Desmin and Protein Aggregate Myopathies

Nineteen clinicians and scientists from seven European countries and the USA recently assembled for the 156th ENMC-sponsored International Workshop on “Desmin and Protein Aggregate Myopathies (PAM)” in Naarden, The Netherlands. The aim of the workshop was to discuss recent advances in this group of neuromuscular conditions, to correlate genetic, clinical, biopsy and imaging findings and to consider ways forward to therapy.


There has been a lot of recent interest in the way that some diseases can be caused by the abnormal accumulation (aggregation) of proteins in cells. This is especially important in cells that do not divide like nerves and muscle. It is now known that several disorders can result from this kind of protein accumulation- examples in the central nervous system include Parkinson’s disease and ALS. Accumulation of proteins in muscle cause the so called “protein aggregate myopathies” and this was the subject of this workshop.

Over the years that it has been possible to study muscle under the microscope, so-called inclusions have often been noticed within muscle fibres. These have been seen mainly in the conditions known as the congenital myopathies. As special staining techniques became applied, many of these inclusions were shown to contain a protein desmin. This observation prompted the foundation of a ‘Consortium on Desmin and Desmin-related Myopathies” within ENMC and to date there have been four ENMC-sponsored workshops on muscle conditions involving desmin.

Exciting advances in the field led to the decision to hold this 5th workshop. At this meeting the discussion encompassed a broader group of conditions which are now recognized to fall into the group of protein aggregate myopathies. Amongst these variable late onset autosomal dominant conditions now also known as the myofibrillar myopathies, several causative genes have been identified including mutations in the desmin gene itself as well as myotilin, filamin c, alphaB-crystallin, VCP and ZASP.

Workshop contents:

The participants discussed diseases due to mutations in all of these various genes including their clinical spectrum, diagnostic tools and the patterns of protein aggregation in muscle by light and electron microscopy. Different ways that protein accumulation might cause disease were also considered, including discussing the ways that cells usually cope with degrading and processing abnormal proteins. Finally a round table discussion was devoted to therapeutic approaches to these disorders. During this session the principles of good medical management of complications with the heart and breathing muscles were discussed as well as novel ways to approach treating the underlying diseases.


The participants were able to identify characteristic clinical signs, imaging findings, and biopsy findings (by light and electron microscopy) in PAM which could help to direct the diagnostic process. For the future, it will be important to find new genes among the many patients with PAM in whom there has already been the exclusion of mutations in known genes. Registries of patients could be a useful resource to study natural history and ultimately identify patients for trials. Other important work will be to create new cell lines and mouse models to study evolution and progression of the various forms of PAM and provide a basis for therapeutic intervention.

A detailed report of these conclusions, including the guidelines, is published in Neuromuscular Disorders (pdf)


Bushby K. (ENMC.)

Carpen, O. (Turku/Finland)

Claeys, K. (Paris/France)

Fardeau, M. (Paris/France)

Ferrer, I. (Barcelona/Spain)

Fidzianska, A. (Warsaw/Poland)

Fürst, D. (Bonn/Germany)

Goebel, H.H. (Mainz/Germany)

Kaminska, A. (Warsaw/Poland)

Kley, R.A. (Bochum/Germany)

Olivé, M. (Barcelona/Spain)

Paulin, D. (Paris/France)

Schröder, R. (Erlangen/Germany)

Schoser, B. (Munich/Germany)

Selcen, D. (Rochester/USA)

Sewry, C. (London/U.K.)

Stoltenburg, G. (Paris/France)

Vicart, P. (Paris/France)

Walter, M. (Munich/Germany)

Polymerase gamma and disorders of mitochondrial DNA synthesis

Twenty-three physicians and basic scientists from fourteen countries gathered in Naarden, The Netherlands for the first ENMC workshop specifically focussing on a recently identified group of diseases due to disorders of mitochondrial DNA (mtDNA) synthesis. Over the last few years it has become clear that mutations in POLG, the gene coding for the mtDNA polymerase, polγ, are a major cause of human disease. The principal aim of the workshop was to share knowledge and establish new collaborations to improve our ability to diagnose and treat patients with POLG mutations.


