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Facioscapulohumeral muscular dystrophy

  • Review Article
  • Published:
Neurotherapeutics

Summary

Facioscapulohumeral muscular dystrophy (FSHD), a dominantly inherited disorder, is the third most common dystrophy after Duchenne and myotonic muscular dystrophy. No known effective treatments exist for FSHD. The lack of an understanding of the underlying pathophysiology remains an obstacle in the development of targeted therapeutic interventions. The genetic defect is a loss of a critical number of a repetitive element (D4Z4) in the 4q subtelomeric region. The loss of the repeats results in specific changes in chromatin structure, although neither the molecular nor the cellular consequences of this change are known. Nevertheless, these epigenetic changes in chromatin structure offer a potential therapeutic target. This review discusses current management strategies in FSHD as well as potential therapeutic interventions to slow down or reverse the progressive muscle atrophy and weakness.

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References

  1. Padberg GW. Facioscapulohumeral disease. Thesis. Leiden, The Netherlands: University of Leiden; 1982.

    Google Scholar 

  2. Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW. Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology 2004;63: 176–178.

    Article  CAS  PubMed  Google Scholar 

  3. Fitzsimons RB, Gurwin EB, Bird AC. Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy: a general association with genetic and therapeutic implications. Brain 1987;110: 631–648.

    Article  PubMed  Google Scholar 

  4. Padberg GW, Brouwer OF, de Keizer RF, et al. On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy. Muscle Nerve 1995:S73–S80.

  5. Shields CL, Zahler J, Falk N, et al. Neovascular glaucoma from advanced Coats disease as the initial manifestation of facioscapulohumeral dystrophy in a 2-year-old child. Arch Ophthalmol 2007;125: 840–842.

    Article  PubMed  Google Scholar 

  6. Laforêt P, de Toma C, Eymard B, et al. Cardiac involvement in genetically confirmed facioscapulohumeral muscular dystrophy. Neurology 1998;51: 1454–1456.

    Article  PubMed  Google Scholar 

  7. Wijmenga C, Hewitt JE, Sandkuijl LA, et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 1992;2: 26–30.

    Article  CAS  PubMed  Google Scholar 

  8. Lunt PW, Jardine PE, Koch MC, et al. Correlation between fragment size at D4F104S1 and age of onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD) [Erratum in: Hum Mol Genet 1995;4:1243–1244]. Hum Mol Genet 1995;4: 951–958.

    Article  CAS  PubMed  Google Scholar 

  9. Tawil R, Forrester J, Griggs RC, et al.; The FSH-DY Group. Evidence for anticipation and association of deletion size with severity of facioscapulohumeral muscular dystrophy. Ann Neurol 1996;39: 744–748.

    Article  CAS  PubMed  Google Scholar 

  10. Tupler R, Berardinelli A, Barbierato L, et al. Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy. J Med Genet 1996;33: 366–370.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Lyle R, Wright TJ, Clark LN, Hewitt JE. The FSHD-associated repeat, D4Z4, is a member of a dispersed family of homeobox-containing repeats, subsets of which are clustered on the short arms of the acrocentric chromosomes. Genomics 1995;28: 389–397.

    Article  CAS  PubMed  Google Scholar 

  12. Gabriëls J, Beckers MC, Ding H, et al. Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 1999;236: 25–32.

    Article  PubMed  Google Scholar 

  13. Hewitt JE, Lyle R, Clark LN, et al. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet 1994;3: 1287–1295.

    Article  CAS  PubMed  Google Scholar 

  14. Clapp J, Mitchell LM, Bolland DJ, et al. Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy. Am J Hum Genet 2007;81: 264–279.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. van Deutekom JCT, Lemmers RJLF, Grewal PK, et al. Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35. Hum Mol Genet 1996;5: 581–590.

    Article  PubMed  Google Scholar 

  16. Grewal PK, Todd LC, van der Maarel S, Frants RR, Hewitt JE. FRG1, a gene in the FSH muscular dystrophy region on human chromosome 4q35, is highly conserved in vertebrates and invertebrates. Gene 1998;216: 13–19.

