99th ENMC international workshop: myotonic dystrophy: present management, future therapy:

Article Outline

• Conclusion
• Acknowledgements
• Appendix A. Workshop participants
• References
• Copyright

This workshop, including 22 participants from nine countries, was the first ENMC workshop specifically related to myotonic dystrophy. Its two main aims, reflected in the workshop's title, were firstly to try to agree on key aspects of clinical management for patients and families, and how this can be effectively delivered; secondly to assess the possibilities for therapy in the light of basic research developments and clinical practice, and in particular to develop Europe-wide patient cohorts on which future therapeutic trials can be founded.

The workshop members were principally clinicians involved with myotonic dystrophy families, but both basic research workers and patient support organisations were also represented. The patient and carer perspective were illustrated at the outset of the workshop by Margaret Bowler (UK Myotonic Dystrophy Support Group), who emphasised the additional problems posed by aspects of behaviour and motivation in addition to physical disability.

This theme was reinforced by Christine de Die-Smulders (Maastricht), who described the features of the childhood onset group of myotonic dystrophy patients, still frequently unrecognised, in which learning, behavioural and psychiatric aspects were predominant, even though lacking the severe perinatal neuromuscular problems characterising those with congenital onset.

The second session, dealing primarily with neuromuscular management, began with discussion, led by Giovanni Meola (Milan) and David Hilton-Jones (Oxford) of the core diagnostic procedures required in myotonic dystrophy. There was widespread agreement on these, and that they had become considerably simplified, with a combination of clinical assessment and molecular analysis of the chromosome 19 CTG repeat being sufficient for diagnosis in most patients; electromyogram (EMG), slit lamp examination of lenses and other investigations can now be reserved for complex situations, notably where molecular analysis proved normal. General availability of analysis for the DM2 CCTG expansion should soon also simplify investigation of patients with no CTG expansion or who present with proximal myotonic myopathy (PROMM) or other atypical neuromuscular disorders.

Protocols for use in the follow up of myotonic dystrophy patients were discussed by Mark Rogers (Cardiff) and Bruno Eymard (Paris). The relatively simple Cardiff protocol had been widely found to be suitable as a basic clinical tool [1], especially in centres without additional resources, but a fuller baseline assessment was recognised as needed as the foundation for both future services and research. The Paris database was felt to be an appropriate starting point for this, but it was recognised that further work was needed to develop a baseline assessment that would be used by all centres and that any regular neuromuscular assessment forming part of future trials would likewise need to be more detailed.

Aspects of physical disability were discussed by Margaret Phillips (Derby), who emphasised that most physical aids to management were comparable to those needed across a wider range of neurological disorders, particularly those involving mobility and provision of social and home based services for daily living.

Two sessions were devoted to systemic aspects of myotonic dystrophy, reflecting the importance of those non-neuromuscular aspects in causing serious ill-health and mortality. Cardiac aspects were presented by Denis Duboc (Paris) and Maxwell Damian (Dresden), leading to an extensive discussion. It was generally agreed that an annual surface electrocardiogram (ECG) remained the foundation for regular surveillance, with further complex and invasive studies such as conduction electrophysiology reserved for patients showing ECG changes or where there were symptoms or other clinical indications. Prospective studies of early pacemaker insertion and anti-arrhythmic therapy were encouraging, but required fuller trials for a definitive result. There was an urgent need for more data on the occurrence of serious heart problems or sudden death in young people, a topic on which systemic data should be collected across the group.

Anaesthetic and surgical risks and protocols (Mark Rogers, Cardiff) were discussed; this was felt to be an area where general agreement existed, but where there was an urgent need for greater dissemination of information so that both patients and anaesthetists/surgeons were more aware of the hazards and how they might be avoided.

