EUMITOCOMBAT International Workshop – 1st Plenary Meeting

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 (www.eumitocombat.org) consists of 12 participating universities/instituteswith 21 scientific group leaders from 9 different European countries. EUMITOCOMBAT will combine mitochondrial research expertise into one, pan-European Consortium, 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.

Workshop

Almost one year after the start of the project and the kick off meeting (130th ENMC International workshop) a second meeting was organised from 2-3 June 2005 in Naarden: 1st Annual Eumitocombat Plenary Meeting.

The workshop wasa plenary meeting open to all researchers involved in the EUMITOCOMBAT consortium. More than fifty participants from Belgium, Czech Republic, Finland, France, Germany, Italy, the Netherlands, Spain, Sweden and the United Kingdom met in Naarden. 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 next 18 months of project period. During this meeting also the scientific officer of the EC as well as the external reviewer were present.

At the same time of this first plenary meeting, the meeting of the Scientific and Ethical Advisory Committee was organised. The members who attended discussed the content of the ethical and social issues arising within the EUMITOCOMBAT project.

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 Commission (EC), Belgium; European Molecular Biology Laboratory (EMBL), Germany; EPPOSI, the Netherlands; Institut National de la Santé et de la Reserche Médicale (INSERM), France; Karolinska Institute (KI), Sweden; Lancaster University, CESAGen, United Kingdom; Medical Research Centre (MRC), United Kingdom; National Institute of Neurology “C. Besta” (INN), Italy; Radboud University Nijmegen Medical Centre (UMCN), 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.

Contact

Project Management Team EUMITOCOMBAT University Medical Centre Nijmegen435 – Dept. of Paediatrics PO Box 9101, 6500 HB Nijmegen, The Netherlands

Tel.: +31-24-361 91 26 / 361 94 70

Fax: +31-24-361 64 28

www.eumitocombat.org

Nemaline Myopathy

Twenty doctors and scientists from 9 countries gathered in Naarden, The Netherlands, from 20th-22nd May 2005 for the sixth ENMC workshop on nemaline myopathy.

The sixth workshop was marked by discussion of disease processes, analysis of nemaline bodies in cell culture and animal models of nemaline myopathy based on genes previously identified as causing the disorder. One of the animal models has been investigated for the effects of exercise on muscle function after immobilisation, with the results supporting the beneficial effect of exercise after immobilisation. Further analysis of the genes identified for nemaline myopathy is ongoing. Mutations of actin account consistently for 20-25% of nemaline myopathy. The commonest cause of nemaline myopathy remains mutations in the giant nebulin gene for which mutation detection continues to be a technical challenge. Identifying further nemaline myopathy genes is a constant goal of the Consortium.

The Consortium had been asked to address the issue of steroid use in nemaline myopathy. After discussion the Consortium agreed that there was insufficient information to support a recommendation and has concerns as to potential adverse effects especially in the treatment of very young children. Members of the Consortium are to further investigate the issue. Any potential benefit of L-tyrosine has also not yet been adequately validated. To properly address the efficacy of any treatment there needs to be multi-centre, well co-ordinated clinical trials.

The multinational and multidisciplinary approach necessary for tackling rare muscle disorders remains the focus of the Consortium. The Consortium recognises that the aim for the next, perhaps considerable number of years, is to work towards effective treatments for the various nemaline myopathies, possibly based on approaches being investigated for the more common muscular dystrophies. An important part of management of nemaline myopathy patients is monitoring of respiratory function and implementation of respiratory support where necessary, the recommendations for which were published in the report of the 117th ENMC workshop: ventilatory support in congenital neuromuscular disorders.

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

This workshop was organised by Dr. C. Wallgren-Petterson (Helsinki, Finland) and Dr. N. Laing (Nedlands, Western Australia)

Pompe Disease/GSDII

The first ENMC workshop on Pompe disease, also referred to as glycogen storage disease type II, was held in Hoofddorp from the 22nd to the 24th of April 2005. Twenty participants from The Netherlands, France, Germany, Italy, Austria, Denmark, the United Kingdom and the Untied States attended this meeting. Workshop participants covered areas of basic research, diagnostics, clinical care and therapies in Pompe disease. Another area that was discussed was nomenclature