    Article  CAS  PubMed  Google Scholar 

  17. van Koningsbruggen S, Dirks RW, Mommaas AM, et al. FRG1P is localised in the nucleolus, Cajal bodies, and speckles. J Med Genet 2004;41: e46.

    Article  PubMed  Google Scholar 

  18. Gabellini D, Green M, Tupler R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 2002;110: 339–348.

    Article  CAS  PubMed  Google Scholar 

  19. Jiang G, Yang F, van Overveld PG, Vedanarayanan V, van der Maarel S, Ehrlich M. Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum Mol Genet 2003;12: 2909–2921.

    Article  CAS  PubMed  Google Scholar 

  20. Winokur ST, Chen YW, Masny PS, et al. Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. Hum Mol Genet 2003;12: 2895–2907.

    Article  CAS  PubMed  Google Scholar 

  21. Osborne RJ, Welle S, Venance SL, Thornton CA, Tawil R. Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy. Neurology 2007;68: 569–577.

    Article  CAS  PubMed  Google Scholar 

  22. Masny PS, Bengtsson U, Chung SA, et al. Localization of 4q35.2 to the nuclear periphery: is FSHD a nuclear envelope disease? Hum Mol Genet 2004;13: 1857–1871.

    Article  CAS  PubMed  Google Scholar 

  23. de Greef JC, Wohlgemuth M, Chan OA, et al. Hypomethylation is restricted to the D4Z4 repeat array in phenotypic FSHD. Neurology 2007;69: 1018–1026.

    Article  PubMed  Google Scholar 

  24. Petrov A, Allinne J, Pirozhkova I, Laoudj D, Lipinski M, Vassetzky YS. A nuclear matrix attachment site in the 4q35 locus has an enhancer-blocking activity in vivo: implications for the facioscapulo-humeral dystrophy. Genome Res 2008;18: 39–45.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Orrell RW, Tawil R, Forrester J, Kissel JT, Mendell JR, Figlewicz DA. Definitive molecular diagnosis of facioscapulohumeral dystrophy. Neurology 1999;52: 1822–1826.

    Article  CAS  PubMed  Google Scholar 

  26. van Deutekom JC, Bakker E, Lemmers RJ, et al. Evidence for subtelomeric exchange of 3.3 kb tandemly repeated units between chromosomes 4q35 and 10q26: implications for genetic counselling and etiology of FSHD1. Hum Mol Genet 1996;5: 1997–2003.

    Article  PubMed  Google Scholar 

  27. Bushby KM, Pollitt C, Johnson MA, Rogers MT, Chinnery PF. Muscle pain as a prominent feature of facioscapulohumeral muscular dystrophy (FSHD): four illustrative case reports. Neuromuscul Disord 1998;8: 574–579.

    Article  CAS  PubMed  Google Scholar 

  28. Fitzsimons RB. Retinal vascular abnormalities in FSHD: a therapeutic message; clues to pathogenesis. In: Upadhyaya M, Cooper DN, Facioscapulohumeral muscular dystrophy (FSHD): clinical medicine and molecular cell biology. New York: BIOS Scientific Publishers, 2004: 185–195.

    Google Scholar 

  29. McCartney N, Moroz D, Gamer SH, McComas AJ. The effects of strength training in patients with selected neuromuscular disorders. Med Sci Sports Exerc 1988;20: 362–368.

    Article  CAS  PubMed  Google Scholar 

  30. Milner-Brown HS, Miller RG. Muscle strengthening through high-resistance weight training in patients with neuromuscular disorders. Arch Phys Med Rehabil 1988;69: 14–19.

    CAS  PubMed  Google Scholar 

  31. Vignos PJ Jr, Watkins MP. The effect of exercise in muscular dystrophy. JAMA 1966;197: 843–848.

    Article  PubMed  Google Scholar 

  32. Olsen DB, Ørngreen MC, Vissing J. Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy. Neurology 2005;64: 1064–1066.

