VCP-related multi-system proteinopathy

Location: Heemskerk, The Netherlands

Description:
Organizers:Teresinha Evangelista (UK); Virginia Kimonis (USA); Hanns Lochmüller (UK); Conrad Weihl (USA); Michael Hanna (UK)

Attendees: Workshop attendees included a multidisciplinary group of 19 participants from 6 countries comprising both basic and clinical researchers and two patient representatives.

VCP is an essential enzyme which regulates cell cycle, organelle biogenesis, and protein degradation via different pathways. VCP mutations cause an age-related, multi-system degenerative disease which displays variable penetrance and gives rise to four dominant symptoms (phenotypes) within families: myopathy, motor neuron disease, Paget’s disease of the bone and frontotemporal dementia. Importantly and distinct to this syndrome, family members may each suffer from a different symptom of the disease.

During the workshop, the group discussed multiple aspects of the disease, such as current patient cohorts in four countries, the variability of genetic disorders related to the VCP disease and the expansion of the phenotypic spectrum to include sporadic disorders. The group also discussed the cellular and molecular aspects of VCP function and dysfunction in diseases, while reviewing the existing animal models and potential therapeutic targets, including VCP-specific therapies. In addition, the group considered patient diagnosis within rheumatology, neuromuscular and dementia clinics and the current clinical management of the three key phenotypes: myopathy, Paget’s disease and dementia. Examples of patient registries, natural history studies and clinical trials in rare neuromuscular diseases also formed part of the discussion.

However, some questions still remain unanswered in regard to VCP disease and a number of areas require further research:

  1. Incomplete understanding of the molecular and cellular consequences of VCP disease mutations.
  2. Lack of consensus on the utilization of animal models for pre-clinical studies.
  3. Correlation between phenotypes and genotypes, disease modifiers and prognostic biomarkers is still unclear.
  4. Lack of clinical trial readiness due to unclear patient outcomes, natural history and active patient registry.
  5. Unclear true prevalence in different populations (muscle, rheumatology, dementia clinics).
  6. Lack of current knowledge regarding dietary and exercise regimes for this group of patients.

What were the outcomes of the workshop and how will they benefit patients?

  1. Development of VCP-related clinical research projects based on collaboration between rheumatologists, cognitive neurologists, neuromuscular specialists and a research consortium with the aim of exchanging clinical results and research resources.
  2. Improved understanding of the VCP disease’s phenotypes and how to standardize clinical care through the multi-disciplinary clinical management of various specialists.
  3. 10 additional mutations that cause the VCP disease were reported, expanding the number to 50.
  4. Exchange of pre-clinical data from promising therapies applied in mouse models.
  5. Open consortium to include other clinical groups with VCP patients

Future plans for the VCP disease consortium include:

  1. Development of a VCP disease global registry and the systematic collection of DNA, patient biomaterial and clinical imaging data into biobanks and other suitable infrastructures that allow controlled access for the wider research community.
  2. Development of an information sheet to inform patients about how patient material and the clinical information of those with VCP disease phenocopies are shared.
  3. Drafting of guidelines for clinical care and clinical research phenotyping of VCP patients.
  4. Update the census of existing, available clinical material (Coriell /EuroBioBank).
  5. Update the Leiden Database with existing mutations.
  6. Census of available VCP patients from the consortium.
  7. Form a working group to focus on clinical trial outcome measures, natural history and study design with the intent of preparing for future clinical trials.
  8. Engage existing patient advocacy groups by providing workshop reports to MDA, ALS, FTD, Paget’s and myositis associations.
  9. Patient initiated social media site on the VCP disease.

