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Does increased desmin in myofibres constitute a storage disease?
Neuromusc. Disord., Vol. 3, No. 1, pp. 3~.. 1993 Printed in Great Britain
0960-8966/93 $6.00 + 0.00 © 1993 Pergamon Press Ltd
EDITORIAL COMMENT DOES INCREASED
DESMIN
IN MYOFIBRES
CONSTITUTE
A STORAGE
DISEASE?
A storage disease is characterized by the excessive accumulation of a metabolic product within cells. That product may be a normal constituent, such as the massive aggregation of normal glycogen particles in glycogenosis II (Pompe disease) or may be an abnormal molecule, such as the abnormally structured glycogen in glycogenosis IV (brancher enzyme deficiency). The storage molecule may be simple, as with triglyceride lipids that accumulate in muscle carnitine deficiency, or complex as with the accumulation of gangliosides in neurons in TaySachs disease or of ceroid-lipofuscin pigment in Batten disease. The cause of storage diseases is usually a genetically-determined deficiency of an enzyme essential for the biosynthesis or further metabolism of the stored product, but in exceptional cases storage occurs secondary to a dietary deficiency, a disease that incidentally interferes with metabolism, or a cytotoxin. Desmin is a normal cytoskeletal protein forming intermediate filaments in muscle cells of all types, best demonstrated in tissue sections by immunocytochemical techniques. It is in high concentration in developing striated myofibres, especially foetal myotubes, but then diminishes to a low level in mature muscle, where it still serves a function in maintaining the alignment or "registry" of Z-bands of adjacent myofibrils [13] and also at neuromuscular junctions [4]. Desmin is abundant in regenerating myofibres [3], as with foetal myotubes. Several neuromuscular diseases are now recognized to exhibit an excess of desmin as one feature and, in some cases, is suspected of playing a major role in pathogenesis. Can such diseases be regarded as "desmin storage diseases"? Vimentin is another intermediate filament protein abundant in foetal muscle but disappearing completely during maturation and reappearing only in regeneration. The conditions in which desmin is pathologically increased may be classified according to its association with increased vimentin and by its distribution:
(A) diffusely increased desmin and vimentin in all myofibres: the single known example is Xlinked recessive myotubular myopathy [1, 3]; (B) diffusely increased desmin without vimentin, in all myofibres: infantile myotonic dystrophy may be an example [2, 3]; (C) scattered non-regenerating myofibres with increased desmin: the myopathy of cerebrohepato-renal (Zellweger) disease and some cases of congenital muscle fibre-type disproportion are examples [3]; (D) focally increased desmin within some myofibres: in nemaline rod disease, desmin is increased in perinuclear zones and in regions of rod aggregation [3, 5]; in spinal muscular atrophy, the small myofibres exhibit a subsarcolemmal ring of increased desmin [2, 3]; many rare myopathies are described that show inclusion-like structures reactive with antidesmin antibodies and ultrastructural filaments consistent with desmin [5-13]. Numerous ribosomes in the sarcoplasm is a feature of regenerating myofibres and distinguishing them from the conditions listed above in which desmin also is increased. The increased RNA is well-demonstrated under ultraviolet light by the fluorochrome acridine orange [2, 3, 14, 15]. In a recent issue of Neuromuscular Disorders, Prelle et al. [16] introduced the provocative concept of a hypothetical "desmin storage myopathy", though they did not use this term to describe their case. By tradition, storage products have included glycogens, simple and complex lipids and lipoproteins. Amyloid might be another example, but is an extracellular deposition. Structural proteins forming the cytoskeleton have never been regarded as storage molecules. An increased number, as well as a disarray, of neurofilaments form the neurofibrillary tangles of Alzheimer disease. Filaments of glial fibrillary acidic protein aggregate in reactive astrocYtes. Intermediate filaments often proliferate in neoplastic cells. None of these
4
Editorial Comment
conditions would be described as "storage" diseases. The criteria of a storage molecule link the q u a n t i t a t i v e increase to a blockage in the biochemical p a t h w a y of degradation. I n those myopathies in which desmin is increased, either generally or focally, a u g m e n t e d biosynthesis is more likely than impaired catabolism. F o r example, in X-linked m y o t u b u l a r m y o p a t h y , it is speculated that (hypothetical) v i m e n t i n a n d desmin suppressor genes at the Xq28 locus are defective so that the synthetic genes for vimentin, at the 10p13, a n d desmin, at the 2q35 loci, c o n t i n u e to be expressed in muscle after early foetal life [1, 3]; if confirmed, this m a y prove to be the pathogenetic m e c h a n i s m that prevents the reorganization o f the architecture o f the m a t u r ing myofibre. Unless a metabolic block in desmin degradation is d e m o n s t r a t e d , increased desmin in myofibres does n o t fulfill the present criteria of storage, a n d from the available data, " d e s m i n storage diseases" do n o t exist. HARVEY B. SARNA~ Editorial Board Member Departments of Pediatrics, Medicine (Neurology) and Pathology (Neuropathology) University of Washington School of Medicine Seattle Washington U.S.A.
