Mitochondrial DNA Disorders

A meeting comprising 20 clinicians, basic scientists and a patient representative gathered on 12-14 December 2008, in Naarden, The Netherlands. Delegates worked in 7 ENMC member states and 3 non-member states.  This workshop was the first one to focus on the most treatable group of all mitochondrial disorders, in particular a disorder known as MNGIE (for myoneurogastrointestinal encephalomyopathy).

Mitochondria are the power house of the cell, supplying energy for all life processes.  The energy required by muscle for movement can be a high proportion of the energy generated.  Not surprisingly, muscle fatigue is a major feature of mitochondrial disease.  Unlike nuclear DNA, where there are usually two copies of each gene in every cell (one from each parent) there are many copies of mtDNA in every cell.  In the mitochondrial DNA depletion that is characteristic of the disorders discussed at this workshop, there is a reduction in the number of copies of mtDNA in some parts of the body.  This often involves muscle, brain and/or liver.   Making accurate copies of mtDNA is vital for keeping cells healthy and in mtDNA depletion the copies may include errors.  Mitochondrial DNA depletion was first identified in children with severe mitochondrial disease in 1991, but it was not until 1999 that gamma polymerase, the enzyme responsible for making copies of mtDNA, was implicated, and not until 2003 that the first mutations were found in DNA from several different genes.  All of these genes appear to be involved maintaining the accuracy of making copies of mtDNA.  Some of them code for proteins that unwind mtDNA or assemble the new copy, others are involved in supplying appropriate quantities of the DNA components needed to elongate the copy (nucleotides).

A recent ENMC workshop highlighted the significant advances in the commonest of these disorders, and proposed guidelines for investigating such patients.  We helped diagnosis by collating an up to date list of all the mutations that have been identified in these patients.  We then focussed on ways to develop treatments.  Dr Michio Hirano (USA, who first identified the defect in MNGIE) told us that diagnosing MNGIE is often difficult, so that patients may be mistakenly given a label of anorexia nervosa at first.  He has tried several approaches to treating MNGIE, and finds that bone marrow transplant is the most successful so far.  Because getting a perfect match between donor and recipient makes a huge difference to the chance of success, a European consortium has been set up to do this for MNGIE.

To assess a possible treatment you need a model, meaning a type of cell or an animal that has a problem representing the disease you are studying.  You can then see whether the problem gets better in response to the treatment you are piloting.  The first such studies looked at the ability of cells to maintain sufficient quantities of mtDNA.  Skin cells from patients with a defect called deoxyguanosine kinase deficiency do not make enough mtDNA when they are growing slowly.  It is becoming clear that the balance of nucleotides (the building blocks for making DNA) is critically important in these disorders.  Hence, altering the supply of nucleotides to mitochondria is a potential treatment avenue that we explored in this workshop.  Adding a chemical mix which the cells can convert into nucleotides improved the mtDNA content of the deoxyguanosine kinase deficient cells.  Now that scientists have been able to develop mice with defects like those causing mitochondrial DNA depletion, it will be possible to try this kind of approach on whole animals.  If these studies confirm a benefit we will try them out on patients.

A detailed report of these conclusions is published in

Neuromuscular Diseases (pdf)

Disorders of muscle lipid metabolism in adults

The first ENMC workshop on disorders of muscle lipid metabolism hosted a group of experts comprising clinicians and basic scientists. It was attended by 17 participants from 7 countries (Denmark, France, Germany, Italy, The Netherlands, UK and USA). The workshop had the following objectives: 1) to state the diagnostic strategies (clinical, biochemical and molecular) to be used for the diagnosis of disorders of muscle lipid metabolism in adults, 2) to share experience on cases of undiagnosed metabolic myopathies presenting as muscle lipidosis, and to describe diagnostic strategies for such patients, and 3) to state on the current treatments and to plan multicenter treatment trials for these disorders.

These rare diseases are increasingly recognised due to the increased use of tandem mass spectrometry (MS/MS), and the various biological techniques used for diagnostic purpose were presented  in order to find the most useful markers for diagnosis. Clinical phenotypes of the main fatty acid oxidation (FAO) disorders were presented, and diagnostic strategies integrating enzymatic and genetic studies were discussed. Other presentations focussed on the phenotype, pathophysiology and genetic analysis of neutral lipid storage diseases (NLSD). Various therapeutic approaches were discussed, in particular dietary supplementation with triheptanoin, and use of agonists of peroxisome proliferator-activated receptors (PPARs), that are potent pharmaceutical tools stimulating FAO. Plans were made to collaborate on assessment of biological tools and future multicenter therapeutic trials.