Pompe disease is an autosomal recessive condition caused by mutations in the gene for acid a-glucosidase, an enzyme responsible for the breakdown of lysosomal glycogen. The reduction or complete loss of a-glucosidase activity leads to lysosomal glycogen storage and finally to an impaired cellular function. The effect of glycogen accumulation on cell function becomes notably effective in muscle cells, in which it compromises contractile activity. As a consequence muscle weakness is one of the predominant clinical features in patients with Pompe disease. A major focus of the workshop was dedicated to the clinical spectrum and natural course of the condition, including unusual clinical presentations and diagnostic pitfalls. It became very clear that Pompe disease is a disorder in which severity, age at onset, rate of disease progression, and extent of organ involvement can vary significantly from individual to individual. Patients present a continuum of clinical phenotypes with a severe infantile form with cardiomyopathy and early death forming one end of the spectrum, and a mild muscle weakness without any cardiac involvement and a normal life expectancy forming the other end of the spectrum. In general, the later the symptoms appear, the less severe the disease will be. But age of onset cannot always be correlated with disease severity as even milder patients can present with motor delay and weakness in early childhood and some adult patients with late onset can rapidly develop severe complains. At present the residual enzymatic activity seems to correlate best with disease progression. The less the enzymatic activity the worse is the clinical course of the disease. Despite the fact that muscle is the most severely affected tissue and most of the adults with Pompe disease present with limb girdle and respiratory weakness, there have been a few reports with involvement of the cerebral vessels in the brain. It is too early to conclude whether this observation is of diagnostic relevance. The heart does not seem to be involved in adults with Pompe disease.

Diagnostic markers that can help to indicate Pompe disease, are an elevated serum creatine kinase activity (CK), lactate dehydrogenase (LDH) and transaminases as well as tetrasaccharides in serum und urine. An air dried blood film stained with periodic acid Schiff’s reagent (PAS) might show lymphocytes with glycogen positive vacuoles. A muscle biopsy with signs of a vacuolar myopathy and glycogen storage is indicative for Pompe disease but a normal muscle biopsy in milder patients does not rule out the condition. Muscle imaging might be helpful to select the muscle for a biopsy. Magnetic resonance imaging (MRI) and computer tomography (CT) investigations have shown that muscles of the trunk and the hamstrings are more severely affected in adults with Pompe disease than the femoral quadriceps or distal muscles. The measurement of enzymatic activity in fibroblasts is currently the gold standard for the diagnosis of Pompe disease, but enzymatic activity can also be reliably measured in muscle tissue, lymphocytes and, depending on the method, in mixed leucocytes or dried blood spots. The diagnosis of Pompe disease can finally be confirmed by mutation analysis. The consortium came to the conclusion that some of the proposed screening tests for Pompe disease have still to be validated but the use of dried blood spots looks very promising.

The assessment of patients with Pompe disease should include manual muscle testing using the scale established by the Medical Research Council (MRC scale) and tests for muscle function (e. g. 10 m walking). Furthermore, the lung function of patients should be tested in an erect and a supine position twice a year. A drop of the vital capacity > 20% indicates diaphragmatic weakness. Respiratory management plays a fundamental part in the care of Pompe disease whereas dietary therapy has been of limited benefit to the patients. For future clinical trials it will become more and more important to also apply quantitative muscle tests (e.g. dynamometer), disability scales and quality of life measurements. The workshop participants have established diagnostic algorithms for the severe infantile form (‘classical’ Pompe disease) of the condition, the juvenile form and the adult form. Future tasks for the consortium will focus on the preparation and monitoring of clinical trials for enzyme replacement therapy.

A summary of the results of the workshop has been presented at the Myology 2005 Meeting in Nantes, May 2005

An extended report of this meeting will be published in Neuromuscular Disorders.

This workshop was organised by Prof. V. Straub (Newcastle, UK) and Dr. A. van der Ploeg (Rotterdam, The Netherland).

Other participants were: Dr. Allan Lund (Denmark), Dr. Anna Pichiecchio (Italy), Prof. Arnold Reuser (The Netherlands), Dr. Bruno Bembi (Italy), Dr. Benedikt Schoser (Germany), Dr. Christian Schwake (Germany), Prof. Corrado Angelini (Italy), Dr. DavidHilton-Jones (UK), Prof. Francesco Muntoni (UK), Dr. Irene Maire (France), Prof. Luciano Merlini (Italy), Prof. Marc Nicolino (France), Dr. Marloes Hagemans (The Netherlands), Prof. Olaf Bodamer (Austria), Dr. Otto van Diggelen (Netherlands), Dr. Pascal Laforet (France), Dr. Priya Kishnani (USA), Ria Broekgaarden (Representative from IPA, The Netherlands).