REFERENCES
1. Sarnat H B. Myotubular myopathy: arrest of myofibres associated with persistence of foetal vimentin and desmin. Four cases compared with foetal and neonatal muscle. Can J Neurol Sci 1990; 17: 109-123. 2. Sarnat H B, Vimentin/desmin immunoreactivity of myofibres in developmental myopathies. Acta Paediatr
Jap 1991;33:238 246. 3. Sarnat H B. Vimentin and desmin in maturing skeletal muscle and developmental myopathies. Neurology 1992; 42: 1616-1624. 4. Askanas V, Bornemann A, Engel W K. Immunocytochemical localization of desmin at human neuromuscular junctions. Neurology 1990;40: 949-953. 5. Thornell L-E, Edstr6m L, Eriksson A, Henriksson K G, Angqvist K A. The distribution of intermediate filament protein (skeletin) in normal and diseased human muscle. J Neurol Sci 1980;47:153-170. 6. Fardeau M, Godot-Guillain J, Tom6 F M S, et al. Une nouvelle affection musculaire familiale d6finie par l'accumulation intrasarcoplasmique d'un mat6riel granulofilamentairedense en microscopie61ectronique. Rev Neurol (Paris) 1978; 134:411-425. 7. Edstr6m L, Thronell L-E, Eriksson A. A new type of hereditary distal myopathy with characteristic sarcoplasmic bodies and intermediate (skeletin) filaments. J Neurol Sci 1980;47:171-190. 8. Fidziafiska A, Goebel H H, Osborn M, et al. Mallory body-like inclusions in a hereditary congenital neuromuscular disease. Muscle Nerve 1983;6: 195-200. 9. Osborn M, Goebel H H. The cytoplasmic bodies in a congenital myopathy can be stained with antibodies to desmin, the muscle-specific intermediate filament protein. Acta Neuropathol (Berl) 1983;62:149-152. 10. Pellissier J P, Pouget J, Charpin C, Figarella D. Myopathy associated with desmin type intermediate filaments. An immunoelectron microscopic study. J Neural Sci 1989;89:49-61. 11. Chapon F, Viader F, Fardeau M, et al. Myopathie familialeavec inclusionsde type ~corps cytoplasmique~> (ou ,sph~roides,) r~v61~e par une insuftisance respiratoire. Rev Neurol (Paris') 1989; 145: 46ff465. 12. Schr6der J M, Commer C, Schmidt B. Desmin and actin associated with cytoplasmic bodies in skeletal muscle fibers: immunocytochemicaland fine structural studies, with a note on unusual 18- to 20-nm filaments. A cta Neuropathol (Berl) 1990; 80: 406-414. 13. Halbig L, Goebel H H, Hopf H C, Moll R. Spheroidcytoplasmic complexes in a congenital myopathy. Rev Neurol (Paris) 1991; 147: 300-307. 14. Perl D P, Little B W. Acridine orange-nucleic acid flourescence. Its use in routine diagnostic muscle biopsies. Arch Neurol 1980;37: 641-644. 15. Sarnat H B. L'acridine-orange: un fluorochrome pour l'6tude des cellulesmusculaireset nerveuses. Rev Neurol (Paris) 1985; 141: 120-127. 16. Prelle A, Moggio M, Comi G P, et al. Congenital myopathy associated with abnormal accumulation of desmin and dystrophin. Neuromusc Disord 1992; 2: 169-175.