Mitochondria are the “engines” present within each human cell which produce adenosine triphosphate (ATP) from the breakdown products of the food we eat. ATP is required for all active processes within the cell, including muscle contraction and nerve cell firing. Mitochondria contain their own genetic code: mitochondrial DNA (mtDNA), which codes for 13 polypeptides and 24 RNA molecules that are essential building blocks for the machinery required to produce ATP. MtDNA is constantly copied and destroyed, even in non-dividing cells. MtDNA is copied by DNA polymerase g (pol g), which is the only enzyme able to copy mtDNA within mitochondria. It has recently become clear that mutations in the gene that codes for polγ (the gene is called POLG), are a major cause of neuromuscular disease. Mutations in POLGcause loss of mtDNA (depletion), or multiple secondary mutations of mtDNA (either single base point mutations of mtDNA or the removal of large segments of the mtDNA, called mtDNA deletions). These secondary mtDNA abnormalities compromise the ability of mitochondria to produce ATP, leading to cellular dysfunction and cell death in vulnerable tissues and organs. This causes the clinical features of the disease.

The first mutations of POLG were published in 2001 in families transmitting the mitochondrial disorder characterised by weakness of the eye muscles, called autosomal progressive external ophthalmoplegia (PEO). Over the last five years, mutations in POLG have been identified in a wide range of mitochondrial diseases, including the severe childhood brain disorder (encephalopathy with epilepsy) associated with liver failure (Alpers-Huttenlocher syndrome), adult onset clumsiness, which eventually becomes severe (spino-cerebellar ataxia), and sensory nerve degeneration with or without epilepsy. In addition, some family members also have features similar to Parkinson’s disease (parkinsonism) and premature ovarian failure causing early infertility.

Over 100 different POLG mutations have been described in the literature, but rather than giving us a clear understanding, the situation is becoming more complex. Some mutations can behave as both dominant and recessive alleles (in other words, for some patients, a POLG mutation on one copy of DNA is enough to cause the disease, but for others, two POLG mutations are required – one from the mother and one from the father). Some patients have three or four mutations in the same gene, and naturally occurring polymorphic genetic variants (found in up to 4% of the population), also seem to modulate the severity of the disease. It is also not clear why the same mutations can cause severe depletion of mtDNA and a fatal childhood disease affecting the brain and the liver in some families, and an adult-onset muscle weakness in others. These observations make genetic counselling difficult, and our rudimentary understanding of the disease mechanism limits our ability to develop new treatments.

Overview of the workshop

The workshop began with an overview of the major clinical phenotypes associated with mutations inPOLG in adults and children, followed by a discussion of the basic science underpinning the replication of mtDNA. There was a detailed discussion of the cellular, animal and in silico (computer) models of mtDNA replication and how these have informed our understanding of disease. Unusual clinical presentations were presented and discussed throughout the meeting, and the final session focussed on the diagnosis and management of patients with suspected and confirmed POLG mutations.

The participants reached a consensus view on the following:

  1. Which patients should be investigated for suspected POLG disease.
  2. The most appropriate way of investigating suspected POLG disease in adults and children.
  3. Treatment guidelines for patients with POLG mutations.

A detailed report of these conclusions, including the guidelines, is published in Neuromuscular Disorders (PDF). This was specifically written with non-specialist clinicians in mind.


Laurence Bindoff (Bergen, Norway), Annette Boersen (ENMC), Patrick F. Chinnery (Newcastle, UK), William Copeland (North Carolina, USA), Rene De Coo (Rotterdam, The Netherlands), Maaike De Vries (Nijmegen, The Netherlands), Iliana Ferrero (Parma, Italy), Christopher Freyer (Stockholm, Sweden), Bert van den Heuvel (Nijmegen, The Netherlands), Ian J. Holt (Cambridge, UK), Rita Horvath (Munich, Germany), Anne Lombès (Paris, France), Ramon Marti (Bareclona, Spain), Anders Oldfors (Gothenburg, Sweden), David C. Samuels (Virginia, USA), Bert Smeets (Maastricht, The Netherlands), Jan Smeitink (Nijmegen, The Netherlands), Hans Spelbrink (Tampere, Finland), Joanna D. Stewart (Newcastle, UK), Anu Suomalainen (Helsinki, Finland), Mar Tulinius (Gothenburg. Sweden), Gert Van Goethem (Antwerp, Belgium), Jiri Zeman (Prague, Czech Republic), Massimo Zeviani (Milan, Italy)

