protein that helps it to interact with components on the outside of the cell. Mutations in some other genes affect dystroglycan function in a slightly less specific way, but can still lead to muscle wasting and some neurological symptoms typical of dystroglycanopathies. A greater clinical awareness of the spectrum of the disease coupled with a greater use of modern DNA sequencing technology has led to the identification of several new genes involved in the dystroglycanopathies. Furthermore detailed biochemical and cell biological analyses have worked out the fine details of the steps leading to the important modifications in dystroglycan that enable it to bind to components outside the cell. Our understanding of dystroglycan function has also developed considerably in the 4,5 years since we held the inaugural workshop on this topic, and in that time 9 new genes involved in the dystroglycanopathies have been identified. Our next challenge is to apply what we know about the modification of dystroglycan to develop therapies for this group of diseased.

Aims

The aims of this workshop were to bring together researchers working on the clinical and basic science aspects of these important modifications of dystroglycan, whether in relation to the pathophysiology of patients, animal models of dystroglycanopathies, or cellular systems addressing the effects of these modifications on dystroglycan function. By combining clinical and basic scientists, and a range of diseases / models / cellular systems, we hoped to provide a platform for the sharing of ideas, reagents, and animal models. We also aimed to generate novel hypotheses thus opening up new avenues of research into these diseases for which there are as yet no forms of therapy.

Achievements

The workshop reviewed a broad range of topics relevant to the dystroglycanopathies, from patient registries and clinical diagnostic approaches to the functional role of dystroglycan in muscle and brain, as well as potential new therapeutic approaches to treat the dystroglycanopathies. There were presentations from a person affected by a particular type of dystroglycanopathy called LGMD2I, supported by insights from his carer. The mother of a boy with LGMD2I, and representative of the organisation Cure CMD, also gave her perspective. These presentations provided a valuable insight into the importance of finding a therapy for this group of diseases particularly to basic scientists who have no direct contact with patients.

We heard how modern DNA sequencing technology has changed the diagnosis of the dystroglycanopathies and how all this information is being collected in registries in order to facilitate the implementation of clinical trials if and when viable therapeutic approaches become available. With a doubling since the previous workshop in the number of identified genes directly responsible for the full function of dystroglycan, much discussion centred around how these genes contribute to the way that dystroglycan performs its role in muscle and brain, as well as in many other tissues and cells where dystroglycan is also present. Presentations also covered potential treatments for the dystroglycanopathies which have so far been tested in mice with similar disease symptoms. This ranged from simple small molecule inhibitor drugs to alleviate symptoms, to more complicated gene replacement therapies using viruses to get new genes into muscle.

The following key conclusions were reached:

1. An agreement from those present to form a consortium to address future major scientific funding programmes that may be announced by National or International agencies, such as the EU Horizon 2020 project

2. A consensus for the naming of dystroglycanopathies which should be classified as:

    • Primary Dystroglycanopathies (affecting the dystroglycan gene directly),
    • Secondary Dystroglycanopathies (affecting genes that directly modify dystroglycan)
    • Tertiary Dystroglycanopathies (mutations in genes that indirectly affect dystroglycan function).

This recommendation will be taken forward to a forthcoming ENMC Workshop that will specifically address naming and nomenclature of LGMD which also encompasses several dystroglycanopathies.

3. To share important research reagents and tools such as antibodies, cells, tissues and mice through existing biobanks, and to encourage the sharing of therapeutic viruses.

4. Agreement to apply for funding to hold another meeting in 4 years time.

Participants

Neil and Lyndsey Bevan (Patient and Carer Representative, UK), Hans van Bokhoven (Nijmegen, The Netherlands), Sue Brown (London, UK), Kevin Campbell (Iowa, USA), Sebahattin Cirak (Cologne, Germany), Bulmaro Cisneros (Mexico City, Mexico), Holly Colognato (New York, USA), Madeleine Durbeej (Lund, Sweden), Erhard Hohenester (London, UK), Dirk Lefeber (Nijmegen, The Netherlands), Monika Liljedahl (Cure CMD Representative, Sweden), Yung-Yao Lin (London, UK), Qi Long Lu (Charlotte, USA)

Nathalie Seta (Paris, France), Halyna Shcherbata (Goettingen, Germany), Volker Straub (Newcastle, UK) and Steve Winder (Sheffield, UK).

