EUMITOCOMBAT

In total 19 participants from 8 countries participated in this Workshop. The EUMITOCOMBAT consortium was established in May 2002 following the call for Expressions of Interest of the 6th EU Framework Programme and consists of scientific group leaders from eight different European Countries, including colleagues from the Czech Republic. The final aim of the consortium is to develop rational treatment strategies combating mitochondrial oxidative phosphorylation disorders. As such, the consortium prepared during the meeting the scientific outline of the full EU application, covering topics ranging from clinical aspects of OXPHOS-disorders to structural and functional aspects of the various individual OXPHOS components. In collaboration with Dr. Henriette van Eijl of the Dutch National Contact Point “Senter-EG liason”, all organisational aspects, as requested by the EU, were discussed in detail. The signed minutes of the meeting will serve as a constitution for the consortium, establishing its goals, management structure and operational procedures.

Prof. Dr. J. Smeitink (Nijmegen, The Netherlands)
Chairman

Bethlem Myopathy and other diseases related to collagen type VI

The ENMC consortium on Bethlem myopathy and other diseases related to collagen type VI held its third meeting in Naarden on the 6th and 7th December 2002. This workshop was sponsored by the European Community as part of the Myo-cluster project BETHLEM.
It was attended by sixteen participants from 7 countries: Australia, France, Italy, The Netherlands, Turkey, United Kingdom and the U.S.A. The aims of this workshop were to present new insights in collagen type VI related disorders: Bethlem myopathy and Ullrich syndrome and in the molecular bases underlying these disorders. Diagnostic criteria were also discussed.

Bethlem myopathy is due to dominant mutations in COL6A1, COL6A2 and COL6A3 while a group of patients with scleroatonic muscular Ullrich syndrome (UCMD) carries recessive mutations in these genes.

The workshop was subdivided as follows:

1. Bethlem myopathy: enlargement of the clinical phenotype, description of families in which pathological, biochemical and genetic studies were performed. Correlation between the location and the nature of the mutation (genotype) and the clinical manifestations, biochemical and pathological features (phenotype).
Interestingly 50% of patients with Bethlem myopathy do not have mutations in COL6 genes suggesting the involvement of a second major gene.

2. Clinical description of families affected by Ullrich scleroatonic muscular dystrophies. Pathology, biochemistry and genetic studies.

3. There seems to be a genetic and phenotypical overlap between the two diseases giving rise to the concept of a continuum of the clinical phenotype as reported for other inherited connective tissue disorders.

4. Studies on the animal model gives new insights in the pathophysiology underlying these diseases: loss of collagen type VI causes abnormal Ca2+ homeostasis, mitochondrial dysfunction and apoptosis (cell death) in skeletal muscle.

5. Molecular diagnosis for known mutation is now available through nanotechnology that allows the analysis of many samples in only few days while molecular analysis of the three COL6 cDNAs (obtained from fibroblast cell cultures) will take a few months.

The meeting ended with the establishment of revised clinical criteria for the diagnosis of Bethlem myopathy and Ullrich scleroatonic muscular dystrophiy associated to mutations in COL6 genes.

An extended report of this meeting will be submitted for publication in Neuromuscular Disorders.

Prof. Guglielmina Pepe, Bethlem Consortium Chairperson (Rome, Italy)

Visit the website of the Myocluster Project BETHLEM at: http://www.myocluster.org

Multi-minicore Disease

Location: Naarden, The Netherlands

 

Fifteen clinicians and basic scientists convened from 8th – 9th November in Naarden, The Netherlands for the 2nd ENMC sponsored Workshop on Multi-minicore Disease (MmD). The 1st ENMC sponsored workshop on MmD in May 2000 had lead to collaborations between the participating groups, resulting over the ensuing two years in a rapid advance in the understanding of this particular, autosomal recessively-inherited congenital myopathy. The main objective of this workshop was to discuss the recent identification of two genes (RYR1 and SEPN1) involved in at least two of the 4 MmD phenotypes that had been defined during the previous MmD consortium meeting. These findings have demonstrated that genetic diversity corresponds to the observed clinical heterogeneity. In the light of these data, the clinical and morphological experience of the different groups was shared and discussed in order to further define the diagnostic criteria for MmD and its phenotypical spectrum, and to establish phenotype-genotype correlations. A further focus of the meeting was to analyse those groups of patients with untypical features and as yet unresolved genetic basis.

