Pathophysiology of Childhood-Onset Myasthenia: What is happening at the neuromuscular junction?
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Abstract
Myasthenia is caused by abnormalities in signal transduction at the neuromuscular junction. Its pathophysiology which is broadly classified into acquired myasthenia gravis and congenital myasthenic syndrome has been elucidated and its treatment has progressed over the past half century. Childhood-onset myasthenia gravis is less common than adult-onset myasthenia gravis, and therefore the pathophysiology has not been well studied, and treatment has continued to be based on research in the adult setting. However, treatment of children should be based on an understanding of their pathophysiology, and research on pathophysiology and treatment methods that take into account their unique growth and development is desired. In recent years, studies on myasthenia have been reported from around the world, confirming that the pattern of the number of patients by age of onset differs between East Asia and Western Europe, and that the Japanese characteristic of a high incidence in childhood is widely seen in East Asia. Furthermore, differences in the incidence of congenital myasthenic syndrome between East Asia and Western Europe are also evident. Thus, there are racial differences in the pathophysiology of myasthenia based on genetic background, and their pathophysiology and relevance are gradually becoming clear.
Congenital myasthenic syndrome is caused by genetic defects in various proteins involved in the assembly of AChRs at the neuromuscular junction, resulting in impaired neuromuscular signaling and the appearance of myasthenic symptoms. On the other hand, myasthenia gravis which is a T cell-dependent, antibody-producing autoimmune disease, is caused by autoantibodies against several proteins, mainly AChR antibodies. These proteins, like congenital myasthenic syndrome, are involved in the assembly of AChRs at the neuromuscular junction. Autoantibodies to these proteins prevent the assembly of AChRs, resulting in myasthenic symptoms due to the inability of neuromuscular signaling.
The ocular muscle type, which is common not only in Japan but also in East Asia, has low antibody titers and seronegative MG is relatively common. In this review, I would like to summarize and discuss what is happening at the neuromuscular junction in myasthenia, especially the pathophysiology of myasthenia gravis with low antibody titers from various viewpoints, such as the presence of antibodies to neuromuscular junction proteins, the inability to measure antibody titers due to measurement sensitivity issues, diversity by muscle site or type, or involvement of cellular immunity.
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HAYASHI, Masatoshi.
Pathophysiology of Childhood-Onset Myasthenia: What is happening at the neuromuscular junction?.
Medical Research Archives, [S.l.], v. 12, n. 7, july 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5473>. Date accessed: 15 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i7.5473.
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Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Elmqvist D, Hofmann WW, Kugelberg J, Quastel DML. An electrophysiological investigation of neuromuscular transmission in myasthenia gravis. J Physiol. 1964; 174:417-434.
2. Patrick J, Lindstrom JM. Autoimmune response to acetylcholine receptor. Science. 1973;180:871-872.
3. Fambrough DM, Drachman DB, Satyamurti S. Neuromuscular junction in myasthenia gravis: Decreased acetylcholine receptors. Science. 1973;182:293-296.
4. Hayashi M. Childhood-onset myasthenia gravis. Shounikihasshou no kinmuryokushou. Article in Japanese. No To Hattatsu. 2022;54:235-242.
5. Hayashi M. Pathophysiology of childhood-onset myasthenia: Abnormalities of neuromuscular junction and autoimmunity and its background. Pathophysiology. 2023;30,599-617. doi.org/103390/pathopysiology30040043
6. Hayashi M. Childhood myasthenia gravis in Japan: Pathophysiology and treatment options. Clin Exp Neuroimmunol .2023;1-10.
Doi: 10.1111/cen3.12762.
7. Koneczny I, Herbst R. Myasthenia gravis: Pathogenic effects of autoantibodies on neuromuscular architecture. Cells. 2019; 8, 671. Doi:10.3390/cells8070671.
8. Witzemann V, Brenner H-R, Sakmann B. Neural factors regulate AChR subunit mRNAs at rat neuromuscular synapses. J Cell Biol. 1991;114(1):125-141.
9. Takamori M. Myasthenia gravis: From the viewpoint of pathogenicity focusing on acetylcholine receptor clustering, trans-synaptic homeostasis and synaptic stability. Front Mol Neurosci. 2020;13:86. Doi: 10.3389/fnmol.2020.00086.
10. Rodriguez Cruz PM, Cossins J, Beeson D, Vincent A. The neuromuscular junction in health and disease: Molecular mechanisms governing synaptic formation and homeostasis. Frontiers in Molecular Neuroscience. 2020;13:610964. Doi: 10.3389/ fnmol. 2020.610964.
11. Ohkawara B, Ito M, Ohno K. Secreted signaling molecules at the neuromuscular junction in physiology and pathology. Int J Mol Sci. 2021;22:2455. doi.org/10.3390/ijms22052455.
12. Almon RR, Andrew Clifford G, Appel SH. Serum globulin in myasthenia gravis: Inhibition of α-bungarotoxin binding to acetylcholine receptors. Science. 1974;186:55-57.
13. Bender AN, Ringel SP, Engel WK, Daniels MP, Vogel Z. Myasthenia gravis: A serum factor blocking acetylcholine receptors of the human neuromuscular junction. Lancet. 1975;1(7907):607-609.Doi:10.1016/s0140-6736’75)91886-3.
14. Engel AG, Lindstrom JM, Lambert EH, Lennon VA. Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and in its experimental autoimmune model. Neurology. 1977; 27:307-315.
15. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest. 2006;116(11):2843-2854.
16. Drachman DB, Adams RN, Josifek LF, Pestronk A, Stanley EF. Antibody-mediated mechanisms of ACh receptor loss in myasthenia gravis: Clinical relevance. Ann N Y Acad Sci. 1981;377: 175-188.
17. Kao I, Drachman DB. Myasthenic immunoglobulin accelerates acetylcholine receptor degradation. Science. 1977;196:527-529.
18. Gomez CM, Richman DP. Anti-acetylcholine receptor antibodies directed against the α-bungarotoxin binding site induce a unique form of experimental myasthenia. Proc Natl Acad Sci. 1983; 80:4089-4093.
