Ongoing updating and dissemination of standards of care for DMD

Location: Naarden, The Netherlands

The 181st ENMC workshop titled “Ongoing updating and dissemination of standards of care for DMD” was held in Naarden, the Netherlands, 10-12 December 2010 with representatives from Western and Eastern Europe and USA.

What was the aim of the workshop?

Comprehensive guidelines to improve the multidisciplinary care of individuals with Duchenne muscular dystrophy were published in January 2010 after a three-year consultation process that involved 84 of the world’s leading Duchenne muscular dystrophy experts.  To follow on from this important step forward, this workshop aimed to find the best ways to disseminate, implement and update the care standards. The workshop discussed the bottlenecks for delivery of the care recommendations, and the best way to overcome them.

What was achieved?

The ENMC workshop began with an initial overview of the status of the current Duchenne muscular dystrophy guidelines in terms of dissemination, translations and planning for further development. This was followed by a session on the roles of various European organizations in this process:

  • CARE-NMD – an EU project to implement best-practice standards of care for Duchenne muscular dystrophy across Europe
  • TREAT-NMD training courses, education activities and clinical trials coordination centre
  • MD-Starnet, and related US activities
  • French DMD network to help disseminate care standards.

Interesting discussions arose also from the presentations on what we can learn from a care perspective from natural history (CINRG, North Star, UPD) and therapeutical studies (Ataluren, cardioprotection, and others), and how tools such as patient registries and The TREAT-NMD Care and Trial Sites Registry can be further developed to act as a resource. In particular, the potential use of “Quality of care indicators”, assessing key outcome indicators was presented and discussed as a means to make use of the TREAT-NMD clinical trials coordination centre for assessing care implementation. Similarly, criteria for DMD reference centers was discussed, based on EU expectations of an expert centre for rare diseases.

Final sessions at the workshop dealt with care areas lacking or in need of updating, and how to promote excellence of care and high quality research.  It was concluded that a major involvement of the patient representatives are crucial for the updating process, and that certain key areas need to be included here, including transition to adulthood, endocrine issues, and oral care. It was also suggested that efforts be made to integrate work on outcome measures to be used for clinical trials with care assessments used in regular clinical settings. A web based program was presented allowing for this and to aid in the process of updating standards of care.

This workshop was organized by Prof. K. Bushby, Prof. T. Sejersen, Drs. E. Vroom and Dr. J.B. Kirschner and held in Naarden in December 2010.
The report for this workshop is not (yet) available. For further information, please contact one of the workshop organizers or the ENMC office.

Myotonic Dystrophy type 2 (DM2)

6The ENMC consortium on myotonic dystrophy type 2, DM2, held its 5th workshop in Naarden, the Netherlands, 3-5th December 2010. It was attended by 19 active participants from Finland, France, Germany, Italy, The Netherlands, Czech republik, and the USA. Participants reported on the occurrence of DM2 in various countries indicating that the overall prevalence of symptomatic patients is very similar to that of DM1. At least in Finland and Czech republik the prevalence of DM2 is even higher than DM1 based on the numbers of genetically diagnosed patients. There is still a too long delay between onset of disease symptoms and final correct diagnosis due to insufficient awareness of DM2 among doctors and due to the large variation of symptoms and signs. Milder forms, the high frequency of muscle pain and abscence of clear myotonia in a large proportion of patients are some of the misleading factors deserving more attention. Exact molecular diagnosis is mandatory for the patients to have a correct understanding of their symptoms and for optimal management. DM2 is still underdiagnosed even in countries with good neuromuscular centers, which indicates that the treshold for requesting DNA-testing should be kept rather low than high. Increasing number of laboratories provide molecular diagnostic testing also in Central-Eastern European countries. Much of the efforts of the workshop focused on the scientific research to understand the abnormal events taking place in the muscles and other affected organs caused by the DM2 mutation. Progress has been made in the clarification of  some of the molecular processes taking place in the cells. Many of these abnormalities have basic similarities with the molecular processes causing DM1, Steinert’s disease. However, other DM2 specific and more complex abnormalities were also identified. The workshop agreed on guidelines for genetic testing and management of DM2 which will be included in the extended report of the meeting which is published in Neuromuscular Disorders (pdf).


Pregnancy in women with NMD

Location: Naarden, The Netherlands

Sixteen doctors and scientists met in Naarden from 5 to 7 November 2010 to review current knowledge in the field of pregnancy in women with neuromuscular disease. The group was joined by three patients and their families. Participants were from 8 countries, namely Belgium, Finland, France, Germany, Italy, Norway, The Netherlands and the United Kingdom. Representatives from a variety of disciplines were represented, including  neuromuscular physicians and a nurse specialist , clinical genetics, cardiology, respiratory medicine, obstetrics and gynaecology and obstetric medicine,  epidemiology, ethics, and a representative from the ENMC research committee.