The skeletal muscle ryanodine receptor gene (RYR1) is a giant gene encoding a sarcoplasmic reticulum calcium channel (RyR1). Mutations of this gene had been previously implicated in two autosomal dominant disorders: the congenital myopathy central core disease (CCD), and the malignant hyperthermia susceptibility (MHS) trait. Recessively-inherited changes in the RYR1 gene have now also been implicated in two clinically distinct groups of patients with MmD, the phenotype previously defined as “moderate MmD with hand involvement” and a phenotype resembling CCD. Preliminary genetic results presented at the workshop suggest that also the group of patients with involvement of the muscles controlling eye movements may have changes in this gene.
These results indicate that the range of clinical and histopathological appearances associated with changes in the RYR1 gene is wider than initially anticipated. This may be partly explained by the fact that RYR1 changes associated with specific phenotypes of MmD affect functionally different parts of the RyR1 protein compared to those mutations associated with CCD. In addition, an evolution of the morphological lesions with age, from “minicores” to “cores”, has been demonstrated in some of these cases. In contrast to histopathological variability, muscle MR imaging data in patients with confirmed RYR1 mutations presented at the workshop indicate a consistent and distinct pattern of selective muscle involvement and suggest muscle MR imaging as a useful ancillary tool. Functional data presented at the workshop suggested the study of RyR1 function in white blood cells from patients as a suitable approach to investigate the pathophysiological consequences of specific RYR1 changes.

Mutations of the selenoprotein N gene (SEPN1) have been recently shown to be responsible for approximately two thirds of the cases presenting with the “classical” MmD phenotype. This gene was previously known to be associated with another autosomal recessive myopathy, termed Rigid Spine Muscular Dystrophy (RSMD). The clinical, morphological and genetic data obtained from both groups of patients carrying SEPN1 mutations were presented and compared, and the reasoning behind the conclusion that all of them share a common disease, now termed “SEPN-related myopathy”, was discussed. An overview on the structure and functions of the selenoprotein family, as well as selenoprotein N expression studies on zebra fish, were presented. We also shared novel, unpublished data on selenoprotein N subcellular localisation and structure, and preliminary data on microarray-based SEPN1 expression studies. The phenotype spectrum of SEPN-related myopathy (including its consistent, recognizable pattern on muscle CT-scan or MRI) was discussed, with a special attempt to establish differential diagnosis criteria with those cases of MmD or RSMD not linked to SEPN1 mutations.

In a concluding session, current concepts on MmD were re-evaluated and future collaborative strategies discussed.

The meeting provided an invaluable opportunity for all participants with a major interest in early-onset myopathies to come together and to share a stimulating forum for multidisciplinary discussion of this quickly evolving field.

A full report of the meeting will be submitted for publication in Neuromuscular Disorders.

Dr. A. Ferreiro (Paris, France)
Dr. H. Jungbluth (London, U.K.)

