Neuromuscular Disorders
Volume 14, Issue 11 , Pages 767-773, November 2004

121st ENMC International Workshop on Desmin and Protein Aggregate Myopathies. 7–9 November 2003, Naarden, The Netherlands

  • HansH. Goebel

      Affiliations

    • Department of Neuropathology, Johannes Gutenberg University Medical Center, Langenbeckstrasse 1, 55101 Mainz, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49-6131-17-7308; fax: +49-6131-17-6606.
    • ,
  • Michel Fardeau

      Affiliations

    • ISERM U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Bâtiment Babinski, 47, Bd. de l'Hôpital, 5651 Paris Cedex 13, France

Received 7 July 2004

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1. Introduction 

The 121st European Neuromuscular Centre (ENMC)-sponsored International Workshop on ‘DESMIN and Protein Aggregate Myopathies’, attended by 16 active participants from France, Germany, Poland, Spain, Sweden, the United Kingdom and the USA, was actually the fourth one in a row addressing the pathology of the muscle fibre intermediate filament desmin, its associated and similar diseases, all four [1], [2], [3] organized by Michel Fardeau and Hans H. Goebel.

In his introduction, the chairman, Hans H. Goebel (Mainz), recorded the evolution of ‘Protein Aggregate Myopathies (PAM)’ which are marked by the accumulation of diverse proteins within muscle fibres as a morphologic hallmark in separate myopathies which now comprise several diverse entities (Table 1). Desmin-related myopathies were first reported as cytoplasmic myopathy, granulofilamentous myopathy [4], spheroid body myopathy [5] and a form of congenital muscular dystrophy [6]. Subsequently, they have been found to have accumulation of desmin as a common morphological denominator but are genetically diverse, comprising desminopathies [7], [8] owing to mutations in the desmin gene, α-B crystallinopathy [9], [10], [11] owing to mutations in the α-B crystallin gene, recently selenoproteinopathies owing to mutations in the selenoprotein N1 gene [12] and newly, added, myotilinopathies [13]. In addition to desmin, a multitude of fibre proteins accrue to respective inclusions or granulofilamentous material. Only briefly, because belonging to other ENMC Consortia, such as one on ‘Nemaline myopathy’, ‘Multi-minicore disease’ and ‘Central core disease’, actinopathy marked by accumulation of aggregates of actin filaments and mutations in the ACTA1 gene [14], [15], core diseases encompassing central core disease and multiminicore disease, the latter again showing a panoply of diverse proteins within cores, were mentioned. Hyaline body myopathy, formerly called ‘Myopathy with probable lysis of myofibrils in type I fibres’ [16] with accumulated ATPase positive granular, i.e. myosin, material apparently represents a new member of these PAM. The group of PAM is slowly emerging, protein aggregation, perhaps, being associated with developmental defects in actinopathy and hyaline body myopathy, and with defective extralysosomal protein degradation in desmin-related myopathies and core diseases. In comparison, protein aggregate disorders have long been identified and nosologically established among human neurodegenerative diseases, e.g. Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis and Alexander disease, with multiple proteins accumulating within nerve cells and astrocytes, respectively. Against this background, the 121st ENMC-sponsored International workshop aimed at giving an overview of desmin mutations, assessing the involvement of the heart and the role of selenoprotein N1 in desmin-related myopathies, recording proteomics of desmin, reviewing other intermediate filament types in muscle fibres and desmin-associated proteins, evaluating the significance of animal models, pursuing elucidation of hyaline body myopathy and attempting at genotyping-phenotyping among desmin-mutant families.