The overarching  aim of the workshop was to harness knowledge about pregnancy in neuromuscular disease with the intention of improving maternal and fetal outcomes. The workshop was structured to review existing knowledge in the field and then to propose practical recommendations for each stage of pregnancy, both in general terms and also specific to individual or groups of conditions, for use by all the specialists involved in a woman’s care. These recommendations will be refined by the group and then submitted to Neuromuscular Disorders as part of the full Workshop Report. The third aim was to discuss proposals for a prospective study via an international registry for those women with neuromuscular disease who are undergoing pregnancy.

As became increasingly clear from the contributions of the participants, including the personal accounts from the three patients, there is little detailed knowledge in this area at present  and much to be learnt.

A full report is published in Neuromuscular Disorders.


Location: Naarden, The Netherlands

This workshop was organized by Prof. L. van den Berg, Prof. E. Beghi, Prof. O. Hardiman and Prof. A. Ludolph and held in Naarden in October 2010.
The report for this workshop is not (yet) available. For further information, please contact one of the workshop organizers or the ENMC office.

Pompe disease

During the weekend of 10 – 12 September 2010, eighteen clinicians and researchers with clinical experience in treating and following larger groups of patients with Pompe disease, or doing research in this disorder, met in Naarden, theNetherlands. Pompe disease is a rare inheritable muscle disorder for which since 2006 enzyme replacement therapy is available. The first studies on effects of therapy show variation in treatment effects and long-term effects of treatment have not been studied.

Aims of the workshop

The aim of this workshop was

  1. To evaluate the effects of enzyme replacement therapy (ERT) in large cohorts of children and adults with Pompe disease, and
  2. To develop guidelines for monitoring patients and treating them.
  3. To discuss the potential value of registries for identification of prognostic factors and assessment of therapeutic outcome

This workshop brought together a panel of physicians and researchers who have been involved in the clinical trials with ERT or who are currently following large groups of patients with Pompe disease in various European countries, so as to create a platform to exchange experiences and discuss new developments and potential collaborations. It was felt that this was a good starting point, that likely requires a follow-up meeting.

What was achieved?

  1. The different studies assessing the effects of ERT were reviewed and discussed. It was concluded that ERT improves patient prospects and slows or halts the progression of the disease. However, it was also recognised that effects differed in individual patients and that identifying prognostic factors for response to treatment is important.
  2. Further research is needed to identify prognostic factors, which may include the level of immune response against the treatment. It was agreed that data will be collected by the different centres that will be used to gather more information on potential prognostic factors related to the effect of ERT which could be combined in future.
  3. An overview of the way patients are monitored in different countries was constructed. Consensus was reached on the minimal set of assessments for adult Pompe patients, which includes the six-minute walk test, manual muscle (strength) testing, pulmonary function tests (VC), cardiac evaluation, and functional tests (Walter Gardner scale and timed tests).
  4. In few countries official guidance for starting and stopping ERT in Pompe patients was available. The approaches presented by the different members of the group nevertheless did show a common thread. It was agreed that treatment in patients with a confirmed diagnosis should only be started when patients are clinically symptomatic. Further years of experience of treating patients and research on prognostic factors is required to define start and stop criteria further.

The full report is published in Neuromuscular Disorders. For an overview, please click here (pdf)


Diagnosis and treatment of Co enzyme Q10 deficiency

During the weekend of 9th to 11th July 2010 fifteen clinicians, basic scientists, and pharmaceutical representatives met in Naarden, The Netherlands. The delegates work in seven ENMC member countries and in two non-member countries. The meeting was the first ENMC workshop devoted to the most treatable subgroup of mitochondrial diseases, namely coenzyme Q10 (CoQ10) deficiency.

Background and Aims of the Workshop
Small structures present inside virtually all human cells, mitochondria produce energy to drive chemical reactions within cells. For this reason, they are sometimes referred to as the ‘powerhouse’ of the cell. CoQ10 is a small molecule that has numerous functions in the cell, including critical roles in mitochondrial energy production and antioxidant defence mechanisms. Some patients with mitochondrial disease are unable to make CoQ10 in their cells and this workshop aimed to improve the clinical recognition, diagnosis, and treatment of these patients.