Congenital non-progressive Ocular Neuromuscular Disorders

A multi-disciplinary group of 13 clinicians and researchers from six countries (Canada, France, Saudi Arabia, The Netherlands, United Kingdom and the U.S.A.) convened for the first time to form an international consortium to study a group of congenital neuromuscular diseases characterized by abnormal eye, eyelid, or facial movement. This group of diseases includes Duane syndrome, congenital fibrosis of the extraocular muscles (CFEOM), Moebius syndrome, horizontal gaze palsy, and ptosis. Although these disorders were previously referred to in the literature under various terms, including ‘congenital fibrosis syndromes’, we have now chosen to refer to them as the ‘congenital cranial dysinnervation disorders’ or CCDD. This name reflects our belief that these disorders result from developmental errors in innervation of the ocular and facial muscles. Thus far, members of the consortium have identified 10 CCDD genetic loci and 2 CCDD disease genes (PHOX2A mutated in CFEOM2 and SALL4 mutated in Duane syndrome with radial ray anomalies). During the meeting, a stimulating and broad review of current CCDD research was undertaken, a preliminary CCDD classification scheme was devised, and an International CCDD Consortium was established. The goals of the Consortium are to foster continuing research into the genetic bases of these disorders by identifying new families and affected individuals and by the sharing of genetic resources. Future studies of the CCDD genes should enhance our understanding of the pathophysiology and treatment of these disorders.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 13, No. 7-8, September 2003.

Dr. N. Gutowski (United Kingdom)
Dr. E. Engle (U.S.A.)

Nemaline Myopathy

17 Doctors and scientists from 7 countries gathered in Naarden, The Netherlands from 11th – 13th October 2002 for the 5th ENMC Workshop on nemaline myopathy.

Considerable progress has been made in the research into nemaline myopathy during the 6 years since the 1st ENMC Workshop on this disease was held and the International Consortium was formed. The international collaboration has brought about an extensive exchange of samples, genetic markers and clinical and muscle biopsy data, allowing a co-ordinated approach to increasing our understanding of the disease.

5 Genes have to date been found causing various forms of this inherited muscle disorder. 2 Of these genes, actin and nebulin, appear to be relatively common causes of nemaline myopathy. Tropomyosin 3, tropomyosin 2 and troponin T1 however are eveidently rare causes of nemaline myopathy. Identifying the genes is the 1st step towards understanding the disease process in the various subgroups of nemaline myopathy. The protein products of the disease genes are now being analysed by various techniques to understand their effect in diseased muscle. Model systems have been developed in order to increase the understanding of the mechanisms of the disease processes and for elucidating potential therapeutic possibilities, including pharmacology.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 13, No. 6, August 2003.

Dr. C. Wallgren-Pettersson (Finland)
Prof. N. Laing (Australia)

Websites:
– This site is dedicated to the world’s 1st NM convention in Canada in 2003
– The official website for NM

3rd Workshop of the MYOCLUSTER project: EUROMEN

The third Workshop of the MYO-CLUSTER project EUROMEN was held in Naarden on 13 and the 14 September 2002. 23 Participants attended it from France, Germany, Italy, The Netherlands, Poland and UK. The aims of this Workshop were to present new insights in laminopathies and emerinopathies, to give recommendations for cardiac management of these disorders and to expose the current status of the mutation databases related to the two genes responsible of these disorders: the lamin A/C gene and the emerin gene.

Whereas mutations in the emerin gene (EMD) give rise to one phenotype, the X-linked form of Emery-Dreifuss muscular dystrophy (XL-EDMD), up to six phenotypes are associated with mutations in the lamin A/C gene (LMNA): the autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (AD- & AR-EDMD), the dilated cardiomyopathy with conduction-system defect (DCM-CD), the autosomal dominant limb-girdle muscular dystrophy type 1B (LGMD1B), the Dunnigan-type familial partial lipodystrophy (FPLD), an autosomal recessive form of axonal Charcot-Marie-Tooth disease (AR-CMT2) and the mandibulo-acral dysplasia (MAD). The clinical spectrum of these disorders was discussed with a special emphasis on the tissue-specificity of the various laminopathies (i.e striated muscles in EDMD, LGMD1B and DCM-CD / adipose tissue in FPLD / bone tissue and adipose tissue in MAD / peripheral nerve in AR-CMT2) and their possible overlaps.
As cardiac disease invariably developed in emerinopathies and in laminopathies affecting the striated muscles, the spectrum and natural history of cardiac involvement was discussed in details. Sudden deaths appear to be more frequent in laminopathies than in emerinopathies. Therefore implantation of an implantable cardiac defibrillator as well as a close cardiac follow-up is essential and highly recommended for patient with laminopathy.
The spectrum of mutations in LMNA and EMD genes was presented through two mutation databases currently under development, which will at term collect all clinical and genetic data of each individual carrying either EMD or LMNA mutations. A consensus was reached regarding the definition of the clinical form that will be used for these databases to collect detailed and relevant clinical symptoms. It was noticed also that additional genes might be responsible for Emery-Dreifuss muscular dystrophy as no mutation was found in some patients with typical EDMD phenotypes. Both positional cloning and candidate gene screening are currently in progress to identify such genes. Several studies on the cellular consequences of mutations in EMD and LMNA genes were presented; interactions of lamin A/C and emerin with different nuclear components were discussed.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 13, No. 6, August 2003.