A full report is published in  Neuromuscular Disorders (pdf).

Titinopathies – International database of TTN mutations and phenotypes

Location: Heemskerk, The Netherlands

This workshop was co-supported by The Joshua Frase Foundation and Cure CMD

  

Organizers:

Peter Hackman, Folkhälsan Institute of Genetics, University of Helsinki (Finland)
Bjarne Udd, Neuromuscular Research Center, Tampere University (Finland)
Carsten Bönnemann, NINDS/NIH (USA)
Ana Ferreiro, Unité de Biologie Fonctionnelle et Adaptative, Université Paris Diderot  (France)

The goal and purpose of this ENMC workshop was to establish an international database of TTN (Titin gene) mutations, variations and their clinical presentations, to be able to determine if particular genetic variants of the gene are the cause of disease. Titin is a giant protein, that functions as a molecular spring responsible for the structural integrity and passive elasticity of the muscleTTN mutations have to date been reported to be the cause of various diseases collectively termed titinopathies, including a range of skeletal muscle and cardiac diseases.

We brought together worldwide leaders in the Titin myopathy field, Titin family advocates, as well as representatives from other successfully developed groups. Some attendees are already collaborating together to identify disease causing genes and their clinical descriptions.

Nederland, Heemskerk, 30 april 2016.
ENMC. Groepsfoto.
Foto: Jeroen Poortvliet.

Discussion

“Titin is complex and our need for answers is urgent.” said Titin patient representative Sarah Foye.  After welcoming remarks by Prof. Bjarne Udd and the ENMC Managing Director, Foye opened the meeting by sharing several patient stories to convey patient perspectives.

The meeting then went on to discuss clinical presentations as well as genetic variations of cases from multiple clinicians and researchers. In the sharing spirit of the conference, people presented various cases that have not yet been published in the medical literature. There is a wide range of clinical symptoms that include things like muscle weakness, rigid spine, upper and lower body contractures (tight joints), breathing problems, heart disease and more. The age when symptoms start ranges from birth to adulthood. It became clear that the range of Titin symptoms is multifaceted and varied.  Dr. Ana Ferreiro suggested using the term “congenital titinopathies” to describe the whole spectrum of infantile-onset muscle diseases, with or without heart involvement, associated with TTN mutations.  Dr. Carsten Bonnemann commented that when diagnosing titinopathies clinicians need to consider genetic information (“genotype”), physical features (“phenotype”), microscopic lesions of the muscle cells (“histiotype”) and functional defects (“physiotype”).

The meeting covered different methods of making a genetic diagnosis. The tools for analysis of whether these variants are disease causing or not were reviewed. The group then assessed several databases in existence to see if they would meet the needs. Due to its large size and intricate nature, determining whether a TTN gene variant causes disease or not is a tough challenge. In addition, the current computer tools available are not adequate to meet this need. Thus, a Titin-specific database is necessary.

Specific database requirements were then discussed.  The database needs to include the ability to make an accurate genetic diagnosis as well as to capture a good clinical picture of symptoms.

Outcomes:

  • Attendees agreed that a Titin-specific database is needed.
  • The group drafted clinical questions to include in the database.
  • Platforms for housing the database were presented and discussed.
  • Patient/family experiences were portrayed and appreciated.
  • A collaborative spirit was strengthened among attendees.
  • A commitment to move forward to making a difference for families with titinopathies was renewed.
  • “Plan B” platform alternatives were mentioned in case the “RD-Connect platform” be deemed unsuitable.

