Advances in Schwartz-Jampel syndromes

11 experts from France, Germany, Turkey, Sweden and the Netherlands, met in Naarden on December 14-15 under the auspices of ENMC to review advances and knowledge in an extremely rare neuromuscular condition called Schwartz-Jampel syndrome (SJS). The classical form of SJS is caused by mutations in a gene encoding a large protein calledperlecan which is located just outside the muscle cell. This protein is a major component of the extracellular matrix.
The SJS is a hereditary disorder characterised by severe and permanent myotonia and skeletal malformations.
Interestingly, the same protein has been found mutated in a totally different disease with bone malformations (DDSH, dyssegmental dysplasia of the Silverman Handmaker type).

A neonatal form of SJS (also known as SJS2) has been reported by some authors and shares clinical and radiological similarities with a bone disorder called Stuve-Wiedemann syndrome. We now have evidence that the two latter disorders are likely to be caused by mutations in a gene which is distinct from the perlecan gene itself.

In view of these new genetic findings, diagnostic criteria of the SJS have been revised.

An animal model lacking perlecan has been extensively studied and ressembles DDSH. The various interactions of perlecan have been reviewed as well the potential mechanisms causing myotonia. Other pathogenetic avenues have been explored such as the potential implication of the neuromuscular junction in myotonia.

An international consortium has been established and stresses the need for collecting more families or cases with these rare conditions, to obtain additional biological samples such as skin and muscle biopsies.
Knowledge of the pathogenesis should benefit from the development of cellular or animal models as well as optimal interaction between clinical and basic scientists.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 13, No. 4, May 2003.

Prof. B. Fontaine (Paris, France)
Prof. H. Topaloglu (Ankara, Turkey)
Dr. S. Nicole (Paris, France)

Therapeutic possibilities in Duchenne dystrophy

A special centennial workshop to celebrate the 100 workshops organised to date by the ENMC was held in Naarden from 30th November to 2nd December 2001. It was devoted to therapeutic possibilities in Duchenne muscular dystrophy and attended by 25 invited participants from Australia, Belgium, France, Germany, Italy, The Netherlands, the United Kingdom, Switzerland and the United States. The workshop brought together experts from a number of different disciplines and was devoted to an active discussion of all the main therapeutic avenues, with opening reviews by individual experts in each area and active discussion by the participants.

All aspects of potential gene therapy were reviewed, ranging from cell therapy with either muscle cells or multipotential stem cells, and various approaches to direct gene therapy, either by replacement of the faulty gene, or by gene repair of the existing gene. Most of this work is still evolving in animal studies but some preliminary studies are in progress as to safety of similar methods of direct gene introduction into dystrophic muscles with specific documented mutations. These studies will need to be completed before any therapeutic trials in patients can be started.

A session was devoted to the provision of alternative proteins such as utrophin and other related proteins to replace to missing dystrophin in the mdx mouse, and a more lowly microscopic nematode worm. Studies of pharmaceutics products in the mdx mouse were reviewed as a possible way of identifying medications that might be of potential use in Duchenne. Current clinical trials of steroids and their potential medication were reviewed. The meeting closed with a special session on ways of translating laboratory studies to clinical trials and the potential partnership of the pharmaceutical industry.

A short report on this workshop is published in Neuromuscular Disorders, Volume 12, No. 4, May 2002, and a more comprehensive publication of all the proceeding of this important and fruitful workshop has been edited as a special supplement toNeuromuscular Disorders in October 2002 (Volume 12, Suppl. 1).

An extended lay version of this report is available here.

Prof. Victor Dubowitz (London, UK)
Director of Therapeutic Studies, ENMC

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 second meeting in Naarden on the 23rd-25th November, 2001. It was attended by seventeen participants from 6 countries: France, Italy, Japan, The Netherlands, Turkey and the United Kingdom.

This workshop was sponsored by the European Community as part of the Myocluster project BETHLEM.