19. Whiting PJ, Vincent A, Newsom-Davis J. Acetylcholine receptor antibody characteristics in myasthenia gravis. Fractionation of alpha-bungarotoxin binding site antibodies and their relationship to IgG subclass. J Neuroimmunol. 1983; 5(1):1-9. Doi:10.1016/0165-5728(83)90022-x.
20. Unwin N. Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol. 2005;346(6):967-989. Doi: 10.1016/j.jmb.2004.12.031. Epub 2005 Jan 25.
21. Tuzun E, Christadoss P. Complement associated pathogenic mechanisms in myasthenia gravis. Autoimmun Rev. 2013; 12(9):904-911.Doi:10.1016/j.autrev.2013.03.003.
22. Sahashi K, Engel AG, Lambert EH, Howard Jr FM. Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis. J Neuropathol Exp Neurol. 1980; 39(2):160-172. Doi:10.1097/005072-198003000-00005.
23. Tsujihata M, Yoshimura T, Satoh A, et al. Diagnostic significance of IgG, C3, and C9 at the limb muscle motor end-plate in minimal myasthenia gravis. Neurology. 1989; 39(10):1359-1363.Doi:10.1212/wnl.39.10.1359.
24. Lennon VA, Seybold ME, Lindstrom JM, Cochrane C, Ulevitch R. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med. 1978; 147:973-983.
25. Donaldson JO, Penn AS, Lisak RP, Abramsky O, Brenner T, Schotland DL. Antiacetylcholine receptor antibody in neonatal myasthenia gravis. Am J Dis Child. 1981;135(3):222-226. Doi:10.1001/archpedi.1981.02130270014006.
26. Namba T, Brown SB, Grob D. Neonatal myasthenia gravis: Report of two cases and review of the literature. Pediatrics. 1970;45(3): 488-504.
27. Lefvert AK, Osterman PO. Newborn infants to myasthenic mothers: a clinical study and an investigation of acetylcholine receptor antibodies in 17 children. Neurology. 1983; 33(2):133-138.Doi:10.1212/wnl.33.2.133
28. Tzartos SJ, Efthimiadis A, Morel E, Eymard B, Bach J-F. Neonatal myasthenia gravis: antigenic specificities of antibodies in sera from mothers and their infants. Clin Exp Immunol. 1990;80:376-380.
29. Gilhus NE. Myasthenia gravis can have consequences for pregnancy and the developing child. Front Neurol. 2020;11:554,
Doi: 10.3389/fneur.2020.00554.
30. Vincent A, Newland C, Brueton L, et al. Arthrogryposis multiplex congenita with maternal autoantibodies specific for a fetal antigen. Lancet. 1995;346(8966):24-25.Doi:10.1016/s0140-6736(95)92652-6.
31. Riemersma S, Vincent A, Beeson D, et al. Association of arthrogryposis multiplex congenita with maternal antibodies inhibiting fetal acetylcholine receptor function. J Clin Invest. 1996;98:2358-2363.
32. 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. Nature med. 2001;7(3):365-368.
Doi: 10.1038/85520.
33. McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, Vincent A. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol. 2014;55(4):580-584.Doi: 10.1002/ana.20061.
34. Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A. Clinical aspects of MuSK antibody positive seronegative MG. Neurology. 2003;60(12):1978-1980.Doi: 10.1212/01.wnl.0000065882.63904.53.
35. Zagar M, Vranjes D, Sostarko M, Vorgrinc Z, Bilic E, Cepe MT. Myasthenia gravis patients with anti-MuSK antibodies. Coll Antropol. 2009;33(4):1151-1154.
36. Chan KH, Lachance DH, Harper CM, Lennon VA. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve. 2007;36(5):651-658. Doi: 10.1002/mus.20854.
37. Zhang Z, Guan Y, Han J, Li M, Shi M, Deng H. Regional features of MuSK antibody-positive myasthenia gravis in Northeast China. Front Neurol. 2020;11.516211.
Doi: 10.3389/fneur.2020.516211.
38. Lee J-Y, Sung JJ, Cho J-Y, et al. MuSK antibody-positive, seronegative myasthenia gravis in Korea. J Clin Neurosci. 2006;13(3):353-355. Doi: 10.1016/j.jocn.2005.04.028.
39. Yang L, Tang Y, He F, Zhang C, Kessi M, Peng J, Yin F. Clinical characteristics and outcome predictors of a Chinese childhood-onset myasthenia gravis cohort. Front Pediatr. 2022;10,996213. Doi:10.3389/fped.2022.996213.
40. Chou C-C, Su I-C, Chou I-J, et al. Correlation of anti-acetylcholine receptor antibody levels and long-term outcomes of juvenile myasthenia gravis in Taiwan: a case control study. BMC Neurol. 2019;19:170. doi.org/10.1186/s12883-019-1397-0
41. Ohta K, Shigemoto K, Fujinami A, Maruyama N, Konishi T, Ohta M. Clinical and experimental features of MuSK antibody positive MG in Japan. Eur J Neurol. 2007;14(9):1029-1034. di: 10.1111/j.1468-1331.2007.01870.x.
42. Murai H, Noda T, Himeno E, et al. Infantile onset myasthenia gravis with MuSK antibodies. Neurology. 2006;67:174.
43. Takahashi Y, Sugiyama M, Ueda Y, et al. Childhood-onset anti-MuSK antibody positive myasthenia gravis demonstrates a distinct clinical course. Brain Dev. 2012;34:784-786.
Doi: 10.1016/j.braindev.2011.12.014.
44. Inoue K, Tsugawa J, Fukae J, et al. Myasthenia gravis with anti-muscle-specific tyrosine kinase antibody during pregnancy and risk of neonatal myasthenia gravis: A case report and review of the literature. Case Rep Neurol. 2020;12:114-120. Doi:10.1159/000506189.
