Familial desmin-related myopathies and cardiomyopathies — from myopathology to molecular and clinical genetics

Neuromusc. Disord, Vol. 6. No. 5, pp. 383-388. 1996 Copyright I~ 1996 Elsevier Science B.V. All rights reserved Printed in Great Britain. 0960--8966:96 $15.00 ÷ 0.00

Pergamon

o96o-.s9~(96)ooooo-o WORKSHOP REPORT FAMILIAL

DESMIN-RELATED

CARDIOMYOPATHIES MOLECULAR 36TH EUROPEAN

-- FROM AND

NEUROMUSCULAR

20-22 OCTOBER,

Within the tradition of the ENMC to follow up the evolution and progress in elucidating neuromuscular diseases, especially hereditary ones, by holding successive workshops devoted to the same topic or neuromuscular disease, a recent, second workshop was held on "Desminrelated Familial Neuromuscular Disorders", organized by Hans H. Goebel, Mainz, Germany and Michel Fardeau, Paris, France. This workshop was held subsequent to an earlier one, i.e. the 24th International Workshop "Desmin in Myoiogy", held in the autumn of 1993, and also organized by Hans H. Goebel and Michael Fardeau, sponsored by

[I].

Desmin, the intermediate filament of skeletal and cardiac muscle fibres as well as of certain types of smooth muscle cells has now repeatedly been found in excess as a non-specific, but also a disease-specific morphological feature in certain patients and families, and therefore another workshop concerning respective myopathies appeared timely and relevant. Prof. Alan Emery, the Scientific Director of ENMC, pointed out in his welcome address to the multinational and multidisciplinary scientists that the basis of this workshop - - as of its predecessor - - was the emphasis on a muscle protein, i.e. desmin, rather than on a muscle disease. Although the concept of other hereditary neuromuscular proteinopathies, dystrophinopathies, merosinopathy and adhalinopathy, comprising different clinical muscular dystrophies evolved from the disease 383

TO

GENETICS

CENTER

(ENMC)-SPONSORED

WORKSHOP

1995, N A A R D E N ,

INTRODUCTION

AND

MYOPATHOLOGY

CLINICAL

INTERNATIONAL

ENMC

MYOPATHIES

THE NETHERLANDS

to the underlying hereditary defects, i.e. protein defects, the concept of desmin-related myopathies developed in an opposite direction, i.e. from a protein abnormality to neuromuscular conditions. Thus "desmin pathology" is in search of its diseases and disease-related connotation. I n t r o d u c t o r y r e m a r k s b y H a n s H. G o e b e l

The aims of this workshop were to: 1. Take account of the familial desmin-related neuromuscular disorders hitherto observed throughout Europe, some of them and others from non-European countries published since 1993 [2], thereby establishing a muitidisciplinary, multinational European "desmin" network; . Define the scope of desmin-related neuromuscular conditions, some of which entail involvement of other tissues, especially the heart, but also peripheral nerves [3], the intestine [4], or mental retardation [5]; . Approach genetic studies on these families and subsequent geno-phenotype correlations originating from the morphological observation that desmin occurs in increased amounts - - rather than being deficient - as proteins are in the above-mentioned proteinopathies of muscle, the dystrophinopathies, merosinopathy, and adhalinopathy. It appeared important to distinguish between a non-specific increase in desmin, e.g. in occasional non-specific cytoplasmic bodies, in target fibres or as a phenomenon of familial myopathology,

384

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e.g. in familial desmin-related myopathies. In the past few years, an increase in desmin has not only been seen frequently in muscle specimens, but has also resulted in a diversity of terms comprising inclusion bodies, e.g. cytoplasmic bodies [6], spheroid bodies [7], cytoplasmic-spheroid complexes [8], sarcoplasmic bodies [9], patches, plaques [10] or hyaline masses [11], or "material" of a granulofilamentous type [12]. The nosological terms "desmin-related myopathies" [13], "desminopathy" [14], or desmin storage disease [15, 16] are consequences of this diversified nomenclature. This report deals with the highlights of this workshop which consisted of two parts: The shorter part was on recent general advances in the significance of desmin: the longer one on familial desminorelated myopathies and cardiomyopathies as they had been recorded throughout Europe. D. Paulin (Paris) presented a mouse model bearing a null mutation in the desmin gene. The absence of desmin did not influence the development of striated muscle and smooth muscle, but resulted in a loss of elasticity of vascular smooth muscle cells. This then led to ischaemia and cardiac infarcts of which the mice died. In skeletal muscle, the absence of desmin produced myopathological features of non-aligned, disorganized and distended muscle fibres as well as fibrosis. Contrary to the invitro studies that desmin is essential for cell fusion, this in-vivo model does not seem to influence muscle cell and muscle fibre fusion but seems to play an essential role in maintaining the structural integrity of both smooth and striated muscle cells. RECENT GENERAL ADVANCES IN THE SIGNIFICANCE OF DESM1N