Bethlem myopathy is an inherited disease that affects the skeletal muscles and the substance that surrounds the cells and represents the back bone of many organs (connective tissue) located between the skin and the muscle. The manifestations of the disorder are the following: weakness of the muscles of the limbs and trunk giving rise to difficulties in walking and shortening of muscles, known as contractures, which particularly affect the fingers, elbows and ankles. In 1996 changes in the three collagen 6 (COL6) genes.that carry the code for the three chains of collagen type VI (one of the connective tissue) were shown to cause Bethlem myopathy. The disease is transmitted as an autosomal dominant (one mutation in one of the two copies of the involved gene) disorder.
Recently, members of the ENMC consortium demonstrated that Ullrich scleroatonic muscular dystrophy, that belongs to  the group of congenital muscular dystrophies is due to autosomal recessive (two mutations, each one on one copy of one of  the COL6 genes) mutations in COL6 genes. Ullrich syndrome is an inherited disorder with the following typical manifestations: generalized slowly progressive muscle weakness, contractures of proximal joints (hips, knees, shoulders, elbows) and of the neck due to shortening of muscles (hyperflexibility and/or hyperextensibility of the hand, foot, finger) and breathing difficulties (respiratory failure) at an early age.


The workshop was subdivided according to three main aspects:

1. Bethlem myopathy: clinical aspects, description of new families or families in which  a mutation in COL6 genes was detected. Discussion on the correlation between the location and the nature of the mutation (genotype) and the clinical manifestations (phenotype).

2. Clinical description of families affected by Ullrich scleroatonic muscular dystrophies from all over the world showed that some families have patients with a very severe clinical phenotype and others with mild clinical features overlapping with Bethlem myopathy. At the moment COL6 gene mutations cause only a certain percentage of patients affected by Ullrich scleroatonic muscular dystrophy because some families show no linkage to COL6 genes.
Lessons from the animal model. Molecular (biochemical, molecular biology) and morphological studies on Ullrich syndrome were reported. Molecular diagnosis is now only possible in a research setting but will be available in the near future.

3. The meeting ended with the establishment of clinical criteria for the diagnosis of Ullrich scleroatonic muscular dystrophy.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 12, No.10, December 2002


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

Visit the website of the Myocluster Project BETHLEM at:

Myotonic dystrophy: present management, future therapy

Location: Naarden, The Netherlands


This Workshop, the first held by the ENMC on the topic of myotonic dystrophy, had as its themes the issue of how optimal management can be defined and delivered to patients with myotonic dystrophy, and how we can plan foundations for trials of therapy, whether symptomatic or, in the future, possibly more definitive.
The needs of myotonic dystrophy patients and families were first put into perspective by Margaret Bowler, of the UK Myotonic Dystrophy Support Group, who described the key symptoms from the viewpoint of the patient and carer. The importance of considering myotonic dystrophy as a childhood as well as an adult disorder were then outlined by Christine de Die-Smulders, who emphasised the learning and behavioural problems in this group, not all of whom had clear features of myotonic dystrophy at birth.
The second session concentrated on neuromuscular aspects of myotonic dystrophy. The core diagnostic procedures were first outlined and it was agreed that these had become considerably simplified, with a combination of clinical assessment and DNA analysis providing the necessary information in most cases, though the situation was still provisional for the few “DM type 2” families not showing the chromosome 19 DNA abnormality.
Discussion next focussed on assessment protocols; it was recognized that there was a need for simple protocols (e.g. Cardiff protocol) for regular patient assessments, as well as for a fuller baseline database and research orientated assessments. In respect to aspects of physical disability myotonic dystrophy patients had much to gain from measures also applicable to other neurological disorders, notably those improving mobility and involving the social and domestic aspects.
The following sessions debated how best to manage the important non-neuromuscular systemic aspects of the disorder, in particular the cardiac aspects, which were recognized as a major cause of serious illness and mortality. Results of the Paris group in particular confirmed the value of regular ECG as the foundation, with more specialist tests being necessary if this were abnormal or if relevant symptoms were present. Preliminary results of a study of early pacemaker insertion were encouraging.
Anaesthetic/surgical problems were then discussed, with a general agreement on measures required, but with both this and cardiac management there remained serious lack of awareness among relevant clinicians.
Other important systemic aspects included gastrointestinal problems, where a need for trials of possible agents was identified; somnolence, where promising preliminary studies required confirmation by full trials; and hormonal and pregnancy aspects,