Table 1. Protein aggregate myopathies
Desmin-related myopathyActinopathy
DesminopathyActin-related myopathy
α-B crystallinopathyMyosinopathy (hyaline body myopathy)
SelenoproteinopathyHereditary inclusion body myopathies
MyotilinopathyOculopharyngeal muscular dystrophy
2q21 MyopathyCore diseases
10q23 MyopathyOther myopathies marked by inclusions
15q22-CRD myopathy(putative)

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2. Animal models and desmin associated proteins 

Following the introduction, Thomas Sejersen (Stockholm) spoke on ‘analyses of L345P desmin mutant transgenic mice’. Different desmin mutations underlie inherited myopathies and cardiomyopathies with varying phenotypic characteristics, both concerning filament-forming ability, and clinical features such as severity and involvement of the cardiac and/or skeletal muscle system. His group has set up a transgenic mouse model of the L345P desmin mutation in order to understand why, and under what circumstances, this mutation causes myopathy and cardiomyopathy. A vector containing desmin cDNA (wt or L345P mutated desmin) and a HA-tag driven by a desmin 4kb-promoter was constructed and used. Three founder mice have been used for further breeding of heterozygous transgenic mice. Integrated transgenes were sequenced and found to be correct. Expression of the transgene construct in skeletal and cardiac muscle, but not smooth muscle, has been ascertained by analysis of HA expression. The transgenic desmin was expressed, though at low levels, in both young and old adult muscle and heart. The mutant mice did not show overt signs of muscle weakness and their life expectancy was normal. For a more detailed phenotype and muscle function assessment, a SHIRPA protocol was used. DM mice, carrying the L345P mutation, but not control mice, were found to exhibit slight signs of hind limb weakness, starting at 16 weeks of age to be more obvious at higher ages. At the age of 40 weeks only 45% of DM mice were able to lift their hindlegs in a wire maneuvre test, compared to 100% in the control group. Hearts from DM mice, but not from control mice, exhibited signs of fibrosis. Further, hearts from the mutant DM mice were, somewhat surprisingly, found to be smaller than those from the control mice. However, in skeletal muscle no gross abnormalities were noted. Despite lack of desmin aggregates in the skeletal muscles of DM mice, isolated soleus muscle from DM mice exhibited slight but significant alterations in force generation parameters. These mild changes in the function of heart and skeletal muscles were aggravated by a 5-week physical exercise protocol (swimming). Weakness was more evident in the limbs as followed by the SHIRPA protocol, in isolated soleus muscle fatiguing was more marked, and in the heart there were echocardiographic signs of ventricular dilation and fraction shortening concomitant with morphologically more evident signs of fatty tissue and fibrosis. From these results can be concluded that transgenic mice carrying a L345P desmin mutation, expressed at low levels, demonstrate a late onset mild myopathy and cardiomyopathy that is aggravated by physical exercise, and that does not correlate to overt desmin aggregate formation in the muscle. The latter indicates that the pathogenetic events arising from desmin mutations involve, at least to some extent, mechanisms independent of the desmin aggregates characteristic of this group of disorders.

Patrick Vicart (Paris) reported on ‘mutant desmin in vitro’, i.e. in SW13 which naturally lack type III intermediate filaments and BHK21 cells which express desmin. The insertional mutation K239fsx242, reported by Schröder et al. [17], showed cytoplasmic aggregates whereas the R454W mutation located in the tail of desmin did not show aggregates. The D399Y mutation revealed a disorganized desmin network and aggregates as previously observed for missense mutations in the end of 2B rod domain.

Denise Paulin (Paris) presented ‘new intermediate filament proteins encoded by the synemin gene’. Her group previously cloned and characterized the human synemin gene, which encodes for two large intermediate filament proteins (IFP) that may play a crucial role in cross linking IFP network with other components of the cytoskeleton. They found that the synemin gene encodes three different synemin-similar isoforms through alternative splicing. Two of them, synemin H and M are respectively human alpha and beta synemin, while the third isoform, synemin L, constitutes a new form of IF protein. It has a typical rod domain and a very short tail (49 residues) with a novel sequence that is produced by an open reading frame shift. Different splicing patterns of the mouse synemin gene also produce two other isoforms, one of 170kDa (H) and the other of 150kDa (M), similar to human alpha and beta synemins. The alternative splicing of synemin pre-mRNA is clearly correlated with its tissue-specific expression. We have shown that the synthesis of H/M synemins starts in the embryo, whereas the L synemin isoform is present in adult muscles. The H/M isoforms are bound to desmin or vimentin in the muscle cells of wild type mice. Using murine models of desmin- and vimentin-deficients, we provide direct evidence that synemin is associated with muscle intermediate filaments in vivo. The synemin fibril organization in skeletal and cardiac muscle is disrupted when desmin is absent and in smooth muscle when vimentin is absent. The fact that the three synemin isoforms differ in their length and the sequences of their tail domains plus their different developmental patterns suggests that they may have different physiological function.

