Inclusion Body Myositis

Location: Naarden, The Netherlands

The 188th ENMC workshop titled “Inclusion Body Myositis” was held in Naarden, the Netherlands, 2nd to 4th  December 2011.

Workshop organiser: Dr. M. Rose, United Kingdom

This workshop was co-sponsored by the Myositis Support Group, United Kingdom

What was the aim of the workshop?

The aims of the workshop were to;

  • follow up on previous IBM meetings held in London 2009 and Paris 2010
  • foster future collaborative working in immunological and genetic IBM research
  • review natural history studies and clinical trial protocols
  • review the current status of clinical trials outcome measures and map the processes required to improve these
  • establish the requirements for a global IBM registry
  • scope the work required for the establishment of standards of care for IBM

Participants

24 representatives from UK, France, Germany, Belgium, Netherlands, Sweden, Denmark, Australia and USA that included neurologists, rheumatologists, physiotherapists, industry representatives and patient representatives.

What was achieved?

After exchange of knowledge, studies and a broad discussion the following was established:

  • the diagnostic criteria for IBM that were modified at the Paris and London IBM meetings were further discussed and refined.  These criteria will now be validated
  •  current genetic research was reviewed with the option of joining current efforts by way of submitting IBM patient DNA samples to the principle investigators (subject to local ethical approval)
  • previous immunology studies were reviewed and current research was presented and options for participation in these studies were discussed
  • previous trial protocols and natural history studies were reviewed and helped inform the implications for future trials planning
  • the elements required for a global registry for IBM were discussed and a steering committee agreed to work further towards its implementation
  • outcome measures used in trials and in current studies were reviewed.  This revealed that a diversity of outcome measures of variable quality are being used.  Strategies for harmonizing and improving the quality of IBM outcome measures were discussed
  • the scope and content of evidence based standards of care for IBM were considered and plans for their development were implemented

A full report is published in Neuromuscular Disorders (pdf)

Dystroglycan and Dystroglycanopathies

Location: Naarden, The Netherlands

The 187th ENMC workshop on dystroglycan and dystroglycanopathies was held at Naarden, The Netherlands, on 11th – 13th November 2011. Nineteen participants from seven countries (Germany, Italy, Netherlands, Sweden, Switzerland, United Kingdom and the USA) with expertise in biochemistry, cell biology, structural biology, animal models of disease, genetic and clinical aspects of muscular dystrophies, clinical trials and patients’ perspectives, attended.

The aims of this workshop were to bring together researchers working on the clinical and basic aspects of the modification of dystroglycan, whether it be in relation to the disease situation in patients, animal models of human dystroglycan-related disease, or cell-based systems addressing the effects of changes or modification of dystroglycan function. Specific issues which were addressed are as follows:-

  • Factors which may determine if a patient develops central nervous system involvement
  • Are current models of the dystroglycanopathies appropriate for the study of the disease and are they useful for therapeutic screening.
  • Can pathways in the cell that send signals that have an effect on dystroglycan provide new insight into the dystroglycanopathies

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, animal models, and to fertilise novel hypotheses and open new avenues of research into these diseases for which there are as yet no forms of therapy. This workshop was the first step in generating a strong working group that is now in a position to lobby and/or bid for future EU Framework research funding, or other such calls.

Specifically the workshop recognised the difficulties in correlating the specific genetic alteration in the patient with the actual disease severity. It was agreed that better diagnostic tools were needed to assess disease severity in patients and model systems, including detection reagents to look at both the amount and the enzyme activity of the affected gene product. Considerable discussion also centred on the idea of dystroglycan as a messenger, delivering signals from the outside to the inside of the cell. The nature of the connection to the outside of the cell, the precise signal pathways activated, and the consequence of the signal generated for the cell – survival, growth, death. The current state of potential therapies including virus-mediated gene replacement and small molecule therapeutics were discussed. Finally a view from a carer of their perspective of dystroglycanopathy and the current patient registry schemes was also considered.