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

Establishing an international consortium for gene discovery and clinical research for Congenital Muscle Diseases

Location: Heemskerk

Organisers:  Assoc. Prof. Daniel MacArthur (Boston, USA); Prof. Carsten Bonnemann (Bethesda, USA); Assoc. Prof. James J. Dowling (Toronto, Canada); Dr. Jocelyn Laporte (Strasbourg, FR)

Participants: Alan Beggs (Boston, USA), Gisele Bonne (Paris, FR), Carsten Bonnemann (Bethesda, USA), Sandra Donkervoort (Bethesda, USA), James Dowling (Toronto, CAN), Victor Dubowitz (London, UK), Michael Goldberg (RYR1 Foundation, USA), Morton Goldberg (RYR1 Foundation, USA), Yann Herault (Paris, FR), Mert Karakaya (Koln, GER), Jocelyn Laporte (Strasbourg, FR), Anne Lennox (MTM Trust, UK), Daniel MacArthur (Boston, USA), Edoardo Malfatti (Paris, FR), Katherine Mathews (Iowa City, USA), Marina Mora (Milan, IT), Ichizo Nishino (Tokyo, JP), Emily Oates (via WebEx) (Sydney, AU), Anne Rutkowski (CureCMD, USA), Melanie Spring (MTM Trust, UK), Nicol Voermans (Nijmegen, NL), Jodi Warman (Ottawa, CAN), Tobias Willer (Regeneron, USA), Hui Xiong (Beijing, CH), Irina Zaharieva (London, UK), Edmar Zanoteli (Sao Paolo, BR)

This workshop was sponsored by the ENMC members, the ENMC Company Forum (Amicus, Genzyme, PTC and Santhera), Foundation Building Strength, Myotubular Trust and Cure CMD.

Description:  The 214th ENMC workshop entitled “establishing an international consortium for gene discovery and clinical research for congenital muscle diseases” took place from the 16th-18th of October 2015 in Heemskerk, Netherlands.  A multidisciplinary group of 26 participants took part in this workshop, including 22 clinical and basic science researchers from 11 different countries (France, the UK, Japan, Canada, Brazil, China, Turkey, Italy, the Netherlands, Australia, and the USA) and 4 patient representatives (Myotubular Trust, RYR1 Foundation and CureCMD).

The participants of the 214th ENMC workshop

Background:   Congenital muscle diseases are a group of conditions encompassing the congenital myopathies (CM) and the congenital muscular dystrophies (CMD).  Individually, these are very rare conditions, but collectively they represent a major subset of neuromuscular diseases across the lifespan.  CM/CMDs are associated with significant disabilities and early mortality in most instances.  While there is good evidence that subtype specific supportive care measures improve symptomatology, there are currently no cures or significant disease modifying specific therapies. A key existing barrier to clinical care and therapy development for CM/CMDs is a lack of genetic diagnosis in the majority of cases.  This is due in some cases to inadequate testing of known CM/CMD genes and in others to currently unknown/unsolved genetic causes.  At present, there are approximately 45 CM/CMD disease genes, and this likely represents 50% of the predicted genetic disease burden.  There is therefore a great need (a) for better access to and application of clinical testing of the known CM/CMD genes and (b) for concerted gene discovery efforts aimed at identifying the remaining genetic causes of disease, each one of which will be very rare, necessitating an international collaborative approach to their discovery.

Aim of this workshop:  The best way to address the barriers created by lack of knowledge of the genetic bases of CM/CMD is to have the experts and stake holders in this field working together.  Therefore, the primary goal of this workshop was to accomplish this by establishing a consortium for the study of the genetics of congenital muscle diseases.  Within this overarching aim, additional goals included defining the mission of the consortium and the initial projects for the group.

What was achieved:  In the first half of the workshop, we defined the existing independent efforts at gene discovery for CM/CMD, discussed infrastructure that currently exists for these efforts (both for CM/CMD and for rare genetic diseases in general), and learned about existing networks related to other disease groups.  In the second half of the workshop, we formally established an international CM/CMD consortium, and decided upon additional prospective members to be invited after the conclusion of the meeting.  We agreed that the mission statement of this consortium is “all individuals with CM/CMD deserve to have defined the genetic basis of their disease”, and proposed to begin addressing this mission through 3 initial efforts.