A full report is published in Neuro Muscular Diseases (pdf)

Guidelines for DMD Genetic testing

Best practice meeting on Duchenne /Becker muscular dystrophies was held in Naarden, the Netherlands on November 14-16, 2008. The meeting was held under the auspices of Eurogentest, TREAT-NMD, EMQN, and was organized by ENMC. It convened 30 scientists and clinicians from 21 countries from Europe, the USA, India, and Australia. In view of recent developments in both molecular testing techniques and therapeutical approaches, the aim of the meeting was to update the guidelines for molecular testing of dystrophinopathies, which dated back to the 1990´s. The presentations included updates on current approaches to testing, novel technologies, and a review on the current concepts for clinical trials, many of which rely on mutation specific approaches. In parallel to this, TREAT-NMD has launched an initiative to set up patient registries in all countries to improve trial readiness. These activities call for a harmonisation of  diagnostic testing procedures, result interpretation, and reporting formats. During the discussions the content of the guideline updates was agreed, which includes the basic characteristics of the gene, the approaches to diagnose affected patients, to carrier detection, and prenatal diagnosis. It also includes recommendations for result interpretations, mutation nomenclature, and report writing.

Stephen Abbs, Thomas Sejersen, Clemens Müller-Reible

MRI in muscle diseases

There is no report or picture available at the moment

Nemaline Myopathy and related disorders

20 doctors and scientists from 7 countries gathered in Newcastle-upon-Tyne on the 28th and 29th September 2008, for the seventh ENMC Workshop on nemaline myopathy and related disorders. A representative of the patient group “A Foundation Building Strength” gave a presentation at the start of the Workshop. This Workshop was held to coincide with the Annual Scientific Meeting of the World Muscle Society. The main themes of the Workshop were: continued gene discovery; better definition of clinical entities; animal and tissue culture models of nemaline myopathy; preliminary experimental investigation in model systems of possible therapeutic strategies; locus-specific mutation databases; establishing databases in preparation for anticipated future clinical trials and finally discussion on better methods for molecular analysis of the known nemaline myopathy and related disorders disease genes, especially nebulin. Expected major efforts in the near future include further analysis of possible therapies, development of additional animal models in which to investigate therapies and the implementation of the databases in order to be ready for any future clinical trials. The Workshop participants recognise that a multinational approach to these rare disorders is essential, especially in relation to enrolling patients in any future clinical trials.

A detailed report of these conclusions, including the guidelines, is published in Neuromuscular Disorders (pdf)

Exercise training in patients with muscle diseases

Workshop organisors:

The ENMC hosted a patient representative and a group of experts from various disciplines (neurology, physiotherapy, genetics, rehabilitation medicine, orthopaedics) for a discussion on Exercise training in patients with muscle diseases.

This was the first of a series of practical care workshop of the ENMC aiming at topics relevant for daily clinical practice and management of the patient. The workshop had the following objectives: 1) to state the available evidence for effects of training on muscle diseases, 2) to identify areas (disease/types of training) in which studies are underway or needed, 3)  to agree on a core set of assessment markers for evaluation of treatment responses to training, and 4) to plan studies on training, both in individual centres and as multicentre studies. The workshop was attended by 20 participants from 7 countries (Denmark, France, Italy, The Netherlands, Slovenia, United Kingdom and U.S.A.)

Exercise has a tremendous effect on health in man. The effect of training patients with diseased muscle, on the other hand, has been considered more questionable.  In recent years, however,  a growing number of studies  have shown that exercise is in fact beneficial for many muscle diseases. This opinion was also agreed on by the workshop members. In addition, agreement was reached on outcome measures to assess the effect of training, and on the neuromuscular diseases in which the effect of training should preferably be investigated. Plans were made to collaborate on future aerobic exercise training trials in specific diseases.