A full report is published in Neuromuscular Disorders (pdf)

Congenital Myasthenic Syndromes

The ENMC hosted a group of experts on Congenital Myasthenic Syndromes (CMS). CMS are inherited disorders in which the safety margin of the neuromuscular transmission is compromised by one or more specific mechanisms. CMS are caused by various genetic defects of neuromuscular junction proteins. Since the last ENMC workshop on CMS in 2004 (126th workshop), additional CMS genes have been identified, of which AGRNDOK7 and GFPT1 were the focus of discussion at the 186rd workshop. As a consequence, the total number of patients with CMS and the diversity of clinical phenotypes have further increased. The workshop discussed the underlying pathophysiology, animal models, current and future approaches to diagnosis, management and therapies of CMS. Furthermore, the group identified gaps in current knowledge and made plans for future collaborative efforts. The workshop was attended by 22 participants from 7 countries (Bulgaria, France, Germany, Spain, Switzerland, United Kingdom, U.S.A.). Participants included scientists, clinicians and a patient representative. CMS patients are often responsive to treatment with different medication, but early and correct diagnosis remains challenging. The awareness and understanding for CMS among health care professionals and the lay public requires further attention.

A full report is published in Neuromuscular Disorders (pdf)

Prof. David Beeson (UK)
Prof. Daniel Hantaï (France)
Prof. Hanns Lochmüller (UK)

Stem/Precursor cells

Location: Naarden

The 185th ENMC workshop on stem/precursor cells as a therapeutic strategy for muscular dystrophies was held at Naarden, The Netherlands, on 3-5 June 2011. Fifteen participants from six countries (United Kingdom, The Netherlands, France, Germany, Italy, Spain and Singapore) with expertise in satellite cells, muscle stem cells, muscle development, muscular dystrophies, clinical trials and patients’ perspectives, attended.

The aims of the workshop were to discuss progress towards the use of stem cells to treat muscular dystrophies and define work that needs to be done, to address the following issues:

  • Develop standard operating procedures for the preparation of stem cells and identify robust reagents permitting their characterisation.
  • Use of standard operating procedures for pre-clinical testing of stem cells to treat muscular dystrophy
  • Lessons to be learnt from previous clinical trials to treat DMD
  • Environmental factors affecting muscle stem cells

The workshop provided an invaluable opportunity to bring together many parties all working on the same problem but with different tools. It provided a platform for participants to report new, often unpublished findings, to highlight problems and how they have been overcome and to share expertise in reagents and animal models.  The main achievements included a decision to put standard protocols for the preparation and identification of different stem cell types and methods for their preclinical testing onto a website, to ensure that different groups achieve comparable results.

We also discussed problems related to the fact that muscle stem cells from different muscles or patients, that appear to be the same, are not always identical and that they may change their properties as they are expanded in culture ready for transplantation.

It is not possible to do a clinical trial using stem cells that is placebo-controlled; design of the trial and methods to measure efficacy of stem cell transplantation should be carefully planned.  The outcome of two ongoing stem cell trials – one with systemically-delivered and one with locally-delivered cells – will be known next year. A significant development made at the meeting was made after hearing from DMD patients that maintenance or restoration of function of a few small muscles, e.g. in the hand, would represent a significant improvement in the quality of life. To this end, the group discussed possibility of extending current work to develop a trial in which small muscles in the finger could be transplanted with myoblasts.  It is however very important to manage the expectations of patients and families and to ensure that good quality, easily-accessible information on stem cell treatment for Duchenne muscular dystrophy is available on the internet.  We plan to hold further meetings of this consortium to advance the possibility of stem cells to treat muscular dystrophies.

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

Pain and Fatigue in NMD, Prevalence and management

The 184st ENMC workshop titled “Pain and fatigue in NMD: prevalence and management” was held in Naarden, the Netherlands, 20-22th May 2011, with representatives from Western and South Europe and USA.

What was the aim of the workshop?

The aim of the workshop was to establish definitions for pain and fatigue in neuromuscular disorders and possible measurement instruments. This will guide the management approaches.