    Article  PubMed  Google Scholar 

  33. van der Kooi EL, Vogels OJ, van Asseldonk RJ, et al. Strength training and albuterol in facioscapulohumeral muscular dystrophy. Neurology 2004;63: 702–708.

    Article  PubMed  Google Scholar 

  34. Bunch WH, Siegel IM. Scapulothoracic arthrodesis in facioscapulohumeral muscular dystrophy: review of seventeen procedures with three to twenty-one-year follow up. J Bone Joint Surg Am 1993;75: 372–376.

    CAS  PubMed  Google Scholar 

  35. Copeland SA, Levy O, Warner GC, Dodenhoff RM. The shoulder in patients with muscular dystrophy. Clin Orthop 1999;368: 80–91.

    PubMed  Google Scholar 

  36. Giannini S, Faldini C, Pagkrati S, et al. Fixation of winged scapula in facioscapulohumeral muscular dystrophy. Clin Med Res 2007;5: 155–162.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Rhee YG, Ha JH. Long-term results of scapulothoracic arthrodesis of facioscapulohumeral muscular dystrophy. J Shoulder Elbow Surg 2006;15: 445–450.

    Article  PubMed  Google Scholar 

  38. Mummery CJ, Copeland SA, Rose MR. Scapular fixation in muscular dystrophy. Cochrane Database Syst Rev 2003;(3): CD003278.

  39. Wolfe GI, Young PK, Nations SP, Bulkhead WZ, McVey AL, Barohn RJ. Brachial plexopathy following thoracoscapular fusion in facioscapulohumeral muscular dystrophy. Neurology 2005;64: 572–573.

    Article  CAS  PubMed  Google Scholar 

  40. Mackenzie WG, Riddle EC, Earley JL, Sawatzky BJ. A neurovascular complication after scapulothoracic arthrodesis. Clin Orthop Relat Res 2003 Mar;(408):157–161.

  41. Sansone V, Boynton J, Palenski C. Use of gold weights to correct lagophthalmos in neuromuscular disease. Neurology 1997;48: 1500–1503.

    Article  CAS  PubMed  Google Scholar 

  42. Munsat TL, Piper D, Cancilla P, Mednick J. Inflammatory myopathy with facioscapulohumeral distribution. Neurology 1972;22: 335–347.

    Article  CAS  PubMed  Google Scholar 

  43. Bates D, Stevens JC, Hudgson P. “Polymyositis” with involvement of facial and distal musculature: one form of the facioscapulohumeral syndrome? J Neurol Sci 1973;19: 105–108.

    Article  CAS  PubMed  Google Scholar 

  44. Wulff JD, Lin JT, Kepes JJ. Inflammatory facioscapulohumeral muscular dystrophy and Coats syndrome. Ann Neurol 1982;12: 398–401.

    Article  CAS  PubMed  Google Scholar 

  45. Tawil R, McDermott MP, Pandya S, et al.; The FSH-DY Group. A pilot study of prednisone in facioscapulohumeral muscular dystrophy. Neurology 1997;48: 46–49.

    Article  CAS  PubMed  Google Scholar 

  46. Benson DW, Foley-Nelson T, Chance WT, Zhang FS, James JH, Fischer JE. Decreased myofibrillar protein breakdown following treatment with clenbuterol. J Surg Res 1991;50: 1–5.

    Article  CAS  PubMed  Google Scholar 

  47. Matlin CA, Hay SM, McMillan DN, Delday MI. Tissue specific responses to clenbuterol; temporal changes in protein metabolism of striated muscle and visceral tissues from rats. Growth Regul 1992;2: 161–166.

    Google Scholar 

  48. Agbenyega ET, Wareham AC. Effect of clenbuterol on skeletal muscle atrophy in mice induced by the glucocorticoid dexamethasone. Comp Biochem Physiol Comp Physiol 1992;102: 141–145.

    Article  CAS  PubMed  Google Scholar 

  49. Choo JJ, Horan MA, Little RA, Rothwell NJ. Muscle wasting associated with endotoxemia in the rat: modification by the β2-adrenoceptor agonist clenbuterol. Biosci Rep 1989;9: 615–621.