Key deliverables and who is taking the lead:

  • The clinical questions on PhenoTips were drafted for the database.  Final touches to these questions will be made within 60 days. (Ferreiro, Saravese, Hackman, Udd)
  • A pilot version of the database based on the RD-connect platform will be tested and data from 100 samples will be uploaded by June 30th 2016. (Saravese, Hackman, Udd, Evangelista)
  • After the RD-Connect pilot has been evaluated an on-line meeting will be held in September to discuss the experiences and the execution of follow up actions. (All, Foye to organize online meeting logistics)
  • If a decision is made based on the pilot study to use RD-connect, then the groups which attend the workshop will submit their data into the database. (All)
  • A computer program for analyzing Titin variants currently named, “Titin Viewer” developed by Isabelle Richard, has been drafted and will be piloted by 30th June 2016. (Hackman, Udd, Saravese, Beggs and other interested parties)

Future meetings:

  • Online meetings as needed to move the database forward.
  • A new ENMC follow up workshop to decide further steps based on the experiences with the utility of the database will be applied for in one year, after the full report has been published in the journal of Neuromuscular Disorders. In this follow up workshop decisions on the wider access to submit data to the database, curation of data submitted from outside the consortium and integration of the cardiomyopathy part will be made.
  • Participants in this workshop were: Bjarne Udd, Neuromuscular Research Center, Tampere University (Finland); Peter Hackman, Folkhälsan Research Center (Finland); Ana Ferreiro Unité de Biologie Fonctionnelle et Adaptative (France); Carsten Bonnemann, NIH/NINDS (USA); Alan Beggs, Boston Children’s Hospital/ Harvard Medical School (USA); Mathias Gautel, King’s College London (UK); Mark Davis, PatheWest Laboratory (Australia); Teresinha Evangelista, Newcastle University (UK); Marco Savarese (via the ENMC Young Scientist Award), Folkhälsan Research Center (Finland); Jelena Nikodinovic Glumac, Clinic for Neurology and Psychiatry for Children and Youth (Serbia); Jocelyn Laporte, IGBMC (France); John Edward Smith, University of Arizona (USA); Isabelle Richard, Genethon (France); Henk Granzier, University of Arizona (USA); Raphäel Schneider, IGBMC (France); Heinz Jungbluth, King’s College (UK); Sarah Foye, Titin family representative, Congenital Muscle Disease International Registry (USA); Alison Rockett Frase, patient representative, Joshua Frase Foundation (USA).Thank you to the ENMC and our sponsors who helped fund with non-European travel expenses. A full report will be published in Neuromuscular Disorders.

A full report is published in Neuromuscular Disorders (pdf).

Revisiting the consensus statement for standards of care in SMA

Location: Naarden

This workshop was made possible with the generous support from:

With preparatory work by:

and Webex support from:

Twenty-one clinical researchers from seven different countries (USA [7], UK [6], Italy [3], Germany [2], France [1], Sweden [1], Denmark [1]), 2 ENMC representatives, 4 representatives of patient advocacy groups (SMA Europe- one patient and one parent of affected children), SMA Foundation [1], Cure SMA [1]), met in Naarden, The Netherlands, on the weekend of the 19th-21st of February 2016. The agenda was to review and update the 2007 standard of guidelines for spinal muscular atrophy (SMA). The workshop was conducted under the leadership of Richard Finkel, Eugenio Mercuri and Thomas Sejersen. The workshop was supported by the 9 ENMC member organizations, 3 partner organizations (SMA Europe, SMA Foundation and Cure SMA), and pharmaceutical company support from AveXis for teleconferencing.

SMA is one of the most common neuromuscular diseases and represents a spectrum of ages and impairments, ranging from infants unable to sit, to children and adults who can walk. SMA has related breathing, feeding/nutrition and orthopedic complications, especially in younger children. There have been noticeable improvements in management of these patients over the past two decades, resulting in improved survival, and maximization of functional capacity. While there is currently no cure for SMA, the evolving understanding of the genetic bases of this disease has inspired several drug treatments that are now in clinical trials. Providing optimal supportive management allows each patient with SMA the prospect of engaging in these new clinical trials, and the opportunity to have a longer, healthier, and more fulfilling life.