Kristen Nowak (Oxford) spoke about a novel desmin-binding protein, ‘syncoilin’. Syncoilin was originally identified as a member of the dystrophin-associated protein complex (DAPC) via its interaction with α-dystrobrevin [18]. Therefore it is proposed that syncoilin tethers the DAPC to the intermediate filament cytoskeleton [19]. Syncoilin shows significant homology to class II and IV intermediate filaments. It is expressed predominantly in skeletal and heart muscle, where it co-localizes with desmin at the neuromuscular junction, the sarcolemma and the Z-lines [18]. Syncoilin has been found in desmin aggregates in muscle biopsies from desmin-related myopathy patients [20]. Dr Nowak discussed results from immunohistochemical and in situ hybridization analyses, highlighting that syncoilin is expressed early and widely during development.

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3. Desmin-related myopathies 

Michel Fardeau (Paris) gave a ‘historical introduction’ to the evolution of desminopathy and α-B crystallinopathy in France, also referring to a very early publication [21]. He documented accumulation of desmin in cardiac myocytes in conjunction with cardiomyopathy. The earliest paper mentioning accretion of desmin [22] actually did not reveal mutations in the desmin gene. The evolution ranged from original electron microsopic studies revealing the now classical granulofilamentous material within muscle fibres [4] through documenting hyperphosphorylation of desmin [23], to the then seminal discovery of a missense mutation in the α-B crystallin gene and, thereby, for the first time, indicating a wider genetic spectrum of desmin-related myopathies [9] which later accrued over the years and have recently been reviewed [10].

Lev Goldfarb (Bethesda) addressed the ‘mutational spectrum of desminopathies’. The inheritance pattern in familial desmin myopathy is autosomal dominant or autosomal recessive, but many cases have no family history. At least some, and probably most, non-familial desmin myopathy cases are associated with de novo desmin mutations. Age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Twenty-four mutations have now been identified in the desmin gene: point substitutions, insertion, small in-frame deletions and a larger exon-skipping deletion. The majority of these mutations are located in conserved α-helical segments of desmin. Many of the missense mutations result in changing the original amino acid into proline, which is known as a helix breaker. Studies of transfected cell cultures indicate that mutant desmin is assembly-incompetent and able to disrupt a pre-existing filamentous network in a dominant-negative fashion. Disease-associated desmin mutations in humans or transgenic mice cause accumulation of chimeric intracellular aggregates containing desmin and other cytoskeletal proteins. Routine genetic testing of patients for mutations in desmin and αB-crystallin genes is now available and necessary for establishing an accurate diagnosis and providing appropriate genetic counseling. Better understanding of disease pathogenesis will stimulate research focused on developing specific treatments for these conditions.

Rolf Schröder (Bonn) elaborated ‘protein patterns in desminopathies’, i.e. αB-crystallin and hsp27 isoform expression patterns in desminopathies, plectinopathies and other myofibrillar myopathies. Cytoplasmic accumulation of small heat shock proteins along with desmin-positive aggregates is an immunohistochemical characteristic in human desminopathies, αB-crystallinopathies, plectinopathies and other myofibrillar myopathies. Among a variety of other functions, small heat shock proteins have been implicated to exert an essential role in preventing abnormal protein folding and accumulation. The aim of the present study was to gain a deeper insight in the role and diagnostic value of small heat shock proteins in myopathies with structural pathology of the intermyofibrillar cytoskeleton. Therefore, we analysed the protein expression pattern of αB-crystallin and hsp27 phosphorylation site-specific isoforms in skeletal muscle and primary myoblasts of genetically confirmed cases of human desminopathies, plectinopathies, and other myofibrillar myopathies by means of 1D- and 2D-gel electrophoresis in conjunction with Western blotting. Analysis of muscle samples after differential centrifugation and immunoblotting showed that hsp27 P82 and hsp27 P15 as well as αB-crystallin P59 and αB-crystallin P45 were the prominent isoforms expressed in normal and diseased human skeletal muscles. These hsp isoforms were predominantly present in the pellet fraction of muscle lysates. As a main finding, 2D-gel electrophoresis in conjunction with immunoblotting revealed an aberrant hsp27 pattern in desminopathies when compared to normal and disease controls. All 5 desminopathy probes analysed showed a slight to moderate shift of the main hsp27 dot to alkaline pH degrees. In contrast, samples derived from the plectinopathy and all other six myofibrillar myopathies showed a main dot in the same range as normal controls. These findings indicate that 2D-gel electrophoresis together with hsp27 immunoblotting may be helpful to differentiate primary desminopathies from other myopathies with structural pathology of the intermyofibrillar cytoskeleton.

