Neuromuscular Disorders
Volume 12, Issue 7 , Pages 687-692, October 2002

Desmin – Protein Surplus Myopathies, 96th European Neuromuscular Centre (ENMC)-sponsored International Workshop held 14–16 September 2001, Naarden, The Netherlands

  • Hans H Goebel

      Affiliations

    • Department of Neuropathology, Mainz University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49-6131-17-7308; fax: +49-6131-17-6606
    • ,
  • Michel Fardeau

      Affiliations

    • INSERM UR 523 – Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Bâtiment Babinski, 47, Bd. de l'Hôpital, 75651 Paris Cedex 13, France

Received 14 February 2002; accepted 21 February 2002.

Article Outline

 

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1. Introduction 

Following earlier European Neuromuscular Centre (ENMC)-sponsored workshops on desmin [1], familial desmin-related myopathies [2] and rare congenital myopathies (CM) [3], a multinational and multidisciplinary workshop on ‘Desmin – Protein Surplus Myopathies’ assembled 16 clinicians and scientists from eight European countries in Naarden, The Netherlands, on September 14–16, 2001.

Introducing the workshop, the chairman, Hans H. Goebel (Mainz) defined ‘Protein Surplus Myopathies’ as an abnormal non-lysosomal aggregation of proteins within muscle fibres. This concept emerged from earlier studies on myopathies in which the cytoplasmic accumulation of desmin, the intermediate filament of striated and smooth muscle cells, is a hallmark of familial and sporadic myopathies. There are several structural desmin-related myopathies (DRM) in this group, including, α-B crystallinopathy, and others; actinopathy, hereditary inclusion body myopathies and, perhaps, hyaline body myopathy. The DRM themselves are heterogeneous disorders consisting of primary desminopathies [4], marked by mutations in the desmin gene, and familial myopathies mapping to chromosome 10q [5], chromosome 2q21 [6], and chromosome 12 [7], and others not yet genetically defined.

At the workshop a written contribution was received from Lev Goldfarb of the National Institutes of Health (NIH), Bethesda/USA, who was unable to attend, summarising the 14 desmin mutations so far identified in 15 affected families. These comprise ten missense mutations, two small in-frame deletions and two larger in-frame exon skipping deletions in eight families with autosomal-dominant inheritance, one family with autosomal-recessive inheritance, one family with a compound-heterozygous pattern, and five sporadic patients with de novo mutations. Desminopathies, due to mutations in the desmin gene, make up one third of the DRM. They have also been termed ‘myofibrillar myopathies’ [8]. Diagnostic genetic testing for DRM in appropriate patients is offered by Lev Goldfarb (goldfarbl@ninds.nih.gov).

In addition to desmin, several other proteins accumulate in DRM without specific genotype-morphologic correlation. Similarly, several proteins have been found to be accumulated or deposited in hereditary inclusion body myopathies (and in inclusion body myositis) though of a different kind. To date, no specific mutant proteins have been identified in these syndromes.

Actinopathy is another ‘Protein Surplus Myopathy’, due to the accumulation of mutant filamentous actin within muscle fibres. More than 50 mutations have been identified in the actin gene. Actinopathy forms a subgroup among the nemaline myopathies, i.e. intrasarcoplasmic and/or intranuclear rods may or may not be associated with actinopathy. A separate ENMC consortium on ‘Nemaline Myopathy’ exists to evaluate this group of disorders, and this topic was not further discussed at this workshop.

Hyaline body myopathy is a putative ‘Protein Surplus Myopathy’ in that granular proteinaceous material accumulates within muscle fibres, in some cases reacting with antimyosin antibodies and displaying adenosine triphosphatase activity.

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2. Basic aspects 

Following this introduction, Denise Paulin (Paris) spoke on ‘desmin partners’: Synemin, originally considered an intermediate filament-associated protein because it co-purified with the type-III intermediate filament proteins desmin and vimentin, is now thought to be a novel protein among the some 50 members of this intermediate filament multi-gene family [9]. Interactions between the rod domains of synemin and desmin as well as between the tail domains of synemin and α-actinin have been reported, placing synemin among the proteins found in the sarcomeric Z-band. Synemin and paranemin co-localize with both plectin and desmin at the Z disc level and also beneath the plasma membrane where they are in close structural relationship to each other. Knock-out mice lacking desmin which in man maps to 2q35 [10] show a severe derangement of synemin in longitudinal sections, but not of plectin. The synemin gene on 15q26.3 encodes 250 and 180 kDa proteins and the intron-exon structure of the synemin gene suggests an origin from the same precursor as genes for nestin, α-internexin and neurofilaments. However, synemin belongs to a different class of intermediate filaments. Synemin-α and synemin-β form heteropolymeric intermediate filaments where desmin and synemin co-localize in protein aggregates in human DRM. The role of synemin in human neuromuscular diseases has not been elucidated. Knock out experiments on the synemin gene in mice are in progress.