This workshop focused upon 8 topics, each with a working group of 2 or 3 co-leaders who then selected approximately 10 international experts on that topic to participate in a structured review and discussion. Detailed literature review of available information preceded the working group’s expert opinion process, which utilized the Delphi technique, a structured sequential analytic process,  to arrive at a group consensus. Input from patient representatives and several pharmaceutical companies working on drug development for SMA was invited. Work was done in advance of the workshop. These 8 groups were:

  1. Diagnostics and Genetic Counseling
  2. Pulmonary
  3. Acute care management in the hospital setting
  4. Orthopaedics  (spinal curvature, joint contractures, fractures)
  5. Physical Therapy and Rehabilitation
  6. Gastrointestinal and Nutrition
  7. Other organ systems involved in SMA
  8. Ethical considerations and Palliative Care.

Each working group presented a summary of their preliminary work at the workshop, which was then discussed by the group at large. This consisted of the organizers, most of the working group leaders, patient/parents and patient advocacy representatives. A WebEx was set up to allow other working group leaders and pharmaceutical representatives to listen to the proceedings, and participate in the open discussion sessions. Additional work was identified for each working group following the workshop. An additional topic of medication use in SMA will also be addressed. The final recommendations of each working group will then be completed and a comprehensive summary will be published shortly thereafter. Family-friendly versions will be created and placed on advocacy group websites for easy public access.

The workshop generated enthusiastic support from the participants and achieved its initial objectives. These updated standard of care recommendations will provide a new framework for the evaluation and management of the most important aspects of SMA, promote improved quality of life for these patients, and reduce the burden of care for their caregivers.

A full report is published in Neuromuscular Disorders (pdf).

RYR-1 related myopathies

This workshop was made possible with the generous support from :

  

Organisers

James Dowling, Heinz Jungbluth, Ana Ferreiro, Francesco Muntoni.

Description of the workshop:

The 217th ENMC workshop entitled “RYR1-Related Myopathies” took place from the 29th to the 31st of January 2016 in Naarden, The Netherlands. A multidisciplinary group of 20 individuals from 7 countries (UK, USA, Italy, Switzerland, France, Netherlands and Canada) attended the workshop, including 17 clinical and basic science researchers, an RYR1 patient, a patient’s parent and representatives from the RYR1 Foundation (www.ryr1.org), the advocacy group for patients affected by RYR1-related conditions.


Patient Representative quote:

“As a parent of a child with a severe congenital neuromuscular condition, I must convey my sincere gratitude to the ENMC for organising the workshop into RYR1-related myopathies at Naarden.  This forum provided the perfect platform for the worlds leading experts to present their latest research, share ideas and develop theories in a collaborative way.  It is truly reassuring to see first hand how so many dedicated individuals are working together with the ultimate objective of finding effective treatments and cures for those that are affected by this and other similar conditions.”

Background:

RYR1 myopathies are due to a change or mutation in the RYR1 gene. This mutation in the RYR1 gene is usually inherited from one or both parents, who may or may not be affected by the disease. There are two types of inheritance patterns for changes in this gene: autosomal dominant and autosomal recessive. “Recessive” means that both “copies” of the gene must have mutations for the patient to be affected; if only one copy is defective, the person (parent or unaffected sibling) will be a carrier and not be affected clinically (that means they will have no signs or symptoms). “Dominant” means that even if only one copy of the gene is defective, the patient and any relative (parent or sibling) carrying the same faulty copy will be affected by the disease.

The term “congenital myopathy” refers to a group of muscle conditions with muscle weakness beginning at birth or in early childhood. Mutations or changes in the RYR1 gene are the most common genetic cause of congenital myopathies. The RYR1 gene encodes for the ryanodine (RYR1) receptor, a channel in muscle cells that regulates the flow of calcium, a critical component of muscle contraction. A reduced number and/or abnormal RYR1 channels lead to dysfunctional muscle contraction and weakness. There is a wide range of symptoms for RYR1-related muscle weakness, but those are typically either non-progressive or very slowly progressive.