Montse Olivé (Barcelona) spoke on ‘proteasomal expression, induction of immunoproteasome subunits, and local MHC class I in desmin and related myopathies’ and summarised the results of an immunohistochemical study performed with Prof. Isidro Ferrer aimed to analyze the expression of different components of the proteasomal system and the immunoproteasome subunits in desmin-related myopathies (DRM) and on inclusion body myositis (IBM). The study was conducted on muscle biopsy specimens from 6 patients suffering from DRM, and 6 patients suffering from IBM. Increased expression of components of the catalytic core of 20S proteasome and its regulators 19S and PA28α/β, co-localizing abnormal protein deposits, was seen in DRM and in IBM. In addition, increased expression of immunoproteasome subunits LMP2, LMP7 and MECL1 was found in muscle specimens from patients suffering from DRM and in patients with IBM. Furthermore, focal MHC class I immunoreactivity was found in IBM and to a lesser degree in DRM in association with protein aggregates, in addition to focal cytoplasmic membrane deposits in muscle fibres in IBM. Direct measurement of proteasome subunit expression levels and peptidase activity showed up-regulation of proteasome expression and increased enzymatic activity in IBM and likely in DRM.

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4. Desmin-related cardiac disease 

Harald Bär (Heidelberg) reported on ‘desmin-related cardiomyopathy—from clinic to molecular function’. Desmin-related myopathy (DRM) is often associated with cardiomyopathy or different forms of rhythm disturbances (such as bundle branch block, various degrees of AV-block and ventricular tachycardia). Patients affected by cardiac disease most often suffer from dilated cardiomyopathy (DCM), which finally causes cardiac failure or arrhythmias potentially leading to sudden death. In contrast, only in a single case of hypertrophic cardiomyopathy the desmin gene was found to be mutated (Patrick Vicart, this ENMC workshop). The reason for the surprising fact that only some desmin mutations are connected with cardiac disease, whereas other families suffer only from skeletal myopathy are so far not known. Nevertheless, it seems reasonable that every patient suffering from skeletal DRM should also be seen by a cardiologist and the appropriate investigations should be repeated perhaps once a year (including ECG, echocardiogram, Holter-ECG and stress test). Once symptoms develop or pathological findings are recorded, therapy should follow the guidelines of the American Heart Association/American College of Cardiologists (AHA/ACC). Many aspects of the biology of desmin filaments are not understood at present. For all the various mutations of the desmin gene, which lead to myopathy associated with intracytoplasmic accumulations of granulofilamentous desmin, we will have to determine, if this is due to misassembly of the desmin protein; altered biophysical properties of the mutated protein leading to increased susceptibility to stress-induced filament breakdown and increased proteolysis; changed ability of the assembled desmin filaments to interact properly with cellular binding partners, again leading to degradation of desmin and/or segregation into protein granules. From the investigation of these mutations and their impact on the desmin cytoskeleton we will certainly be able to gain a deeper insight into intermediate filament biochemistry, physiology as well as cellular function. Hopefully, this knowledge will eventually help to develop cures for the patients affected from this devastating illness.

