Thick Filament Diseases

  • Anders Oldfors
  • Phillipa J. Lamont
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 642)


Hereditary myosin myopathies are a newly emerged group of diseases caused by mutations in skeletal muscle myosin heavy chain (MyHC) genes. The phenotypes of these diseases are varied, ranging from prenatal nonprogressive arthrogrypotic syndromes to adult-onset progressive muscle weakness. They are caused by mutations in skeletal muscle myosin heavy chain (MyHC) genes. Mutations have been reported in two of three MyHC isoforms expressed in adult limb skeletal muscle: type I (slow/β-cardiac MyHC; MYH7) and type IIa (MYH2). Most of the mutations described in MYH7 are associated with hypertrophic/dilated cardiomyopathy, with no skeletal muscle involvement. However, some mutations are associated with two distinct skeletal myopathies, namely Laing distal myopathy and myosin storage myopathy. Although initially thought not to have associated cardiac involvement, recent reports have indicated co-existent cardiac and skeletal muscle disease can occur in both. A myopathy associated with a specific mutation in MYH2 is associated with congenital joint contractures and external ophthalmoplegia. Mutations in embryonic MyHC (MYH3) and perinatal MyHC (MYH8) are associated with distal arthrogryposis syndromes with no or minor muscle weakness. This may be expected in myosin isoforms expressed predominantly during muscle development. Clinical findings, muscle morphology and molecular genetics in hereditary myosin myopathies are summarized in this chapter.


Distal Myopathy Skeletal Myopathy Skeletal Muscle Disease Hyaline Body Hereditary Inclusion Body Myopathy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Oldfors A. Hereditary myosin myopathies. Neuromuscul Disord 2007; 17:355–367.PubMedCrossRefGoogle Scholar
  2. 2.
    Kjellgren D, Thornell LE, Andersen J et al. Myosin heavy chain isoforms in human extraocular muscles. Invest Ophthalmol Vis Sci 2003; 44:1419–25.PubMedCrossRefGoogle Scholar
  3. 3.
    Ching YH, Ghosh TK, Cross SJ et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nat Genet 2005; 37:423–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Zhu L, Vranckx R, Khau Van Kien P et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet 2006; 38:343–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Poetter K, Jiang H, Hassanzadeh S et al. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat Genet 1996; 13:63–69.PubMedCrossRefGoogle Scholar
  6. 6.
    Darin N, Kyllerman M, Wahlstrom J et al. Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia and rimmed vacuoles. Ann Neurol 1998; 44:242–248.PubMedCrossRefGoogle Scholar
  7. 7.
    Martinsson T, Darin N, Kyllerman M et al. Dominant hereditary inclusion-body myopathy gene (IBM3) maps to chromosome region 17p13.1. Am J Hum Genet 1999; 64:1420–1426.PubMedCrossRefGoogle Scholar
  8. 8.
    Martinsson T, Oldfors A, Darin N et al. Autosomal dominant myopathy: Missense mutation (Glu-706 to Lys) in the myosin heavy chain IIa gene. Proc Natl Acad Sci USA 2000; 97:14614–14619.PubMedCrossRefGoogle Scholar
  9. 9.
    Sunnerhagen KS, Darin N, Tasjharghi H. The effects of endurance training in persons with a hereditary myosin myopathy. Acta Neurol Scand 2004; 110:80–86.PubMedCrossRefGoogle Scholar
  10. 10.
    Tajsharghi H, Stibrant Sunnerhagen K, Darin N et al. Induced shift in myosin heavy chain expression in myosin myopathy by endurance training. J Neurol 2004; 251:179–183.PubMedCrossRefGoogle Scholar
  11. 11.
    Tajsharghi H, Thornell LE, Darin N et al. Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age. Neurology 2002; 58:780–786PubMedGoogle Scholar
  12. 12.
    Jansson M, Darin N, Kyllerman M et al. Multiple mitochondrial DNA deletions in hereditary inclusion body myopathy. Acta Neuropathol (Berl) 2000; 100:23–28.CrossRefGoogle Scholar
  13. 13.
    Li M, Lionikas A, Yu F et al. Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys). Neuromuscul Disord 2006; 16:782–791.PubMedCrossRefGoogle Scholar
  14. 14.
