Newborn screening for DMD

Location: Naarden

Co-sponsored by:
The Italian Duchenne Parent Project
The Dutch Duchenne Parent Project
Parent Project Muscular Dystrophy (USA)

Organisers: Dr. F. Muntoni (United Kingdom), Drs E. Vroom (The Netherlands) and Dr. J. A. Ellis (United Kingdom).

The 195th ENMC workshop entitled “Newborn Screening for Duchenne muscular dystrophy” was held on 14th– 16th December 2012 with representatives from Europe, Canada, USA and Australia.


Twenty-one individuals from different professional backgrounds e.g. neuropediatricians, neurologists, geneticists, biochemists, pathologists, ethicists and patient representatives from seven countries.

Aim of the workshop:

The aim of this workshop was to assess the status of newborn screening programs for Duchenne muscular dystrophy around the world, and to assess technical, ethical, practical aspects on this topic, based on our current understanding of treatment options for boys affected by this disorder. Experiences of families of boys with Duchenne muscular dystrophy who have been diagnosed via newborn screening programme, or following the traditional route, were additionally considered.

What was achieved?

The criteria used in different countries to evaluate the suitability of individual programmes for a newborn screening were presented, in particular the different emphasis placed on treatment versus cure. A number of presentations highlighted the early symptomatic features of boys with Duchenne muscular dystrophy, already in the first years of life. This not only results on a long diagnostic journey and considerable associated costs, but also in the perception of poor parenting skills by the parents. The experience of several presenters, together with results of qualitative and quantitative interviews suggests that a true pre-symptomatic i.e. carefree period does not exist in Duchenne muscular dystrophy, or, when it does exists, it is confined to the first few months of life. Regulatory screening committees need to be informed of this fact.

Experience of the practicalities surrounding a number of pilot newborn screening projects worldwide was presented. These comprehensive studies indicate that the current incidence of Duchenne muscular dystrophy is less than quoted, with an average figure of ~1: 5,000 male births. Technical aspects and limitations of some of the pilot programmes test assays and follow-up (i.e. false negative rates; pathways for communication of diagnosis and referral to comprehensive multidisciplinary teams), were highlighted. Benefit of early disease recognition and intervention were discussed, including the fact that due to the delay in diagnosis, standards of care and treatment are initiated late in a significant proportion of affected boys. Evidence of benefit and risk for the child and the families of early diagnosis was described. Encouraging results of novel experimental therapies, some of which are well advanced in phase III studies were discussed. Examples of best practice and pathways followed in other conditions included in newborn screening programmes were presented. The meeting was very productive; it informed the participants on issues that need to be taken into account in preparing the individual countries screening applications, but also areas in which further evidence should be gathered, including effect of early intervention on neurodevelopmental and physical outcomes.

A full workshop report has been published in Neuromuscular Disorders.
(For a copy of the report, click here).

Towards clinical applications of antisense-mediated exon skipping for DMD

Location: Naarden, The Netherlands

Co-sponsored by: the American and Dutch Duchenne Parent Project

With antisense-mediated exon 51 skipping in phase II and III clinical trials and early phase trials targeting additional dystrophin exons ongoing or planned for the near future, the question on how to clinically develop this approach for as much patients as possible in a safe and timely fashion becomes more imminent. Twenty seven key stakeholders from 8 countries including The Netherlands, United Kingdom, Italy, Belgium, USA, Germany, Japan and Australia met in Naarden from December 7-9 2012 for the 194th ENMC International Workshop (the 3rd ENMC Workshop on Antisense Oligonucleotides). The participants included patient representatives, clinicians, academics, representatives from industry involved in exon skipping trials and a representative from the European Medicine Agency –EMA, and discussed:

  • The state of the art of exon skipping (including eteplirsen and drisapersen)
  • Concerns of patients and parents regarding the current and future development of this approach
  • The challenge of a sustainable clinical developmental program for antisense  oligonucleotides to skip additional subsequent exons for increasingly smaller patient subpopulations
  • The challenge of developing the next generation of compounds and delivery systems targeting skeletal and cardiac muscle more efficiently
  • Methods to detect antisense oligonucleotides concentration and distribution and response to treatment both in preclinical models and in boys with Duchenne muscular dystrophy.
  • Functional outcome measures and additional potential biochemical outcome measures that could indicate early response to therapeutic intervention
  • The challenge of heart delivery

Presentations to introduce and illustrate these topics were given by the participants and discussed extensively.