Charcot-Marie-Tooth disease Type 1A

Charcot-Marie-Tooth disease (CMT) is the commonest inherited neuropathy. The most common form of CMT is type 1A due to a duplication of a 1.5 Mb portion of chromosome 17 containing the peripheral myelin protein 22 gene (PMP-22). A recent study has shown that ascorbic acid has been beneficial in the treatment of a mouse model of this disease. The purpose of this workshop was to explore the possibility of a trial of ascorbic acid in CMT1A patients.

The workshop had participants from all over Europe, the US and Canada as well as two patient representatives from the UK and Italy. The workshop strongly supported a trial of ascorbic acid in CMT1A and agreed that a new scale devised specifically for CMT1A, the Charcot-Marie-Tooth Neuropathy Score (CMTNS) should be used as a primary outcome in any trial. Various secondary outcomes were also agreed with flexibility for individual groups to investigate additional outcome measures. A core set of criteria were agreed as a protocol for a trial, including details of dosage, monitoring etc.

The workshop participants recognised that although some centres were already initiating trials that an international collaboration would be the ideal way for a trial to be performed, especially to optimise recruitment allowing the trial to be timely.

Finally, there was strong support for an international CMT trial network to plan and perform future trials.

Chairs: Prof. P. de Jonghe (Belgium), Dr. D. Pareyson (Italy) Dr. M. Reilly (United Kingdom)

Participants: Dr. M. Auer-Grumbach (Austria), Dr. J. Berciano (Spain), Dr. J. Blake (United Kingdom), Prof. O. Blin (France), Ms. K. Butcher (United Kingdom), Ms. A. Detomas (Italy), Dr. O. Dubourg (France), Prof. H. Ehrenreich (Germany), Prof. M. Fontes (France), Prof. A. Hahn (Canada), Prof. R. Hughes (United Kingdom), Dr. R. Lewis (U.S.A.), Dr. R. Mazanec (Czech Republic), Dr. K. A. Nave (Germany), Dr. V. Planté Bordeneuve (France), Dr. A. Schenone (Italy), Dr. A. Solari (Italy), Dr. F. Visioli (Italy), Prof. M. de Visser (The Netherlands), Dr. P. Young (Germany)

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

Nutrition in ALS

Meeting attendants: Albert Ludolph (Germany), Vincenzo Silani (Italy), Hans Biesalski (Germany), Adriano Chiò (Italy), Philippe Couratier (France), Edward Kasarskis (USA), Magdalena Kuzma (Poland), Philippe Löffler (France), Gabriele Mora (Italy), Orna O’Toole (Ireland), Alan Rio (United Kingdom), Oskar Schindler (Italy), Anne-Dorte Sperfeld (Germany), Dietmar Stippler (Germany), Maaike Van der Graaff (Netherlands).

Aims of the meeting:

It was the aim of the workshop to review the nutritional needs of patients suffering from motor neuron disease. On this basis we had the goal to:

1. define a protocol for interventional studies for optimal nutrition in ALS patients.

2. to improve the nutritional support given by PEG and RIG for the ALS patient.

3. to identify any other nutritional issues relevant for the healths of the ALS patients.

In a broader view, the neuromuscular aspects of the work were the following:

I The prognosis of ALS is largely predicted by its neuromuscular component.

II The major cause for impaired nutrition in ALS patients is impaired neuromuscular function. Difficulty swallowing and the associated threat of aspiration pneumonia are caused by weakness of the tongue, pharyngeal and laryngeal muscles.

III Similar findings are seen in other neuromuscular diseases, such as polymyositis and inclusion body myositis/myopathy, and in rare cases also myasthenia gravis. Although this workshop was specifically focused on ALS, it might have implications for other neuromuscular diseases.

During our 48 hours meeting we achieved a basis for future discussions and studies with several experts in nutrition. The meeting was fruitful by itself since it brought together experts which were interested in complementary discussions on hither to distinct fields.

We achieved the following consensus on the future strategy of working:

1. To perform a three-armed trial on patients with standard nutritional diets with ALS and PEG or RIG. Diets will be stratified according to caloric intake. Outcome parameters will be survival, quality of live (QoL), body mass index (BMI), the ALS/FRS and bioimpedance measurements (BI).

2. We identified the problem of the refeeding syndrome as potentially hazardous for the ALS patients receiving PEG. As a basis for a future interventional study and/or the development of guidelines for refeeding the starved ALS patient we will collect data in a multicenter approach.