Common symptoms include weakness of the eye muscles (in particular in recessive forms) and generalized muscle weakness, typically affecting the muscles closest to the torso of the body.  Some individuals experience muscle cramping and pain, difficulties exercising, and intolerance to heat. There are typically no heart problems and intelligence is not affected.

At this time, no cure exists for RYR1 myopathies

Discussions and Achievements:

Leading experts gave multiple presentations during the course of this weekend workshop into RYR1-related myopathies. The main presentation themes and discussion points have been summarised below:

  • Presentations were conducted on the correlations that exist between muscle disease characteristics and RYR1 sequence variants.  It was made clear that better understanding these correlations is essential for clinicians to be able to provide families and patients with accurate information on disease diagnosis, prognosis and to develop effective treatments moving forward.  A number of examples were provided to illustrate real-life similarities and patterns amongst:
    • Patients that are affected by the disease from a young age (early onset myopathy)
    • Patients that developed muscle disease symptoms later in life (adult onset myopathy)
    • Patients within the same family that have an RYR1 myopathy of varying severity
    • Patients of certain ethnic backgrounds
    • Patient muscle tissue sample correlation analysis and implied disease severity
    • Correlations between RYR1 muscle disease and Malignant Hyperthermia susceptibility (MHS), an inherited tendency to develop severe, potentially life-threatening reactions to certain anaesthetics and muscle relaxants.
  • A number of presentations were also dedicated to the basic science of RYR1 myopathies.  Specifically, recent advances in the ability to model the crystal-like structure of the ryanodine receptor at extremely high resolutions, has enabled researchers to observe the workings of the receptor in incredible clarity. In turn, this has significantly improved our understanding of how the receptor is actually impacted by different variants in the RYR1 gene.  This level of understanding is essential in the quest to find new effective treatments, which can improve the function of the ryanodine receptor and alleviate disease symptoms. The development of Rycals, pharmacological compounds with the potential to modify defective RYR1 function, was discussed as one such new treatment that may help to properly regulate the flow of calcium from the ryanodine receptor to the muscle. This treatment has been tested on mice that have an RYR1 myopathy and has been shown to improve ryanodine receptor function and increase muscle strength. It is expected that human clinical trials of Rycals will commence sometime next year.
  • Information was also provided on drugs that are in clinical trials or that are already FDA approved, and which may be used as treatments in the not too distant future for patients suffering from an RYR1-related myopathy.  These drugs include:
    • N-Acetlylcysteine (NAC)
      • This drug has been shown to reduce oxidative stress in zebra fish that are suffering from an RYR1 myopathy.  Evidence was shown that this drug may help to increase endurance, stamina and improve muscle function in affected zebrafish. This drug has been used to treat varying conditions in humans for many years, seems to have relatively few side effects and is inexpensive. A clinical trial of NAC in humans with RYR1-related myopathies is currently underway and preliminary findings seem positive. The clinical trial is due to be completed in 2017 and official results will be published shortly thereafter.
    • AICAR
      • It was suggested that AICAR may help to increase cell energy release and improve muscle function in those affected by muscle weakness due to RYR1 mutations.  However, relatively few studies have been conducted which analyse its side-effects and the drug would need to be administered in high concentrations to be effective, which may be cost prohibitive as it is expensive.
    • Dantrolene
      • Information was provided which showed that Dantrolene is an effective treatment for Malignant Hyperthermia (MH) but may also be of benefit to patients that have a MH-related RYR1 mutation with additional symptoms such as exertional rhabdomyolysis (i.e. severe muscle breakdown provoked by exercise).
    • CRISPR
      • CRISPR is a gene therapy tool, which is recognised to have huge potential. However, it is recognised that there are significant hurdles to overcome before this treatment will be ready for human clinical trials. Efficiency of gene editing mechanisms, eliminating off target effects, the removal of CAS9 after editing and reducing the cost of creating customised treatments are seen to be the main challenges. Currently, this gene editing tool is being tested in RYR1 affected mice and preliminary results on whether this has improved the mouse phenotype should be available later this year. Although it will be many years before CRISPR will be available as a treatment that can correct genetic variants in humans, its huge potential is clear.

