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. 2005 May;76(5):714–718. doi: 10.1136/jnnp.2004.043125

Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis

Y Nemoto 1, S Kuwabara 1, S Misawa 1, N Kawaguchi 1, T Hattori 1, M Takamori 1, A Vincent 1
PMCID: PMC1739635  PMID: 15834033

Abstract

Objectives: To compare the clinical and electrophysiological features of myasthenia gravis (MG) patients with (seropositive) or without (seronegative) antibodies to acetylcholine receptor. To investigate whether antibodies to muscle specific kinase (MuSK) and ryanodine receptor (RyR) are associated with particular features.

Methods: Clinical profiles and single fibre electromyography (SFEMG) in the extensor digitorum communis (EDC) were reviewed in consecutive 57 seropositive and 13 seronegative patients. Antibodies to MuSK and RyR were measured by immunoassays.

Results: Of the 13 seronegative patients, four (31%) were positive for MuSK antibodies and seven (54%) were positive for RyR antibodies, including all four MuSK positive patients. Clinical features were similar at presentation for seropositive and seronegative patients, but MuSK positive patients frequently developed myasthenic crises. Despite the similar clinical severities at the time of examination, the proportion with positive jitter (93% of seropositive patients, 50% of MuSK positive patients, and 44% of MuSK negative patients) and the extent of jitter (mean consecutive difference: 76 µs in seropositive patients, 36 µs in MuSK positive patients, and 30 µs in MuSK negative patients) were less in seronegative MG patients compared with seropositive MG patients.

Conclusions: Seronegative MG is heterogeneous with respect to the presence of antibodies to MuSK. Impairment of neuromuscular synaptic transmission in EDC is less marked in seronegative than seropositive MG despite the similar clinical severity. This discrepancy may partly reflect the distribution of affected muscles in seronegative patients, but it is possible that other factors, such as impaired excitation-contraction coupling resulting from RyR antibodies, contribute to the clinical phenotype.