3. We developed a protocol for interventional nutritional studies.

4. We developed a collaboration with both industry and leaders in the field of nutrition of establish more scientific exchange. During the next international meetings on nutrition, there will be satellite symposia with experts from neuromuscular and neurodegenerative diseases.

A report of this meeting is published in Neuro Muscular Diseases. (pdf)

Outcome Measures and Treatment of Spinal Muscular Atrophy

The ENMC consortium on Outcome Measures and Treatment of Spinal Muscular Atrophy held its 1st workshop in Naarden, the Netherlands during the weekend of the 11-13th February 2005. It was attended by 31 participants from Belgium, France, Germany, Italy, Poland, Spain, Swizerland, Turkey, the Netherlands, the United Kingdom, and the USA, and included 3 patient parent representatives. The meeting opened with an overview on the recent knowledge on pathogenesis and pathophysiology of spinal muscular atrophy (SMA). This was followed by discussion on previously performed clinical trials and past experience that could be of help for designing future trials.

The second day was focused on the natural history, of how SMA progresses in the mild, moderate and severe forms of SMA and means of measuring muscle strength and motor function. The importance of having a uniform standard of care in the follow-up of SMA patients was also discussed not only because of the obvious implication for the health of SMA patients, but also because lack of uniformity might indirectly affect both the outcome of future trials.

The outcome measures of future therapeutic trials for patients affected by SMA type I, type II, or type III were discussed in detail; this included functional scales, strength measurements, standards of care for respiratory and feeding complications, quality of life and caregiver burden questionnaires. The state of the art regarding the use of surrogate biological markers was also discussed, and in particular the fact that the monitoring of the full length SMN transcript or of the SMN protein obtained from white blood cells is not sufficinetly robust for its use in therapeutic trials at the moment.

Future collaborative work on trials of valproate in the three different forms of SMA was discussed. A task force to harmonise outcome measures was agreed. A separate task force will prepare guidelines on standards of care. The European effort will be shared with the American SMA organizations. The Workshop agreed to support the Indiana University SMA register data base. Throughout the Workshop ethical considerations were paramount and the parent patient representative input was highly valued.

We thank the Jennifer Trust for SMA (UK) for generous support to make this Workshop possible.

An extended report of the meeting has been published in Neuromuscular Disorders. Please click here to view the full report.

Enrico Bertini

Congenital Muscular Dystrophy (CMD)

The ENMC Consortium on Congenital muscular dystrophy (CMD) held its 9th meeting in Naarden during the weekend of the 21st-23rd January 2005. It was attended by 23 participants from 9 countries, including France, Germany, Japan, Italy, The Netherlands, Spain, Turkey, United Kingdom and USA. The participants were basic scientists with biochemical, cell biology and molecular biology background, and clinicians and muscle pathologists, all sharing an established expertise in neuromuscular disorders or in muscle cell biology.

Congenital muscular dystrophies (CMD) are a heterogeneous common group of disabling neuromuscular disorders usually inherited as autosomal recessive conditions. Affected children present with muscle weakness and hypotonia at birth, or within the first six months of life and motor development is delayed. The severity and progression of the disease is very variable and dependent on the disease subtype. Brain involvement in the form of mental retardation and abnormal formation of different parts of the brain is a feature of several forms of CMD.

A substantial advance in our understanding of CMD derives from the identification of novel genes responsible for their development. Currently mutations in 11 genes have been identified, and recent classifications of CMD take into account the primary metabolic defect and/ or the subcellular localisation of defective proteins. The present meeting focused on 2 separate groups of CMD syndromes characterized by deficiency in proteins located in similar cellular structures known as the Endoplasmic Reticulum (ER) and the Golgi apparatus. While pathogenesis of some of these conditions is different, this workshop focused on better understanding the localisation and function of these cellular structures during different stages of muscle maturation. One session was therefore devoted to general cell biological aspects of the ER and the Golgi apparatus in muscle; this was followed by a session focused on Rigid Spine Syndrome, a condition due to mutations in the Selenoprotein N, an ER resident protein. The remaining sessions were all devoted to the further characterisation of 5 forms of CMD due to mutations in putative or demonstrated glycosyltransferases (i.e. proteins involved in adding sugar to dystrolgycan), proteins which are localised in either the ER or the Golgi apparatus, or both.