45. Bennett DLH, Mills KR, Riordan-Eva P, Barnes PRJ, Rose MR. Anti-MuSK antibodies in a case of ocular myasthenia gravis. JNNP. 2005;564.075812. Doi:10.1136/jnnp.2005.075812.
46. Hosaka A, Takuma H, Ohta K, Tamaoka A. An ocular form of myasthenia gravis with a high titer of anti-MuSK antibodies during a long-term follow-up. Intern Med. 2012;51:3077-3079.
Doi: 10.2169/internalmedicine.51.8196
47. Shiraishi H, Motomura M, Yoshimura T et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody positive myasthenia gravis. Ann Neurol. 2005;57(2):289-293. Doi:10.1002/ana.20341..
48. Koneczny I, Cossins J, Waters P, Beeson D, Vincent A. MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters. Plos One. 2013, 8(11).e80695. Doi:10.1371/journal.pone.0080695.
49. Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009; 8(5):475-490. Doi:10.1016/S1474-4422(09)70063-8.
50. Otsuka K, Ito M, Ohkawara B, et al. Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling. Sci Rep. 2015;5:13928/Doi: 10.1038/srep13928.
51. Rodriguez Cruz PM, Al-Hajjar M, Huda S, et al. Clinical features and diagnostic usefulness of antibodies to clustered acetylcholine receptors in the diagnosis of seronegative myasthenia gravis. JAMA Neurol. 2015;72(6):642-649. Doi:10.1001/jamaneurol.2015.0203.
52. Pevzner A, Schoser B, Peters K, et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol. 2012;259(3):427-435. Doi:10.1007/S00415-011-6194-7. Epub2011Aug5.
53. Higuchi O, Johko H, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol. 2011; 69(2):418-422. Doi:10.1002/ana.22312.
54. Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012; 69(4):445-451. Doi:10.1001/archneurol.2011.2393.
55. Shen C, Lu Y, Zhang B, et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest. 2013; 123(12):5190-5202. Doi:10.1172/JCI66039.
56. Gasperi C, Melms A, Schoser B, et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology. 2014; 82(22):1976-1983. Doi:10.1212/WNL.0000000000000478. Epub2014May2.
57. Zhang B, Shen C, Bealmear B, et al. Autoantibodies to agrin in myasthenia gravis patients. PLOS ONE. 2014; 9(3): e91816. Doi:10.1371/journal.pone.0091816.
58. Yan M, Liu Z, Fei E, et al. Induction of anti-agrin antibodies causes myasthenia gravis in mice. Neuroscience. 2018; 373:113-121. Doi:10.1016/j.neuroscience.2018.01.015.
59. Rivner MH, Quarles BM, Pan J-X, et al. Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study. Muscle and Nerve. 2020;62:333-343. Doi:10.1002/mus.26985.
60. Kaminski HJ. Seronegative myasthenia gravis---A vanishing disorder? JAMA Neurol. 2016; 73(9):1055-1056.
61. Shigemoto K, Kubo S, Maruyama N, et al. Induction of myasthenia gravis by immunization against muscle-specific kinase. J Clin Invest. 2006; 116(4):1016-1024. Doi:10.1172/JCI21545.
62. Viegas S, Jacobson L, Waters P, et al. Passive and active immunization models of MuSK-Ab positive myasthenia: Electrophysiological evidence for pre and postsynaptic defects. Exp Neurol. 2012;234:506-512. Doi:10.1016/j.ezpneurol.2012.01.025.
63. Ulsoy C, Cavus F, Yilmaz V, Tuzun E. Immunization with recombinantly expressed LRP4 induces experimental autoimmune myasthenia gravis in C57BL/6 mice. Immunol Invest. 2017; 46(5):490-499. Doi: 10.1080/08820139.2017.1299754. Epub 2017 Apr 4.
64. Mori S, Motohashi N, Takashima R, Kishi M, Nishimune H, Shigemoto K. Immunization of mice with LRP4 induces myasthenia similar to MuSK-associated myasthenia gravis. Exp Neurol. 2017; 297:158-167. Doi:10.1016/j.expneurol.2017.08.006.
65. Yu Z, Zhang M, Jing H, et al. Characterization of LRP4/Agrin antibodies from a patient with myasthenia gravis. Neurology. 2021; 97(10): e975-e987. https://doi.org/10.1212wnl.0000000000012463
66. Engel AG, Shen X-M, Selcen D, Sine SM. Congenital myasthenic syndrome: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015; 14(4):420-434. Doi:10.1016/S1474-4422(14)70201-7.
67. Parr JR, Andrew MJ, Finnis M, Beeson D, Vincent A, Jayawant S. How common is childhood myasthenia? The UK incidence and prevalence of autoimmune and congenital myasthenia. Arch Dis Child. 2014; 99:539-542. Doi: 10.1136/archdischild-2013-304788.
68. Mansukhani SA, Bothun E, Diehl NN, Mohney BG. Incidence and ocular features of pediatric myasthenias. Am J Ophthalmol. 2019; 200:242-249. Doi:10.1016/j.ajo.2019.01.004
69. Azuma Y, Nakata T, Tanaka M, et al. Congenital myasthenic syndrome in Japan: Ethnically unique mutations in muscle nicotinic acetylcholine receptor subunits. Neuromuscular Disorders. 2015; 25:60-69. Doi:10.1016/j.nmd.2014.09.002.
70. Ohno K, Ohkawara B, Shen M-X, Selcen D, Engel AG. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—A comprehensive review. Int J Mol Sci. 2023,24,3730. https://doi.org/10.3390/ijms24043730
71. Hayashi M, Kid Ka, Yamada I, et al. Anti-acetylcholine receptor antibody in juvenile and adult myasthenia gravis. Acta Paediatr Jpn. 1986; 28(5):781-787.
72. Murai H, Yamashita N, Watanabe M, et al. Characteristics of myasthenia gravis according to onset-age: Japanese Nationwide survey. J Neurol Sci. 2011; 305:97-102.
