Respiratory Pathophysiology in Congenital Onset Neuromuscular Disease: Implications for Pro-active Care and Clinical Research

Location: Naarden

This workshop was co-sponsored by Cure Congenital Muscular Dystrophy and the Muscular Dystrophy Association.

Background
Respiratory insufficiency is the primary cause of morbidity and mortality for congenital onset muscle disorders, which includes congenital muscular dystrophy (CMD) and congenital myopathy (CM). Respiratory complications have serious indirect effects such as caregiver days off work, patient days off school, fatigue and failure to thrive combined with in increased need for medical resources (durable medical equipment, hospitalizations, intensive care unit admissions).   These highlight the importance of identifying an early intervention and consistent treatment approaches as well as identifying primary respiratory endpoints for clinical trials.

Rationale for the Workshop
With decades of basic science research clinical trial readiness in the CMD community is important. In congenital onset muscle disorders, changes in respiratory function are caused by a combination of factors including diaphragm, intercostal, and abdominal wall muscle weakness, scoliosis, chest wall distortion due to costovertebral contractures and bulbar dysfunction.  These changes, which lead to abnormal breathing mechanics, may worsen lung and chest wall compliance (mobility), lung volumes and gas exchange.  To the extent that  pulmonary reserve (lung volume) can be maintained, the onset of respiratory difficulties can be delayed.  Doing so requires sensitive early indicators of respiratory decline and standard pulmonary measurements such as PImax, PEmax, FVC and % predicted FVC may not be sensitive enough to identify these sometime asymptomatic changes. Additionally, as therapeutic targets to preserve muscle function and a mandate to be able to perform reliable testing in younger patients, robust endpoints in the under 5 year old age range is critically important.

Identifying opportunities to characterize ventilatory support through timed weaning trials and validating changes in ventilator settings and hours on ventilator as surrogate endpoints may become a priority to enroll cohorts with early dependency on full time ventilatory support.  Whether thoracic imaging or the use of stress mimetics to induce a respiratory challenge would provide rigorous, reproducible measurements of chest wall apparatus mechanics remain untested in this cohort.  Polysomnography has both a clinical application to determine initiation of an intervention (ventilation) and a potential role as a clinical trial endpoint.

Objective of the meeting
1. Discuss current respiratory endpoints and their validity and reproducibility in congenital onset muscle disorders both for clinical management and and research .
2. Discuss core protocols for surveillance, peri-operative management and initiation of non-invasive ventilation.
3. Review respiratory muscle physiology, interventions and pro-active management of respiratory insufficiency during initial decline towards needing full time ventilation.

Conclusions of the meeting
The meeting was co-organized between the ENMC and Cure Congenital Muscular Dystrophy, a non-profit organization from the US.  Seventeen participants from 8 different countries provided expertise in sleep medicine, pulmonary function testing, applied respiratory physiology and clinical outpatient and peri-operative management of early onset congenital muscle disorders. Key conclusions achieved during the meeting:

  • A recognition that the current respiratory care experience for people with congenital onset muscle disorders is highly variable.  To successfully address this variability, a parallel bottom-up (patient organization driven) and top-down (clinician and scientific expert driven) approach is needed.
  • A key priority is to develop retrospective and prospective clinical research projects across a respiratory physiology consortium.  Key issues to be addressed by these projects include:
    • the timing of polysomnography (PSG) in congenital onset muscle disorders, the interpretation of PSG results in the paradigm of respiratory failure and the application of ventilator support in the way that each patient needs.
    •  the suitability of forced vital capacity versus slow vital capacity as both an acceptable and reproducible measure and an early indicator of respiratory difficulty in congenital onset disorders
    • the role of hypertonic saline in the acutely hospitalized congenital muscle disorders with significant airway clearance difficulty
    • the role of daily hyperinsufflation and lung recruitment techniques as an early intervention to maintain chest wall compliance (mobility) and delay ventilatory impairment.
    • the characterization of respiratory impairment (natural history study) using non-invasive and invasive cardiopulmonary parameters across distinct congenital onset disorders
    • Additional priorities include the validation of existing NINDS Common Data Elements for polysomnography and the evaluation of baseline sleep studies prior to ventilation to determine the frequency of detected abnormalities in various congenital muscle disorder subtypes at any given age.  Use of de-identified data from the Congenital Muscle Disease International Registry (CMDIR) will facilitate clinical research.