Key deliverables:  These efforts, to be promoted by working groups within the consortium, represent the key deliverables of the workshop, and include (1) development of a clinical genetic testing platform for individuals without current access to testing, (2) creation of a data sharing platform for existing cohorts, and (3) development of a common phenotyping platform.  The goal is that the working groups will have formulated plans for each of these initiatives within 8 weeks of the meeting.  The secondary goal is that these deliverables will be successfully implemented within 18 months of the workshop, whereupon a second meeting of the consortium will take place.

A full report is published in Neuromuscular Disorders (pdf)

Groups discussions on Sunday

Outcome measures and clinical trial readiness in Idiopathic Inflammatory Myopathies (IIM)

Location: Heemskerk, The Netherlands.

This workshop was sponsored by ENMC members, ATyr pharma, LFB Biopharmaceuticals, MedImmune/AstraZeneca, The Myositis Association USA and Myositis Group UK.

           

Organizers: Prof. Olivier Benveniste (France) and Dr. Lisa Rider (USA).

A multidisciplinary group of 22 participants from 8 different countries took part in this workshop, including clinical and basic researchers and 3 patient representatives.

The participants of the 213th ENMC workshop

Background and aim of the workshop: 

Idiopathic Inflammatory Myopathies (IIM) are classified as polymyositis (PM), overlap myositis (OM), dermatomyositis (DM), immune mediated necrotizing myopathy (IMNM) and sporadic inclusion body myositis (sIBM). These are all rare diseases. The follow up of these patients is shared between rheumatologists, neurologists, dermatologists, internists and paediatricians from various hospitals in different countries and as a result disease evaluation and treatments may vary.

The former IIM classification is based on clinical and pathological criteria (e.g. muscle biopsies), but lately different myositis specific (or associated) auto-antibodies are increasingly being used as a diagnostic tool. Different auto-antibodies are associated with different health problems, for example: anti-MDA5 antibodies are frequently associated with interstitial lung disease and skin ulcers.

This is an important step forward, because it is a relatively less invasive and expensive way to distinguish IIM from other myopathies.

Regarding treatment, outcome measures (measuring the effects of treatment on a patient) are important in clinical care as well as in measuring the responses to treatments as part of therapeutic trials of new medications. These may be measured in different ways. Objective measures for example are imaging findings or results of a blood test. Subjective outcomes are based on the opinion of the patient, for example questionnaires.

Many initiatives by medical experts on this subject have resulted in a lot of data, but precise longitudinal data, essential for statistical analysis, are lacking.

The aim of this workshop is to find a consensus between rheumatologists and neurologists regarding the evaluation of response to treatment in the different subgroups of IIM.

The workshop attendants: Dr. R. Aggarwal (rheumatologist, USA), Dr. Y. Allenbach (internist, France), Prof. O. Benveniste (internist, France), Prof. J. de Bleecker (neurologist, Belgium), Ms. I. de Groot (Member of the Myositis Workgroup of Spierziekten Nederland, myositis patient, The Netherlands), Dr. H. Devilliers (internist, France), Dr. D. Hilton-Jones (neurologist, UK), Dr. J-Y. Hogrel (bio-engineer, France), Prof. I. Lundberg (rheumatologist, Sweden), Dr. A. Mammen (neurologist, USA), Mr and Mrs. Oakley (Myositis Support group UK), Dr. C. Oddis (rheumatologist, USA), Prof. G. Padberg (research director ENMC), Mr. D. Ponce (AFMTELETHON, manager of Group of Interest Inflammatory Myositis & myositis patient, France), Dr. L. Rider (pediatric rheumatologist, USA), Dr. M. Rose (neurologist, UK), Dr. H. Sanner (pediatric rheumatologist, Norway), Dr. A. Selva O Callaghan (internist, Spain), Prof. M. de Visser (neurologist, The Netherlands), Prof. A. Wells (pulmonologist, UK) and Dr. V. Werth (dermatologist, USA).