Next steps/key deliverables

  • It was explained that a particular challenge to clinical trials for rare neuromuscular diseases is the lack of a central global database or register that lists affected patients and their symptoms. This makes it difficult for pharmaceutical companies to understand the breadth of the disease and to make contact with suitable clinical trial candidates. As a result, a key deliverable was to establish a central register of those patients affected by an RYR1 related myopathy and to accurately capture their symptoms.
  • The need to provide RYR1 patients with access to consensus care guidelines and disease information resources was listed as a key deliverable.
  • The participants discussed potential for further collaborations, in particular concerning modelling of RYR1 variants to ascertain there precise effects on the ryanodine receptor structure and function. Systematic capture of symptoms of RYR1-related myopathies (for example, increased bleeding, bowel and bladder dysfunction) that are not strictly related to skeletal muscle dysfunction was identified as another area where further collaborative work is needed.

Participants

Robert Dirksen (USA), Susan Hamilton (USA), Andrew Marks (USA),  Katy Meilleur (USA), Sheila Riazi (Canada), Francesco Zorzato (Italy), Susan Treves (Switzerland), Heinz Jungbluth (UK), Carsten Bönnemann (USA),  James Dowling (Canada), John-Paul Cutajar (UK), Julian Faure (France), Isabelle Marty (France), Caroline Sewry (UK), Phil Hopkins (UK), Ana Ferreiro (France), Francesco Muntoni (UK), Mike Goldberg (USA), Nicol Voermans (Netherlands), Jennifer Ryan (USA).

A full report is published in Neuromuscular Disorders (pdf)

Clinical trial readiness for FKRP related muscular dystrophies

Location: Naarden, The Netherlands

This workshop was made possible with the generous support from :

         

Organizers:

Dr. Isabelle Richard (Evry, France), Prof. John Vissing (Copenhagen, Denmark), Dr. Sebahattin Cirak (Cologne, Germany), Dr. Jean-Pierre Laurent (Bellevue, WA USA)

Description of the workshop:

The 216th ENMC workshop entitled “Clinical trial readiness for FKRP related muscular dystrophies” took place from the 15th to the 17th of January 2016 in Naarden, The Netherlands. A multidisciplinary group of 20 persons from 8 countries (UK, USA, Germany, France, Netherlands, Turkey, Canada and Denmark) attended the workshop, including 17 clinical and basic science researchers, a patient, a patient’s parent and representative from the Cure CMD foundation and a representative of the LGMD2i Research Fund. It is unique, since a meeting on muscle dystrophies due to mutations in the FKRP gene has never been organized before.

Background:

Deficiencies in the Fukutin-related protein (FKRP) are part of the dystroglycanopathies group, which are diseases caused by defects in the glycosylation processing of a protein called ‘alpha-dystroglycan’. This protein forms an important link between the muscle cell and its surroundings. When defects in the ‘alpha-dystroglycan’ are due to mutations in the FKRP gene, it creates a wide range of pathologies from the milder and more frequent Limb Girdle Muscular Dystrophy type 2I (LGMD2I) to the rarer and very severe cases of Congenital Muscle Dystrophy (CMD), Muscle Eye Brain (MEB) disease and Walker Warburg Syndrome (WWS). There are no treatments for these diseases. The emergence of new therapeutic approaches like gene therapy generated the need for an expert discussion on the readiness for future clinical trials.

Discussions and achievements:

The discussions were divided in 4 sessions, encompassing the following topics: clinical presentation and natural history of FKRP deficiencies; patient landscape, registries and databases; FKRP function, models and therapies; and biomarkers and outcome measures.