A full report is published in Neuromuscular Disorders (pdf)

Clinical Characteristics, Pathomechanisms and Trial Design for Calpainopathy (LGMD2A)

Location: Naarden

This workshop was co-sponsored by Coalition to Cure Calpain 3, The Clifton R. Lewis Good Life Foundation and Beyond Labels&Limitations.

Background

The limb girdle muscular dystrophies (LGMDs) are comprised of 18 different genetically inherited diseases that present with progressive proximal skeletal muscle wasting. LGMD type 2A is due to mutations in CAPN3, and is considered one of the most prevalent LGMD.  CAPN3 encodes for the proteolytic enzyme calpain 3, which is the muscle specific member of a large protease family with pleiotropic functions.  It is not yet clear why mutations in calpain 3 lead to muscle disease.

Rationale for the Workshop

LGMD2A patients have a clinically distinct phenotype from other LGMDs.  A prominent phenotypic feature is severe involvement of the posterior thigh muscle and adductors, with abductor sparing.  The disease is strongly associated with muscle atrophy without rampant muscle degeneration, no cardiac involvement and mildly elevated CK.  Membrane damage and muscle degeneration are not prominent features.  Because of the unique clinical presentation of these patients, identification of LGMD2A-specific therapies will require development of LGMD2A-specific clinical trial outcome measures.  Furthermore, there is a need for more basic science studies aimed at understanding pathomechanisms of disease to identify therapeutic targets.  As therapeutic targets are identified, there is increased need to consider the steps that will be necessary to move the field forward to trials.  A workshop specific to LGMD2A allows for concentrated discussion specific to the unique features of LGMD2A.

Objective of the meeting

The objective of this meeting was to gather various neuromuscular experts and scientists together to discuss basic science data and clinical information pertaining to calpainopathy to achieve two primary goals: (1) to facilitate data exchange and communication on the state of the calpainopathy field among scientists working in different countries around the world and (2) to bring these experts together to determine the steps necessary to move the field toward clinical trials in calpainopathy; specifically, to determine whether the current clinical knowledge about the phenotypic features of calpainopathy is sufficient to develop a protocol for muscle testing.

Conclusions of the meeting

The meeting was co-organized between ENMC and the Coalition to Cure Calpain 3, a non profit organization from the US.  Twenty three participants from 10 different countries, spanning 4 different continents met and exchanged information pertaining to LGMD2A research, clinical phenotyping, outcome measures and drug development.  Specific outcomes that were achieved during the meeting were as follows:

  • There is a strong need to better understand mechanisms of disease.  To achieve this goal, the calpain 3 knock out mouse needs to be crossed to a more severe background and patient material needs to be more available for study.  Also, there is a need for new models, such as the zebrafish model, that can be used to identify drugs in high throughput screens.
  • There is a need to better understand natural history of LGMD2A and to develop LGMD2A-specific outcome measures.  Since this is a slowly progressing disease, natural history studies will need to be carried out over at least a 3-year time span.
  • There is a strong need to develop outcome measures for non-ambulant patients.
  • The current LGMD2A patient registry should be expanded to capture patients in Europe and elsewhere around the world.  To involve non-English speaking countries, the Coalition to Cure Calpain 3 website should be translated to other languages.
  • Those interested in developing therapies need to consider the regulatory and IP aspects very early in the process.
  • Efforts should be made to increase patient involvement in data collection. One way to do this is through self-reporting through iphone apps, which could be used to track daily activity and some aspects of disease progression.