L.E. Thornell (Umea) addressing ‘too much and too little desmin’ first stressed differences in amounts of desmin within different striated muscle cells in that cardiac Purkinje fibres in hoofed animals are composed of 50–70% of desmin, regular ventricular myocardiocytes contain 2%, skeletal muscle fibres 0.35%, and smooth muscle cells 3–4% desmin, forming an intracellular network of horizontal connections between Z discs and M bands and the sarcolemma, as well as longitudinal connections in cardiomyocytes extending to the intercalated disc [11], [12], [13]. The richness of cardiac Purkinje fibres in desmin is further demonstrated by preservation of their three-dimensional forms after detergent treatment that even removes membranes [14]. The desmin in Purkinje fibres is highly phosphorylated but regular in cardiomyocytes allowing differential demonstration by different monoclonal antibodies [15]. The proteins which anchor desmin to each intracellular component are still largely unknown. The intermediate filaments desmin, nestin, and vimentin are present during development of striated muscle fibres but are subsequently down-regulated. Desmin remains as a major component within mature muscle fibres while nestin is confined to myotendinous and neuromuscular junctions [16]. Regeneration and subsequent maturation of muscle fibres recapitulate this course of events. In humans too much desmin is associated with desminopathies and desmin-related myopathies, but too little desmin has not been reported in humans. In the mouse desmin may be completely eliminated by knocking out the murine desmin gene. This transgenic mouse develops severe cardiomyopathy, myopathy, and vasculopathy, degenerating muscle fibres being particularly prominent in highly used muscles such as the soleus, diaphragm and tongue muscles.

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3. Desmin-related myopathies 

3.1. Genes cloned 

Co-chairman Michel Fardeau (Paris) elaborated on the evolutionary saga of the DRM. He described the clinical, light microscopic and ultrastructural data on an index family in whom muscle fibres were charged with granulofilamentous material [17] later found to contain desmin [18] but lacking a mutation in the desmin gene [19]. The patients in this family had small lens opacities in conjunction with a mutation in the α-B crystallin gene on chromosome 11 [20]. Interestingly, apart from this family, seven other families with a similar accumulation of granulofilamentous material in their muscle fibres were studied, five from France, and one from Spain and Denmark, each. Cardiomyopathy was present to a variable degree in all these patients. Six of these seven families showed dominant inheritance, but mutations could not be established in exons 4–6 of the desmin gene or in the CRYAB gene in these families, suggesting a separate non-desmin, non-CRYAB locus in at least two of these families.

Patrick Vicart (Paris) (originally in the group of Denise Paulin, Paris) who discovered the missense mutation in the α-B crystallin gene as the cause of one form of DRM, now called α-B crystallinopathy [20], recently showed that differentiated cultured satellite cells from one of these α-B crystallinopathy patients demonstrated enhanced localization of α-B crystallin beneath the plasma membrane when exposed to glucocorticoid – a phenomenon which could not be observed in normal differentiated satellite cells [21]. Moreover, dexamethasone upregulated expression of both α-B crystallin and the small heat-shock protein Hsp27 in control and DRM-derived myoblast cultures.

In cooperation with Lev Goldfarb he had also identified a new heterozygous Q389P mutation in the desmin gene located at the C-terminal part of the rod domain inducing a desminopathy expressing cardiomyopathy with distal and proximal muscle weakness [22]. When the mutated gene was transfected to C2.7, MCF7, and SW13 cells, its mutant protein failed to form a functional intermediate filament network giving evidence of a dominant negative effect on filament formation.

Anna Kaminska (Warsaw) presented two families with adult autosomal-dominant proximal myopathy beginning in mid-adult life in the thighs and subsequently spreading to the arms, without facial, bulbar, respiratory and cardiac muscles involvement. In one 70-year-old patient the disorder had been present for 20 years. Biopsy specimens from three patients revealed accumulation of material containing desmin and α-B crystallin in many muscle fibres. At the electron microscopic level this material was composed of irregularly arranged filaments sometimes mixed with dense granulo-amorphous material. These inclusions differed in size and shape and were located both under the plasma membrane as well as among sarcomeres at the level of the Z disc. In cooperation with Lev Goldfarb deletion of three amino acids in exon 6 of the desmin gene was found in both families indicating that this syndrome was a true desminopathy.