This workshop was organized by Prof. J. Vissing and Prof. B. van Engelen  and held in Naarden in June 2008.
A full report is published in Neuromuscular Disorders (pdf)

4th Annual Plenary meeting EUMITOCOMBAT

the lay report will be published shortly

XIIth International workshop on Congenital Muscular Dystrophy

The ENMC Consortium on Congenital muscular dystrophy (CMD) held its 10th meeting in Naarden during the weekend of the 8th-10th February 2008. It was attended by 22 participants from 11 countries, including Australia, Canada, Denmark, France, Germany, Japan, Italy, The Netherlands, Turkey, United Kingdom and USA. The participants were basic scientists with biochemical and molecular biology background, and clinicians and muscle pathologists, all sharing a substantial expertise in neuromuscular disorders.

Congenital muscular dystrophies (CMD) are a heterogeneous common group of disabling neuromuscular disorders almost invariably inherited as autosomal recessive conditions. Affected children present with muscle weakness and hypotonia at birth, or within the first six months of life and motor development is delayed. The severity and progression of the disease is very variable and dependent on the disease subtype. Brain involvement in the form of mental retardation and abnormal formation of different parts of the brain is a feature of several forms of CMD. Thirteen genetic separate CMD subtypes are now recognised, but many mores are predicted to exist.

The present meeting focused on a group of CMD syndromes characterized by deficiency in proteins with enzymatic activity (glycosyltransferases). These proteins all are involved in the process of adding sugars to alpha-dystroglycan, a molecule that plays a central role in the organisation of the muscle fibre. Six defective genes have already been identified in this group of conditions, now also known as “dystroglycanopathies”, and are responsible for the conditions known as Walker-Warburg syndrome, Fukuyama CMD, Muscle Eye Brain disease, MDC1C and MDC1D); and a related disorder that occurs spontaneously in mice. In addition, a similar mechanism of disease clearly plays a role in a number of other CMD syndromes of which one was mapped to chromosome 1q (MDC1B), but many more in which the primary defect is unknown.

The widening spectrum of the conditions due to a known gene defect was presented by various participants, and this included milder variants of several conditions typically associated with a congenital onset and with or without brain involvement, which follow a much milder limb-girdle muscular dystrophy course (LGMD2I, LGMD2K, LGMD2L, LGMD2M).

Studies focused on the dysfunction of the genes in the patients, the function of the defective genes and strategies for the identification of the genes responsible for dystroglycanopathies which are still unknown was presented.

One session of the meeting was devoted to the discussion of the existing animal models of dystroglycanopathies; and of therapeutic strategies aimed at reducing muscle degeneration and improving long term outcome for these conditions.

A number of collaborative studies were agreed.

A full report has been published in Neuro Muscular Diseases, for the pdf file please click here

For the full report, click here

Patient registries of rare, inherited muscular disorders


157th ENMC International Workshop

The ENMC hosted a group of experts for a discussion on patient registries for rare, inherited muscular disorders. The ENMC Workshop was aimed at collaborative action towards patient registries for these disorders in Europe and world-wide. Harmonizing practices, joining forces and merging experience on patient registries should facilitate research into rare, inherited muscle disorders, support upcoming clinical trials, and deliver standards of care. This workshop provided an excellent ENMC development of the work into rare muscle diseases towards clinical trial readiness and complements recent TREAT-NMD activities on DMD and SMA. The workshop was attended by 20 participants from 8 countries (Finland, France, Germany, The Netherlands, Spain, Switzerland, United Kingdom and U.S.A.). Participants included bioinformatics experts, geneticists, neurologists, paediatricians and representatives of patient advocacy organizations. The databases and registries discussed varied from simple laboratory based databases to patient led initiatives, and the diseases included several types of congenital muscular dystrophy and myopathy, limb girdle muscular dystrophies, oculopharyngeal muscular dystrophy, myofibrillar myopathies, Pompe Disease, facioscapulohumeral muscular dystrophy and myotonic dystrophy. Agreement was reached on the importance of European and global harmonized and coordinated patient registries for accelerating progress, in particular in translational research. This will be facilitated by action taken by individual, disease-specific ENMC workshops and consortia, but also through joint action across diseases. This includes a web-based inventory of patient registries to be published, harmonization of registration practices and registry content, increased collaboration with patient organizations and empowerment of patients, and sharing of resources and dissemination through ENMC and TREAT-NMD. The participants of the workshop wish to invite additional representatives for rare, inherited muscle disorders to get involved and form a consortium for further work in this area. A full report will be published in Neuromuscular Disorders and will be complemented by an inventory of the registries available.

A report of this workshop has been published in Neuromuscular diseases

full text pdf

Prof. Hanns Lochmüller (UK)

Prof. Christophe Beroud (France)