On Day 1 the group focused on the different phenotypes of IIM, inclusion criteria for Polymyositis, Dermatomyositis and IMNM and outcome measures on muscle weakness. Presentations from different specialists about the importance of the muscle biopsy, myositis auto-antibodies and ways to test muscle strength  led to discussions about the best way to classify the different IIM:  is that done based on clinical features, pathological findings and/or auto-antibodies?

Mr and Mrs Oakley, founders of Myositis UK told us the results of an inquiry among British myositis patients regarding outcome assessment: questions like what are outcome measures, why and for whom are these important (for doctors or for patients?). The patients agree that the information gathered by tests and questionnaires is important, but that it is also important for doctors to focus on symptoms which reflect patients’ needs and problems, e.g. fatigue. Ms De Groot, a Dutch dermatomyositis patient told her story of her daily life with the illness and the way it affects social life, work etc. Mr. Ponce, a French myositis patient and manager of a Myositis Group of AFMTelethon, contributed to discussions and pointed out the importance of making assessments feasible and relevant for patients.

A full report is published in Neuromuscular Disorders

On Day 2 the discussion continued. We spoke about functional disability, the Myositis Damage Assessment Tool and the Myositis Activity Assessment Tool and evaluations in neuromuscular disorders during clinical trials. Mr. Hogrel from France told us about the possibilities of mechanical innovation. The invention of the Biogrip, a wrist worn accelerometer, seems a promising way to monitor daily activity of IIM patients.

After lunch we talked about the most fatal complication in Myositis, Interstitial Lung Disease, and the challenge of how to determine if breathing muscles are involved and the lungs are affected or responding to treatment. We ended the day talking about  cutaneous features in both adult and juvenile DM and ways to assess these.

On the morning of Day 3 D. Ponce presented Quality of Life (QOL) survey results of the French Myositis interest group, then we focussed on QOL and the usefulness of the many tools (questionnaires) for measuring QOL. For example: skin (related) problems have a huge physical and emotional impact on DM patients, but these are not considered in the various questionnaires. It is stated that physical health and environment are the most highly affected domains in myositis, but patients score lower on all domains regarding Quality of Life compared with healthy volunteers.

Conclusion: after a summary of all the topics which were addressed this weekend, the organizers Dr. L. Rider and Prof. O. Benveniste proposed a new study to re-examine the Core Set Outcome Measures and to develop new measures:

  • MMT (manual muscle testing) 4 or 8,
  • the use of accelerometry (and other mobile Health Apps),
  • QMT (quantitative muscle testing),
  • Physical disability, including observational functional tools such as the Myositis Functional Index, the 6 minute walking test and TUG (timed up and go) and,
  • QoL (Quality of Life) questionnaires.

100 patients in the subgroups DM, PM, IMNM and ASS (anti-synthestase syndrome) are needed and will be seen twice at the appointed hospitals: once at the start of the illness or at the onset of a disease flare and once after 6 months.

An unanimous decision to accept this proposal ended this workshop.

Prof. I. Lundberg proposed to use the Myonet database for this new study. She also invited the attendants to participate in Omeract’s MAP (Myositis Activity Profile) study. Prof. Lundberg emphasized the importance to get as many patients (representatives) involved as possible. Participants from France, UK and The Netherlands accepted her invitation.

October 2015, Ingrid de Groot (The Netherlands)

A full report is published in Neuromuscular Disorders (pdf)

Animal models in CMD

Location:  Naarden, The Netherlands

This 212th ENMC workshop was made possible by co-funding of Cure CMD:

Organisers 

Valérie Allamand (Paris, France); Madeleine Durbeej-Hjalt (Lund, Sweden); Carsten G. Bönnemann (Bethesda, USA).

Description

The 212th ENMC workshop entitled « Animal models of Congenital Muscular Dystrophies » took place on the weekend of the 29th to the 31st of May 2015 in Naarden, The Netherlands. Thirteen participants from 8 countries (France, Israël, Italy, Japan, Sweden, Switzerland, United Kingdom and USA) attended this workshop, including clinical and basic science researchers. A PhD student participated with support from the ENMC Young Scientist Program.