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Selected References

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  1. Beeson D., Jacobson L., Newsom-Davis J., Vincent A. A transfected human muscle cell line expressing the adult subtype of the human muscle acetylcholine receptor for diagnostic assays in myasthenia gravis. Neurology. 1996 Dec;47(6):1552–1555. doi: 10.1212/wnl.47.6.1552. [DOI] [PubMed] [Google Scholar]
  2. Buckley C., Newsom-Davis J., Willcox N., Vincent A. Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence? Neurology. 2001 Nov 13;57(9):1579–1582. doi: 10.1212/wnl.57.9.1579. [DOI] [PubMed] [Google Scholar]
  3. Evoli Amelia, Tonali Pietro A., Padua Luca, Monaco Mauro Lo, Scuderi Flavia, Batocchi Anna P., Marino Mariapaola, Bartoccioni Emanuela. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain. 2003 Jun 23;126(Pt 10):2304–2311. doi: 10.1093/brain/awg223. [DOI] [PubMed] [Google Scholar]
  4. Graef L. M., Lutsep H. L., Norbash A., Albers G. W. Use of fluid attenuating inversion recovery, MR angiogram, and diffusion-weighted MRI techniques for assessment of pontine infarction in a patient treated with radiation therapy for pituitary neoplasm. Neurology. 1997 Feb;48(2):540–542. doi: 10.1212/wnl.48.2.540. [DOI] [PubMed] [Google Scholar]
  5. Hoch W., McConville J., Helms S., Newsom-Davis J., Melms A., Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med. 2001 Mar;7(3):365–368. doi: 10.1038/85520. [DOI] [PubMed] [Google Scholar]
  6. Iwasa K., Komai K., Takamori M. Spontaneous thymoma rat as a model for myasthenic weakness caused by anti-ryanodine receptor antibodies. Muscle Nerve. 1998 Dec;21(12):1655–1660. doi: 10.1002/(sici)1097-4598(199812)21:12<1655::aid-mus5>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  7. Iwasa K. Striational autoantibodies in myasthenia gravis mainly react with ryanodine receptor. Muscle Nerve. 1997 Jun;20(6):753–756. doi: 10.1002/(sici)1097-4598(199706)20:6<753::aid-mus16>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  8. Jaretzki A., 3rd, Barohn R. J., Ernstoff R. M., Kaminski H. J., Keesey J. C., Penn A. S., Sanders D. B. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000 Jul 12;55(1):16–23. doi: 10.1212/wnl.55.1.16. [DOI] [PubMed] [Google Scholar]
  9. Lefvert A. K., Bergström K., Matell G., Osterman P. O., Pirskanen R. Determination of acetylcholine receptor antibody in myasthenia gravis: clinical usefulness and pathogenetic implications. J Neurol Neurosurg Psychiatry. 1978 May;41(5):394–403. doi: 10.1136/jnnp.41.5.394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lindstrom J. M., Seybold M. E., Lennon V. A., Whittingham S., Duane D. D. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology. 1976 Nov;26(11):1054–1059. doi: 10.1212/wnl.26.11.1054. [DOI] [PubMed] [Google Scholar]
  11. Liyanage Yohan, Hoch Werner, Beeson David, Vincent Angela. The agrin/muscle-specific kinase pathway: new targets for autoimmune and genetic disorders at the neuromuscular junction. Muscle Nerve. 2002 Jan;25(1):4–16. doi: 10.1002/mus.1218. [DOI] [PubMed] [Google Scholar]
  12. Mygland A., Aarli J. A., Matre R., Gilhus N. E. Ryanodine receptor antibodies related to severity of thymoma associated myasthenia gravis. J Neurol Neurosurg Psychiatry. 1994 Jul;57(7):843–846. doi: 10.1136/jnnp.57.7.843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Sanders D. B., El-Salem K., Massey J. M., McConville J., Vincent A. Clinical aspects of MuSK antibody positive seronegative MG. Neurology. 2003 Jun 24;60(12):1978–1980. doi: 10.1212/01.wnl.0000065882.63904.53. [DOI] [PubMed] [Google Scholar]
  14. Skeie G. O., Mygland A., Aarli J. A., Gilhus N. E. Titin antibodies in patients with late onset myasthenia gravis: clinical correlations. Autoimmunity. 1995;20(2):99–104. doi: 10.3109/08916939509001933. [DOI] [PubMed] [Google Scholar]
  15. Soliven B. C., Lange D. J., Penn A. S., Younger D., Jaretzki A., 3rd, Lovelace R. E., Rowland L. P. Seronegative myasthenia gravis. Neurology. 1988 Apr;38(4):514–517. doi: 10.1212/wnl.38.4.514. [DOI] [PubMed] [Google Scholar]
  16. Stalberg E. Clinical electrophysiology in myasthenia gravis. J Neurol Neurosurg Psychiatry. 1980 Jul;43(7):622–633. doi: 10.1136/jnnp.43.7.622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Trontelj J. V., Stålberg E. Jitter measurement by axonal micro-stimulation. Guidelines and technical notes. Electroencephalogr Clin Neurophysiol. 1992 Feb;85(1):30–37. doi: 10.1016/0168-5597(92)90098-v. [DOI] [PubMed] [Google Scholar]
  18. Verma P. K., Oger J. J. Seronegative generalized myasthenia gravis: low frequency of thymic pathology. Neurology. 1992 Mar;42(3 Pt 1):586–589. doi: 10.1212/wnl.42.3.586. [DOI] [PubMed] [Google Scholar]
  19. Vincent A., Li Z., Hart A., Barrett-Jolley R., Yamamoto T., Burges J., Wray D., Byrne N., Molenaar P., Newsom-Davis J. Seronegative myasthenia gravis. Evidence for plasma factor(s) interfering with acetylcholine receptor function. Ann N Y Acad Sci. 1993 Jun 21;681:529–538. doi: 10.1111/j.1749-6632.1993.tb22936.x. [DOI] [PubMed] [Google Scholar]
  20. Vincent Angela, Bowen John, Newsom-Davis John, McConville John. Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets. Lancet Neurol. 2003 Feb;2(2):99–106. doi: 10.1016/s1474-4422(03)00306-5. [DOI] [PubMed] [Google Scholar]

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