TREAT-NMD workshop on Outcome Measures for Experimental Studies in DMD

for a report of this meeting, please click here

3rd Annual Plenary Meeting EUMITOCOMBAT

Location: Hoofddorp, The Netherlands


The EUMITOCOMBAT project is a Sixth Framework Programme Integrated Project granted by the European Commission and is entitled “Rational Treatment Strategies Combating Mitochondrial Oxidative Phosphorylation (OXPHOS) Disorders” (Contract No LSHM-CT-2004-503116).

The EUMITOCOMBAT consortium ( consists of 12 participating universities/institutes with 21 scientific group leaders from 9 different European countries.EUMITOCOMBAT will combine mitochondrial research expertise into one, pan-EuropeanConsortium, aiming at an understanding of the underlying basic molecular mechanisms of OXPHOS disease and at the eventual development of treatments for these devastating disorders. The official starting date of the EUMITOCOMBAT project is the 1st July 2004 and the duration shall be 48 months.

The major objectives, around which the scientific and technological work is structured, apply to each of these disease categories:

  • To understand properly the natural history of the disease, its clinical manifestations and their time-course, and the relationship between genotype and phenotype. The eventual goal will be to provide routine and rapid diagnosis, which will form the rational basis for future therapy.
  • To elucidate the pathophysiology of the disease by the analysis of biological models, thus revealing potential new therapeutic strategies or targets.
  • To characterize in detail the cellular machinery primarily affected by the disease process (i.e. complexes I and IV, the components involved in their assembly, and the machinery of mtDNA maintenance and expression). A complete understanding of basic biological processes underlying OXPHOS will lead to the discovery of novel drug targets.
  • To apply the knowledge gathered from such approaches to the rational design and testing of therapeutic agents and manipulations to ameliorate the manifestations of OXPHOS disease.


Since the start of the EUMITOCOMBAT project in 2004, plenary meetings are organized annually together with the ENMC. In 2007 the 3rd Annual Plenary Meeting EUMITOCOMBAT was organised from 24 – 25 May in Hoofddorp, The Netherlands.

The workshop was a meeting open to all researchers involved in the EUMITOCOMBAT consortium. About fifty participants from Austria, Czech Republic, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden and the United Kingdom met in Hoofddorp. The most important goal during this meeting was to present and review the progress of the scientific work. Therefore each of the researchers involved, gave a presentation of the research work within their action line (starting date, progress, eventual deviations, deliverables, etc.). The meeting was closed with a discussion between the research leaders (Consortium Council and Consortium Board) about the main conclusions and consequences for the final 12 months of project period. During this meeting the external reviewer of the project (Italy) was present as well as a representative from the Scientific and Ethical Advisory Committee (Spain).

Participating universities/institutes

Participants from the following universities/institutes attended the meeting:

Academy of Sciences of the Czech Republic (ASCR), Czech Republic; Charles University (CU), Czech Republic; European Molecular Biology Laboratory (EMBL), Germany; Institut National de la Santé et de la Reserche Médicale (INSERM), France; Karolinska Institute (KI), Sweden; Ugichem, Austria; Medical Research Centre (MRC), United Kingdom; National Institute of Neurology “C. Besta” (INN), Italy; Radboud University Nijmegen Medical Centre (RUNMC), the Netherlands; University of Bari (UBAR), Italy; University of Bologna, Italy; University of Newcastle (UNEW), United Kingdom; University of Tampere (UTA), Finland; University of Zaragoza (UNIZAR), Spain; University of Madrid, CSIC, Spain.