Studies on the L345P desmin missense mutation present in a large multi-generational Ashkenazi Jewish family [23] were reported by Thomas Sejersen (Stockholm). The mutation affects the coiled-coiled domain important for dimer formation by disrupting the α-helical structures with a prolin amino acid replacement. In transfected HeLa cells the desmin network is defective and cultured satellite cells of one of the patients accumulated perinuclear aggregates of desmin. Not only vimentin co-localized to the desmin aggregate, but also nestin, the latter even more so. The author and his co-workers are currently conducting experiments with transgenic mice carrying this mutation.

3.2. Genes mapped 

Anders Oldfors (Gothenburg) reviewed a Swedish family linked to chromosome 10q22.3 [5]. This family showed myopathy with varying muscle involvement. When severe, muscle weakness was generalized and when moderate, it was axial and distal, marked by a myopathic EMG pattern. Mildly affected muscle specimens showed accumulation of desmin, dystrophin, and sarcoglycans within muscle fibres, together with intermyofibrillar granulofilamentous material with marked disorganization of myofilaments. Advanced muscle pathology consisted of muscle fibre necrosis and increased endomysial fibrosis. N-CAM positive fibres were encountered in each muscle biopsy specimen.

Cardiomyopathy was also present in this family, with features of a variant of arrythmogenic right ventricular cardiomyopathy, with severe biventricular cardiac failure. At autopsy there was marked replacement of large parts of the free wall of the right ventricle by fat cells.

Over the years, Françoise Chapon (Caen) [6], [24], [25], [26] reported on four related females in three successive generations, possibly indicating an autosomal-dominant mode of inheritance, who suffered from diffuse weakness and respiratory insufficiency in early infancy but lived well into adulthood, two members dying at 52 and 81 years of age, respectively. These patients displayed numerous cytoplasmic bodies (CB) with accumulation of desmin, dystrophin, actin, utrophin, and ubiquitin, but not α-actinin and α-B crystallin in the periphery of the CB of which by immunoelectron microscopy dystrophin was present in the halo of the CB. Using Western blot analysis and two-dimensional electrophoresis, the acidic isoform only of desmin was shown to be increased, due to hyperphosphorylation of desmin (as shown by applying alkaline phosphatase technique). An increase in desmin RNA was also demonstrated. Clinically, these patients resembled those recently observed in Sweden [27]. The Swedish patients were found to link to chromosome 2q24-3.1 [28], whereas the French family, by linkage study, contained a low score of 2.11 at 2q21 [6], suggesting Arp3 (actin-related protein 3) as a candidate gene.

3.3. Further nosological aspects 

A large cohort of DRM patients, five with autosomal-dominant, one with autosomal-recessive modes of inheritance and two sporadic cases, were reported by Montse Olivé (Barcelona). In these eight patients whose ages varied between 12 and 50 years when the disease started, distal muscle weakness prevailed in six, and three had axial and cervical muscle involvement, two of whom also had nasal speech and dysphagia. Four of these eight patients had cardiac conduction defects or cardiomyopathy; in two cardiomyopathy preceded skeletal muscle weakness. Only one patient experienced severe respiratory insufficiency. Four of the eight patients had cataract. In biopsied muscles, cytoplasmic inclusions devoid of oxidative and ATPase enzyme activities were rich in desmin and several other proteins such as dystrophin, actin, gelsolin, nebulin, β-A4 amyloid (residues 8–17), ubiquitin, and α-B crystallin. Rimmed vacuoles were also a common finding. Ultrastructurally, granulofilamentous material in areas of myofibrillar disorganization was noted.

Among the different forms of DRM, a myopathy associated with neuropathy was reported by Enrico Bertini (Rome) in two unrelated girls who developed limb-girdle muscle weakness at 8 and 10 years, respectively, restrictive cardiomyopathy requiring cardiac transplantation at ages 15 and 17 years, respectively, and who died at 20 and 19 years of age, respectively. Morphologically, enlarged axons were filled with neurofilaments, while muscle fibres contained increased amounts of hyperphosphorylated desmin detected by Western blot, and showed granulofilamentous material at EM. Mutations in the α-B crystallin gene had already been excluded by Patrick Vicart (Paris) and screening for mutations in the desmin gene is currently in progress. This somewhat unusual childhood myopathy, cardiomyopathy, and neuropathy resembled the disease earlier described by Liu and Gumbinas [29], perhaps represented a distinct entity within the spectrum of DRM.