Among the different forms of DRM, a cardiomyopathy was reported by Anna Fidziańska (Warsaw) in a 25-year-old patient with skeletal dysfunction which lasted for two years. He underwent cardiac transplantation at the age of 14 years because of dilated cardiopathy diagnosed at 9 years of age. Morphological analysis of skeletal muscle showed hyaline, desmin-decorated Mallory body-like inclusions. In deparaffinized heart muscle, embedded in Spurr-resin, taken 9 years prior to skeletal involvement, identical changes were observed. Significantly earlier affection of cardiac compared to skeletal muscle could be explained by abundant presence of abnormal desmin in the conduction system of the heart.

Simone Spuler (Berlin) spoke on ‘predominantly cardiac myopathy’: a large family from Berlin with 43 family members was presented who had been followed for 5 generations since 1955. Affected family members presented with cardiac arrhythmias around age 20 years. Later they developed cardiomyopathy and many died prematurely. Only the index patient, a 34-year old male, and his mother, both carrying cardiac pace makers, had noticeable involvement of their skeletal muscles with a predominantly distal slightly asymmetrical distribution. SSCP (single strand conformation analysis) and sequencing of cDNA identified a heterozygous G to A change at the +1 position of the splice donor site of intron 3 (780+1 g→a) in the desmin gene, resulting in deletion of the entire exon 3 during the pre-mRNA splicing.

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5. Other desmin-related myopathies 

Ana Ferreiro (Paris) presented ‘the nosographic spectrum of SEPN1 mutations from desminopathies to selenoproteinopathies’ and summarized her recent work leading to molecular characterization of the early-onset, recessive form of desmin-related myopathy with Mallory body-like inclusions (MB-DRM). MB-DRM was first described as ‘a form of congenital muscular dystrophy’ in 5 patients originating from a genetic isolate, in the Eichsfeld region (Northern Germany) [6], [24], four of whom were related by remote family links [MIM 253850]. Since then, approximately 14 additional patients have been reported [3], [25]. Each patient presented with neonatal hypotonia, axial and proximal muscle weakness, scoliosis and normal or mildly elevated CK levels; 11 patients died of respiratory insufficiency before adulthood [3]. Morphologically, MB-DRM was defined by the presence, in about 10% of muscle fibres, of hyaline plaques that, at the ultrastructural level, correspond to peculiar intramyofibrillar inclusions [24], [25], composed of helical filaments, 10–12 nm in diameter, arranged in bundles and surrounded by irregular masses of electron-dense amorphous material. Finer filaments of 8–10nm in diameter frequently created a lighter perilesional halo [25]. The finding that these deposits were immunoreactive for desmin, dystrophin and ubiquitin [3] led eventually to the inclusion of this entity in the group of desmin-related myopathies [26], [27]. Recently, the selenoprotein N gene (SEPN1) was identified as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: Rigid Spine Muscular Dystrophy and the severe form of classical Multi-minicore Disease ([MIM 602771]) [28]. SEPN-RM is characterized by predominantly axial weakness, early scoliosis and respiratory failure, and a variable degree of spinal rigidity. The myopathological spectrum of SEPN-RM is broad, and may or may not include dystrophic features such as regenerating fibers or endomysial fibrosis, while minicore-type lesions are a fairly constant finding [28], [29]. Lately, we evaluated second muscle biopsies from two brothers with SEPN-RM caused by a missense SEPN1 mutation. The unexpected finding of Mallory body-like inclusions in these samples, together with the previously described accumulation of desmin [30] and α-B crystallin [31] within the core lesions, led us to suspect a relationship between SEPN1 and MB-DRM. In the original MB-DRM German family, we demonstrated a linkage of the disease to the SEPN1 locus in 1p36, and subsequently a homozygous SEPN1 deletion (del 92 nt −19/+73) in the affected patients. Clinical reassessment of the surviving patients in the original family showed that the clinical features of MB-DRM are indistinguishable from those recognized in SEPN-RM, suggesting that MB-DRM is in fact part of the SEPN-RM spectrum [12]. These findings substantiate the molecular heterogeneity of DRM, expand the morphological spectrum of SEPN-RM and implicate a necessary reassessment of the nosological boundaries in early-onset myopathies.