As is the case with other proteins, tissue recognition of desmin depends upon immunomorphoiogical identification with a respective antibody. The current Manufacturers' Specifications and Reference Synopsis (MSRS) catalogue [17] lists numerous separate desmin antibodies, some monocional, others polyclonal, as emphasized by L.-E. Thornell (Umea) which can be used to recognize desmin in cells in general, or can be used as a marker for muscle cells including neoplastic cells and

may identify alterations of the cytoskeleton. A panel of monoclonal antidesmin antibodies (D33, De U-10, De B-5, D9, 37 EH) binding to different parts of desmin epitopes ought to be employed, especially because desmin may occasionally be present in epithelial cells, e.g. of the renal glomerulus, in lymphocytes and sweat gland epithelial cells. Different anti-desmin antibodies may also distinguish between cardiac Purkinje fibres and skeletal muscle fibres. Conversely, although desmin is increasingly expressed in regenerating fibres, regeneration can be more reliably recognized by demonstrating vimentin or the nueral cell adhesion molecule (N-CAM). Because desmin is a physiological muscle protein and no complete deficiencies of desmin have been reported, pathology entails the decrease or increase of desmin, the demonstration of which may also be influenced by photographic techniques. The significance of desmin pathology may be further emphasized by a respective change in messenger RNA (mRNA), in particular to recognize the secondary formation of desmin, e.g. in conjunction with polysaccharide deposits which may be desmin-positive, but are further distinguished by the polysaccharide-marking technique of Thi6ry [18]. Interestingly, in rabbits exercise induced a decrease in desmin, whereas in humans exercise induced an increase in desmin. On several occasions, the formation of other proteins such as actin [3], dystrophin [10], and a-B crystallin [19] together with an excess of desmin has been reported. J. De Bleecker (Mayo Clinic, Rochester, USA, Dr Andrew Engel's laboratory, and Gent) reported on his systematic studies of the accumulation of other proteins with desmin in muscle biopsy specimens of 10 patients. Two types of excess of desmin were observed, hyaline structures and lakes of amorphous material together with small vacuoles, based on the monoclonal antibody D33 and a rabbit polyclonal antibody recognizing residues 29-35 in the desmin head domain with identical staining patterns. Western blot analysis confirmed an increase in the levels of desmin, but also of dystrophin and geisolin. Congophilia occurred in the hyaline material and to a lesser extent also in the lakes of amorphous material. Both types of abnormalities expressed the soluble part of the ~amyloid precursor protein (residues 60-100 and 8-17), a-anti-chymotrypsin, and ubiquitin.