Doi: 10.1016/j.jns.2011.03.004
73. Lee H.N.; Kang H-C.; Lee J.S., et al. Juvenile myasthenia gravis in Korea: Subgroup analysis according to sex and onset age. J Chil Neurol. 2016; 31(14),1561-1568.
Doi: 10.1177/0883073816666206
74. Huang X, Liu WB, Men LN, et al. Clinical features of myasthenia gravis in southern China: a retrospective review of 2154 cases over 22years. Neurol Sci.2013; 34:911-917. Doi: 10.1007/s10072-012-1157-z.
75. Gui M.; Luo X.; Lin J., et al. Long-term outcome of 424 childhood-onset myasthenia gravis patients. J Neurol. 2015;262:823-830. Doi: 10.1007/s00415-015-7638-2
76. Popperud TH, Boldingh MI, Rasmussen M, Kerty E. Juvenile myasthenia gravis in Norway: Clinical characteristics, treatment, and long-term outcome in a nationwide population-based cohort. Eur J Pediatr Neurol. 2017;21:707-714. http://dx.doi.org/10.1016/j.ejpn.2017.04.003
77. Vecchio D, Ramdas S, Munot P, et al. Pediatric myasthenia gravis: Prognostic factors for drug free remission. Neuromusc Disord. 2020;30:120-127. http://doi.org/10.1016/j.nmd.2019.11.008
78. Finnis MF, Jayawant S. Juvenile myasthenia gravis: A pediatric perspective. Autoimmune Diseases. Volume 2011. Article ID 404101, Doi: 10.4061/2011/404101
79. Dresser L, Wlodarski R, Rezania K, Soliven B. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021; 10, 2235. http://doi.org/10.3390/jcm10112235
80. Kaminski HJ, Maas E, Spiegel P, Ruff RL. Why are eye muscles frequently involved in myasthenia gravis? Neurology. 1990; 40:1663-1669.
81. Horton RM, Manfredi AA, Conti-Tronconi BM. The ‘embrionic’ gamma subunit of the nicotinic acetylcholine receptor is expressed in adult extraocular muscle. Neurology.1993; 43:983-986. Doi:10.1212/wnl.43.5.983.
82. Missias AC, Chu GC, Klocke BJ, Sanes JR, Merlie JP. Maturation of the acetylcholine receptor in skeletal muscle: Regulation of the AChR γ-to-ε switch. Develop Biol. 1996; 179:223-238.
83. Oda K. Motor innervation and acetylcholine receptor distribution of human extraocular muscle fibers. J Neurol Sci. 1986; 74:125-133. Doi: 10.1016/0022-510x(86)90099-7.
84. Kaminski HJ, Kusner LL, Block CH. Expression of acetylcholine receptor isoforms at extraocular muscle endplates. Invest Ophthalmol Vis Sci. 1996; 37:345-351.
85. Ruff RL, Lennon VA. How myasthenia gravis alters the safety factor for neuromuscular transmission? J Neuroimmunol. 2008; 201-202:13-20. Doi: 10.1016/j.jneuroim.2008.04.038.
86. Serra A, Ruff R, Leigh RJ. Neuromuscular transmission failure in myasthenia gravis: decrement of safety factor and susceptibility of extraocular muscle. Ann N Y Acad Sci. 2012; 1275:129-135. Doi: 10.1111/j.1749-6632.2012.06841.x.
87. Zhao G, Wang X, Yu X, Zhang X, Guan Y, Jiang J. Clinical application of clustered-AChR for the detection SNMG. Sci Rep. 2015; 5:10193. Doi: 10.1038/srep10193
88. Oda K. Differences in acetylcholine receptor-antibody interactions between extraocular and extremity muscle fibers. Ann N Y Acad Sci. 1993;681:238-255. Doi:10.1111/j.1749-6632.1993. tb 22889.x.
89. Nomura Y, Hachimori K, Nagao Y, Masamio S, Kimura K, Segawa M. Childhood myasthenia gravis in Japan; Clinical analysis of 184 cases at Segawa Neurological Clinic for Children for 30 years. Neuro-Ophthalmol. 2007;31:201-205.
90. Hayashi M, Nomura Y. Aims of the childhood myasthenia gravis study group in Japan. Clin Exp Neuroimmunol. 2020;11:185-191. Doi:10.1111/cen3.12585.
91. Abraham A, Breiner A, Barnett C, et al. Electrophysiological testing is correlated with myasthenia gravis severity. Muscle Nerve. 2017;56:445-448.
92. Tomschill M, Renaud E, Jager F, et al. The diagnostic and prognostic utility of repetitive nerve stimulation in patients with myasthenia gravis. Sci Rep. 2023;23:2985.
93. Yoshikawa H, Adachi Y, Nakamura Y, Kuriyama N, Murai H, Nomura Y, et al. Two-step nationwide epidemiological survey of myasthenia gravis in Japan 2018. PLOS ONE. 2018; 17(9):e0274161. http://doi.org/10.1371/journak.pone.0274161.
94. Park J-S, Eah KY, Park J-M. Epidemiological profile of myasthenia gravis in South Korea using the national health insurance database. Acta Neurol Scand. 2022; 145:633-640. Doi: 10.1111/ane.13596.
95. Heckmann JM, Europa TA, Soni AJ, Nel M. The epidemiology and phenotypes of ocular manifestations in childhood and juvenile myasthenia gravis: A review. Front Neurol. 2022; 13: Article 834212. Doi: 10.3380/fneur.2022.834212
96. Thapa P, Farber DI. The role of the thymus in the immune response. Thorac Surg Clin. 2019; 29:123-1312.
97. Kondo K, Ohigashi I, Takahama Y. Thymus machinery for T-cell selection. Int Immunol. 2019; 31:119-125.
98. Thome JJ, Grinshpun B, Kumar BV, et al. Long-term maintenance of human naïve T cell through in situ homeostasis in lymphoid tissue sites. Sci Immunol. 2016;1: eaah6506.
99. Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immunity & Ageing. 2019; 16:25. https://doi.org/10.1186/s12979-019-0164-9
100. Perlo VP, Poskanzer DC, Schwab RS, Viets HR, Osserman KE, Genkins G. Myasthenia gravis: Evaluation of treatment in 1,355 patients. Neurology. 1966; 16:431-439.
101. Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC neurology. 2010; 10:46. http://www.biomedcentral.com/1471-2377/10/46
102. Compston DAS, Vincent A, Newsom-Davis J, Batchelor JR. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain. 1980; 103:579-601.
103. Vandiedonck C, Beaurain G, Giraud M, et al. Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia. Proc Nat Acad Sci. 2004; 101(43):15464-15469. http://www.pnas.org/cgi/doi/10.1073/pnas.0406756101
104. Popperud TH, Viken MK, Kerty E, Lie BA. Juvnile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset. PLOS ONE. 2017; 12(10): e0186383. https://doi.org/10.1371/journal.pone.0186383
105. Fang F, Sveinsson O, Thormar G, et al. The autoimmune spectrum of myasthenia gravis: a Swedish population-based study. J Int Med. 2015; 277:594-604. Doi: 10.1111/joim.12310
106. Santos E, Bettencourt A, Duarte S, et al. Refractory myasthenia gravis: Characteristics of a Portuguese cohort. Muscle Nerve. 2019; 60(2):188-191. Doi: 10.1002/mus.26507.Epub 2019 May 15.
107. Fekih-Mrissa N, Klai S, Zaouali J, Gritli N, Mrissa R. Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients. Clin Neurol Neurosurg. 2013; 115(1):32-36. Doi: 10.1016/j.clineuro.2012.04.001.Epub 2012 Apr 18.
108. Feng H-y, Yang L-x, Liu W-b, Huang X, Qiu L, Li Y. The HLA-B*4601-DRB1*0901 haplotype is positively correlated with juvenile ocular myasthenia gravis in a southern Chinese Han population. Neurol Sci. 2015; 36:1135-1140. Doi:10.1007/ｓ10072-015-2235-9
109. Matsuki K, Juji T, Tokunaga K, et al. HLA antigen in Japanese patients with myasthenia gravis. J Clin Invest. 1990; 86:392-399.
110. Shinomiya N, Nomura Y, Segawa M. A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan. Clin Immunol. 2004; 110:154-158. Doi:10.1016/j.clim.2003.10.004.
111. Tokunaga K, Kay PH, Christiansen FT, Saueracker G, Dawkins RL. Comparative mapping of the human major histocompatibility complex in different racial groups by pulsed field gel electrophoresis. Human Immunol. 1989; 26(2):99-106. Doi:10.1016/0198-8859(89)90095-5
112. Kida K, Hayashi M, Yamada I, et al. Heterogeneity in myasthenia gravis: HLA phenotypes and autoantibody responses in ocular and generalized types. Ann Neurol. 1987;21:274-278.
113. Hayashi M, Kida K, Yamada I, et al. Involvement of HLA in clinical courses of myasthenia gravis. J Neuroimmunol. 1988; 18:171-179.
114. Berman PW, Patrick J. Experimental myasthenia gravis: A murine system. J Exp Med. 1980; 151:204-223.
115. Christadoss P, Lennon VA, Krco CJ, David CS. Genetic control of experimental autoimmune myasthenia gravis in mice III. Ia molecules mediate cellular immune responsiveness to acetylcholine receptors. J Immunol. 1982; 128(3):1141-1144.
116. McIntyre KR, Seidman JG. Nucleotide sequence of mutant I-Aβbm12 gene is evidence for genetic exchange between mouse immune response genes. Nature. 1984; 308:551-553.
117. Bellone M, Ostlie N, Lei S, et al. The I-Abm12 mutation, which confers resistance to experimental myasthenia gravis, drastically affects the epitope repertoire of murine CD4+ cells sensitized to nicotinic acetylcholine receptor. J Immunol. 1991; 147(5):1484-1491.
118. Infante AJ, Thompson PA, Krolick KA, Wall KA. Determinant selection in murine experimental autoimmune myasthenia gravis: Effect of the bm12 mutation on T cell recognition of acetylcholine receptor epitopes. J Immunol. 1991; 146(9):2977-2982.
119. Christadoss P, Lindstrom JM, Melvold RW, Talal N. Mutation at I-A beta chain prevents experimental autoimmune myasthenia gravis. Immunogenet. 1985; 21:33-38.
120. Namba T, Shapiro MS, Brunner NG, Grob D. Myasthenia gravis occurring in twins. J Neurol Neurosurg Psychiat. 1971; 34:531-534.
121. Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis—autoantibody characteristics and their implications for therapy. Nature Review Neurology. 2016; 12: 259-268. Doi: 10.1038/nrneurol.2016.44
122. Hayashi M, Kida K, Yoshinaga J. Possible distinct pathogenesis in low responder myasthenia gravis: association of soluble interleukin-2 receptor with acetylcholine receptor antibody titre or abnormal thymus. J Neurol Neurosurg Psychiat. 1996; 61:207-208. Doi: 10.1136/jnnp.61.2.207.
123. Wiesendanger M, D’Alessandri A. Myasthenia gravis mit fokaler infiltration der endplattenzone. Acta Neuropathologica. 1963; 2:246-252.
124. Fenichel GM, Shy GM, Bethesda. Muscle biopsy experience in myasthenia gravis. Arch Neurol. 1963; 9:237-243.
125. Fenichel GM. Muscle lesions in myasthenia gravis. Ann N Y Acad Sci. 1966; 135:60-67.
126. Pascuzzi RM, Campa JF. Lymphorrhage localized to the muscle end-plate in myasthenia gravis. Arch Pathol Lab Med. 1988; 112:934-937.
127. Maselli RA, Richman DP, Wollmann RL. Inflammation at the neuromuscular junction in myasthenia gravis. Neurology. 1991; 41:1497-1504.
128. Nakano S, Engel AG. Myasthenia gravis: Quantitative immunocytochemical analysis of inflammatory cells and detection of complement membrane attack complex at the end-plate in 30 patients. Neurology. 1993; 43:1167-72.