Genetic counselling was discussed as part of the overall management and risk figures were presented for different situations, together with the approaches needed for genetic testing of healthy family members.
The important topic of providing information received detailed discussion, with special emphasis on Internet based information and providing this direct to patients as a way of helping to both improve their management and also in educating professionals. This approach was proving successful in both UK and other countries.
The second part of the Workshop opened with descriptions of major scientific advances which have radically increased our understanding of how the genetic change in myotonic dystrophy actually produces disease. These advances have already produced animal models which can be used both for further understanding and also in assessing further potential therapeutic agents that may not be ready or appropriate for testing in patients. Already trials of a number of agents on patients have taken place in relation to specific symptoms; however as yet none has shown a clear effect on the course of this disorder and it was recognised that it would still be some years before this stage would be reached.
The final session discussed the need for establishing reproducible and standardised assessment protocols that would allow accurate measurement of the natural history of the disorder and that could provide the foundations for large-scale clinical trials. Here it was clear that considerable further work was needed.
The Workshop agreed that it was important to form an ENMC Consortium, the Myotonic Dystrophy Management and Therapy Consortium, which would meet again in two years to assess progress, and which would undertake a series of co-ordinated activities meanwhile.
It was clear that the wider development of trials would require additional expertise from basic research, statistics and other areas, and that co-ordination would be needed with those planning trials for other neuromuscular disorders. This will be discussed among the Workshop members and ENMC, particularly in relation to possibilities for short and longer-term support.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 12, No.6, August 2002

Prof. Peter Harper, Cardiff (UK)
Dr. Baziel van Engelen, Nijmegen (The Netherlands)
Prof. Bruno Eymard, Paris (France)
Dr. Douglas Wilcox, Glasgow (UK)

Congenital Muscular Dystrophy (CMD)

Location: Naarden, The Netherlands



(7th Workshop of the International consortium on CMD/2nd Workshop of the MYO CLUSTER project GENRE)

The ENMC Consortium on Congenital muscular dystrophy (CMD) held its seventh meeting in Naarden during the weekend of the 26th-28th October 2001. It was attended by 24 participants from 6 countries, including Denmark, France, Germany, Italy, Turkey and United Kingdom. This workshop was sponsored by the European Community as part of the Myocluster project GENRE.

Congenital muscular dystrophies (CMD) are a heterogeneous group of disabling neuromuscular disorders inherited as autosomal recessive conditions; their overall frequency is approximately 1:10,000. Affected children present with muscle weakness and hypotonia at birth, or within the first six months of life. Motor development is delayed and contractures are common. The progression of the disease is variable and a proportion of children never achieve the ability to walk independently. Mental retardation is a feature of several forms of CMD.

The present meeting focused on the recent clinical, genetic and biochemical advances on the subtypes of CMD characterized by:
i) rigidity of the spine (rigid spine syndrome); ii) CMD with distal laxity;iii) CMD due to deficiency in proteins with enzymatic activity (glycosyltransferases).

CMD and Rigid Spine Syndrome. The gene for one form of CMD with severe rigidity of the spine has recently been identified . This form is now known as RSMD1 (for Rigid Spine Muscular Dystrophy 1) and the defective gene is a novel selenoprotein for which a function has yet to be assigned.
CMD with distal laxity. Recessive mutations in the genes for collagen VI subunits have recently been shown to be responsible for another form of CMD. ( “Ullrich” CMD variant with distal laxity, UCMD). As only some, not all , cases show abnormal expression of collagen VI in muscle , the possibility of heterogeneity was discussed.

CMD due to deficiency in glycosyltransferases. Mutations in genes with possible glycosyltransferase enzymatic activity have recently been identified into 2 other forms of CMD (Muscle Eye Brain disease, with associated mental retardation; and MDC1C, a novel form characterized by muscle hypertrophy and no central nervous system involvement). In addition, a defect in a similar enzyme has recently been reported in an animal model for muscular dystrophy, the myd mouse, providing further evidence for the relevance of these enzymes in CMD.

Refined diagnostic criteria for these forms of CMD were discussed, together with the strategy aimed at arriving a diagnosis in each of these conditions. Management strategies for these disorders and therapeutic approaches to animal models were also discussed, and collaborative studies agreed.