Workshop Report

385

Actin was encountered within the hyaline autophagic vacuoles. The other familial bodies, but not within the lakes of amorphous myopathy of autosomal-dominant type in four material. The immunolocalization of a multi- families who might, nevertheless, be related to tude of proteins within the zones of myofibril- each other suggesting a common origin of this lar degeneration in affected muscle fibres of familial myopathy, was of late onset, but these 10 patients, some with autosomal- without cardiac abnormalities. Morpholodominant inheritance, suggested that at least gically, separ-ate aggregates of desmin and part of the observations were secondary to actin were prominent. Linkage studies are myofibrillar degeneration. A partly similar under way in these families. Two reports came from France; one given by pattern of proteins was immunolocalized to other sites of myofibrillar degeneration includ- M. Fardeau (Paris) concerned four families ing unstructured central cores and target with 19 affected members altogether originating formation, i.e. an increase in desmin, a-actinin, from Normandy and Alsace, originally discovnebulin, dystrophin, and a terminal component ered by Jean Gruner at Strasbourg. The second of the fl-A4 amyloid protein [20]. report concerned a family from Southern P. Vicart (Paris) reported on new molecular France studied by J. Pellissier (Marseilles). This genetic data derived from a family with desmin- myopathy, associated with a cardiomyopathy, related myopathy published earlier [12]. is marked by rubbed-out lesions in oxidative Comparative analysis of desmin cDNA enzyme preparations and diffusely amassed sequences derived from patient and control granulofilamentous material which contains individuals revealed no difference in the coding both desmin and actin in increased amounts, sequence. A linkage analysis was also the desmin being hyperphosphorylated, but not performed using the highly polymorphic associated with respectively increased mRNA, markers A F M 119xcF, AFM 165zh8 and AFM which suggests a defect in degradation. The b354we5. The desmin gene involvement in this structure of the sarcomeres had not been disease was clearly excluded in three unrelated affected by the formation of the intersarcomfamilies. eric granulofilamentous material. Respective myopathoiogical studies on cardiac and smooth muscles have not been performed. FAMILIAL CONDITIONS WITH EXCESSOF Another family from Normandy was DESMIN - - D E S M I N - R E L A T E D MYOPATHIES reported by F. Chapon and A. Caron (Caen), Eight participants reported on such In this family, however, cytoplasmic bodies European neuromuscular conditions which can contained desmin, but also dystrophin as docucurrently best be subclassified into two groups, mented by antibodies dysl, dys2, and dys3, as one marked by inclusion body type-excess of well as actin which, by immunoelectron desmin, the other by granulofilamentous mater- microscopy was found in the core of the cytoial [2], the latter group also more often display- plasmic bodies, which were present in 1-10% of ing an associated cardiomyopathy. Both muscle fibres, whereas desmin and dystrophin autosomal-dominant and autosomal-recessive were present in the halo. Western blot analysis modes of inheritance have been reported (Table also revealed increased amounts of desmin and 1), having occurred in several European coun- dystrophin, somewhat correlating with the tries. Among families with desmin-related frequency of the cytoplasmic bodies, desmin myopathies from Europe, Edstr6m apparently of the acidic isoform when studied (Stockholm) had studied two types of by two-dimensional electrophoresis whereas myopathies, one marked by the formation of actin did not differ from controls. Using bisarcoplasmic bodies [9] somewhat resembling directional electrophoresis, three isoforms of Welander's distal myopathy which, however, desmin have been discovered by some [3, 21]. may give a mixed myopathic-neurogenic elec- [Chapon and Caron: this report], but six tromyographic pattern and autophagic isoforms by others [22]. vacuoles within muscle fibres as well as M. Wagner (G6ttingen) updated information intrasarcoplasmic and intranucelar filaments, as on a German family with Mallory body-like also seen in inclusion body myositis, whereas inclusions, reported earlier [23]. The older sarcoplasmic-body myopathy displays a purely patient, now 27 years old, had characteristic myopathic electromyographic pattern and no facial proximal muscle weakness, progressive

386

Workshop Report Table I. Familialconditions with excessof desmin - desmin-related myopathies

Inclusion body type: Goebel et al. [7], Clark et al. [24] Edstr6m e t al. [9] Fidzianska et al. [23] Dickoffet al. [29], Dickoff[30] Chapon e t al. [31], Caron et al. [32] Fidzianska et al. [33] Granulofilamentous type: Fardeau et al. [12], Rappaport et al. [22] Porte e t al. [34], Stoeekelet aL [35] Goebel et al. [19]: (brothers) Vajsar e t

al.

[14]:(siblings)

Helliwell et al. [25] Horowitz and Sehmalbruch [16] Pellissier et al. [36]

scoliosis, respiratory insufficiency, and clinical cardiomyopathy with an atrioventricular block. Compared to an earlier muscle biopsy specimen his plastic-embedded biopsy specimen revealed fewer Mallory body-like inclusions. The younger brother, now 19 years old, also showed facial proximal muscle weakness as well as progressive scoliosis, but no cardiac or respiratory functional impairment. Seven children from four different Polish families, reported by A. Fidzianska (Warsaw), showed similar clinical and myopathological features, the Mallorybody type inclusions not only containing desmin but also dystrophin marked by antibodies dysl, dys2, dys3, and helical filaments at the ultrastructural level. Scoliosis was a very early and prominent sign, possibly not secondary to weakness of the paraspinal muscle, but an independent clinical sign. As with the family of Wagner (G6ttingen), cardiomyopathy was not present. In both the German and Polish families, autosomal-recessive mode of inheritance of the myopathy was suggested. Another family from Poland was reported by A. Fidzianska and A. Kaminska (Warsaw). Two patients with autosomal-recessive slowly progressive, late-onset inclusion body myopathy with desmin accumulation had autophagic vacuoles, intrasarcoplasmic and intranuclear filaments as well as granulofilamentous material positive for desmin (antibody Dako D33). As a special guest, M. Conneally (Indianapolis) reported on the first genetic links within a large family affected with spheroid body myopathy residing in Indiana [7], Oregon [24] and Ohio, based on personal neurological

Autosomal-dominant Autosomal-dominant Autosomal-recessive Autosomal-dominant Autosomal-dominant Autosomal-recessive

U.S.A. Sweden Germany U.S.A. France Poland

Autosomal-dominant Unknown Autosomal-recessive, X-linked recessive? Autosomal-recessive, X-linked recessive? Autosomal-dominant Autosomal-dominant Autosomal-dominant