The wide spectrum of phenotypes was underlined, as well as the predominance of the so-called “L276I founder” mutation, leading to a mild form of LGMD2I, especially in Northern Europe. The importance of the registries as tools to resolve the fragmentation of patient data was repeated in several presentations. Importantly, registries help to facilitate recruitment for clinical trials and natural history studies. Individuals with FKRP deficiencies have usually been part of local or national registries for neuromuscular diseases. In 2011, a unique global FKRP registry (Newcastle, UK) was started to centralize clinical data of people with FKRP deficiencies on a global scale as a way to increase the strength of patient representation. Three main challenges were highlighted: specific national regulatory requirements on the sharing of patient information prevent some countries to participate; information about the FKRP registry needs to be disseminated to reach as many patients as possible; and the clinicians of registered patients need to take the time to enter relevant clinical information.

The function of FKRP is still not biochemically proven even though it is known that FKRP at least participates in the complex process of alpha-dystroglycan glycosylation. There are several teams working on studying the functions of the FKRP protein. Preliminary data were presented on techniques to produce and purify FKRP, the first necessary steps to study FKRP function.

Studies in FKRP-deficient mouse models are complicated by the fact that the deletion of the FKRP gene is lethal to mice embryos. On the contrary, mice that contain the same mutations in the FKRP gene as human patients suffer from very mild muscle damages. This type of mice has been used to show the efficacy of a gene transfer therapy to restore muscle function.

Biomarkers are molecules in our body fluids (blood, urine, or saliva) indicative of a disease state. For example, creatine kinase has elevated level in individuals with muscle diseases. There are biomarkers that vary in concentration in response to specific activities or treatments. Finding and validating effective biomarkers is critical to design clinical trials and test experimental treatments in patients. Some ongoing studies have identified a panel of several hundreds of blood biomarkers for LGMD2I. The next step is to test the effectiveness of these markers.

Several presentations focused on outcome measures (ways to measure improvement in muscle strength by a drug e.g.) and on their usefulness in measuring changes in muscle function. Finding a useful functional test for LGMD2I patients is quite challenging because of the slow progression of the disease. New devices to measure muscle strength were discussed.

To understand how a disease progresses and how the medical condition of patients changes, studies called natural history studies need to be performed. For a slow progressing disease, natural history studies are several-year long. The more patients monitored during the study, the higher the quality of the data collected. Several results of natural history studies were interesting and will be studied further. For example, it was mentioned that changes in the 10-meter walk test and the 6-minute walk test in individuals with LGMD2I over long period of time were quite small. Importantly, it was mentioned that fatigue was the most noticeable symptom for some patients. The ability to get up –from a chair for example- was more representative of the condition of people with LGMD2I than the number of minutes they were able to walk.

The following key deliverables were achieved:

  1. Constitution of an integrated network of experts on clinical readiness for FKRP deficiencies, comprising of all the participants of this meeting.
  2. Establishment of a natural history working group with the tasks of designing a natural history study, including the proper patient group and outcome measures.
  3. Constitution of a group working on biochemical outcomes, including blood and urine biomarkers.

Participants :

Susan Brown (London, UK); Kevin Campbell (Iowa City, Iowa, USA); Sebahattin Cirak (Cologne, Germany); Evelyne Gicquel (Evry, France); Jean-Yves Hogrel (Paris, France); Géraldine Honnet (Evry, France); Nynke Koelma (The Netherlands); Jean-Pierre Laurent (Bellevue, WA USA); Katherine Mathews (Iowa City, Iowa, USA); Francesco Muntoni (London, UK); Susana Quijano-Roy (Garches, France); Isabelle Richard (Evry, France); Agata Robertson (Newcastle, UK); Herb Stevenson (Fitchburg, MA USA); Tanya Stojkovic (Paris, France); Volker Straub (Newcastle, UK); Haluk Topaloglu (Ankara, Turkey); Jiri Vajsar (Toronto, Canada); John Vissing (Copenhagen, Denmark); Maggie Walter (Munich, Germany).

A full report of this ENMC workshop is published in the Journal Neuromuscular Disorders (pdf).