European Spinal Muscular Atrophy Randomized Clinical Trial II (EUROSMART II)

On 11-12 May 2007, a group of scientists met in Naarden in order to discuss the results of a recently completed clinical study. The analysis of the results of the EUROSMART trial of acetyl-L-carnitine on 110 SMA type II-III patients revealed no significant improvement in muscle strength or function in treated patients. However subgroup analysis might indicate that the drug might have had a limited  positive effect in a proportion of ambulant patients. The difference was not statistically significant, which might be due to small sample size or short duration of the treatment; in addition these results should be taken with caution as subgroup analysis was not a pre-treatment intended mode of analysis. Nevertheless the drug was well tolerated, without any adverse events. Based on these observations, a new trial was discussed for ambulant SMA patients with a larger sample size and longer duration of treatment.

The aims of this workshop included 

  • devising and validating methods to measure muscle strength, motor function, lung function and quality of life, to be used as standard outcome measures in any future SMA trials.
  • designing a standard procedure and carrying out a double blind, placebo controlled trial with acetyl-L-carnitine to ambulant SMA patients, to determine whether acetyl-L-carnitine improves muscle strength, motor function or lung volumes.
  • broadening the European multi-national clinical network of investigators to study children and adults with SMA.

The first EUROSMART trial was conducted between 2004 and 2006, with the participation of six neuromuscular centers from different countries, including Germany, Israel, Italy, Poland, Spain, and Turkey. This trial, the first of its kind in SMA, has successfully accomplished its aims of creating a multi-national European network and performing a drug trial in SMA. Broadening this network with participation of new countries/centers should serve to share the expertise and also enable to reach a critical mass of patients for new trials.

During the workshop, it was agreed that the parameters and scales used for the previous study are substantially valid, but the addition of functional scale was considered essential. There is enough expertise accumulated and the group is confident to carry on with further similar projects related to SMA, provided that there are other promising drugs identified in addition to or apart from acetyl-L-carnitine.

Funding would be crucial for such large cohort studies. For this purpose,  efforts will be made to inquire policies to obtain further international sources. 

TREAT-NMD workshop on Spinal Muscular Atrophy- outcome measures, databases and standards of care. Naarden 12-13th May 2007

A TREAT-NMD meeting on spinal muscular atrophy (SMA) was held to coincide with a European Neuromuscular Centre workshop on SMA which had assembled representatives of many of the European centres caring for patients with spinal muscular atrophy for discussion of possible clinical trials. Several members of the ICC group for SMA attended from the USA, and we are delighted that this collaboration is extremely fruitful. The discussion was also broadened to have a discussion on outcome measures in Duchenne muscular dystrophy as so many of the areas of interest overlap between ambulant SMA and DMD.

1. Outcome measures for SMA type 1, 2 and 3 and DMD.

Work in the last couple of years has led to the development of several scales for functional assessment. Various scales are available for use now in different trial scenarios and the choice of outcome measures will depend on factors such as the length of a planned trial and the level of disability of the participants. There is also scope for further development of outcome measures, particularly when considering the current emphasis of the regulatory agencies on outcomes which are perceived to be “life altering”.

Natural history studies are helping to inform the development of prognostic indicators especially in SMA 1. The definition of these areas will be crucial for the execution of successful clinical trials. Three studies have collected data on survival of SMA 1, but there may be scope to develop a further prospective dataset based on the newly adopted standards of care.

TREAT-NMD will be working in several areas to evaluate, improve and train centres in use of specific outcome measures:

1. Development of registry and systematic reviews of outcome measures (for further information contact Michael Rose at King’s College Hospital, Denmark Hill, London SE5 9RS, UNITED KINGDOM. Telephone number  (44) 020 3299 8352, faxnumber (44) 020 3299 8341, email address

2. Evaluation of myometry in extended range of muscle groups in SMA (discussion forum to be set up and moderated by Marion Main- interested parties to contact Marion at Hammersmith Hospital, Du Cane Road, London W12 OHS, United Kingdom, telephone number 00 44 2083834734, faxnumber 00 44 20 83831555 email .