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

Prof. Francesco Muntoni, London, UK
Dr. Pascale Guicheney, Paris, France
Chairpersons, CMD consortium

Visit the website of the Myocluster Project GENRE at:

2nd Workshop of the MYO CLUSTER project: EUROMEN

Location: Naarden, The Netherlands


The second Workshop of the MYO CLUSTER project EUROMEN was held in Naarden on the 28th and the 29th September 2001. It was attended by 18 participants from France, Italy, Germany, The Netherlands and UK. This workshop aimed to collate the clinical findings of disorders caused by defects in proteins of the nuclear membrane, in particular lamins and emerin, and to relate these to cellular functions.
Four disorders are caused by mutations in the lamin A/C gene (LMNA): autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), dilated cardiomyopathy with conduction-system defect (DCM-CD), dominant limb-girdle muscular dystrophy (LGMD1B) and Dunnigan-type familial partial lipodystrophy (FPLD). Mutations in the emerin gene (STA) lead to the X-linked form of EDMD. The wide clinical spectrum of the “laminopathies” was discussed. Clinical onset can occur in early childhood and these cases are characterised by early contractures, slowly progressive muscle wasting and weakness with a predominantly humero-peroneal distribution and a cardiomyopathy, associated with conduction defects. Sometimes an abnormal distribution of adipose tissue can be observed. Cardiac involvement poses a substantial risk of sudden death, which can be controlled by insertion of an implantable cardiac defibrillator (a sophisticated type of pace maker). This latter issue was highlighted during the workshop and a close cardiac follow-up is essential and highly recommended. To date, there is no clear correlation between the genotype and the phenotype and several modes of inheritance have been detected. Analysis performed of patient’s tissues (skin, muscle biopsies, blood cells) were presented and discussed to understand the role of lamin A/C mutations in these diseases. The interactions of lamin A/C and emerin with different nuclear components were discussed.

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

Dr. Gisèle Bonne (Paris, France)

Visit the website of the Myocluster Project GENRE at:


DESMIN – Protein Surplus Myopathies

Location: Naarden, The Netherlands


Subsequent to earlier ENMC-sponsored Workshops on desmin, familial desmin related myopathies and rare congenital myopathies, a multinational and multidisciplinary Workshop on ‘DESMIN – Protein Surplus Myopathies’ assembled 16 clinicians and scientists from 8 European countries on September 14-16, 2001 in Naarden, The Netherlands. ‘Protein Surplus Myopathies’ are marked by the accumulation of proteins within muscle fibers possibly owing to impaired non-lysosomal proteolysis some of the accruing proteins being mutant ones. Current state of knowledge on these structural congenital myopathies was reported and further lines of research were discussed. The major group comprises desmin-related myopathies, among them desminopathies marked by more than 10 mutations in the desmin gene, alpha-B-crystallinopathy marked by a mutation in the alpha-B-crystallin gene, and other myopathies with additionally known (linkage to 10q) or even gene loci. An example of these conditions discussed in this Workshop was ‘hyaline body myopathy’ marked by accumulation of granular material (myosin?).

Further research will target identification of new genes in respective families, unknown gene products in already mapped genes and further insight into the processes of protein accretion and protein degradation.

In spite of the rarity of these conditions, due to their usual clinical severity at the cardiac and skeletal muscle levels, a concerted investigation on their pathogenic mechanisms is justified, in order to improve their prevention and lead to therapeutic approaches.

The Consortium further decided on an application to the European Union to further investigate desmin-related myopathies and other very rare structural myopathies with individual members of the Consortium in charge of the different structural congenital myopathies.

An extended report of this meeting is published in Neuromuscular Disorders, Volume 12, Nos.7-8, October 2002

Prof. H.H. Goebel (Mainz, Germany)
Prof. M. Fardeau (Paris, France)

Cognitive Impairment in Neuromuscular Disorders

Location: Naarden, The Netherlands


As many neuromuscular disorders involve brain as well as muscle, the ENMC consortium on cognitive impairment in neuromuscular disorders held its first meeting in Naarden (The Netherlands) on the 13-15 July 2001. It was attended by 15 participants from the United Kingdom, France and Italy. The meeting opened with reviews of the historical background, clinical features, genetic analysis, neuropsychological studies used to define the diseases within this group.
Over the last 10 years several approaches concerning possible correlation between molecular defects in gene mainly responsible for muscular diseases and the cognitive impairment or between neuroradiological analysis and mental retardation have been published. With the aim of identifying the particular characters of neurofunctional, cognitive, psychiatric and visual deficit in neuromuscular disorders, different groups reported a wide spectrum of patients. Possible correlations between gene and protein alterations were discussed in Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Myotonic Dystrophy, Limb-Girdle Muscular Dystrophies, Congenital Myopathies and Mitochondrial Myopathies.
The avalanche of interesting data already present in the literature, needs a formal organization. Our proposal for this workshop on cognitive impairment in neuromuscular disorders aimed to gather a panel of experts, review the available scientific information and find a common strategy of analysis of the patients, establishing the criteria of selection of the patients and define the objectives of shared research projects.
As a first step, the participants agreed to organize themselves into groups whose objectives are to examine how the brain is involved in Duchenne and Becker Muscular Dystrophies. They all agreed on the following aims:
1. to characterize the nature and specificity of the cognitive profiles in these disorders;
2. to answer the outstanding problems in genotype-phenotype correlations (how particular faults in the gene lead to problems in the brain);
3. to use these results to direct further molecular studies;
4. to use these results in the design of therapeutic strategies (including parental guidance, speech therapy, psychotherapy and neurorehabilitation ).