Anna Kamińska (Warsaw) spoke on the ‘rigid spine syndrome’ compared to ‘Mallory body-like myopathy’ in cooperation with Anna Fidziańska (Warsaw) and Francesco Muntoni (London). In this context, she reported a 13-year-lasting observation of a girl with congenital myopathy who developed muscle weakness at the age of 3 years and who was investigated in the Department of Neurology in Warsaw for the first time at the age of 5 years. At that time, clinical examination revealed general thinning of the musculature, limitation in neck flexion and mild proximal weakness of lower extremities. In the muscle biopsy only minimal changes, such as small areas devoid of enzyme activity in NADH and SDH, were present light microscopically. At the electron microscopic level, foci of Z-line streaming and myofibrillar disorganization were found. Six years later, clinical examination revealed pronounced dorsolumbar scoliosis, marked flexion limitation of the neck, contractures at the elbows and ankles with relatively well-preserved muscle strength. A second muscle biopsy revealed sparse Mallory body-like inclusions with strong desmin reactivity by light microscopy and plaques composed of helical filaments and dense granulo-amorphous material by electron microscopy. The diagnosis of Mallory body-like myopathy was finally made. At the age of 14 the girl underwent surgical Achilles tendon elongation and 2 years later an operation of scoliosis with satisfactory results. At the same time she developed respiratory insufficiency and required nocturnal ventilation. She was also seen at the age of 15 years at the Hammersmith Hospital and diagnosed as Rigid Spine Syndrome. Subsequently, Ana Ferreiro (Paris) identified a mutation in the SEPN 1 gene in this patient.

Lars-Eric Thornell (Umea) elaborated on ‘desmin aggregates caused by eccentric exercise as part of myofibrillar remodelling’. Z-disc alterations are the morphological hallmark of delayed onset muscle soreness (DOMS) caused by eccentric exercise and are considered to be due to damage to the cytoskeleton leading to loss of desmin. By contrast recent immunohistochemical studies of muscle biopsies, taken at different time periods after a bout of eccentric exercise, which caused severe DOMS, revealed, instead of loss of desmin, an increased labelling [32]. This was suggested to reflect an upregulation of desmin synthesis as part of a repair and/or adaptation process. Using antibodies to nebulin, titin, alpha-actinin and a ligand to F-actin and in combination with electron microscopy and immuno-electron microscopy, Thornell's group has collected results indicating that the Z-disc lesions observed, instead of disruption, reflect remodelling of myofibrils leading to sarcomerogenesis and lengthening of myofibrils [32], [33].

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6. Other protein aggregate myopathies 

Anders Oldfors (Gothenburg) presented ‘protein aggregate myopathies associated with mutations in myosin heavy chain genes’. By the discovery and characterization of two familial myopathies caused by mutations in myosin heavy chain genes, a new entity within the field of neuromuscular disorders is introduced: Myosin myopathy. Both myopathies are to some extent associated with accumulation of proteins in the muscle fiber cytoplasm. The first myopathy affected a family in Western Sweden [34], [35] and was associated with a MYH2 mutation (706Glu>Lys) affecting a highly conserved residue in the head of myosin heavy chain (MyHC) IIa. The mutated amino acid is located in the SH1-helix, which is important for the conformational changes that take place in the myosin head at hydrolysis of ATP. The clinical features included congenital joint contractures in several cases. The disease was in most cases mild in young individuals, whereas some adults experienced a progressive course with marked proximal muscle weakness. External ophthalmoplegia was a consistent finding. In some cases muscle fibers showed rimmed vacuoles with inclusions of 15–20 nm filaments identical to those in sporadic inclusion body myositis (s-IBM). All these fibers expressed the mutant myosin isoform, indicating the possibility that breakdown of sarcomeric proteins is of pathogenetic importance for the formation of rimmed vacuoles and filamentous inclusions. The second type of myosin myopathy was identified in several members of a family [36] with apparent autosomal dominant inheritance and in a sporadic patient. Signs and symptoms started in childhood with proximal muscle weakness, and there was slow progression. Muscle biopsies showed characteristic morphological changes with type 1 fiber predominance and large inclusions in most type 1 fibers. Analysis of the muscle biopsy specimens indicated that there was storage of slow/β myosin (MyHC I) in the inclusions. Sequencing of MYH7, which encodes MyHC I, disclosed a heterozygous missense mutation, 1845Arg>Trp, affecting a highly conserved residue in the distal rod region of the protein. The mutation segregated with the disease in the familial cases and it was not identified in any of the relatives of the sporadic case. In spite of the fact that MYH7 is expressed also in the heart, there was no cardiomyopathy. We conclude that the mutated amino acid is important for the assembly of thick filaments in the sarcomeres of skeletal muscle, and propose the term Myosin storage myopathy for this disease, which should be included among disorders in the novel entity Myosin myopathy.