Dr. Gisèle Bonne (Paris, France)

Or visit the website of the Myocluster Project GENRE at: http://www.myocluster.org

The management of cardiac complications in muscular dystrophy and myotonic dystrophy

Many muscle disorders have significant involvement of the heart, and recognizing and treating this can be very important for patient care, even life-saving.

Sixteen participants from Austria, France, Germany, Italy, the Netherlands and the United Kingdom met to discuss the evidence for the way that we manage the cardiac involvement often found in different muscular dystrophies and myotonic dystrophy. The group included both myologists and cardiologists from nine different European centers.
The aims of the workshop were to agree and report recommendations for the investigation and treatment of cardiac complications.
During the workshop, there was review of the published literature in this area and an assessment of the current practice amongst the group.
Consensus statements for practice in Duchenne and Becker muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophy, Emery Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy and congenital muscular dystrophy were produced, and will be published in a full report of the workshop in Neuromuscular Disorders (see below).
The conclusions will also be disseminated to cardiologists. It was recognized that there are some areas where we do not have good evidence on which to base practice, and there was discussion of the trials which are necessary to establish this, which the group will move forward with on a collaborative basis.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 13, No. 2, February 2003.

Prof. K. Bushby (United Kingdom)

Non-Invasive positive Pressure Ventilation (NIPPV) in Amyotrophic Lateral Sclerosis (ALS)

Location: Naarden, The Netherlands

 

21 participants from France, Germany, Italy, Portugal, The Netherlands, and the United Kingdom met in Naarden on 3-5 May 2002. This was the first meeting of the European Amyotrophic Lateral Sclerosis (ALS) Consortium under the auspices of the ENMC. The aim of the Consortium is to develop collaborative research into the causes, consequences, and treatment of ALS, and thus to raise standards of care for people with ALS throughout Europe. The Consortium has previously surveyed non-invasive positive pressure ventilation (NIPPV) in Europe, and found large differences in clinical practice. Although there is evidence suggesting that NIPPV both prolongs survival and improves quality of life, there are as yet no published prospective, randomised trials on the efficacy and tolerability of this intervention in ALS. The aim of the meeting, therefore, was to agree on a common approach to prospective and randomised studies of NIPPV. The group comprised neurologists and respiratory physicians involved with research into respiratory problems in ALS patients, as well as experts in statistics, clinical trial design, and health economics. The MND Association was also represented. The group agreed in deciding how respiratory muscle strength should be assessed, and in defining practical criteria for starting NIPPV. There was agreement that randomised studies are needed to demonstrate efficacy for survival and quality of life if there is to be equity of access and funding. The group agreed on two options for trial design, and outlined the primary and secondary efficacy measures, power calculations, and statistical approaches to data analysis. The first option was a trial of early NIPPV versus current ‘standard’ practice. The second was a randomised trial of NIPPV versus no NIPPV. It was recognised that this option might not be feasible in some countries where NIPPV is accepted treatment. A third option for non-randomised prospective studies was discussed briefly. In summary, the workshop was helpful in crystallising a consensus on the investigation and management of respiratory failure in ALS. The draft protocols will be discussed with the European ALS Consortium in June 2002 at the European Neurological Society (ENS) Meeting in Berlin. Overall this was a very enjoyable, creative and fruitful workshop that will lead to new collaborations and contribute significantly to advancing the field and improving patient care.