0960-8966/93 $6.00 + 0.00 © 1993 Pergamon Press Ltd
EDITORIAL COMMENT DOES INCREASED
DESMIN
IN MYOFIBRES
CONSTITUTE
A STORAGE
DISEASE?
A storage disease is characterized by the excessive accumulation of a metabolic product within cells. That product may be a normal constituent, such as the massive aggregation of normal glycogen particles in glycogenosis II (Pompe disease) or may be an abnormal molecule, such as the abnormally structured glycogen in glycogenosis IV (brancher enzyme deficiency). The storage molecule may be simple, as with triglyceride lipids that accumulate in muscle carnitine deficiency, or complex as with the accumulation of gangliosides in neurons in TaySachs disease or of ceroid-lipofuscin pigment in Batten disease. The cause of storage diseases is usually a genetically-determined deficiency of an enzyme essential for the biosynthesis or further metabolism of the stored product, but in exceptional cases storage occurs secondary to a dietary deficiency, a disease that incidentally interferes with metabolism, or a cytotoxin. Desmin is a normal cytoskeletal protein forming intermediate filaments in muscle cells of all types, best demonstrated in tissue sections by immunocytochemical techniques. It is in high concentration in developing striated myofibres, especially foetal myotubes, but then diminishes to a low level in mature muscle, where it still serves a function in maintaining the alignment or "registry" of Z-bands of adjacent myofibrils [13] and also at neuromuscular junctions [4]. Desmin is abundant in regenerating myofibres [3], as with foetal myotubes. Several neuromuscular diseases are now recognized to exhibit an excess of desmin as one feature and, in some cases, is suspected of playing a major role in pathogenesis. Can such diseases be regarded as "desmin storage diseases"? Vimentin is another intermediate filament protein abundant in foetal muscle but disappearing completely during maturation and reappearing only in regeneration. The conditions in which desmin is pathologically increased may be classified according to its association with increased vimentin and by its distribution:
(A) diffusely increased desmin and vimentin in all myofibres: the single known example is Xlinked recessive myotubular myopathy [1, 3]; (B) diffusely increased desmin without vimentin, in all myofibres: infantile myotonic dystrophy may be an example [2, 3]; (C) scattered non-regenerating myofibres with increased desmin: the myopathy of cerebrohepato-renal (Zellweger) disease and some cases of congenital muscle fibre-type disproportion are examples [3]; (D) focally increased desmin within some myofibres: in nemaline rod disease, desmin is increased in perinuclear zones and in regions of rod aggregation [3, 5]; in spinal muscular atrophy, the small myofibres exhibit a subsarcolemmal ring of increased desmin [2, 3]; many rare myopathies are described that show inclusion-like structures reactive with antidesmin antibodies and ultrastructural filaments consistent with desmin [5-13]. Numerous ribosomes in the sarcoplasm is a feature of regenerating myofibres and distinguishing them from the conditions listed above in which desmin also is increased. The increased RNA is well-demonstrated under ultraviolet light by the fluorochrome acridine orange [2, 3, 14, 15]. In a recent issue of Neuromuscular Disorders, Prelle et al. [16] introduced the provocative concept of a hypothetical "desmin storage myopathy", though they did not use this term to describe their case. By tradition, storage products have included glycogens, simple and complex lipids and lipoproteins. Amyloid might be another example, but is an extracellular deposition. Structural proteins forming the cytoskeleton have never been regarded as storage molecules. An increased number, as well as a disarray, of neurofilaments form the neurofibrillary tangles of Alzheimer disease. Filaments of glial fibrillary acidic protein aggregate in reactive astrocYtes. Intermediate filaments often proliferate in neoplastic cells. None of these
4
Editorial Comment
conditions would be described as "storage" diseases. The criteria of a storage molecule link the q u a n t i t a t i v e increase to a blockage in the biochemical p a t h w a y of degradation. I n those myopathies in which desmin is increased, either generally or focally, a u g m e n t e d biosynthesis is more likely than impaired catabolism. F o r example, in X-linked m y o t u b u l a r m y o p a t h y , it is speculated that (hypothetical) v i m e n t i n a n d desmin suppressor genes at the Xq28 locus are defective so that the synthetic genes for vimentin, at the 10p13, a n d desmin, at the 2q35 loci, c o n t i n u e to be expressed in muscle after early foetal life [1, 3]; if confirmed, this m a y prove to be the pathogenetic m e c h a n i s m that prevents the reorganization o f the architecture o f the m a t u r ing myofibre. Unless a metabolic block in desmin degradation is d e m o n s t r a t e d , increased desmin in myofibres does n o t fulfill the present criteria of storage, a n d from the available data, " d e s m i n storage diseases" do n o t exist. HARVEY B. SARNA~ Editorial Board Member Departments of Pediatrics, Medicine (Neurology) and Pathology (Neuropathology) University of Washington School of Medicine Seattle Washington U.S.A.
