Skip to main content

Advertisement

SpringerLink
Log in

Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

An Erratum to this article was published on 11 January 2011

Abstract

Patients with myasthenia gravis (MG) with antibodies to muscle-specific receptor tyrosine kinase (MuSK) differ from acetylcholine receptor (AChR)-positive MG patients, as they frequently present with severe oculobulbar muscle weakness or with neck, shoulder, and respiratory muscle involvement. The neuromuscular junction (NMJ) has been confirmed to be the main target of both AChR- and MuSK-MG. However, histopathological investigation disclosed that muscle fiber atrophy was prevalent in AChR-MG, whereas mild myopathic changes and mitochondrial abnormalities were more frequently observed in MuSK-MG. As the pathogenetic mechanism in MuSK-MG remains unclear, this study investigated the submicroscopic pattern of muscle histopathology to establish a possible correlation between clinical involvement and subcellular morphological findings. Muscle biopsies from seven MuSK-MG patients and from seven patients with AChR-MG were analyzed by transmission electron microscopy. Myopathic and mitochondrial abnormalities were more prominent in MuSK-MG and show giant, swollen, and degenerated mitochondria with fragmented cristae. The most common changes in AChR-MG muscles were fiber atrophy, myofibrillar disarray, and Z-line streaming, consistent with mild neurogenic abnormalities. A different pathogenetic mechanism is emerging in MuSK-MG compared to AChR-MG. Mitochondrial abnormalities seem to be more prominent in MuSK-MG, whereas neurogenic atrophy is observed in AChR-MG.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Drachman DB (1994) Myasthenia gravis. N Engl J Med 330:1797–1810

    Article  PubMed  CAS  Google Scholar 

  2. Keesey JC (2004) Clinical evaluation and management of myasthenia gravis. Muscle Nerve 29:484–505

    Article  PubMed  Google Scholar 

  3. Angelini C (1994) Miastenia grave: progressi clinici. Piccin Editor, pp 209–220

  4. Jaretski III, Bahron RJ, Ernstoff RM et al (2000) Myasthenia gravis: recommendations for clinical research standards. Neurology 55:16–23

    Google Scholar 

  5. Mossman S, Vincent A, Newsom-Davis J (1986) Myasthenia gravis without acetylcholine receptor antibody: a distinct disease entity. Lancet 1:116–119

    Article  PubMed  CAS  Google Scholar 

  6. Hoch W, McConville J, Helms J et al (2001) Auto-antibodies to the receptor tyrosin-kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7:365–368

    Article  PubMed  CAS  Google Scholar 

  7. Nemoto Y, Kuwabara S, Misawa N et al (2005) Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis. J Neurol Neurosurg Psychiatry 76:714–718

    Article  PubMed  CAS  Google Scholar 

  8. Rostedt Punga A, Ahlqvist K, Bartoccioni E et al (2006) Neurophysiological and mitochondrial abnormalities in MuSK antibody seropositive myasthenia gravis compared to other immunological subtypes. Clin Neurophysiol 117:1434–1443

    Article  PubMed  CAS  Google Scholar 

  9. DeChiara TM, Bowen DC, Valenzuela DM et al (1996) The receptor tyrosin kinase MuSK is required for neuromuscular junction formation in vivo. Cell 85:501–512

    Article  PubMed  CAS  Google Scholar 

  10. Deymeer F, Gungor-Tuncer O, Yilmaz V et al (2007) Clinical comparison of anti-MuSK vs anti-AChR-positive and seronegative myasthenia gravis. Neurology 68:609–611

    Article  PubMed  CAS  Google Scholar 

  11. Romi F, Aarli, Gilhus NE (2005) Seronegative myasthenia gravis: disease severity and prognosis. Eur J Neurol 12:413–418

    Article  PubMed  CAS  Google Scholar 

  12. Guptill JT, Sanders DB (2010) Update on muscle-specific tyrosine kinase antibody positive myasthenia gravis. Curr Opin Neurol 23:530–535

    Article  PubMed  CAS  Google Scholar 

  13. Sanders DB, El-Salem K, Massey JM et al (2003) Clinical aspects of MuSK antibody positive seronegative MG. Neurology 60:1978–1980

    PubMed  CAS  Google Scholar 

  14. Martignago S, Fanin M, Albertini E et al (2009) Muscle histopathology in myasthenia gravis with antibodies against MuSK and AChR. Neuropathol Appl Neurobiol 35:103–110

    Article  PubMed  CAS  Google Scholar 

  15. Farrugia ME, Robson MD, Clover L et al (2006) MRI and clinical studies of facial and bulbar muscle involvement in MuSK antibody-associated myasthenia gravis. Brain 129:1481–1492

    Article  PubMed  Google Scholar 

  16. Selcen D, Fukuda T, Shen XM et al (2004) Are MuSK antibodies the primary cause of myasthenic symptoms? Neurology 62:1945–1950

    PubMed  Google Scholar 

  17. Niks EH, Kuks JBM, Wokke JHJ et al (2010) Pre-postsynaptic neuromuscular junction abnormalities in MuSK. Myasthenia Muscle Nerve 42:283–288