A remarkable widening of the spectrum of the conditions due these 6 gene defects was presented by various participants, together with novel data regarding the spectrum of the pathological changes in muscle and brain. A number of likely novel conditions in which the primary genetic defect is not known yet were presented. Collaborative diagnostic strategies were discussed, together with novel therapeutic approaches to animal models. A number of collaborative studies were agreed.

An extended report of this meeting has been published in Neuromuscular Disorders. Please click here to view the full report.

Prof. Francesco Muntoni, London, UK

Prof. Thomas VoitEssen, Germany

Chairpersons, CMD consortium

 

Planning steroid dosage trials in DMD

Twenty-six participants from Belgium, Canada, France, Italy, the Netherlands, Sweden, the UK and the USA met in Naarden, the Netherlands, on 3rd-5th January under the auspices of the European Neuromuscular Centre Clinical trials unit. The participants at the meeting comprised the steering committee of the ENMC/ Muscle Study Group on development of trials in DMD and members of various working groups involved in developing aspects of the trial protocol. The meeting was a follow up of the124th ENMC workshop held in April 2004 at which the initial plans to establish a trial of corticosteroid dosage regimes in DMD were made, and following which patient information material on the use of steroids in DMD was generated.

Plans to submit an application for a planning grant to implement a randomised controlled trial of corticosteroid dosage regimes are well advanced. Investigators from 14 countries have expressed an interest in joining the trial. The basic protocol was discussed. As the unresolved clinical question is about the relative benefits and side effects of different steroid dosage regimes over the long term, it was decided to test four regimes (0.75mg/kg/day prednisone, 0.9mg/kg/day deflazacort/ 0.75mg/kg/day prednisone 10 days on and 10 days off and 0.5mg/kg/day prednisone) over a three year period initially with the intention to have in total a 10 year period of follow up. Children with a confirmed diagnosis of DMD around the age of diagnosis or shortly thereafter (4 to 7 years old) will be recruited and randomised to one of the four arms of the trial. In order to ensure a high degree of clinical relevance a primary outcome measure related to muscle function (the ability or time to get up from a lying position) was chosen as a surrogate for the functional milestone of ultimate interest: the loss of ability to walk independently, which will be the primary outcome measure for the longer follow up period. Other functional outcomes including respiratory function will also be measured. Side effects will be monitored and managed essentially according to the table presented in the last workshop report, and working groups will generate standardised information for other areas of management including physiotherapy support, dietetic advice, advice on the management of behavioural problems, etc. which will be made available through the ENMC website.

Three areas were addressed in more detail. The first relates to issues of health services research: quality of life, health economics and caregiver burden. This trial provides a unique opportunity to collect data on these areas across a broad group of children, and choice of the most relevant instruments is the focus of a working group led by Michael Rose. The second area, of bone protection, is led by Doug Biggar and Roz Quinlivan. As the effects of steroid use on bone health is an area of major concern, a protocol is under development to monitor this carefully during the trial. Finally, John Bourke is leading a group to study the effects of the steroid regimes on cardiac function. All of these discussions will continue after the workshop through electronic forums hosted by the ENMC.

It is important to note that because of the scale and of complexity of the planned trial, this will not start for at least another 18 months. It is not appropriate for treatment with one of the proposed steroids regimens to be withheld from DMD patients in the meantime.

The workshop was organised and chaired by Kate Bushby (Newcastle upon Tyne, UK) and Robert Griggs (Rochester, NY, USA). Other participants were Anna Ambrosini (Milan, Italy), Anne d’Andon (Paris, France), Corrado Angelini (Padua, Italy), Maria Luisa Bianchi (Milan, Italy), Doug Biggar (Toronto, Canada), John Bourke (Newcastle upon Tyne, UK), Gunnar Buyse (Leuven, Belgium), Emma Ciafaloni (Rochester, NY, USA), Michael Davie (Oswestry, UK), Michelle Eagle (Newcastle upon Tyne, UK), Imelda de Groot (Huizen, The Netherlands), Mike Haddaway (Oswestry, UK), Elaine McColl (Newcastle upon Tyne, UK), Mike McDermott (Rochester, NY, USA), Jerry Mendell (Columbus, OH, USA), Phil Miller (St. Louis, USA), Lucia Morandi (Milan, Italy), Francesco Muntoni (London, UK), Giovanni Nigro (Naples, Italy), Shree Pandya (Rochester, NY, USA), Roz Quinlivan (Oswestry, UK), Michael Rose (London, UK), Thomas Sejersen (Stockholm, Sweden), Adrian Trenholme (New Zealand), Elizabeth Vroom (Amsterdam, The Netherlands)