The following conclusions were reached:

  • A lot of progress has been made in this field over the past few years
  • Communication about the status of ongoing trials to the patient community should be improved. Industry representatives present agreed to provide a brief update on ongoing and planned trials every 3 months. The “patient community working group” of TREAT-NMD will translate the information into lay terms and will make this information available to the patient community.
  • Trials towards approval of exon skipping compounds are still ongoing. Regulators are willing to assess whether class approval and a quicker development path is possible when two compounds of the same class have been approved, but this will depend on the outcome of these ongoing studies.
  • The next generation of exon skipping compounds shows very promising results in animal models. However, clinical development of these compounds will take time and safety issues have yet to be addressed.
  • Approval of exon skipping compounds will depend on showing drug efficacy, i.e. functional improvement and/or delayed disease progression, as currently assessed by the 6 minute walk test. Ideally, this should be accompanied by improved muscle strength. Furthermore, patient evaluation of the benefit received will be taken into account.
  • Additional functional outcome measures are needed, especially for non-ambulant patients.
  • Dystrophin restoration in a muscle biopsy is a good marker for showing that an antisense oligonucleotide is active, but not necessarily for grading the overall response to treatment. Thus, additional biochemical outcome measures that correlate with efficiency on a functional level would be supportive.
  • Exon skipping compounds restore dystrophin in muscle, but are less effective in heart. This is cause for some concern and heart function should receive special attention in patients treated with exon skipping compounds.
  • Patients, investigators and industry are equal partners in all trials and are mutually dependent on each other to continue to advance this field

A full workshop report has been published in Neuromuscular Disorders.
(For a copy of the report, click here).

Pathology Diagnosis of Idiopathic Inflammatory Myopathies

Location: Naarden

Co-sponsored by:
The European Science Foundation
The Dutch ZonMw Foundation
The European Myositis Network

When people experience progressive muscle weakness, muscle pains and fatigue with onset less than a year ago, sometimes accompanied by non-muscle symptoms such as skin rash, they could be suffering from an idiopathic inflammatory myopathy (IM), also known as myositis. There are various subgroups of IIM.

In cases without a characteristic skin rash, it is necessary to perform a muscle biopsy to diagnose  IIM. The muscle biopsy serves to distinguish IIM from other myopathies and to identify subgroups. This is very important as the treatment options and prognosis may vary depending on diagnosis. Classification criteria for the neuropathological features of the different myositis subgroups are based on consensus but have not been validated.

World experts in the field of idiopathic inflammatory myopathy gathered in Naarden to address this issue. The workshop brought together neurologists, rheumatologists, immunologists and pathologists active in patient care and research. Knowledge was exchanged regarding classification, testing the classical views with new scientific insights, also making room for discussing the disease subtypes. The focus lay also on the comparison with inflammatory changes that occur in other muscle diseases, to avoid that patients that have diseases of hereditary origin are falsely diagnosed with idiopathic inflammatory myopathy.

A recommendation was developed stating which histopathological stainings should be part of a minimum diagnostic set, and how best to define and score disease signs. The views that were developed, were tested in a practical session at the Amsterdam Medical Center, in which typical and atypical muscle biopsy slides were discussed. At the end of the workshop, a consensus text was drafted. Participants agreed unanimously to continue work on a standardized diagnostic work up and to reconvene in the near future to fine-tune the proposed strategies.

A full workshop report will be published in Neuromuscular Disorders

ENMC Strategic workshop, shaping a stronger future

Location: Korsor, Denmark

Musholm centre, Korsør, DK, June 15-17, 2012

The ENMC, celebrating its 20th anniversary, invited a group of representatives from its members, from disease-specific patient organisations and from industry to attend a special workshop, addressing the future role and positioning of the ENMC.