Kristen Nowak (Oxford) in her presentation ‘Hyaline body myopathy—the Belgian–Australian cooperation’ reported on two Belgian patients with hyaline body myopathy, already documented at the preceding desmin-related workshop [3]. An identical mutation of Arg1845Trp in the MYH-7 gene was found as earlier reported [36]. Thus, skeletal myosin diseases comprise hyaline body myopathy, central core disease [37] and hypertrophic cardiomyopathy. If mutations appear in the head of the protein, hypertrophic cardiomyopathy results and, if in the tail, either hypertrophic cardiomyopathy [38] or hyaline body myopathy may develop.

Michel Fardeau (Paris) together with Anna Fidziańska (Warsaw) presented the latest development in ‘cap disease’, comprising a 35-year-old man having two muscle biopsies, the first one with enzyme histochemical ATPase defects due to caps, the second biopsy several years later without caps but with type-I fibre uniformity. His data were augmented by those already published by Anna Fidzianka [39]. According to the report by Montse Olivé (Barcelona), the biopsy specimen of a 15-year-old girl suffering from hypotonia since birth, proximal muscle weakness and scoliosis leading to respiratory insufficiency also showed caps.

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7. Conclusion 

While protein aggregation has earlier been established as an important pathogenetic principle in numerous degenerative diseases, for many years, largely affecting nerve cells such as in Alzheimer disease, Parkinson disease and Lewy body disease, similar non-lysosomal aggregation of diverse proteins, some of them mutant ones others not, have now been identified within muscle fibres in several neuromuscular disorders, often of hereditary nature. Hence, a similar pathogenetic principle, i.e. impaired extralysosomal degradation of proteins can now been implicated in respective myodegenerative diseases.

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Acknowledgements 

This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC), Baarn/The Netherlands, and its main sponsors: Association Française contre les Myopathies, Italian Telethon Committee, Muscular Dystrophy Group of Great Britain and Northern Ireland, Unione Italiana Lotta alla Distrofia Muscolare, Vereniging Spierziekten Nederland as well as its associate members: Schweizerische Stiftung für die Erforschung der Muskelkrankheiten, Deutsche Gesellschaft für Muskelkranke, and Muskelsvindfonden, Denmark. Furthermore, we are grateful to Prof. Andoni Urtizberea for his scientific advice and to Michael Rutgers and Mira Klein for organizational support. We also thank Astrid Wöber for editorial assistance.

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Appendix. Workshop participants 

Harald Bär (Heidelberg, Germany)

Michel Fardeau (Paris, France)

Ana Ferreiro (Paris, France)

Anna Fidziańska (Warsaw, Poland)

Hans H. Goebel (Mainz, Germany)

Lev G. Goldfarb (Bethesda, USA)

Anna Kaminska (Warsaw, Poland)

Kristen Nowak (Oxford, UK)

Anders Oldfors (Gothenburg, Sweden)

Montse Olivé (Barcelona, Spain)

Denise Paulin (Paris, France)

Rolf Schröder (Bonn, Germany)

Thomas Sejersen (Stockholm, Sweden)

Simone Spuler (Berlin, Germany)

Lars-Eric Thornell (Umea, Sweden)

Patrick Vicart (Paris, France)

[Complete addresses of the individual workshop participants are available at the ENMC and the workshop organizers]

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PII: S0960-8966(04)00209-3

doi:10.1016/j.nmd.2004.08.003

Neuromuscular Disorders
Volume 14, Issue 11 , Pages 767-773, November 2004

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