3. The assessment of activity monitoring as an outcome measure in SMA (discussion forum to be set up and moderated by Sonia Messina- interested parties to contact Sonia at Policlinico Universitario of Messina, Via C. Valeria, 98125, 98125 – Messina , Italy. Telephone 0039|3477052202 email address

4. Develop an active working group to interact with the ICC outcome measures group (Eugenio Mercuri to convene).

5. Explore plans to get European translations of neuromuscular module of PedsQOL

6. Discussion of whether further data collection in SMA 1 is indicated- discussion forum to be moderated by Sabine Rudnik-Schoeneborn)

7. Initiate a debate of the patient and parent view on the impact of different outcomes to clinical trials (Discussion forum initiated: for access contact

7. Via the education and training network in conjunction with the outcomes measures group provide resources for teaching materials and exchange visits for evaluators (contact

2. Registries for SMA

Establishment of a harmonised database/ registry for SMA patients is a major aim of the network, led by Hanns Lochmueller and Christophe Beroud. Work is moving forward alongside the plans for registry development in DMD:

1.       Plans are in place for UMD based registry with harmonisation where possible with existing registries

2.       Content definition ongoing- contributions/ comments welcome via website

3.       Curator meeting will take place in June

4.       National plans to be assembled

5.       Patient group involvement in interface

3. Standards of care.

TREAT-NMD has an activity to develop and disseminate standards of care in SMA and DMD. This workshop concentrated on SMA where a very representative international working group within the ICC has already used literature review and expert consensus via the Delphitechnique to generate care standards. The workshop participants were able to share this document ahead of publication, and there was general agreement that this is an excellent and very thorough starting point for the development of care standards to be adopted and disseminated via the network, though some areas require further work which will be carried out with the original members of the ICC working group. Treat-NMD work in this area will move forward in the following areas:

1. Develop a précis of the ICC document for clinical use and circulate via website (deadline July 31st)

2. Set up working groups to develop document further in specific areas (Discussion group ongoing)

3. Involve patient groups in dissemination of standards (Contact Ria Broekgaarden at VSN, Lt. Gen. van Heutszlaan 6, 3743 JN Baarn, The Netherlands, telephone 00 31 35-5480480, faxnumber  00 31 35 5480499, email address

4. Involve national networks on dissemination of standards (partners to take forward)

5. Use registries as a tool to disseminate standards of care (long term goal)

6. Use registries as a tool to monitor standards of care/ natural history

General areas for development

The TREAT-NMD group is committed to seeking opportunities to move forward with clinical trials in SMA in collaboration with other similar efforts, such as those based in the USA. Specific examples where there is already active include the collaborations with the ICC on outcome measures and standards of care, and cross talk with the Indianapolis Registry. Other areas to be developed include sharing of data from previous and ongoing trials to allow cross validation of control data and the systematic testing of new target molecules.

For international trials (likely to be necessary given the small patient numbers) there will be the need for collaborations of funding groups, which TREAT-NMD will explore. Contact with industrial groups interested in bringing drugs to trial will also be encouraged, as the TREAT-NMD network would be a good portal for the delivery of trials of promising compounds. Prioritisation of such potential drug targets will be addressed.

List of participants of the workshop

A. Ambrosini (Italy), C. Berard (France), E. Bertini (Italy), R. Bittner (Austria), K. Bushby (United Kingdom), J.M. Cobben (The Netherlands) A. Febrer (Spain), J. Florence (USA), A. Glanzman (USA), N. Goemans (Belgium), J. Gray (United Kingdom), L. Hynan (USA), G. Ihorst (Germany), J. Kirschner (Germany), H. Lochmueller (Germany), M. Main (United Kingdom), A. Mahyew (United Kingdom), E. Mazzone (Italy), E. Mercuri (Italy), L. Merlini (Italy), S. Messina (Italy), F. Muntoni (United Kingdom), C. Dohna-Schwake (Germany), M. Rose (United Kingdom), S. Rudnik-Schoeneborn (Germany), R. Sadjadi (United Kingdom), E. Scott (United Kingdom), T. Sejersen (Sweden), Y. Shapira (Israel),  B. Steffensen (Denmark), B. Talim (Turkey), E. Tizzano (Spain), H. Topaloglu (Turkey), M. Tulinius (Sweden), M. De Visser (The Netherlands), J. Vissing (Denmark), T. Voit (France), C. Vuillerot (France) C. Wang (USA)