129. Oosterhuis HJGH. Animal model of myasthenia gravis. In Myasthenia gravis. Clinical Neurology Neurosurgery Monographs; Gilbert H Glaser, Andre Barbeau, eds; Churchilll Livingstone; Edinburgh, London, Melbourne and New York,1984; Vol 5, pp. 131-141.
130. Lindstrom JM, Engel AG, Seybold ME, Lennon VA, Lambert EH. Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine receptor antibodies. J Exp Med. 1976; 144:739-753.
131. Gomez CM, Wollmann RL, DP Richman. Induction of morphologic changes of both acute and chronic experimental myasthenia by monoclonal antibody directed against acetylcholine receptor. Acta Neuropathol. 1984; 63(2):131-143. Doi: 10.1007/BF00697195
132. Zhou Y, Kaminski HJ, Gong B, Cheng G, Feuerman JM, Kusner L. RNA expression analysis of passive transfer myasthenia supports extraocular muscle as a unique immunological environment. Invest Ophthalmol Vis Sci. 2014;55:4348-4359. Doi: 10.1167/iovs.14-14422.
2. Patrick J, Lindstrom JM. Autoimmune response to acetylcholine receptor. Science. 1973;180:871-872.
3. Fambrough DM, Drachman DB, Satyamurti S. Neuromuscular junction in myasthenia gravis: Decreased acetylcholine receptors. Science. 1973;182:293-296.
4. Hayashi M. Childhood-onset myasthenia gravis. Shounikihasshou no kinmuryokushou. Article in Japanese. No To Hattatsu. 2022;54:235-242.
5. Hayashi M. Pathophysiology of childhood-onset myasthenia: Abnormalities of neuromuscular junction and autoimmunity and its background. Pathophysiology. 2023;30,599-617. doi.org/103390/pathopysiology30040043
6. Hayashi M. Childhood myasthenia gravis in Japan: Pathophysiology and treatment options. Clin Exp Neuroimmunol .2023;1-10.
Doi: 10.1111/cen3.12762.
7. Koneczny I, Herbst R. Myasthenia gravis: Pathogenic effects of autoantibodies on neuromuscular architecture. Cells. 2019; 8, 671. Doi:10.3390/cells8070671.
8. Witzemann V, Brenner H-R, Sakmann B. Neural factors regulate AChR subunit mRNAs at rat neuromuscular synapses. J Cell Biol. 1991;114(1):125-141.
9. Takamori M. Myasthenia gravis: From the viewpoint of pathogenicity focusing on acetylcholine receptor clustering, trans-synaptic homeostasis and synaptic stability. Front Mol Neurosci. 2020;13:86. Doi: 10.3389/fnmol.2020.00086.
10. Rodriguez Cruz PM, Cossins J, Beeson D, Vincent A. The neuromuscular junction in health and disease: Molecular mechanisms governing synaptic formation and homeostasis. Frontiers in Molecular Neuroscience. 2020;13:610964. Doi: 10.3389/ fnmol. 2020.610964.
11. Ohkawara B, Ito M, Ohno K. Secreted signaling molecules at the neuromuscular junction in physiology and pathology. Int J Mol Sci. 2021;22:2455. doi.org/10.3390/ijms22052455.
12. Almon RR, Andrew Clifford G, Appel SH. Serum globulin in myasthenia gravis: Inhibition of α-bungarotoxin binding to acetylcholine receptors. Science. 1974;186:55-57.
13. Bender AN, Ringel SP, Engel WK, Daniels MP, Vogel Z. Myasthenia gravis: A serum factor blocking acetylcholine receptors of the human neuromuscular junction. Lancet. 1975;1(7907):607-609.Doi:10.1016/s0140-6736’75)91886-3.
14. Engel AG, Lindstrom JM, Lambert EH, Lennon VA. Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and in its experimental autoimmune model. Neurology. 1977; 27:307-315.
15. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest. 2006;116(11):2843-2854.
16. Drachman DB, Adams RN, Josifek LF, Pestronk A, Stanley EF. Antibody-mediated mechanisms of ACh receptor loss in myasthenia gravis: Clinical relevance. Ann N Y Acad Sci. 1981;377: 175-188.
17. Kao I, Drachman DB. Myasthenic immunoglobulin accelerates acetylcholine receptor degradation. Science. 1977;196:527-529.
18. Gomez CM, Richman DP. Anti-acetylcholine receptor antibodies directed against the α-bungarotoxin binding site induce a unique form of experimental myasthenia. Proc Natl Acad Sci. 1983; 80:4089-4093.
19. Whiting PJ, Vincent A, Newsom-Davis J. Acetylcholine receptor antibody characteristics in myasthenia gravis. Fractionation of alpha-bungarotoxin binding site antibodies and their relationship to IgG subclass. J Neuroimmunol. 1983; 5(1):1-9. Doi:10.1016/0165-5728(83)90022-x.
20. Unwin N. Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol. 2005;346(6):967-989. Doi: 10.1016/j.jmb.2004.12.031. Epub 2005 Jan 25.
21. Tuzun E, Christadoss P. Complement associated pathogenic mechanisms in myasthenia gravis. Autoimmun Rev. 2013; 12(9):904-911.Doi:10.1016/j.autrev.2013.03.003.
22. Sahashi K, Engel AG, Lambert EH, Howard Jr FM. Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis. J Neuropathol Exp Neurol. 1980; 39(2):160-172. Doi:10.1097/005072-198003000-00005.
23. Tsujihata M, Yoshimura T, Satoh A, et al. Diagnostic significance of IgG, C3, and C9 at the limb muscle motor end-plate in minimal myasthenia gravis. Neurology. 1989; 39(10):1359-1363.Doi:10.1212/wnl.39.10.1359.
24. Lennon VA, Seybold ME, Lindstrom JM, Cochrane C, Ulevitch R. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med. 1978; 147:973-983.