This workshop took place from June 15-17 at the Musholm center in Korsør, Denmark, and was prepared by an organizing committee consisting  of representatives from the ENMC member organisations.

The current status and (possible) future developments were presented and addressed by a number of invited presentations:

A patient voice for 40 years
Evald Krog (Muskelsvindfonden, Denmark)

EU policy in the field of rare diseases: opportunities and challenges for the neuromuscular community
Dr Ségolène Aymé (EUCERD, France)

Prospects in neuromuscular disorders: from micro to macro perspective and vice versa
Dr Andoni Urtizberea (Assistance-Publique Hôpitaux de Paris, France)

In order to prepare for a common vision and agenda for the ENMC, the view from different groups of stakeholders (patients, scientists/clinicians and industry) were obtained from separate, parallel sessions, the results of which were subsequently discussed in depth by all participants.

Using the input from these sessions, the participants also discussed and defined the priorities for the future strategy of the ENMC, taking into account the unique position the ENMC has been able to obtain in the neuromuscular research community.

The participants unanimously shared their enthusiasm and appreciation for what the ENMC has accomplished and how the organisation has been operating as a small, independent and well-respected entity with a large impact.

From this strong position, the ENMC should strive to become more visible and also develop tools, activities and procedures that will further strengthen the patient´s voice in the future research agenda.

The participants specifically agreed:

1)     to sharpen the patient profile in ENMC’s workshops

2)     that all ENMC workshops should have attendance of up to three patient representatives

3)     that patient representatives should be subject to certain requirements and expectations

4)     that ENMC will offer support to the work of patient representatives

5)     that patient representatives should be part of ENMC’s ‘Patient Voice’ and communicate the results of the workshops

6)     that patient representatives can take initiative to apply for ENMC workshops

7)     that this type of Patient Voice workshop should be repeated within an appropriate period of time.

For a summary report of this event, please click here

Recent advances in OPMD research

Location: Naarden


This workshop was co-sponsored by the Netherlands Organisation for Health Research and Development ZonMw

During the weekend of 8th to 10th June 2012 twenty clinical, basic scientists funding agency representatives were gathered in Naarden, The Netherlands to discuss clinical and molecular aspects of the late-onset muscular disorder oculopharyngeal muscular dystrophy (OPMD). Delegates were from ENMC member countries (France, Denmark, the Netherlands and the UK) and three non-member countries (United States and Canada). The meeting was the first ENMC workshop dedicated to OPMD.

Background and Aims of the Workshop

Single amino acid repeat expansions are now recognized to be a common cause of human disease. While most of these expansion mutations create increasing lengths of polyglutamine (poly-Q) tracts that cause progressive neurodegenerative disorders, polyalanine tract expansions have also been identified as underlying several monogenic disorders. These disorders are recognized by the presence of salt-resistant insoluble bodies, which results from accumulation of the expanded mutant proteins. The protein aggregation disorders are usually characterized by late onset and progressive neurodegeneration. Among these, a polyalanine tract expansion in the poly(A)-binding protein nuclear 1 (expPABPN1) causes oculopharyngeal muscular dystrophy (OPMD). PABPN1 is ubiquitously expressed and it regulates mRNA stability. Nevertheless it is unclear how is causes muscle weakness OPMD. It is not known why symptoms develop only after midlife and in subsets of skeletal muscles So far, there are no medical options to recover muscle weakness in OPMD.

Outcomes of the Workshop

During the workshop, we discussed:

  • current clinical efforts being carried out by the various centers in different countries.
  • possible strategies for coordinated approaches to clinical care.
  • available model systems for OPMD and their relevance to the disease. therapeutic approaches in OPMD animal model systems and potential treatment approaches in humans.
  • recent progress in understanding OPMD disease mechanisms.
  • recent advances in comprehension of the molecular function of PABPN1.
  • the role of normal aging process in OPMD onset and progression.
  • how to set up an international standard for clinical and genetic criteria for OPMD diagnosis.
  • how to translate the new discoveries from basic research to realistic therapeutic approaches in patients with OPMD.