Outcomes of the Workshop
During the workshop, we discussed the functions of CoQ10 in the body and how low levels of CoQ10 may disrupt these normal functions, resulting in disease. We also discussed new information about how CoQ10 is made, which may impact how we diagnose this condition in the future. We recognized the importance of accurate and rapid diagnosis of this disorder because the outcome appears to be related, at least in part, to how quickly treatment can be initiated. We therefore debated the best methods for the clinical detection and diagnosis of CoQ10 deficiency, and how precise genetic diagnoses can be achieved most rapidly and efficiently. Presentations given by clinicians during the workshop revealed the highly variable clinical features of CoQ10 deficiency; therefore, we concluded that all patients with suspected mitochondrial disease should probably be tested for CoQ10 deficiency, as well as patients with cerebellar ataxia and those with a kidney disease known as steroid-resistant nephrotic syndrome. Plasma CoQ10 levels fail to provide a measure of CoQ10 deficiency in the tissues. The apparent tissue specificity of CoQ10 deficiency also poses a challenge for diagnosis. Sampling of patient fibroblasts and muscle appear to provide a better indication of CoQ10 content, and we concluded that white blood cells should also be sampled.

We talked about cell and animal models that have been developed for CoQ10 deficiency and how these are being used to evaluate possible treatments for this disorder. We discussed the best formulations and dosage for treating CoQ10 deficiency. Our pharmaceutical partners also presented some very preliminary results of early clinical trials that are being carried out in mitochondrial disease, using CoQ10 and related compounds.

How this will Benefit Patients
As a result of the workshop we plan to develop and publish a diagnostic protocol for CoQ10 deficiency, so that clinicians and laboratories around the world can work together to identify patients with this potentially treatable form of mitochondrial disease as rapidly as possible. We will also form an international consortium to improve the genetic diagnosis and treatment of this condition.

 A full report is published in Neuromuscular Disorders.(pdf)

Mitochondrial protein synthesis in health and disease

Mitochondria constitute a subcompartment found within all cells of the body, which routinely make up more than 20% of their total mass. These subcellular structures (or organelles) perform many essential functions. One of these is to act as the battery or power supply for the cell, turning nutrients into a readily utilisable energy source. Consequently, if there is any problem with these specific organelles, any body tissues could potentially be affected. Mitochondria rely on the cell in which they are housed to provide the great majority of proteins that are absolutely required for them to function normally but this on its own it not enough. Mitochondria also actually contain many copies of their own small piece of DNA, different to that of the nucleus that acts as the blueprint for the production of thirteen essential proteins. In the past few years, it has become apparent that some patients have specific problems with the production of these proteins, a process that takes place within the mitochondrion, and such difficulties result in major problems with the cells battery.

In the majority of adult patients who make abnormally low levels of these proteins, it is the mitochondrial DNA (mtDNA) that carries the disease transmitting mutations or it is the number of copies of the mtDNA within the cell that is reduced and is too low for normal function. However, there are numerous situations where both the amount and composition of mtDNA is completely normal and yet these mitochondrial proteins are still not made correctly. This report summarises the first ever international meeting dedicated to this particular cluster of diseases. Until this meeting, no estimate of the prevalence for this category of disorders had ever been described. Further, the difficulties associated with diagnosing these protein synthesis defects had not been discussed and this is in part because the situation is complicated by our lack of understanding of the exact molecular mechanisms that are involved in this key cellular process.

During this meeting, several prominent clinicians from around Europe, who have patients referred to them with these suspected disorders, shared their experiences and provided estimates of the relative prevalence of these disorders. A number of scientists also aided substantially in bringing to the attention of these clinicians and diagnosticians how our understanding of translation in human mitochondria has grown. It was estimated that in children with combined respiratory chain deficiency as many as 75% have putative disorders of mitochondrial translation that is not caused by mtDNA abnormalities, however this number is much lower in adults (<20%). The consensus from the clinical/diagnostic contributors was that there were no easily identifiable, common groupings of disorders or common genetic defects. A variety of diagnostic suggestions were made, such as direct analysis of mitochondrial translation or assays for the products made by translation, but there was no clear differential diagnosis that should be followed. It was agreed that within one or two years, the most sensible approach to identify pathogenetic mutations underlying mitochondrial translation defects was likely to include whole exome sequencing, a way of looking at the part of a gene that contains the blueprint for the entire set of proteins in a cell. This technique should be performed in tandem with powerful new software methods to identify whether mutations were likely to be harmful or not, methods which were being developed and presented by clinical members of this meeting. It was also apparent from the scientific presentations that the exciting breakthroughs in characterising the structures and visualising the factors involved in mitochondrial protein synthesis may eventually lead to novel therapeutics for this group of disorders.