    Article  Google Scholar 

  18. Vincent A (2008) Autoimmune disorders of the neuromuscular junction. Neurol India 56:305–313

    Article  PubMed  Google Scholar 

  19. Shiraishi H, Motomura M, Yoshimura T et al (2005) Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol 57:289–293

    Article  PubMed  CAS  Google Scholar 

  20. Wang Q, Zhang B, Xiong WC et al (2006) MuSK signalling at the neuromuscular junction. J Mol Neurosci 30:223–226

    Article  PubMed  CAS  Google Scholar 

  21. Benveniste O, Jacobson L, Farrugia ME et al (2005) MuSK antibody positive myasthenia gravis plasma modifies MURF-1 expression in C2C12 cultures and mouse muscles in vivo. J Neuroimmunol 170:41–48

    Article  PubMed  CAS  Google Scholar 

  22. Farrugia ME, Bonifati DM, Clover L et al (2007) Effect of sera from AChR-antibody negative myasthenia gravis patients on AChR and MuSK in cell cultures. J Neuroimmunol 185:136–144

    Article  PubMed  CAS  Google Scholar 

  23. Caress JB, Hunt CH, Batish SD (2005) Anti-MuSK myasthenia gravis presenting with purely ocular findings. Arch Neurol 62:1002–1003

    Article  PubMed  Google Scholar 

  24. Hain B, Hanisch F, Deschauer M (2004) Seronegative myasthenia with antibodies against muscle-specific tyrosin kinase. Nervenartz 75:362–367

    Article  CAS  Google Scholar 

  25. Lavrnic D, Losen M, Vujic A et al (2005) The features of myasthenia gravis with autoantibodies to MuSK. J Neurol Neurosurg Psychiat 76:1099–1102

    Article  PubMed  CAS  Google Scholar 

  26. Stickler DE, Massey JM, Sanders DB (2005) MuSK- antibody positive myasthenia gravis: clinical and electrodiagnostic patterns. Clin Neurophysiol 116:2065–2068

    Article  PubMed  CAS  Google Scholar 

  27. Soltys J, Gong B, Kaminski HJ et al (2008) Extraocular muscle susceptibility to myasthenia gravis. Unique immunological environment? Ann N Y Acad Sci 1132:220–224

    Article  PubMed  CAS  Google Scholar 

  28. Yu Wai Man CY, Chinnery PF, Griffiths PG (2005) Extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain disorders. Neuromuscul Disord 15:17–23

    Article  PubMed  CAS  Google Scholar 

  29. Dupuis L, Gonzales de Aguilar JL, Echaniz-Laguna A et al (2009) Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. Plos One 4:e5390

    Article  PubMed  Google Scholar 

  30. Xu K, Jha S, Hoch W, Dryer SE (2006) Delayed synapsing muscles are more severely affected in an experimental model of MuSK-induced myasthenia gravis. Neuroscience 143:655–659

    Article  PubMed  CAS  Google Scholar 

  31. MacAskill AF, Rinholm JE, Twelvetrees AE et al (2009) Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondrial at synapses. Neuron 61:541–555

    Article  PubMed  CAS  Google Scholar 

  32. Pesce V, Cormio A, Fracasso F et al (2001) Age-related mitochondrial genotypic and phenotypic alterations in human skeletal muscles. Free Rad Biol Med 30:1223–1233

    Article  PubMed  CAS  Google Scholar 

  33. Dobbins GC, Luo S, Yang Z et al (2008) Alpha-actinin interacts with rapsyn in agrin-stimulated AChR clustering. Mol Brain 1(1):18

    Article  PubMed  Google Scholar 

  34. Spillane J, Beeson DJ, Kullmann DM (2010) Myasthenia and related disorders of the neuromuscular junction. J Neurol Neurosurg Psychiatry 81:850–857

    Article  PubMed  Google Scholar 

  35. Vincent A, Leite MI (2005) Neuromuscular junction autoimmune disease: muscle specific kinase antibodies and treatments for myasthenia gravis. Curr Opin Neurol 18:519–525

    Article  PubMed  CAS  Google Scholar 

  36. Vincent A, Bowen J, Newsom-Davis J et al (2003) Seronegative generalised myasthenia gravis: clinical features, antibodies, and their target. Lancet Neurol 2:99–106

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This paper has been partly supported by a Fondazione Carisbo and by Bologna University EF 2008 grants. The funding sources had no involvement in study design, collection, analysis, or interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. The authors acknowledge Telethon Italy for their support (project # GTB07001 to C.A.).

Conflict of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Clinical Department of Radiological Histopathological Sciences, “Alma Mater Studiorum” University of Bologna, Via Massarenti, 9, 40137, Bologna, Italy

    Giovanna Cenacchi & Papa Valentina

  2. Department Neurosciences, University of Padua, Padua, Italy

    Fanin Marina, Pegoraro Elena & Angelini Corrado

Authors
  1. Giovanna Cenacchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Papa Valentina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fanin Marina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pegoraro Elena
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angelini Corrado
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giovanna Cenacchi.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00415-010-5881-0

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cenacchi, G., Valentina, P., Marina, F. et al. Comparison of muscle ultrastructure in myasthenia gravis with anti-MuSK and anti-AChR antibodies. J Neurol 258, 746–752 (2011). https://doi.org/10.1007/s00415-010-5823-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-010-5823-x

Keywords

Search

Navigation