A full report is published in Neuro Muscular Diseases (pdf)

International Inflammatory Neuropathy Consortium

Neurologists, other experts and patient representatives from Europe and the USA met under the auspices of this ENMC workshop to consider the management of inflammatory neuropathy. Existing treatments for Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and related disorders leave unacceptable numbers of patients with persistent severe disability. Despite the evident need for better treatments, no trials are in progress for GBS and few for CIDP and related disorders. This workshop has launched an international consortium to discover new treatments for these conditions. Participants reviewed the evidence from Cochrane systematic reviews, randomised trials and observational studies for treating GBS, CIDP, multifocal motor neuropathy (MMN) and paraprotein associated demyelinating neuropathy (PDN). They then debated ways of making advances and reached the following conclusions.


· There is a need for better education of health care professionals to enable the earlier diagnosis of these potentially treatable diseases

· There is a need for more research into the pathogenesis of inflammatory neuropathy

· There is a need for more evidence in children

· In GBS there is a need for trials of

o Intravenous immunoglobulin (IVIg) in mild GBS and the related disorder Fisher syndrome

o Plasma exchange versus IVIg in axonal forms

o complement inhibitors in acute severe GBS

o a second course of IVIg in patients who are still bed bound 2 weeks after the first course

o sodium channel blockers

· In CIDP there is a need for trials of high doses of methotrexate or else of rituximab additional to existing treatments depending on the result of the trial of methotrexate which will conclude in February 2008.

· In MMN there is a need for trials of methotrexate additional to existing treatments.

· In PDN the choice of trials depends on the outcome of the ongoing French-Swiss trial of rituximab with an intended 60 participants. However there would be likely to be a need for trials of higher dose or more frequent rituximab. Chlorambucil was also considered worth trying.

· For all these diseases, there is a need for improved outcome measures and the Consortium should support the PERINOMS study designed by the Rotterdam-Maastricht group.

· Treatments for symptoms of particular concern to patients, particularly fatigue and pain, should also be tested. A trial of exercise for residual symptoms after GBS and in CIDP should be further considered.

· For all these rare disorders there is a need to implement statistical trial methods for identifying candidate treatments more efficiently

Future plans

  • The consortium will seek official status as a special interest group of the Peripheral Nerve Society
  • The Consortium will liaise closely with the GBS-CIDP Foundation International to ensure the relevance of their work to the needs of patients
  • The Consortium will maintain an up to date account of the current trial evidence and support the Cochrane Collaboration in maintaining up-to-date systematic reviews of the evidence
  • The consortium will maintain a register of relevant ongoing and planned trials, drawing on existing sources of evidence
  • The consortium will prioritise the agents which need to be tried
  • The consortium will establish and maintain initially retrospective but eventually prospective registers of patients with rare inflammatory neuropathies and their treatments. An initial register of multifocal motor neuropathy will be set up.
  • The consortium will facilitate development of prioritised trials
  • The consortium will publish its recommendations in an appropriate journal, the newsletters of the GBS-CIDP Foundation International and on the World Wide Web.

Participants: J. Berciano (Spain), P. van den Bergh (The Netherlands), P. Blomkwist (The Netherlands) D. Cornblath (USA), S. Delsignore (Italy), P. van Doorn (The Netherlands), H. Hartung (Germany), R. Hughes (United Kingdom, chair) I. Illa (Spain), R. Korinthenberg (Germany), J.M. Leger (France), R. Lewis (USA), M. Lunn (United Kingdom), I. Merkies (The Netherlands), J. Pouget (France), G. Sanders (United Kingdom), I. Van Schaik (The Netherlands) E. Steyerberg (The Netherlands)

A full report of this meeting has been published in Neuro Muscular Diseases. (pdf)

Next meeting

Peripheral Nerve Society meeting Monday July 16 2007 Snowbird, Utah.