A full report of the meeting will be submitted for publication in Neuromuscular Disorders

Prof. J. Moxham and Prof. N. Leigh (United Kingdom)

Limb-girdle muscular dystrophy – exploring the pathophysiology of the non-sarcoglycan types of limb-girdle muscular dystrophy

20 participants from the Austria, Brazil, Canada, Finland, France, Germany, Israel, Italy, Japan, the U.K. and the U.S.A. met in Naarden on 12th – 14th April 2002. This was the fourth meeting of the limb-girdle muscular dystrophy consortium. Previous meetings of the consortium had discussed the identification of many of the genes and proteins involved in different types of limb-girdle muscular dystrophy and the clinical features associated with these particular disorders. With this progress behind us, the specific remit of this workshop was to address issues of disease causation in the types of limb-girdle muscular dystrophy which are caused by gene faults not involving the proteins of the dystrophin and sarcoglycan complex. The meeting discussed the recent identification of the genes involved in three new types of limb-girdle muscular dystrophy, LGMD2H, LGMD2I and LGMD2J. A further focus of the meeting was to explore the different groups of proteins which are now known to be involved in limb-girdle muscular dystrophy and are known to interact with each other or work in similar pathways. The identification of the way or ways that these groups of proteins may be altered to cause disease is being addressed in a variety of model systems and may in the long term provide targets for treatments. It also became clear that a significant problem which remains in our understanding of these diseases is the variability of presentation or severity which may be associated with single genes or even with single mutations. Strategies to address this variability in patients and in animal models of disease were discussed, and will make good proposals for applying for funding to try and answer these questions on a collaborative basis. The meeting provided an invaluable opportunity for many of the groups with a major interest in the limb-girdle muscular dystrophies to come together, and was a very fruitful forum for discussion.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 13, No.1, January 2003

Prof. K. Busby (United Kingdom)

Distal myopathies

The 2nd ENMC workshop on distal myopathies was held in Naarden, The Netherlands, from 8th to 10th March 2002. It was attended by 26 active participants from Australia, Austria, Belgium, Finland, France, Germany, Israel, Italy, Japan, The Netherlands, Spain, Sweden, The United Kingdom and the U.S.A. The meeting reviewed the extensive scientific progress since its 1st workshop in 1994: All of the four previously clinically defined entities have reached the point of genetic definition by linkage assignment and some have been defined by their gene and causative mutations. In addition a large number of new disorders have been reported in single families in which linkage has been established or linkage to loci for the known distal myopathies has been excluded. Participants reported on three new genes involved in muscle diseases with marked distal wasting and weakness discovered during the last year. Titin was shown to be the causative gene for Tibial muscular dystrophy. Mutations in the GNE gene were reported in the so called quadriceps sparing myopathy and in the recessive distal myopathy with rimmed vacuoles (Nonaka type). Two mutations in a myosin gene were associated with childhood onset distal myopathy (Laing type). In seven other distal myopathies the localisation of the genetic cause to a certain chromosome has been achieved, awaiting further progress to find the gene. Clinical findings in a number of families with undetermined status regarding linkage were reported in detail. Many presentations extended the current concepts of distal myopathies including occasional atypical findings in patients with GNE, dysferlin and caveolin3 mutations and in patients with tibial muscular dystrophy. The known molecular causes of distal myopathies do not yet allow specific treatment. In order to expand the knowledge of basic mechanisms leading to progressive muscle cell loss in these diseases, more research is needed to identify disturbed protein interactions caused by the mutations. The participants established a large number of agreements on collecting further families and collaborating with the research groups doing molecular genetic studies on distal myopathies.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 12, No.9, November 2002.

Dr. B. Udd (Finland)
Chairman

For further information contact:
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