A full report is published in Neuromuscular Disorders (pdf)

Applying Pre-implantation Genetic Diagnosis to mtDNA Diseases

Location: Naarden, The Netherlands

One in 400 people has a maternally inherited, mitochondrial DNA (mtDNA) disease mutation, causing a range of illnesses, including deafness, blindness, diabetes, loss of skills, heart and liver failure. We aim to improve the genetic management of these diseases. At the moment we do not understand the mechanisms that underlie mitochondrial genetics very well. MtDNA is inherited via the female line only. The chances that a woman carrying an mtDNA mutation will pass the mutation on to her child, and that child develops symptoms, are difficult to predict. This is because both mutant and normal mtDNA are often found in the same individual. This is called heteroplasmy. If the proportion of abnormal mtDNAs in particular cells of the body is high, people develop symptoms of disease. The disease will be most severe in people with the highest proportions of mutant mtDNA. However, this proportion varies from one generation to the next and cannot be predicted. The variability in the proportion of abnormal mtDNAs inherited is caused by an event known as the mitochondrial bottleneck.

The meeting discussed reproductive options for women from families with maternally inherited mtDNA disease. Current reproductive options include oocyte donation (where an egg is donated from an unrelated woman) and prenatal diagnosis (where the fetus is tested early in pregnancy). However, these strategies may not be possible or desirable in many families for a number of reasons. Recent scientific advances suggest that preimplantation genetic diagnosis (PGD) is feasible for some common mtDNA diseases. In PGD, the eggs are fertilised by sperm in the laboratory (IVF) so that the resulting embryos can be tested, and low risk embryos selected to start a pregnancy. The mitochondrial diseases where this is possible include some types of maternally inherited Leighs disease (MILS or NARP), maternally inherited diabetes and deafness (MIDD) and myoclonic epilepsy with ragged red fibres (MERRF). Although PGD for mtDNA diseases remains challenging, we feel that there have been significant advances in enabling affected families to have healthier children.

The meeting also discussed techniques for replacing disabled mitochondria with healthy ones. “Nuclear transfer” is one of these techniques that became well know when it generated Dolly the sheep. Some of these approaches might become available in future years once we are sure they are safe.

A full report is published in Neuromuscular Disorders. For an overview, please click here (pdf)

Congenital Muscular Dystrophy (CMD) Outcome measures

The 173rd ENMC/TREAT-NMD Workshop organized by Prof. Francesco Muntoni, Prof. Eugenio Mercuri, Dr. Carsten Bonnemann and Dr. Anne Rutkowski (Cure CMD) complemented current efforts to support congenital muscular dystrophy clinical trial readiness, including launch of an international CMD registry and development of CMD Care Guidelines. An opening introduction by Dr. Jeremy Hobart and Dr. Stefan Cano reviewed both the purpose of outcome measures and the importance of getting the outcome measure scale right, based upon an interative process involving statistical analysis of existing data and an understanding of clinical disease progression.

The workshop focused upon meeting two concrete objectives: a review of available CMD data with regard to natural history and motor function to identify a set of clinical functional classes and the need of appropriate scales that could be used as outcome measures ; and a review of available CMD case report forms to launch an international CMD longitudinal study.  Each clinician presented CMD subtype specific patient cohort data with an emphasis on assessing functional vital capacity decline, start of assisted ventilation and weight/diet supplementation versus age.  The physiotherapists presented limited data sets regarding CMD cohorts across a variety of motor scales. A new upper limb scale validated in spinal muscular atrophy, an upper limb strength test developed for nonambulatory boys with Duchenne and a novel motriplate were presented.  Complex integrated motor scales, including the EK2 scale and actimetry by accelerometry were described, along with existing neuromuscular-oriented quality of life and caregiver burden scales that are not currently validated in the CMD population.

A consensus decision to approach outcome measure development based upon age and ambulatory status over disease subtype was endorsed. The 6 CMD outcome measure categories are: age 0-2 yrs not sitting, age 0-2 yrs sitting, 2-5 yrs ambulatory, 2-5 yrs nonambulatory, >5 ambulatory, >5 nonambulatory.  To ensure adequate coverage of outcome measures that address CMD subtype specific issues, a second round of discussion delineated key issues per CMD subtype with a focus on: collagen VI myopathies, merosin deficient CMD, dystroglycanopathies and SEPN1 myopathies.