This meeting will be open to other interested members of the PNS and relevant pharmaceutical company representatives will be invited.

Core Myopathies

Location: Naarden, The Netherlands

This workshop was held from 9 – 11 March 2007 in Naarden, The Netherlands.

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

Planning Phase I/II Clinical trials Using Systemically Delivered AON in DMD

Thirty-one participants from 7 countries (Australia; England; France; Germany; Italy; The Netherlands; USA) attended an ENMC workshop on the topic of “Planning Phase I/II Clinical Trials Using systemically delivered Antisense Oligonucleotides in Duchenne Muscular Dystrophy”. The workshop was organized with the support of the TREAT-NMD EU Network of Excellence ( and Parent Project Muscular Dystrophy (PPMD).

Duchenne muscular dystrophy (DMD) is a severe muscle wasting condition with onset in early childhood, progressive disability and ultimately reduced life expectancy. It is caused by errors in the DMD gene that lead to the failure to produce an essential muscle protein called dystrophin. Most of these errors are deletions, so named because a portion of the gene is missing. Laboratory studies over the last few years have shown that the addition of small molecules named antisense oligonucleotides to cultured patient muscle cells, and their injection into muscles of a mouse model for the disease can restore the production of the protein dystrophin. Although this was a temporary effect, it improved the structure of the patient cells and mouse muscle. More recently, the repeated systemic (intravenous) administration of antisense oligonucleotides was shown to be capable of restoring a sustained dystrophin expression in the mouse model of DMD. It is therefore hoped that a similar approach, if effective in people, would also be able to slow down disease progression in DMD.

Two European groups, one in the Netherlands and one in England, are taking these observations into clinical trials. In the Netherlands, a trial has been performed and in England a trial is planned in individuals with DMD to assess if the intramuscular administration of antisense oligos is safe and if dystrophin production can be restored following a single dose in an injected human muscle. The aspects related to intramuscular administration of antisense oligonucleotides were the topic of a previous ENMC workshop held in 2005. Following the demonstration that the intramuscular delivery of antisense oligonucleotides is safe and effective, both groups are planning future systemic delivery of the antisense oligonucleotides, as this is the kind of route that would be more clinically useful. In addition, other groups in USA and Australia are also considering additional clinical systemic delivery trials in the near future.

The scope of this workshop was therefore for these groups to discuss the new findings regarding the efficacy of different types of antisense oligonucleotides (that is different “chemistries” known as 2-O-methyl modified and morpholino oligomers) in animal models, in order to plan for the systemic delivery trials. The procedures that will be followed in the two planned European trials were discussed in detail, and also how other international groups could be involved so that this approach, if effective, could be used in other centres.

The discussion also took into consideration safety issues regarding the administration of antisense oligonucleotides and the regulatory issues that will have to be taken into account when developing this as a therapeutic approach for DMD. The commercial aspects regarding the development of antisense oligonucleotides as a therapeutic option for DMD were also discussed with the two companies involved in the current trials, Prosensa for the 2-O-methyl modified and AVI Biopharma for the morpholino modified oligomers.

The need for a comparable set of outcome measures between the 2 planned European studies, and other studies in this field, was discussed. This will ensure that data generated in the different studies are comparable. These aspects will be addressed in an already planned “outcome measure” workshop which is to be organized by the TREAT-NMD EU Network of Excellence. In addition, a web forum to allow further discussion on aspects of the protocol for systemic delivery of antisense oligonucleotides was set up and will be accessible to researchers involved in this field. Ethical issues and concerns related to these new therapeutic interventions for DMD were also discussed.

An extended report of this meeting has been published in Neuromuscular Disorders (pdf).

Prof. Francesco Muntoni1, Prof. Kate Bushby1 and Prof. Gertjan van Ommen2; England 1 and The Netherlands2.