    Article  CAS  PubMed  Google Scholar 

  50. Hayes A, Williams DA. Examining the potential drug therapies for muscular dystrophy utilising the dy/dy mouse: I. Clenbuterol. J Neurol Sci 1998;157: 122–128.

    Article  CAS  PubMed  Google Scholar 

  51. Zeman RJ, Ludemann R, Etlinger JD. Clenbuterol, a β2 agonist, retards atrophy in denervated muscles. Am J Physiol 1987;252: E152-E155.

    CAS  PubMed  Google Scholar 

  52. Martineau L, Horan MA, Rothwell NJ, Little RA. Salbutamol, a β2-adrenoceptor agonist, increases skeletal muscle strength in young men [Erratum in: Clin Sci 1993;84(6):following XX]. Clin Sci (Lond) 1992;83: 615–621.

    CAS  Google Scholar 

  53. Kissel JT, McDermott MP, Mendell JR, et al.; The FSH-DY Group. Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral muscular dystrophy. Neurology 2001;57: 1434–1440.

    Article  CAS  PubMed  Google Scholar 

  54. Kemp GJ, Taylor DJ, Dunn JF, Frostick SP, Radda GK. Cellular energetics of dystrophic muscle. J Neurol Sci 1993;116: 201–206.

    Article  CAS  PubMed  Google Scholar 

  55. Pulido SM, Passaquin AC, Leijendekker WJ, Challet C, Walliman T, Ruegg UT. Creatine supplementation improves intracellular Ca2+ handling and survival in mdx skeletal muscle cells. GEBS Lett 1998;439: 357–362.

    CAS  Google Scholar 

  56. Walter MC, Lochmüller H, Reilich P, et al. Creatine monohydrate in muscular dystrophies: a double-blind placebo controlled clinical study. Neurology 2000;54: 1848–1850.

    Article  CAS  PubMed  Google Scholar 

  57. Rose MR, Tawil R. Drug treatment for facioscapulohumeral muscular dystrophy. Cochrane Database Syst Rev 2004;(2): CD002276.

  58. Patel K, Amthor H. The function of myostatin and strategies of myostatin blockade: new hope for therapies aimed at promoting growth of skeletal muscle. Neuromuscul Disord 2005;15: 117–126.

    Article  CAS  PubMed  Google Scholar 

  59. Wagner KR, Fleckenstein JL, Amato AA, et al. A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol 2008;63: 561–571.

    Article  CAS  PubMed  Google Scholar 

  60. van Overveld PG, Enthoven L, Ricci E, et al. Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy. Ann Neurol 2005;58: 569–576.

    Article  PubMed  Google Scholar 

  61. van der Kooi EL, de Greef JC, Wohlgemuth M, et al. No effect of folic acid and methionine supplementation on D4Z4 methylation in patients with facioscapulohumeral muscular dystrophy. Neuromuscul Disord 2006;16: 766–769.

    Article  PubMed  Google Scholar 

  62. Lee SJ, Reed LA, Davies MV, et al. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci U S A 2005;102: 18117–18122.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Lachey J, Pullen A, Pearsall R, Seehra J. Novel myostatin inhibitors increase muscle mass in wild-type and mdx mice. Neuromuscul Disord 2007;17: 785 (abstract).

    Google Scholar 

  64. Vilquin JT, Marolleau JP, Sacconi S, et al. Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients. Gene Ther 2005;12: 1651–1662.

    Article  CAS  PubMed  Google Scholar 

  65. Morosetti R, Mirabella M, Gliubizzi C, et al. Isolation and characterization of mesoangioblasts from facioscapulohumeral muscular dystrophy muscle biopsies. Stem Cells 2007;25: 3173–3182.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Rabi Tawil.

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Tawil, R. Facioscapulohumeral muscular dystrophy. Neurotherapeutics 5, 601–606 (2008). https://doi.org/10.1016/j.nurt.2008.07.005

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