Inger Nennesmo (Stockholm) reported a new Finnish family with several members suffering from cardiomyopathy, some of them also having had strokes but no skeletal muscle symptoms. However, the index patient, a 58-year-old woman, not only had cardiomyopathy marked by arrythmia, syncope and neurological symptoms interpreted as transient ischaemic attacks, but also had muscle pain. EMG showed myopathic changes. In biopsied muscle, a myopathic pattern with vacuoles and inclusions resembling spheroid bodies was noted. Desmin, α-B crystallin, and dystrophin were found upregulated in abnormal fibres, but mutational analysis did not identify mutations in the desmin and α-B crystallin genes.

Anna Fidzianska (Warsaw) reported 20-year-observations of the Mallory body-like form of DRM in 10 children with a familial type and four children with a sporadic form. These children were hypotonic at birth, had reduced muscle bulk and skeletal dysmorphism with a striking limitation in flexion of their neck. The disorder was progressive affecting axial and proximal limb muscles to such an extent that of the 14 children only five were alive, three from affected families and two sporadic cases; the others died of respiratory insufficiency before adulthood. Each child's muscle biopsy specimen had revealed ‘hyaline’ plaques rich in desmin, α-B crystallin, ubiquitin and dystrophin, but devoid of oxidative and ATPase enzyme activities. At the ultrastructural level, desmin filaments measuring 10–12 nm in diameter and amorphous material were present. Clinical and morphological similarities among these 14 children suggested a separate form of DRM, without, recognized genetic abnormalities.

Carsten Bönnemann (Philadelphia) who was also unable to attend the workshop, communicated by e-mail that the original family, earlier reported as having ‘Mallory body-like inclusions’ [30], [31] had recently been studied under his care while in Göttingen. Of the originally four patients, two girls had died whereas the two boys, now adults, have considerable muscle weakness and respiratory problems. A genome-wide study is currently under way.

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4. Other protein surplus myopathies 

Plectin co-localizes with desmin at the periphery of Z discs. Disorganization of the desmin cytoskeleton in plectin-related muscular dystrophy was reported by Rolf Schroeder (Bonn). Mutant plectin is coded by a mutated plectin gene on chromosome 8q24, responsible for autosomal recessive epidermolysis bullosa simplex with muscular dystrophy. Plectin appears to be responsible for the formation of the sarcoplasmic desmin network during maturation which appears disrupted by the mutant plectin owing to improper spacing, stabilization and subcellular attachment of deformed desmin filaments. Subsequently, sarcoplasmic and subsarcolemmal desmin accrues, so that this plectinopathy shows features of DRM, although accumulation of desmin does not result in formation of granulofilamentous material or distinct inclusion bodies as seen in desminopathies and α-B crystallinopathy.

Hyaline body myopathy (HBM) marked by hyaline bodies and earlier called myofibrillar lysis myopathy had been described in two siblings [32].

Chantal Ceuterick de-Groote (Antwerp) reviewed current knowledge on HBM which is now known to occur both sporadically as well as in a familial fashion affecting children as well as adults. The hyaline bodies occur in type-I muscle fibres and give an intense reaction with acid (pH 4.2) myosin ATPase. Their ultrastructure consists of finely granular material, amassed beneath the plasma membrane, largely devoid of glycogen, lipids, mitochondria, and any other structures and, thus, oxidative enzymes are not reacting. This granular material, though sharply demarcated from other components of the muscle fibre is not limited by any defined membrane. A comparative study of a 10-year-old boy [33] and a 57-year-old woman [34] showed an increase of hyaline bodies and atrophic muscle fibres over time. Immunohistochemically, there is evidence of myosin accumulation, but the precise isoform, i.e. whether myosin heavy-chain-fast [33] or myosin heavy-chain-slow [35] predominates, remains controversial requiring a larger number of patients and biopsy specimens as well as more systematic immunohistochemical and ultrastructural studies.

Michael Swash (London) associated with J.F. Geddes, D.P. Macleod, and J.A. Wedzicha broadened the spectrum of HBM by reporting on three affected siblings (two boys and one girl), of four siblings altogether, who developed muscle weakness. Associated features in these affected siblings, suggesting an autosomal-recessive mode of inheritance, were respiratory failure and hypertrophic cardiomyopathy. The hyaline bodies within muscle fibres did not show activity of the NADH-related oxidative enzyme; and only faint activity of acid (pH 4.3) ATPase was present. Immunohistochemically, neither antibodies against dystrophin nor against myosins reacted with the hyaline bodies which were composed of finely granular material, in continuity with surrounding myofibrils, whereas remaining sarcomeres appeared unremarkable. Genetic data from this family are not yet available.