For further information contact:

European Neuromuscular Centre (ENMC) 
Lt.Gen. van Heutszlaan 6
3743 JN Baarn
tel. (31) 35 5480481
fax (31) 35 5480499

European Amyotrophic lateral sclerosis (EURALS)

Present: Beghi (Milano), Chiò (Torino), Esteban (Madrid), Hardiman (Dublin), Logroscino (Boston), Millul (Milano), Mitchell (Preston), Mora (Madrid), Preux (Limonges), Pupillo (Milano), Stevic (Belgrade), Swingler (Dundee), Traynor (Washington DC), van den Berg (Utrecht), Velding (Utrecht), Zoccolella (Bari)

The meeting was endorsed by the European Amyotrophic Lateral Sclerosis Consortium (EURALS) to highlight the most controversial current issues in the epidemiology of ALS. In a comprehensive review of the literature on the prognosis of epilepsy, special emphasis was put on the heterogeneity of the disease, which represents a major impediment when assessing treatment efficacy in randomized clinical trials. The best prognostic predictors include age, respiratory status and the rate of disease progression at study entry. The reliability of El-Escorial diagnostic criteria for ALS can be contended if they are not used by experienced physicians working in the same institution. In this context, the EURALS members performed a validation study which showed moderate to substantial agreement, tested with the kappa statistics in a sample of patients and controls with variable source data. Based on pooled data from the six EURALS population-based registries (three regions of Italy, Ireland, Scotland, and Preston, UK), a fairly homogeneous and different picture of the main clinical features of ALS can be obtained as compared to the available referral series (older age at onset of symptoms, peak incidence at age 70-74 for men and 75-79 for women, 1.2:1 male:female ratio, shorter interval from onset to diagnosis). However, an as yet unexplained difference was observed across registries for site of symptom onset (predominantly bulbar in Ireland and predominantly spinal in Italy.

Using data from the Scottish registry (1226 cases), data on 70 autopsies (6% of patients who died) were presented. Almost all autopsies confirmed the ALS diagnosis and in only five cases was ALS documented only at necropsy. The results of this study confirm the high sensitivity and specificity of case ascertainment in this registry.

In a sample of patients with ALS enrolled in Piemonte, Ireland and Puglia, registered patients were compared to a subgroup of cases who were referred to tertiary ALS centers. The two groups differed significantly in terms of age at referral, M:F ratio, and family history of ALS.

A pilot study was undertaken by EURALS members from Lombardy, Piemonte, Puglia and Ireland (44 cases and 82 age- and sex-matched controls) to assess the feasibility of a case-control study on physical activity, trauma and sports. In this study, a significant association was found between ALS and strenuous physical activity at work, blue collar occupation, length of exposure to heavy manual activities, organized sports and professional sports. These findings are consistent with other reports but require confirmation in a larger study to be undertaken when financial support is made available.

The advantages and limitations of capture-recapture method were discussed to investigate the similarities and differences of case ascertainment across registries.

A number of new population-based registries have been activated in Limousin, Holland and Belgrade using fairly homogeneous diagnostic criteria and multiple sources for case ascertainment, The incidence rates range from about 1.1 per 100,000 per year (Holland) to 2.2 per 100,000 per year (Limousin). Other regional registries are in progress in the Russian Federation where 9 geographic areas and 14 million persons will be the target for epidemiological studies on ALS.

A comprehensive review of 55 published randomized clinical trials was recently performed. Except for Riluzole, the tested compounds proved to be apparently ineffective. However, the negative results can be mostly explained by overall poor methodological quality of the studies (lack of rationale, the negative results of animal studies, the small sample size, the heterogeneity of the study populations, the short follow-up, the use of inadequate measures of efficacy).

A number of drugs have been subjected to systematic reviews by the Cochrane collaboration, including Riluzole, rhIGF, Cochrane, rhIGF-I, CNTF, branched-chain amino acids, antioxidants and percutaneous gastrostomy. Except for Riluzole, found to be safe and prolong survival by about 2 months, evidence is insufficient to demonstrate the efficacy of the other compounds for the treatment of ALS.

For the full report in NMD, please click here and for the pdf click pdf