Autophagy in Muscular Dystrophies: Translational approach

Location: Naarden

This workshop was co-sponsord by the Dutch ZonMw Association

Organisers: Luciano Merlini (Bologna, Italy), Ichizo Nishino (Tokio, Japan)

Twenty participants from 10 countries (France, Finland, Germany, Italy, Japan, Sweden, The Netherlands, Turkey, United Kindom, and USA) convened for the 201st ENMC International workshop on Autophagy in Muscular Dystrophies. Participants included biochemists, biologists, pathologists, molecular geneticists, neurologists, and paediatricians. The workshop was also attended by Victor Dubowitz as Honorary Member of the ENMC.

Autophagy is a cellular process that helps to maintain cellular energy homeostasis and remove damaged organelles. Research during the last decade has made it clear that malfunctioning or failure of autophagy is associated with a wide range of human pathologies and age-related diseases. In particular dysfunction of autophagy (excessive activation or inhibition) has been recognized as a fundamental pathophysiological mechanism of several muscle disorders.

The first session of the workshop focused on the basic mechanism of autophagy in particular autophagosome formation and regulation, selective types of autophagy (chaperone-assisted and mitophagy), and the role of autophagy in muscle homeostasis. Further sessions concentrated on the current understanding of the role of autophagy in several muscle disorders including Pompe disease, Danon disease, XMEA, laminopathies, GNE myopathy, centronuclear myopathies, myofibrillar myopathies, limb-girdle muscular dystrophies, OPMD, distal myopathies, IBMPFD/VCP myopathy, Vici syndrome, collagen type VI related myopathies, congenital muscular dystrophies (MDC1A and megaconial type), and Duchenne muscular dystrophy. The result of pilot therapeutic approaches in distal myopathies with rimmed vacuoles and of a low protein diet in COL6-related myopathies were presented. A mayor topic was the presentation of the new methods of monitoring autophagy with electron microscopy or in vivo in skeletal muscle, and to monitor autophagic flux in vivo in patients. The last session was dedicated to the provision of guidelines on how to monitor autophagy in clinical trials.

The meeting succeeded in forming a new “muscle autophagy” consortium with the aim to promote and coordinate an international clinical and scientific collaborative effort to accelerate progress toward modulation of dysfunctional autophagy for therapeutic interventions in different muscular dystrophies.

A full report is submitted for publication in Neuromuscular Disorders (pdf).

European Reference Networks (ERN) – recommendations and criteria in the Neuromuscular field

Location: Naarden

co-sponsored by the Dutch ZonMw Association.     

The 200th ENMC workshop took place in Naarden on 18th-20th October with 18 attendees from 9 countries.

The group came together to discuss ways to apply for funding to the European Union and establish a new type of network across Europe that focuses solely on neuromuscular conditions. The initiative would be part of a larger activity called European Reference Networks (ERN).  ERNs are being established in order to improve health care across Europe for patients with rare diseases and other conditions where expertise is rare. The aim is to give Centres of Expertise (CoE) in different countries incentives to work together to allow expertise and knowledge to travel rather than patients themselves. At the same time the network will permit for patients to travel to cross-border CoE when necessary.  For CoE to be part of a network they have to fulfill a set of criteria that involve the expertise to diagnose, follow a multi-disciplinary approach to provide high quality care, make a contribution to research and organize teaching and training opportunities for professionals. The funding and resources that CoE will need to fulfill these criteria will have to be provided nationally by the different European member states.

The final way that ERNs will work is not yet fully decided, but the legal framework setting them up is likely to be in place from 2014 with the first networks coming into existence in 2015. The group agreed that it was likely that having a neuromuscular ERN could offer new opportunities for patients with neuromuscular conditions across Europe to benefit from better and more uniform care. In order to not reinvent the wheel and make use of already existing infrastructure they reviewed different organizations and initiatives which have already in place to try and improve collaboration and cross talk between different centres. The work of the ENMC in uniting patient organisations and to act as a think tank and incubator for new ideas was highlighted. The work of previous networks and projects such as TREAT-NMD and CARE NMD was also discussed, and many of the resources developed through these projects such as the patient registries, work on care standards and outcome measures and the Care and Trial Site Registry could be highly relevant to the establishment of an ERN.