Hence, information and cooperation on additional patients and families with HBM are solicited which may further support current molecular studies by Nigel G. Laing (Perth/Western Australia – e-mail: nlaing@cyllene.uwa.edu.au).

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5. Conclusion 

This ENMC-sponsored workshop had pursued four goals:

1.to take stock of the current knowledge on DRM;

2.to expand the concept of DRM by adding data on synemin and plectin;

3.to add HBM as another ‘protein surplus myopathy’;

4.to initiate future tasks concerning DRM and other congenital myopathies.

Among the workshop participants Dres. L. Goldfarb (Bethesda), T. Sejersen (Stockholm) and P. Vicart (Paris) will further study the genetics of the desmin and α-B crystallin genes and their mutational manifestations in future patients and families while Dr. R. Schröder (Bonn) will study the protein patterns in DRM as well as other proteomics. The molecular background of patients and families afflicted with the cytoplasmic body and Mallory body-like myopathy types will be further investigated by Dres. A. Fidzianska (Warsaw), F. Chapon (Caen), C. Ceuterick de-Groote (Antwerp), and C. Bönnemann (Philadelphia), respectively. Plectin deficiency in relation to desmin abnormalities will be explored by Dr R. Schröder (Bonn). The study of cap disease, a congenital myopathy not further discussed at this workshop, will be in charge of Dres Fidzianska (Warsaw) and M. Fardeau (Paris). Dr D. Paulin (Paris) will be responsible for investigations on synemin and syncoilin, other desmin-related intermediate filaments. Further molecular clarification of the 10q DRM will be pursued by Dres. A. Oldfors (Gothenburg) and N. Dahl (Uppsala). Additional rarer congenital myopathies will also be explored such as reducing body myopathy by Dr E. Bertini (Rome), fingerprint body myopathy by Dres. M. Romero (Paris) and M. Fardeau (Paris), and sarcotubular aggregate myopathies by Dres. M. Mora (Milan) and L. Morandi (Milan). Studies on hyaline body myopathy will be supervised by Dr Ch. Ceuterick-de Groote (Antwerp), while the chairmen of this Consortium, Dres. H.H. Goebel (Mainz) and M. Fardeau (Paris) will continue to coordinate and monitor progress within the Consortium.

Thus, these workshop participants may well be contacted by clinicians caring for patients and families concerning these diverse forms of congenital myopathies and by scientists interested and engaged in the respective research aspects discussed at this workshop.

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6. Workshop participants
E. Bertini (Rome/Italy)

C. Bönnemann (Philadelphia/USA: invited but unable to attend)

C. Ceuterick-de Groote (Wilrijk, Antwerp/Belgium)

F. Chapon (Caen/France)

L. Edström (Stockholm/Sweden: invited but unable to attend)

M. Fardeau (Paris/France)

A. Fidzianska (Warsaw/Poland)

H.H. Goebel (Mainz/Germany)

L.G. Goldfarb (Bethesda/USA: invited but unable to attend)

A. Kaminska (Warsaw/Poland)

I. Nennesmo (Stockholm/Sweden)

A. Oldfors (Gothenburg/Sweden)

M. Olivé (Barcelona/Spain)

D. Paulin (Paris/France)

R. Schröder (Bonn/Germany)

T. Sejersen (Stockholm/Sweden)

M. Swash (London/England, UK)

L.-E. Thornell (Umea/Sweden)

P. Vicart (Paris/France)

  

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

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Acknowledgements 

This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Association Française contre les Myopathies (France); Deutsche Gesellschaft für Muskelkranke (Germany); Telethon Foundation (Italy); Muscular Dystrophy Campaign (United Kingdom); Muskelsvindfonden (Denmark); Prinses Beatrix Fonds (The Netherlands); Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland); Verein zur Erforschung von Muskelkrankheiten bei Kindern (Austria); Vereniging Spierziekten Nederland (The Netherlands) and ENMC associate member: Muscular Dystrophy Association of Finland. We also thank Astrid Wöber (Mainz University, Germany) for editorial assistance.

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Neuromuscular Disorders
Volume 12, Issue 7 , Pages 687-692, October 2002

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