Presentations by pharmaceutical industry representatives helped guide the conversation to clinical trial readiness from a pharmaceutical and regulatory agency perspective, underscoring the need to define primary and secondary outcome measures that are not only clinically meaningful yet address conservative survival endpoints and quality of life.  Preliminary results from a recent caregiver and affected individual survey organized by Cure CMD, demonstrated caregiver burden correlates to changes in the affected individual’s strength and ability to complete activities of daily living, while for affected individuals, positive and negative meaningful change correlates most highly with changes in strength and ambulation.

A priority has been placed on gathering FVC (forced ventilation capacity) data for collagen VI and SEPN1 patients in light of 2 potentially imminent clinical trials in these patient cohorts.  In addition, over 100 CMD patient charts with motor scale data will be extracted in London and subjected to Rasch analysis in the next month to identify how the particular motor scale employed captures children with CMD on both ends of the spectrum: weak and stronger (with some thought given to implications of score in the setting of contractures and/or cognitive impairment).  A Rasch analysis is a psychometric tool to evaluate the ability of a scale to measure meaningful change across an entire patient population.

A follow up international physiotherapy meeting has been set for May 14-15th 2010 to review Rasch analysis and pull core CMD elements from a group of existing motor scales (Hammersmith, MFM32, MFM20, Northstar, Upper Limb Scale).  This meeting will determine whether the current scales capture the CMD population. If current motor scales are not adequate, the meeting will devise a new CMD motor scale for those children who are ambulatory/nonambulatory age >5 yrs.

A subsequent international CMD Outcome Measure validation study will take place on June 12-13th 2010 at the National Institute of Health in Washington, DC with a focused approach on children >age 5 with collagen VI myopathy and merosin deficient CMD.

CMD case report forms were reviewed to streamline and revise common data elements. A decision was made to bring together an international CMD consortium, including physicians, advocacy and the pharmaceutical industry to assist with strategic development of a therapeutic roadmap and data collection using a set of defined guidelines.The 173rd ENMC /TREAT-NMD  CMD Outcome Measure workshop was funded by ENMC, TREAT-NMDSanthera and Cure CMD.

A full report is published in Neuromuscular Disorders (pdf)


Location: Naarden, The Netherlands

Organisers : Kate Bushby, Isabel Illa, Martin Krahn, Nicolas Levy

The 172nd ENMC International workshop was dedicated to dysferlinopathies, a group of diseases due to mutations in dysferlin, the best known of which are limb-girdle muscular dystrophy 2B (LGMD2B) and  Miyoshi Myopathy. In the past years, there has been increasing clinical interest in these conditions and the diagnosis is more readily available at least in some labs. The workshop was organized to consider how the diagnosis should be made, what we need to do to understand why the condition develops and work out what needs to be done to see possible therapies for these conditions developed. Seventeen international participants reviewed and discussed the current issues in the field of dysferlinopathies.

A first session dedicated to diagnostics, reviewed the current procedures and difficulties of dysferlin mutational analyses, and the importance of dysferlin protein testing on monocytes and/or muscle tissue in the diagnostic process. The discussions allowed the identification of central points to be included in a more formalized development of diagnostic guidelines, through the creation of an informal Network on Dysferlin Mutational Analysis. This session also included an overview on clinical and mutational data of a new gene Anoctamin 5 which has now been shown to cause a different condition which is very similar clinically to LGMD2B or MM but where dysferlin is normal. Finally, the importance of inflammatory features in dysferlin deficient muscle tissues from patients was outlined. The central importance of inflammation was subsequently largely developed in the sessions on animal and cellular models of dysferlinopathy, and novel insights into why there is such a prominent inflammatory infiltrate were presented. Major data on a novel muscle-specific dysferlin transgenic mouse model however indicate that the primary disease-causing event originates from the muscle tissue, and that the inflammatory events should therefore represent an aggravating cascade of secondary events. Working out exactly the way that dysferlinopathy happens at the cellular level will also require a better understanding of what proteins it interacts with which will need novel antibodies. All presentations and discussion further outlined the need for standardization of both animal and cellular models and the group was committed to working together to make this happen.

The final session was dedicated to therapeutic approaches. Preliminary data from the German trial on the use of corticosteroids in dysferlinopathies do not suggest any improvement in muscle strength, which is important data to be shared within the community towards avoiding steroids in proven dysferlinopathies in the future. Several innovative gene therapy (AAV gene transfer, mini-dysferlin, exon-skipping…) based strategies are currently under development. Finally, the central role of inflammation opens a novel field of possible pharmacological targets. A full report is published in Neuromuscular Disorders (pdf)

The workshop was concluded by a general discussion on efforts to be made towards harmonising registry development, and a planned Natural History Study as an essential step towards trial readiness in dysferlinopathies. A full report is published in Neuromuscular Disorders (pdf).