REFERENCES
1. Sarnat H B. Myotubular myopathy: arrest of myofibres associated with persistence of foetal vimentin and desmin. Four cases compared with foetal and neonatal muscle. Can J Neurol Sci 1990; 17: 109-123. 2. Sarnat H B, Vimentin/desmin immunoreactivity of myofibres in developmental myopathies. Acta Paediatr
Jap 1991;33:238 246. 3. Sarnat H B. Vimentin and desmin in maturing skeletal muscle and developmental myopathies. Neurology 1992; 42: 1616-1624. 4. Askanas V, Bornemann A, Engel W K. Immunocytochemical localization of desmin at human neuromuscular junctions. Neurology 1990;40: 949-953. 5. Thornell L-E, Edstr6m L, Eriksson A, Henriksson K G, Angqvist K A. The distribution of intermediate filament protein (skeletin) in normal and diseased human muscle. J Neurol Sci 1980;47:153-170. 6. Fardeau M, Godot-Guillain J, Tom6 F M S, et al. Une nouvelle affection musculaire familiale d6finie par l'accumulation intrasarcoplasmique d'un mat6riel granulofilamentairedense en microscopie61ectronique. Rev Neurol (Paris) 1978; 134:411-425. 7. Edstr6m L, Thronell L-E, Eriksson A. A new type of hereditary distal myopathy with characteristic sarcoplasmic bodies and intermediate (skeletin) filaments. J Neurol Sci 1980;47:171-190. 8. Fidziafiska A, Goebel H H, Osborn M, et al. Mallory body-like inclusions in a hereditary congenital neuromuscular disease. Muscle Nerve 1983;6: 195-200. 9. Osborn M, Goebel H H. The cytoplasmic bodies in a congenital myopathy can be stained with antibodies to desmin, the muscle-specific intermediate filament protein. Acta Neuropathol (Berl) 1983;62:149-152. 10. Pellissier J P, Pouget J, Charpin C, Figarella D. Myopathy associated with desmin type intermediate filaments. An immunoelectron microscopic study. J Neural Sci 1989;89:49-61. 11. Chapon F, Viader F, Fardeau M, et al. Myopathie familialeavec inclusionsde type ~corps cytoplasmique~> (ou ,sph~roides,) r~v61~e par une insuftisance respiratoire. Rev Neurol (Paris') 1989; 145: 46ff465. 12. Schr6der J M, Commer C, Schmidt B. Desmin and actin associated with cytoplasmic bodies in skeletal muscle fibers: immunocytochemicaland fine structural studies, with a note on unusual 18- to 20-nm filaments. A cta Neuropathol (Berl) 1990; 80: 406-414. 13. Halbig L, Goebel H H, Hopf H C, Moll R. Spheroidcytoplasmic complexes in a congenital myopathy. Rev Neurol (Paris) 1991; 147: 300-307. 14. Perl D P, Little B W. Acridine orange-nucleic acid flourescence. Its use in routine diagnostic muscle biopsies. Arch Neurol 1980;37: 641-644. 15. Sarnat H B. L'acridine-orange: un fluorochrome pour l'6tude des cellulesmusculaireset nerveuses. Rev Neurol (Paris) 1985; 141: 120-127. 16. Prelle A, Moggio M, Comi G P, et al. Congenital myopathy associated with abnormal accumulation of desmin and dystrophin. Neuromusc Disord 1992; 2: 169-175.