Background

Congenital muscular dystrophies (CMD) constitute a heterogeneous group of rare genetic muscle disorders, the symptoms of which start at birth or within the first few months of life. Over the past decade, the understanding of their defective molecular basis has expanded greatly, with close to 20 genes known to be involved to date. For the majority of the CMD cases, the proteins involved play major roles in the connection between muscle fibers and the surrounding extracellular matrix (ECM), but some cases are also caused by defects of several proteins from the envelop of the nucleus, the compartment of the cell that contains the DNA.

This workshop focused on the three most common forms of CMD:

  • alpha-dystroglycanopathies, caused by an abnormal glycosylation of alpha-dystroglycan (α-DG), a central protein of the dystrophin-glycoprotein complex (DGC) which is one of the major receptors on muscle cell surface;
  • LAMA2-related muscular dystrophies, due to a deficiency of laminin-211 (also known as merosin), a protein that forms a network surrounding skeletal muscle cells, and which directly binds to cell surface receptors of muscle fibers;
  • COLVI-related muscular dystrophies, due to a deficiency or dysfunction of collagen type VI (COLVI), a major extracellular matrix protein in many tissues.

In order to further understand the pathogenic mechanisms at play, and to assess therapeutic options for these disorders several animal models have been developed, mostly in mice and zebrafish. As clinical trials are commencing or are reaching advanced planning stages, the characterization of these animal models has highlighted the need for a detailed comparison of their disease features, onset and evolution, as well as their adequacy to translate to the human conditions.

Aims of this workshop

  • to determine the value of the animals models currently available for each of the three disease groups, and whether some aspects of the human disease features need further modeling (e.g. brain, skin, overall severity…)
  • to assess the tools (i.e. antibodies, protocols…) available to study these models, to define the most adequate tool(s) to use for different types of experiments and to consider sharing them between laboratories
  • to discuss whether standard operating procedures (SOPs) for animal studies should be implemented or refined to improve reproducibility between laboratories
  • to identify outcome measures to enable comparison of the data emanating from the various models

 What was achieved?

In the first part of this workshop, for each CMD subgroup a short clinical introduction was given by Dr. Bönnemann. Then participants presented novel information, covering the models available and the different therapeutic strategies currently under development. The different approaches ready for clinical trial were also summarised. Then, the participants collectively discussed the actual needs in terms of animal models and tools, and several points were raised, such as whether cellular models should be developed in parallel. Collaborative strategies to share antibodies and biological samples to address some of these points were discussed and agreed upon. The discussion also included reminders on the importance of SOPs and the need to compare the information across the different models and laboratories. The development of a registry of the several models, with information on their disease features, the laboratories where they are available, etc. was discussed and well received by all participants. Finally, the current preclinical therapeutic “pipeline” was reviewed and the role of animal models in advancing the pipeline was assessed.

The following key deliverables were achieved:

  1.  The need for creating animal models on different strains was recognized and the consortium will try and petition for a central facility to carry out this time-consuming and expensive task.
  2. Several collaborations were initiated and future common funding applications for research projects were discussed. Participants will keep in contact should funding opportunities arise in the future.
  3. A registry will be developed which catalogues the different animal models available and all known/relevant information.

Participants

Valérie Allamand (Paris, France); Paolo Bonaldo (Padova, Italy); Carsten Bönnemann (Bethesda, USA); Susan Brown (London, UK); Dean Burkin (Reno, USA); Kevin Campbell (Iowa City, USA); Madeleine Durbeej-Hjalt (Lund, Sweden); Mahasweta Girgenrath (Boston, USA); Yoram Nevo (Israël); Markus Rüegg (Basel, Switzerland); Margot Saunier (Paris, France); Tatsushi Toda (Kobe, Japan); Raffaella Willmann (Zürich, Switzerland).