Participants

22 persons with different specialities: neurologists, rehabilitation physicians, physiotherapists, occupational therapist, neurophysiologists, researchers, psychologists and patient representatives of  various countries (USA, Netherlands, France, United Kingdom, Sweden, Denmark, Germany, Italy)

What was achieved?

After exchange of knowledge, studies and a broad discussion the following was established:

  • Despite many different NMD and many different ways used to measure pain and fatigue are a major, common problem in adults and children in NMD.
  • Pain and fatigue are defined as being multidimensional experiences and definitions have been established
  • Pain and fatigue should be measured by a proposed core-set in clinical settings: proposed are Numeric Rating Scales or Numeric Faces for children for both pain and fatigue; for pain also Brief Pain Inventory, Hospital Anxiety Depression Scale, and possible organic/biomechanical causes of pain; for fatigue CIS (Checklist Individual Strength) or FSS (Fatigue Severity Scale) and possible organic/biomechanical causes for fatigue
  • No treatment approaches were discussed
  • Collaboration between centres to collect data on feasibility of the core set and data on pain and fatigue, which will be the base for further discussion on treatment and measurement.

A full report is published in Neuromuscular disorders (pdf)

Pre-clinical studies in animal models of Charcot-Marie-Tooth

The 183th ENMC workshop organized from 29 April-1 May 2011 in The Netherlands was the first ENMC workshop on pre-clinical studies in animal models of Charcot-Marie-Tooth. Twenty-five participants from 7 countries (; United Kingdom; France; Germany; Italy; Switzerland, U.S.A. and The Netherlands) attended this ENMC workshop on Outcome Measures in rodent models of CMT. Participants included adult neurologists, biologists, and molecular geneticists.

The ENMC workshop on outcome measures and clinical trials in CMT was very successful.
The main aims of the workshop were:

  1. To improve and standardize outcome measures used for preclinical trials of mouse and rat models for CMT
  2. To generate a CMTNS for mice and rats
  3. To catalogue mouse and rat models for various forms of CMT
  4. To determine methods to investigate the role of genetic background in preclinical trials for CMT
  5. To identify guidelines on the features of animal models that make them appropriate for particular preclinical studies
  6. To formalize an international CMT animal model consortium to drive all of these aims forward

Achievements.
1)     During the workshop we worked on how to design potential outcome measures in rodents and determine which of these were subject to change over time. At this point combining these into a modified version of the CMT Neuropathy Score (CMTNS) or evaluation tool for animals is being considered. A working group to address these issues has been created.

2)     The group agreed to formalize as a CMT animal model consortium to carry forward the aims of the meeting
3)     An animal registry will be created and maintained
4)     Suggestions of ideal transgene design for animal disease models of CMT were proposed
5)     Suggestions on ideal standardized approaches for neurophysiological evaluation of CMT animal models were agreed upon and novel EPS approaches to be evaluated in the future were discussed
6)     Suggestions on specific nerves to analyze in CMT models were made as well as specific procedures to analyze the nerves.

An approach to preclinical trial design was presented and discussed

A full report will be published in Neuromuscular Disorders.

RYR1 related myopathies

Location: Naarden

19 scientists and clinicians from Europe, the United States and Australia convened between the 15th and 17th of April 2011 in Naarden, the Netherlands, for the ENMC workshop on RYR1-related myopathies, namely Central Core Disease (CCD), Multi-minicore Disease (MmD) and other muscle conditions related to changes in this gene.

The skeletal muscle ryanodine receptor (RYR1) gene plays an important role in normal muscle function and over recent years disturbances of this gene have emerged as one of the more common causes of neuromuscular disease. The first part of the workshop focused on the clinical characterization of these conditions and description of typically associated muscle biopsy features. Subsequently, experimental models of disturbed ryanodine receptor function were presented and secondary RYR1 alterations, a recently emerged important mechanism in the development of other neuromuscular disorders, were discussed. The last sessions of the workshop focussed on mechanisms of RYR1-related disorders potentially amenable to treatment and the development of patient registries in preparation for future therapeutic studies.

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