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

Prof. N. Bresolin (Bosisio Parini (Lecco), Italy)

On behalf of the participants

Basic methodologies for clinical trials in myopathies

Location: Naarden, The Netherlands


The ENMC workshop “Basic methodologies for clinical trials in myopathies”was held in Naarden from 11th – 13th May 2001. It was attended by 17 active participants from Belgium, Denmark, France, Germany, The Netherlands, United Kingdom and Switzerland.

The meeting opened with a review of studies performed in athletes to understand mechanisms to improve muscle function and in animal models of muscular dystrophy. Reviews of the present status in surgical and physiotherapeutic studies followed.

In a second session, the practical organisation of multicenter clinical trials was examined, taking into consideration the fact that many myopathies are rare disorders.
Co-ordination between the different groups is important, in order to avoid duplication and to be able to compare results in systematic reviews with metaanalyses where possible.

In a third session assessment instruments were discussed, in the light of experience in other neuromuscular disorders, in particular amyotrophic lateral sclerosis.
Different methods to quantify force, using manual testing and apparatus, to assess functional capacity and impairment, and to measure quality of life were reviewed.
No consensus has yet been achieved in the use of these instruments, and a lack of uniformity hampers generalised use even of common methods.
Laboratory measurements, such as blood sampling, muscle biopsy, imaging and magnetic resonance spectroscopy are important within specific trials, but not for broader therapeutic trials.

In a last session, statistical methods were examined and the importance of obtaining professional advice from the onset of trial planning was stressed.
The participants agreed upon continuing this evaluation process in order to provide a framework for the organisation of therapeutic trials within ENMC.

An extended report of the meeting and a critical evaluation of available assessment methods will be submitted for publication in Neuromuscular Disorders.

Prof. J.-M. Burgunder (Bern, Switzerland)

Non 5q-spinal muscular atrophy (SMA)

Location: Naarden, The Netherlands


The ENMC workshop on Non-5q-SMA took place in Naarden on 6th – 8th April 2001. It was attended by 13 active participants from Belgium, Finland, France, Germany, The Netherlands and United Kingdom.The meeting opened with the re-evaluation of the clinical picture, pathology and electro-physiology of classical SMA linked to 5q. Of special interest were the pathoanatomical features of the two existing SMA animal models for SMA 5q in comparison to the pathology in humans.The major topic was the re-evaluation of so called SMA plus types of childhood including diaphragmatic SMA (SMARD), SMA with (ponto-)cerebellar hypoplasia, SMA with myo-clonic epilepsy as well as the Brown-Vialetto-van Laere syndrome. SMA with arthro-gryposis and congenital fractures was included as a heterogeneous group of disorders. Published cases were reviewed and the definition of certain types was broadened by the discussion of new families.After reviewing the differential diagnoses of autosomal dominant and adult SMA different families were discussed. It turned out that rare autosomal dominant proximal SMA families with onset in adulthood exist. It was agreed that there are pedigrees with congenital autosomal dominant SMA as well. Distal SMA (often referred to as hereditary motor neuropathy) and scapuloperoneal SMA are observed in dominant and recessive families. The distinction of distal SMA and axonal Charcot-Marie-Tooth disease may be impossible in single families. Segmental SMA is a different condition which is usually not inherited.The participants underlined the necessity to define distinct phenotypes and to collect further families with rare Non 5q-SMA entities in order to perform linkage studies and to identify genes involved in different forms of spinal muscular atrophy.

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

Prof. K. Zerres (Aachen, Germany)