There are many very sophisticated systems in place in different countries of how clinicians and health professionals are organized that allow them to provide high quality neuromuscular care and these were discussed. The mechanisms for networks, recognition of centres and national registries which are already in place offers good examples of how this might translate to an ERN. While many examples of highly organized care do exist it is also clear that there are other areas where this is lacking and addressing this inequality of access to good care and diagnosis could be a major positive output of a neuromuscular ERN.  The current role of scientific societies in training and education and how they would fit in an ERN was also discussed.

A report outlining the current status of neuromuscular networking in the different European countries and our understanding of the opportunities offered by an application to develop neuromuscular ERN is published in Neuromuscular Disorders (pdf).

FHL1 related myopathies: towards an FHL1 related myopathy consortium

Location: Naarden

Twenty participants from 10 countries (Australia, Austria, Canada, Egypt, France, Germany, Italy, Japan, United Kingdom, USA) attended an ENMC workshop on the topic of “Four-and- an-Half LIM protein 1” (FHL1) related myopathies which include the diseases known as Reducing Bodies myopathies (RBM), X-linked scapula-peroneal myopathy (X-SPM), X-linked myopathy with postural muscle atrophy (X-MPMA), Emery-Dreifuss muscular dystrophy (EDMD6) and hypertrophic cardiomyopathy (HCM). Participants included biochemists, biologists, pathologists, molecular geneticists, neurologists, cardiologists, and paediatricians.

FHL1-related myopathies are a newly described group of neuromuscular disorders caused by mutations in the FHL1 gene, all first recognized over a brief period of time in 2008-2009. The spectrum ranges from severe and progressive early childhood forms to milder adult onset disease, often with important cardiac manifestations. The FHL1 gene is located on the X-chromosome and encodes for 3 isoforms of the protein, that are referred to as FHL1A, B and C. While FHL1A appears to be the more abundantly expressed form, the others are also expressed in both skeletal and cardiac muscle, but their precise respective roles are not yet clear.

The meeting covered a wide area of topics, ranging from the clinical presentations associated with FHL1mutations, muscle pathology, molecular genetics to the exploration of the molecular processes leading to the diseases.

The update of the different clinical phenotypes and their associated gene defects were reported by several participants and clearly highlighted two subgroups of diseases: one comprising RBM and X-SPM associated to mutations modifying the LIM2 domain of the 3 isoforms and leading to the occurrence of reducing bodies in the muscle biopsy, and the second comprising X-MPMA, EDMD and HCM associated to mutations modifying differently the FHL1 isoforms either by affecting the LIM3/LIM4 domain or by leading to truncated proteins. The participants clearly recognized the need for patient registry to better evaluate the natural history of these disorders and hence arrive at better proactive management of patients afflicted by an FHL1 related disorder.

Studies on the mechanisms linking FHL1 mutations to muscle and heart pathology were reported in animal models of the disease and in cell cultures systems reproducing patient mutations, at the moment focused on the major FHL1A isoform. These ongoing studies will be essential in identifying the molecular mechanisms and opportunities for therapeutic interventions in this newly recognized group of disorders of muscle.

The meeting succeeded in forming a new FHL1 related myopathies consortium, which then put into place, concrete steps towards a productive international clinical and scientific collaborative effort to accelerate progress across the entire nascent field.

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

Centronuclear Myopathies

Location: Naarden

Organizers:

Heinz  Jungbluth (London, UK)
Jocelyn Laporte (Illkirch, France)
Carina Wallgren-Pettersen (Helsinki, Finland)

21 participants (including basic scientists, clinicians, patients and industry representatives) from different countries convened for the 198th ENMC International workshop on Myotubular/Centronuclear Myopathies (MTM/CNM), a group of inherited muscle disorders with characteristic muscle biopsy findings and associated with a wide spectrum of clinical severity and features. Since the most recent ENMC workshop on MTM/CNM in 2009, the field has seen an exponential increase in knowledge concerning these conditions, with therapy development becoming an increasingly realistic prospect.