A full report is published in Neuromuscular Disorders (pdf)

Development of diagnostic criteria and management strategies for McArdle Disease and related rare glyco(geno)lytic disorders to improve standards of care

Location: Naarden, Netherlands

Ros Quinlivan, Toni Andreu, Ramon Marti

The workshop was organised in collaboration with the EUROMAC consortium, an EU funded network to develop a registry for McArdle disease and related disorders. The workshop aimed to agree diagnostic criteria for these rare disorders, best practice for management to improve standards of care in McArdle disease and to plan a strategy for future international clinical trials.

There were 20 participants, from 9 countries (UK, Spain, France, Sweden, Finland, Denmark, Italy, Germany and USA) including one patient representative from the UK. Participants included experts in Neurology, Paediatrics, Sport and Exercise medicine and physiology, Basic Science, Respiratory Physiology, Genetics and Veterinary Science.

We discussed data from the Spanish registry for McArdle disease (GSDV), outcome measures, evidence for exercise as therapy and the evidence for dietary intervention in GSDV. Two phase 2a/b  therapeutic trials for McArdle disease, currently recruiting, were described. Participants presented data from their own patients and published reports of very rare muscle glycogenoses including: GSD0, GSDIII, GSDIV, GSDVII, GSDIX, GSDX, GSDXIII, GSDV, PGK deficiency and RCBK1, diagnostic delay was common.

The following deliverables were achieved:

  1. Diagnostic algorithm to aid diagnosis of these rare conditions.
  2. A recommendation that physical activity is the most important therapy for McArdle disease.
  3. For the other very rare muscle glycogenosis there was no evidence that physical activity was harmful and should be encouraged.
  4. We identified the need to develop a quality of life questionnaire specific to this patient population.
  5. We agreed a plan to develop a randomised controlled trial for exercise training in people with McArdle disease.
A full report is published in Neuromuscular Disorders (pdf).
 

Towards a European consortium for research and patient clinical management in Spinal and Bulbar Muscular Atrophy (SBMA)

Location: Naarden

Co-sponsored by the Kennedy Disease Association (KDA), Genzyme and F. Hoffmann – La Roche Ltd.

Nineteen scientists working in academia, hospitals and industry from 10 different countries (Austria, Denmark, Finland, France, Germany, Israel, Italy, Spain, United Kingdom and USA), along with three patients and family members, met in the Netherlands on the weekend of 27- 29 March 2015. They discussed the current state of the art of research and shared the most recent clinical observations in the field of Kennedy’s disease, also known as Spinal and Bulbar Muscular Atrophy (SBMA). The Workshop was conducted under the leadership of Maria Pennuto, Gianni Sorarù, Linda Greensmith and Pierre-Francois Pradat.

SBMA is a rare inherited, adult onset, slowly progressing neuromuscular disease that results in the death of specialized cells, called motor neurons, in the brain and spinal cord that control movement of skeletal muscles. SBMA is caused by an abnormal ‘mutation’ of a protein, called the androgen receptor, which plays an essential role in mediating the effects of male hormones called androgens. However, when mutated, the androgen receptor fails to function normally, resulting in muscle fatigue, weakness and atrophy of muscles in the arm and leg as well as muscles in the face and neck involved in speech, chewing and swallowing. Twitching or cramping of muscles can also occur. SBMA is an ‘X-linked disease’, which means that females are carriers of the mutant gene which they pass down to their male children. As a result SBMA only affects men.

Tremendous advances in basic and clinical research have been made in recent years that have improved our understanding of how the abnormal androgen receptor causes disease. The Workshop has been a unique opportunity to bring together all of the European groups working on SBMA, together with Dr. Fischbeck from the National Institutes of Health, USA, who first identified the mutation that causes SBMA. In addition, Dr. ElMouelhi, from Novartis, USA, also attended the Workshop to present the viewpoint of industry in supporting the development of novel treatments for SBMA patients.