France France Germany Canada U.K. U.S.A. France

examinations and review of the family histories which also allowed the identification of new affected members since the earlier reports [7, 24]. The size of this family and the large number of living patients being the largest kinship reported so far among desmin-related myopathy patients' families form a most promising basis for linkage studies to identify the gene that causes this autosomal-dominant slowly progressive late-onset congenital myopathy. Such linkage studies will be initiated in conjunction with Genethon (France). T. Helliwell (Liverpool) summarized the findings on a family spread across England whose studies have been performed in Liverpool and Cambridge [25], using desmin antibodies DER-I I and D33. This familial adult-onset autosomal-dominant desmin-related myopathy showed granulofilamentous material positive for increased amounts of desmin, dystrophin and vimentin as well as ubiquitin, whereas other proteins of the dystrophin-glycoprotein complex were not present. He also reported two additional unrelated male patients, 50 and 78 years old, respectively. They had increased amounts of desmin, in the older patient of unknown cause, but in the younger patient possibly related to organophosphate exposure because the formation of cytoplasmic bodies has been described after organophosphate intoxication [26]. He further reported on different myopathoiogical features of the D33 antidesmin antibodies, showing an increased labelling in intensive care unit muscle atrophy with loss of myosin, but no increase in labelling in steroid-induced type-II muscle fibre atrophy. A. Di Muzio (Chieti) and E. Bertini (Rome)

387

Workshop Report

reported on an autosomal-dominant familial desminopathy from central Italy whose affected members also had a neuropathy. Finally, a multi-system disorder marked by increased amounts of desmin in skeletal muscle fibres, cardiac myocytes and intestinal smooth muscle using the D33 antidesmin antibody was reported by A. Ariza (Barcelona), based on biopsy and autopsy studies. This excess of desmin was marked ultrastructurally by granular material, but increased numbers of mitochondria were also present as were reducing bodies. Spinal cord and spinal nerve roots contained spheroids within axons rich in neurofilaments. This study reported results similar to those recorded by Vajsar et al. [14] in two siblings and another study by Prelle et al. [27], thereby further augmenting the number of patients who had a generalized increase in intermediate filaments, i.e. desmin in skeletal muscle fibres and neurofilaments in axons. These desmin-related myopathies differ from the familial myopathy reported by Muntoni et al. [5] which is marked by retardation, cardiomyopathy, X-linked inheritance, accumulation of desmin with autophagic vacuoles and thereby representing glycogen storage with normal acid maltase activity.

List o f participants

A Ariza (Barcelona, Spain); E Bertini (Rome, Italy); A Caron (Caen, France); F Chapon (Caen, France); J M Conneally (Indianapolis, U . S . A . ) ; J De Bleecker (Gent, Belgium); M Fardeau (Paris, France); A Fidzianska (Warsaw, Poland); H H Goebel (Mainz, Germany); T Helliwell (Liverpool, U.K.); A Kaminska (Warsaw, Poland); D Paulin (Paris, France); A Di Muzio (Chieti, Italy); L Edstr6m (Stockholm, Sweden); L-E Thornell (Umea, Sweden); P Vicart (Paris, France); M Wagner (G6ttingen, Germany). Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and its main sponsors: Association Franeaise contre les Myopathies, Italian Telethon Committee, Muscular Dystrophy Group of Great Britain and Northern Ireland, Unione ltaliana Lotta alia Distrofia Muscolare, Vereniging Spierziekten Nederland as well as its associate members: Sehweizeriscbe Stiftung far die Erforschung der Muskelrankheiten, Deutsche Gesellschaft f'tir Muskelkranke, and Muskeisvindfonden. Furthermore, we are grateful to Prof. Alan E. H. Emery for his scientific advice and to Michael Rutgers and Janine de Vries for organizational support. We also thank Mrs A. W6ber for editorial assistance. Acknowledgements--This

H. H. GOEBEL Division of Neuropathology Mainz University Medical School Mainz, Germany

CONCLUSION

This workshop aspects:

featured two

prominent

1. A considerable heterogeneity of the familial desmin-related myopathies as to clinical symptoms, involvement of the heart, and myopathological features including immunohistochemical data which have now been enlarged considerably. This nosological heterogeneity of desmin-related familial myopathies requires the establishment of diagnostic criteria as have been developed for other neuromuscular disorders [29]. . As no abnormal gene has been recognized in these familial desmin-related myopathies, the application of these diagnostic criteria appears essential to proceed with and augment further genetic research as initiated by linkage studies in spheroid body myopathy (Conneally, Indianapolis) and sarcoplasmic body myopathy (Edstr6m, Stockholm).

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