    Zeng W, Conibear PB, Dickens JL et al. Dynamics of actomyosin interactions in relation to the cross-bridge cycle. Phil Trans R Soc B 2004; 359:1843–1855.PubMedCrossRefGoogle Scholar
  15. 15.
    Tajsharghi H, Pilon M, Oldfors A. A Caenorhabditis elegans model of the myosin heavy chain IIa E706K mutation. Ann Neurol 2005; 58:442–448.PubMedCrossRefGoogle Scholar
  16. 16.
    Tajsharghi H, Darin N, Rekabdar E et al. Mutations and sequence variation in the human myosin heavy chain IIa gene (MYH2). Eur J Hum Genet 2005; 13:617–622.PubMedCrossRefGoogle Scholar
  17. 17.
    Kimber E, Tajsharghi H, Kroksmark AK et al. A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis. Neurology 2006; 67:597–601.PubMedCrossRefGoogle Scholar
  18. 18.
    Sung SS, Brassington AM, Grannatt K et al. Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am J Hum Genet 2003; 72:681–690.PubMedCrossRefGoogle Scholar
  19. 19.
    Sung SS, Brassington AM, Krakowiak PA et al. Mutations in TNNT3 cause multiple congenital contractures: A second locus for distal arthrogryposis type 2B. Am J Hum Genet 2003; 73:212–214.PubMedCrossRefGoogle Scholar
  20. 20.
    Tajsharghi H, Kimber E, Holmgren D et al. Distal arthrogryposis and muscle weakness associated with a β-tropomyosin mutation. Neurology 2007; 68:772–775.PubMedCrossRefGoogle Scholar
  21. 21.
    Toydemir RM, Chen H, Proud VK et al. Trismus-pseudo camptodactyly syndrome is caused by recurrent mutation of MYH8. Am J Med Genet A 2006; 140:2387–2393.PubMedGoogle Scholar
  22. 22.
    Toydemir RM, Rutherford A, Whitby FG et al. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet 2006; 38:561–565.PubMedCrossRefGoogle Scholar
  23. 23.
    Veugelers M, Bressan M, McDermott DA et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med 2004; 351:460–469.PubMedCrossRefGoogle Scholar
  24. 24.
    Bamshad M, Jorde LB, Carey JC. A revised and extended classification of the distal arthrogryposes. Am J Med Genet 1996; 65:277–281.PubMedCrossRefGoogle Scholar
  25. 25.
    Hall JG. Arthrogryposis multiplex congenita: Etiology, genetics, classification, diagnostic approach and general aspects. J Pediatr Orthop B 1997; 6:159–166.PubMedGoogle Scholar
  26. 26.
    Stevenson DA, Carey JC, Palumbos J et al. Clinical characteristics and natural history of Freeman-Sheldon syndrome. Pediatrics 2006; 117:754–762.PubMedCrossRefGoogle Scholar
  27. 27.
    Laing NG, Laing BA, Meredith C et al. Autosomal dominant distal myopathy: Linkage to chromosome 14. Am J Hum Genet 1995; 56:422–427.PubMedGoogle Scholar
  28. 28.
    Lamont PJ, Udd B, Mastaglia FL et al. Laing early onset distal myopathy: Slow myosin defect with variable abnormalities on muscle biopsy. J Neurol Neurosurg Psychiatry 2006; 77:208–215.PubMedCrossRefGoogle Scholar
  29. 29.
    Voit T, Kutz P, Leube B et al. Autosomal dominant distal myopathy: Further evidence of a chromosome 14 locus. Neuro muscul Disord 2001; 11:11–19.CrossRefGoogle Scholar
  30. 30.
    Hedera P, Petty EM, Bui MR et al. The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: Genetic and clinical analysis. Arch Neurol 2003; 60:1321–1325.PubMedCrossRefGoogle Scholar
  31. 31.
    Caforio AL, Rossi B, Risaliti R et al. Type 1 fiber abnormalities in skeletal muscle of patients with hypertrophic and dilated cardiomyopathy: Evidence of subclinical myogenic myopathy. J Am Coll Cardiol 1989; 14:1464–1473.PubMedCrossRefGoogle Scholar
  32. 32.
    Fananapazir L, Dalakas MC, Cyran F et al. Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 1993; 90:3993–3997.PubMedCrossRefGoogle Scholar
  33. 33.