25. Donaldson JO, Penn AS, Lisak RP, Abramsky O, Brenner T, Schotland DL. Antiacetylcholine receptor antibody in neonatal myasthenia gravis. Am J Dis Child. 1981;135(3):222-226. Doi:10.1001/archpedi.1981.02130270014006.
26. Namba T, Brown SB, Grob D. Neonatal myasthenia gravis: Report of two cases and review of the literature. Pediatrics. 1970;45(3): 488-504.
27. Lefvert AK, Osterman PO. Newborn infants to myasthenic mothers: a clinical study and an investigation of acetylcholine receptor antibodies in 17 children. Neurology. 1983; 33(2):133-138.Doi:10.1212/wnl.33.2.133
28. Tzartos SJ, Efthimiadis A, Morel E, Eymard B, Bach J-F. Neonatal myasthenia gravis: antigenic specificities of antibodies in sera from mothers and their infants. Clin Exp Immunol. 1990;80:376-380.
29. Gilhus NE. Myasthenia gravis can have consequences for pregnancy and the developing child. Front Neurol. 2020;11:554,
Doi: 10.3389/fneur.2020.00554.
30. Vincent A, Newland C, Brueton L, et al. Arthrogryposis multiplex congenita with maternal autoantibodies specific for a fetal antigen. Lancet. 1995;346(8966):24-25.Doi:10.1016/s0140-6736(95)92652-6.
31. Riemersma S, Vincent A, Beeson D, et al. Association of arthrogryposis multiplex congenita with maternal antibodies inhibiting fetal acetylcholine receptor function. J Clin Invest. 1996;98:2358-2363.
32. 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. Nature med. 2001;7(3):365-368.
Doi: 10.1038/85520.
33. McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, Vincent A. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol. 2014;55(4):580-584.Doi: 10.1002/ana.20061.
34. Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A. Clinical aspects of MuSK antibody positive seronegative MG. Neurology. 2003;60(12):1978-1980.Doi: 10.1212/01.wnl.0000065882.63904.53.
35. Zagar M, Vranjes D, Sostarko M, Vorgrinc Z, Bilic E, Cepe MT. Myasthenia gravis patients with anti-MuSK antibodies. Coll Antropol. 2009;33(4):1151-1154.
36. Chan KH, Lachance DH, Harper CM, Lennon VA. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve. 2007;36(5):651-658. Doi: 10.1002/mus.20854.
37. Zhang Z, Guan Y, Han J, Li M, Shi M, Deng H. Regional features of MuSK antibody-positive myasthenia gravis in Northeast China. Front Neurol. 2020;11.516211.
Doi: 10.3389/fneur.2020.516211.
38. Lee J-Y, Sung JJ, Cho J-Y, et al. MuSK antibody-positive, seronegative myasthenia gravis in Korea. J Clin Neurosci. 2006;13(3):353-355. Doi: 10.1016/j.jocn.2005.04.028.
39. Yang L, Tang Y, He F, Zhang C, Kessi M, Peng J, Yin F. Clinical characteristics and outcome predictors of a Chinese childhood-onset myasthenia gravis cohort. Front Pediatr. 2022;10,996213. Doi:10.3389/fped.2022.996213.
40. Chou C-C, Su I-C, Chou I-J, et al. Correlation of anti-acetylcholine receptor antibody levels and long-term outcomes of juvenile myasthenia gravis in Taiwan: a case control study. BMC Neurol. 2019;19:170. doi.org/10.1186/s12883-019-1397-0
41. Ohta K, Shigemoto K, Fujinami A, Maruyama N, Konishi T, Ohta M. Clinical and experimental features of MuSK antibody positive MG in Japan. Eur J Neurol. 2007;14(9):1029-1034. di: 10.1111/j.1468-1331.2007.01870.x.
42. Murai H, Noda T, Himeno E, et al. Infantile onset myasthenia gravis with MuSK antibodies. Neurology. 2006;67:174.
43. Takahashi Y, Sugiyama M, Ueda Y, et al. Childhood-onset anti-MuSK antibody positive myasthenia gravis demonstrates a distinct clinical course. Brain Dev. 2012;34:784-786.
Doi: 10.1016/j.braindev.2011.12.014.
44. Inoue K, Tsugawa J, Fukae J, et al. Myasthenia gravis with anti-muscle-specific tyrosine kinase antibody during pregnancy and risk of neonatal myasthenia gravis: A case report and review of the literature. Case Rep Neurol. 2020;12:114-120. Doi:10.1159/000506189.
45. Bennett DLH, Mills KR, Riordan-Eva P, Barnes PRJ, Rose MR. Anti-MuSK antibodies in a case of ocular myasthenia gravis. JNNP. 2005;564.075812. Doi:10.1136/jnnp.2005.075812.
46. Hosaka A, Takuma H, Ohta K, Tamaoka A. An ocular form of myasthenia gravis with a high titer of anti-MuSK antibodies during a long-term follow-up. Intern Med. 2012;51:3077-3079.
Doi: 10.2169/internalmedicine.51.8196
47. Shiraishi H, Motomura M, Yoshimura T et al. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody positive myasthenia gravis. Ann Neurol. 2005;57(2):289-293. Doi:10.1002/ana.20341..
48. Koneczny I, Cossins J, Waters P, Beeson D, Vincent A. MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters. Plos One. 2013, 8(11).e80695. Doi:10.1371/journal.pone.0080695.
49. Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009; 8(5):475-490. Doi:10.1016/S1474-4422(09)70063-8.
50. Otsuka K, Ito M, Ohkawara B, et al. Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling. Sci Rep. 2015;5:13928/Doi: 10.1038/srep13928.
51. Rodriguez Cruz PM, Al-Hajjar M, Huda S, et al. Clinical features and diagnostic usefulness of antibodies to clustered acetylcholine receptors in the diagnosis of seronegative myasthenia gravis. JAMA Neurol. 2015;72(6):642-649. Doi:10.1001/jamaneurol.2015.0203.