The Workshop started on Friday afternoon with presentations from basic scientists investigating the pathogenic mechanisms that underlie the toxicity of the mutant androgen receptor. The scientists discussed how the mutation affects the structure of the androgen receptor in order to define how this may alter the function of the protein, resulting in pathology. An understanding of the pathogenic properties of the mutant androgen receptor will help to identify strategies to correct it. The discussion opened up to the cellular mechanisms that are altered by the mutant protein, highlighting how the androgen receptor disturbs the processes that are normally in place within all cells which ensure the cell can function optimally. One of these essential processes is involved in ensuring that cells can dispose of unwanted proteins that do not work properly, in order to prevent them building up and forming ‘clumps’ in the cell which stop it functioning. Another important process that is disturbed by the mutant androgen receptor is the way the cell is provided with energy. Normally, cells are provided with energy by specialized cellular ‘batteries’ called mitochondria. In SBMA, these mitochondria may not work normally, resulting in insufficient energy for the motor neurons to function. Tackling protein mishandling and mitochondrial dysfunction may help to halt or slow disease progression in SBMA. Finally, a new development in our understanding of SBMA is that muscle plays a key role in the disease pathogenesis. This is important as it suggests that deficits in muscle may be promising new targets for the development of novel therapies.

The first day ended with a general discussion on the advantages and limitations of cellular and animal models the scientific community has generated to study SBMA. The scientists present at the Workshop, who generated these models, agreed to make them available to the scientific community.

The second day of the Workshop opened with a discussion about the critical need to identify better markers of disease progression in SBMA, as well as more sensitive and reproducible clinical measures. This is important as SBMA is a slowly progressing disease, and in order for clinical trials to be able to detect if they are altering the rate of progression of the disease, it is essential to have a way to reliably quantify exactly how the disease progresses. Tools to measure disease severity, such as the ALS-FRS scale used in another disorder of motor neurons called amyotrophic lateral sclerosis, and which scores the ability of patients to undertake a number of daily functions, may not be useful in SBMA. For this reason, SBMA-specific rating scales are being developed.

The participants shared an urgency to develop a European or global SBMA registry, which would gather clinical data and possibly tissue samples. This registry will facilitate natural history studies, identification of new biomarkers, and early recruitment of suitable patients into clinical trials. An SBMA registry could be built in a similar way to a pre-existing large international registry for Charcot-Marie-Tooth-disease.

Detailed clinical characterization of SBMA patients shows that SBMA not only affects the neuromuscular system but also many other organs. Besides breast enlargement and sexual dysfunction, patients may experience urinary problems, cardiac abnormalities, a reduction in bone mineral density and possibly also liver involvement. Since muscle weakness is a major problem in SBMA, the possibility that exercise may be helpful has been tested. Exercise in the form of endurance training has been found to be efficacious in several muscle diseases. However, data presented at the Workshop showed that this form of exercise is less effective in SBMA. Other forms of exercise in SBMA are currently under study.

One section was dedicated to patients. One patient from The Netherlands and his wife, and two patients from Italy described their life with disease, asking questions to scientists and medical doctors. The discussion was focused on quality of life, disease management and potential future therapies.

On the final day of the Workshop, the participants agreed to form an SBMA Consortium to address the issues discussed during the Workshop. This important development will enable experts in the field of SBMA to collaborate in future preclinical and clinical studies. The full Workshop scientific report is published in the journal Neuromuscular Disorders (pdf).

Participants: Aria Beniahmad, Manuela Basso, Marco Bertolotti, Andrew Cato, Ad de Wijer, Mohamed ElMouelhi, Gianni Fabris, Josef Finsterer, Kenneth Fischbeck, Pietro Fratta, Illana Gozes, Linda Greensmith, Manu Jokela, Davide Pareyson, Maria Pennuto, Angelo Poletti, Pierre-Francois Pradat, Carlo Rinaldi, Xavier Salvatella, Gianni Soraru, John Vissing, Patrick Weydt.