    Darin N, Tajsharghi H, Oldfors A. New skeletal myopathy and cardiomyopathy associated with a missense mutation in MYH7. Neurology 2007; (68)23:2041–2042.PubMedCrossRefGoogle Scholar
  34. 34.
    Overeem S, Schelhaas HJ, Blijham PJ et al. Symptomatic distal myopathy with cardiomyopathy due to a MYH7 mutation. Neuromuscul Disord 2007; 17:490–493.PubMedCrossRefGoogle Scholar
  35. 35.
    Meredith C, Herrmann R, Parry C et al. Mutations in the slow skeletal muscle fiber myosin myosin chain gene (MYH7) cause Laing early-onset distal myopathy (MPD1). Am J Hum Genet 2004; 75:703–708.PubMedCrossRefGoogle Scholar
  36. 36.
    Cancilla PA, Kalayanaraman K, Verity MA et al. Familial myopathy with probable lysis of myofibrils in type I fibers. Neurology 1971; 21:579–585.PubMedGoogle Scholar
  37. 37.
    Sahgal V, Sahgal S. A new congenital myopathy: A morphological, cytochemical and histochemical study. Acta Neuropathol (Berl) 1977; 37:225–230.CrossRefGoogle Scholar
  38. 38.
    Engel A, Banker BQ. Ultrastructural changes in diseased muscle. In: Engel A, Banker BQ, eds. Myology Basic and Clincal. New York: McGraw-Hill Company, 1986; 909–1044.Google Scholar
  39. 39.
    Ceuterick C, Martin JJ, Martens C. Hyaline bodies in skeletal muscle of a patient with a mild chronic nonprogressive congenital myopathy. Clin Neuropathol 1993; 12:79–83.PubMedGoogle Scholar
  40. 40.
    Barohn RJ, Brumback RA, Mendell JR. Hyaline body myopathy Neuromuscul Disord 1994; 4:257–262.PubMedCrossRefGoogle Scholar
  41. 41.
    Masuzugawa S, Kuzuhara S, Narita Y et al. Autosomal dominant hyaline body myopathy presenting as scapuloperoneal syndrome: Clinical features and muscle pathology. Neurology 1997; 48:253–257.PubMedGoogle Scholar
  42. 42.
    Bohlega S, Lach B, Meyer BF et al. Autosomal dominant hyaline body myopathy: Clinical variability and pathologic findings. Neurology 2003; 61:1519–1523.PubMedGoogle Scholar
  43. 43.
    Önengüt S, Ugur SA, Karasoy H et al. Identification of a locus for an autosomal recessive hyaline body myopathy at chromosome 3p22.2–p21.32. Neuromuscul Disord 2004; 14:4–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Tajsharghi H, Thornell LE, Lindberg C et al. Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol 2003; 54:494–500.PubMedCrossRefGoogle Scholar
  45. 45.
    Laing NG, Ceuterick-de Groote C, Dye De et al. Myosin storage myopathy: Slow skeletal myosin (MYH7) mutation in two isolated cases. Neurology 2005; 64:527–529.PubMedGoogle Scholar
  46. 46.
    Dye DE, Azzarelli B, Goebel HH, Laing NG. Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred. Neuromuscul Disord 2006; 16:357–360.PubMedCrossRefGoogle Scholar
  47. 47.
    Tajsharghi H, Oldfors A, Macleod DP et al. Homozygous mutation in MYH7 in myosin storage myopathy and cardiomyopathy. Neurology 2007; 68:962.PubMedCrossRefGoogle Scholar
  48. 48.
    Shingde MV, Spring PJ, Maxwell A et al. Myosin storage (hyaline body) myopathy: A case report. Neuromuscul Disord 2006; 16:882–886.PubMedCrossRefGoogle Scholar
  49. 49.
    Pegoraro E, Gavassini BF, Borsato C et al. MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy. Neuromuscul Disord 2007; 17:321–329.PubMedCrossRefGoogle Scholar
  50. 50.
    Sohn RL, Vikstrom KL, Strauss M et al. A 29 residue region of the sarcomeric myosin rod is necessary for filament formation. J Mol Biol 1997; 266:317–330.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  1. 1.Royal Perth HospitalPerthAustralia
  2. 2.Department of PathologySahlgrenska University HospitalGoteborgSweden

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