How this Will Benefit Patients

Recent progress in identifying molecular mechanisms that are associated with OPMD and the molecular function of PABPN1 offer the prospect of transforming this knowledge to medical options for patients. Retaining close interaction between clinical and molecular teams will speed up speed the development of specific therapeutic approaches for OPMD. OPMD is a rare disorder and therefore international efforts can help in developing new treatments for transfer into the clinic.

A full report of the workshop has been published in Neuromuscular Disorders.
(For a copy of the report, click here.

SMARD type 1

Location: Naarden, The Netherlands

Workshop organisers: Dr. L. van der Pol (The Netherlands), dr. K. Von Au (Germany), dr. M. Pitt (United Kingdom) and dr. B. Talim (Turkey)

This workshop was co-funded by the Dutch Abel Schuiling Stichting


The 190th ENMC workshop titled “SMA-RD Type 1” was held in Naarden, The Netherlands, on 11-13th May 2012 with representatives from Europe, The Middle East and USA.


23 persons with different specialities, e.g. clinicians (neuropediatricians, neurologists, geneticists), researchers, patient representatives of various countries and a boy affected by SMARD1 with his parents

Aim of the workshop:

The aim of this workshop was to get an update on the clinical phenotype, outcome and management of SMARD1 patients and on the current research to establish new collaborations as the basis for the development of therapeutic strategies for the treatment of SMARD1.

What was achieved?

After exchange about the current knowledge about SMARD1 and broad discussions we agreed on the following:

–        an international SMARD1 patient registry with more detailed clinical information will be established for better genotype-phenotype relations, for recruitment of patients into clinical studies, to provide families with better predictions on outcomes and prognosis, and to compare practices for treatment and care

–        collaborations between centres will be established to exchange about research progress and to provide experimental tools for e.g. drug screening or gene transfer to develop therapeutic strategies for SMARD1 patients

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

Complex I Deficiency

Location: Naarden, The Netherlands

Naarden, The Netherlands, 20-22 April 2012

During the weekend of 20th to 22nd April 2012 seventeen clinical and basic scientists and a patient representative met in Naarden, The Netherlands to discuss Complex I deficiency. Delegates work in six ENMC member countries (Finland, France, Germany, Italy, the Netherlands and the UK) and three non-member countries (Australia, Canada and Israel). The meeting was the first ENMC workshop dedicated to Complex I deficiency, the most common subgroup of mitochondrial diseases.

Background and Aims of the Workshop

Mitochondria are the cell’s powerplants and contain more than one thousand different proteins, many of which are essential for producing energy inside the cell. Disorders of mitochondrial energy generation are the most common inherited metabolic disorders. Five enzymes are critical for mitochondrial energy production and genetic defects of the first and largest of these enzymes, known as complex I or NADH:ubiquinone oxidoreductase, cause about one third of all mitochondrial diseases, particularly those presenting early in childhood. Currently fewer than half of patients with complex I deficiency receive a genetic diagnosis, and there are no curative treatments.

Outcomes of the Workshop

During the workshop, we discussed:

  • current knowledge regarding the structure, function and assembly of the complex I enzyme
  • methods for biochemical assessment of complex I deficiency
  • known genetic defects associated with complex I deficiency (33 genes coding for components of the enzyme or factors required for its correct assembly within the mitochondrial membrane)
  • new high throughput genetic diagnostic tools
  • new mouse models for studying disease mechanisms and preclinical trials
  • approaches to treatment for complex I deficient patients

How this Will Benefit Patients

Recent progress in identifying genetic causes (such as exome sequencing) offer the prospect of transforming the speed and effectiveness of genetic diagnosis for affected families. The importance of retaining close interaction between clinical, biochemical and genetic teams to ensure robust and accurate diagnoses was emphasised. New mouse models of complex I deficiency offer great potential for understanding this highly complex and puzzling group of diseases, and are the first step in developing new treatments for transfer into the clinic.

A full report of the workshop will be published in Neuromuscular Disorders.
(For a copy of the report, click here.)