The area of gastro-intestinal symptoms (Han Brunner, Baziel van Engelen (Nijmegen) Asa Johannson (Umea)) was recognised as being an area of widespread and important clinical involvement, with the basis of many aspects still poorly understood. The assessment of drugs for abdominal pain was identified as an area where trials using a common protocol across the group would be of value.

Similarly, co-ordinated data would be of value in assessing problems of pregnancy in myotonic dystrophy; a prospective study was being developed by Christine de Die-Smulders and Sabine Rudnik, who were encouraged to circulate any proposed protocol so that multicentre data could be collected.

Wider endocrine problems were found to be numerous on special investigations (Asa Johannson), but not of frequent clinical importance. It remained uncertain whether clinical diabetes (in contrast to insulin resistance) was significantly increased.

An important systemic aspect that has already been the subject of preliminary trials is of increased daytime somnolence (David Hilton Jones and Maxwell Damian). A double blind trial of modafinil for this is now in progress.

Provision of genetic counselling, presymptomatic testing, and the estimation of genetic risks were presented by Peter Harper; the importance of taking into account clinical and molecular status and the type of parental transmission was stressed; there was considerable discussion around issues of how and to what extent family members should be approached and offered testing.

The importance of active and innovative approaches to dissemination of more general information to patients and families was shown by Douglas Wilcox (Glasgow), Margaret Bowler (Myotonic Dystrophy Support Group) and Martine de Villers (AFM, Paris). Hand held information such as the alert card and care sheet (available from MDSG at www.mdsguk.org) proved highly successful, as had development of a specific web-site www.gla.ac.uk/muscle/dm.htm. The workshop felt that this was a key area that could be developed by the group.

The second part of the workshop looked at the prospects for more definitive therapy for myotonic dystrophy and at what clinical foundations needed to be developed now for future clinical trials. Two reviews on recent basic research results by Darren Monckton (Glasgow), and Tetsuo Ashizawa (Houston) showed how recent research developments had been of direct relevance to planning of possible therapeutic approaches. The somatic instability of DNA in the expanded DM1 repeat (and probably also in DM2) may itself contribute to the disease process. Likewise the concept, now firmly established, that trapping of DMPK RNA in the nucleus can lead to widespread disturbance of RNA binding and splicing abnormalities in a range of other RNA types, gives a new perspective for understanding the multiple systemic aspects of myotonic dystrophy.

The availability of transgenic models will allow assessment of how agents affecting these processes might modify disease phenotype, something of great potential importance in therapy for human myotonic dystrophy. However, it is clear that using these advances in human clinical trials remains some years away.

The quality of the evidence base was considered to be very limited for both approaches to therapy and for many of the studies of clinical complications and natural history. Actual trials of therapy until now were limited in number – a useful summary was provided by Richard Moxley (Rochester). In terms of grading, the available evidence, almost all would be in categories C or D (open studies or expert opinion).

The final part of the workshop involved discussion of how clinical centres could prepare for and co-ordinate future clinical trials, especially bearing in mind that the variable nature and slow deterioration in the disorder would necessitate large patient numbers. This was linked with discussion of the future role, development and activities of the group and resulted in a number of decisions.

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Conclusion 

This valuable workshop produced widespread agreement on a range of management areas for myotonic dystrophy but identified others where evidence was much less clear. Even for the agreed areas, there was an urgent need for increasing awareness of the problems and their management for clinicians generally.

Although recent research advances have opened up possible avenues which may be productive for definitive therapy in future, the immediate focus of trials needs to be in establishing a large and well documented cohort of patients in major European centres, and for standardised and reproducible methods of assessment. A range of trials for specific symptoms is already possible if such a resource can be established, and these will prove useful when more definite and scientifically based therapies become available.

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Acknowledgements 

This workshop was made possible by the financial support of the European Neuromuscular Centre (ENMC) and its main sponsors and associated members:

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Appendix A. Workshop participants 

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References 

1. Harper PS. Myotonic dystrophy. London, UK: W.B. Saunders; 2001; p. 422–3
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