The first session of the workshop focussed on already known forms of MTM/CNM, in particular those due to mutations in the MTM1, DNM2, BIN1 and RYR1 genes, and more recently recognized disorders identified through systematic application of powerful novel genetic techniques. Further sessions concentrated on the current understanding of disease mechanisms, as studied in cells and animal models – including zebrafish, mouse and dog – faithfully replicating many aspects of MTM/CNM in humans. The results of experimental therapeutic approaches in animal models of MTM/CNM were presented, with a particular view to their potential applicability in humans affected by these disorders. The final session summarized the current state of the tools needed – patient registries and studies of the natural history of the disorders– to translate recent insights derived from animal studies into therapy development of direct benefit for patients.
Lastly, the importance of joint international efforts for the study of rare conditions such as MTM/CNM was emphasized, and plans for further collaborations and meetings were drafted.

A full report is published in Neuromuscular Disorders (pdf)

Neuromuscular disorders of mitochondrial fusion and fission – Molecular mechanisms and therapeutic strategies

Location: Naarden

Organisers:

Dr. Patrick Yu-Wai-Man (Newcastle, UK); Dr. Valerio Carelli (Bologna, Italia); Prof. Patrick F. Chinnery (Newcastle, UK)

Description:

The 197th ENMC workshop entitled “Neuromuscular disorders of mitochondrial fusion and fission – molecular mechanisms and therapeutic strategies” took place from the 26th to the 28thof April 2013 in Naarden, The Netherlands. A multidisciplinary group of 19 participants took part in this workshop, including 18 clinical and basic science researchers from 6 different countries (France, Germany, Italy, Spain, the UK, and the USA), and 1 patient representative from CMT UK.

Background

Mitochondria are essential components of all human cells and they function as very efficient “powerhouses” that produce most of the energy required for normal cell function. If insufficient energy is produced by mitochondria, cells cannot function properly and they eventually die causing a range of human diseases. It is now clear that mitochondria do not exist in isolation, but instead, they form long, branching, tubular networks that extend throughout the cell. Mitochondrial segments break apart and fuse together continuously and this highly dynamic process is tightly coordinated by a number of key proteins. Unsurprisingly, strong evidence has recently emerged implicating disturbed mitochondrial fusion and fission as the explanation for a number of debilitating progressive neuromuscular disorders.

Two major proteins, MFN2 and OPA1, work closely together to coordinate the sequential steps involved in mitochondrial fusion. Mutations in the MFN2 gene result in autosomal-dominant Charcot-Marie-Tooth disease (CMT-2A). In CMT-2A, the peripheral nerves that supply the arms and the legs get progressively damaged (peripheral neuropathy). As a result, patients develop varying degrees of limb weakness and loss of sensation. Interestingly, MFN2 mutations have also been found in families with a specific CMT-2A subtype where the peripheral neuropathy is complicated by loss of vision secondary to damage to the optic nerve. The optic nerve is the specialised high-speed cable that sends visual information from the back of the eye to the brain and when damaged, the optic nerve becomes pale (optic atrophy).

Autosomal-dominant optic atrophy (DOA) is an important cause of inherited childhood blindness and it is caused by irreversible optic nerve damage. OPA1 is the major causative gene and it accounts for about 60% of cases worldwide. Unfortunately, up to 1 in 6 OPA1 mutation carriers will develop a more severe form of the disease (DOA plus) where visual loss is complicated by the development of prominent neuromuscular features, usually from the third decade of life onwards.

Aim of this workshop

To establish an integrated research network in order to better understand the basic mechanisms responsible for the development of neuromuscular disease in patients harbouring MFN2 and OPA1 mutations.

What was achieved?

The first half of this workshop reviewed the fundamental and interrelated roles mediated by the MFN2 and OPA1 proteins in normal cellular function. The pathogenetic mechanisms directly implicated in the development of CMT2A and DOA were discussed in the context of both in vitro and in vivo disease models. In the second half of this workshop, the participants collectively described the range of clinical features linked to MFN2 and OPA1 mutations, including novel disease manifestations and the natural history of this heterogeneous group of disorders. The final session focused on how to translate recent scientific advances for the benefit of patients and the best way to design future clinical trials in this challenging area of research.

The following key deliverables were achieved:

  1. A comprehensive description of the expanding neuromuscular phenotypes associated with pathogenic MFN2 and OPA1 mutations.
  2. Collaborative biobank access to patient tissue samples and animal models to further explore fundamental disease mechanisms in CMT-2A and DOA.
  3. Pooled clinical registry of well-characterised patient cohorts for the purpose of future clinical studies, including treatment trials.

Participants:

Dominique Bonneau (Angers, France); Karen Butcher (CMT UK Representative); Valerio Carelli (Bologna, Italy); Patrick F Chinnery (Newcastle, UK); Padraig Flannery (Newcastle, UK); Guy Lenaers (Montpellier, France); Deborah Naon (Padova, Italy); Veronique Paquis-Flucklinger (Nice, France); Joanna Poulton (Oxford, UK); Hemachandra Reddy (           Portland, Oregon, USA); Mary Reilly (London, UK); Manuel Rojo (Bordeaux, France); Elena Rugarli (Cologne, Germany); Hiromi Sesaki (Baltimore, Maryland, USA); Orian Shirihai (Boston, Massachusetts, USA); Marcela Votruba (Cardiff, UK); Patrick Yu-Wai-Man (Newcastle, UK); Antonio Zorzano (Barcelona, Spain).

A full report of this ENMC workshop is published in Neuromuscular Disorders.

Outcome Measures in inflammatory peripheral neuropathies (PeriNoms)

Location: Naarden, The Netherlands

Co-sponsored by the Dutch ZonMw Association

This workshop took place from February 8th -10th, 2013 in Naarden, The Netherlands. There were 20 researchers from 8 different countries (USA, Canada, Spain, Italy, France, Belgium, the Netherlands, UK), including a patient representative of the GBS CIDP Foundation International (Glennys Sanders). The workshop was conducted under the leadership of Ingemar S.J. Merkies and Catharina G. Faber.

There has been inadequate agreement about outcome measures (the instruments used to measure treatment response) for use in clinical trials of treatments in inflammatory neuropathies (Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, monoclonal gammopathy-related neuropathy and multifocal motor neuropathy). In 2007 the international Peripheral Neuropathy Outcome Measures Standardisation (PeriNomS) Study was started, with the aim to define a minimum core set of specific outcome measures for each inflammatory neuropathy.  The workshop heard the results of new ordinal scales developed in the PeriNomS Study for measuring strength, sensation, activity and participation.

The workshop participants agreed

  • That trials should have outcome measures which address each of strength, sensation, activities, participation and   quality of life.
  • That outcome measures should fulfil the most stringent biometric standards which will often involve switching from historical ordinal scales to interval scales including those now developed and validated in the PeriNomS Study.
  • A minimum core set of outcome measures for GBS, CIDP and MMN, which differed between each of the diseases.
  • A recommended set of outcome measures for MGUSP that requires further exploration.

The workshop identified gaps in existing knowledge and proposed topics for future research.

Participants:

Prof. P. Van den Bergh, Prof. V. Bril, Prof. P. van Doorn, Dr. C.G. Faber, Prof. K. Gorson, Prof. A. Hahn, Prof. R. Hughes, Dr. A. van der Kooi, Dr. G. Lauria, Prof. J-M Leger, Prof. R. Lewis, Dr. M. Lunn, Dr. I.S.J. Merkies, Prof. E. Nobile-Orazio, Dr. N.C. Notermans, Dr. L. Querol, Mrs G. Sanders MBE, Prof. I. van Schaik, Drs. E. Vanhoutte.

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