52. Pevzner A, Schoser B, Peters K, et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol. 2012;259(3):427-435. Doi:10.1007/S00415-011-6194-7. Epub2011Aug5.
53. Higuchi O, Johko H, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol. 2011; 69(2):418-422. Doi:10.1002/ana.22312.
54. Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012; 69(4):445-451. Doi:10.1001/archneurol.2011.2393.
55. Shen C, Lu Y, Zhang B, et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest. 2013; 123(12):5190-5202. Doi:10.1172/JCI66039.
56. Gasperi C, Melms A, Schoser B, et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology. 2014; 82(22):1976-1983. Doi:10.1212/WNL.0000000000000478. Epub2014May2.
57. Zhang B, Shen C, Bealmear B, et al. Autoantibodies to agrin in myasthenia gravis patients. PLOS ONE. 2014; 9(3): e91816. Doi:10.1371/journal.pone.0091816.
58. Yan M, Liu Z, Fei E, et al. Induction of anti-agrin antibodies causes myasthenia gravis in mice. Neuroscience. 2018; 373:113-121. Doi:10.1016/j.neuroscience.2018.01.015.
59. Rivner MH, Quarles BM, Pan J-X, et al. Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study. Muscle and Nerve. 2020;62:333-343. Doi:10.1002/mus.26985.
60. Kaminski HJ. Seronegative myasthenia gravis---A vanishing disorder? JAMA Neurol. 2016; 73(9):1055-1056.
61. Shigemoto K, Kubo S, Maruyama N, et al. Induction of myasthenia gravis by immunization against muscle-specific kinase. J Clin Invest. 2006; 116(4):1016-1024. Doi:10.1172/JCI21545.
62. Viegas S, Jacobson L, Waters P, et al. Passive and active immunization models of MuSK-Ab positive myasthenia: Electrophysiological evidence for pre and postsynaptic defects. Exp Neurol. 2012;234:506-512. Doi:10.1016/j.ezpneurol.2012.01.025.
63. Ulsoy C, Cavus F, Yilmaz V, Tuzun E. Immunization with recombinantly expressed LRP4 induces experimental autoimmune myasthenia gravis in C57BL/6 mice. Immunol Invest. 2017; 46(5):490-499. Doi: 10.1080/08820139.2017.1299754. Epub 2017 Apr 4.
64. Mori S, Motohashi N, Takashima R, Kishi M, Nishimune H, Shigemoto K. Immunization of mice with LRP4 induces myasthenia similar to MuSK-associated myasthenia gravis. Exp Neurol. 2017; 297:158-167. Doi:10.1016/j.expneurol.2017.08.006.
65. Yu Z, Zhang M, Jing H, et al. Characterization of LRP4/Agrin antibodies from a patient with myasthenia gravis. Neurology. 2021; 97(10): e975-e987. https://doi.org/10.1212wnl.0000000000012463
66. Engel AG, Shen X-M, Selcen D, Sine SM. Congenital myasthenic syndrome: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015; 14(4):420-434. Doi:10.1016/S1474-4422(14)70201-7.
67. Parr JR, Andrew MJ, Finnis M, Beeson D, Vincent A, Jayawant S. How common is childhood myasthenia? The UK incidence and prevalence of autoimmune and congenital myasthenia. Arch Dis Child. 2014; 99:539-542. Doi: 10.1136/archdischild-2013-304788.
68. Mansukhani SA, Bothun E, Diehl NN, Mohney BG. Incidence and ocular features of pediatric myasthenias. Am J Ophthalmol. 2019; 200:242-249. Doi:10.1016/j.ajo.2019.01.004
69. Azuma Y, Nakata T, Tanaka M, et al. Congenital myasthenic syndrome in Japan: Ethnically unique mutations in muscle nicotinic acetylcholine receptor subunits. Neuromuscular Disorders. 2015; 25:60-69. Doi:10.1016/j.nmd.2014.09.002.
70. Ohno K, Ohkawara B, Shen M-X, Selcen D, Engel AG. Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes—A comprehensive review. Int J Mol Sci. 2023,24,3730. https://doi.org/10.3390/ijms24043730
71. Hayashi M, Kid Ka, Yamada I, et al. Anti-acetylcholine receptor antibody in juvenile and adult myasthenia gravis. Acta Paediatr Jpn. 1986; 28(5):781-787.
72. Murai H, Yamashita N, Watanabe M, et al. Characteristics of myasthenia gravis according to onset-age: Japanese Nationwide survey. J Neurol Sci. 2011; 305:97-102.
Doi: 10.1016/j.jns.2011.03.004
73. Lee H.N.; Kang H-C.; Lee J.S., et al. Juvenile myasthenia gravis in Korea: Subgroup analysis according to sex and onset age. J Chil Neurol. 2016; 31(14),1561-1568.
Doi: 10.1177/0883073816666206
74. Huang X, Liu WB, Men LN, et al. Clinical features of myasthenia gravis in southern China: a retrospective review of 2154 cases over 22years. Neurol Sci.2013; 34:911-917. Doi: 10.1007/s10072-012-1157-z.
75. Gui M.; Luo X.; Lin J., et al. Long-term outcome of 424 childhood-onset myasthenia gravis patients. J Neurol. 2015;262:823-830. Doi: 10.1007/s00415-015-7638-2
76. Popperud TH, Boldingh MI, Rasmussen M, Kerty E. Juvenile myasthenia gravis in Norway: Clinical characteristics, treatment, and long-term outcome in a nationwide population-based cohort. Eur J Pediatr Neurol. 2017;21:707-714. http://dx.doi.org/10.1016/j.ejpn.2017.04.003
77. Vecchio D, Ramdas S, Munot P, et al. Pediatric myasthenia gravis: Prognostic factors for drug free remission. Neuromusc Disord. 2020;30:120-127. http://doi.org/10.1016/j.nmd.2019.11.008
78. Finnis MF, Jayawant S. Juvenile myasthenia gravis: A pediatric perspective. Autoimmune Diseases. Volume 2011. Article ID 404101, Doi: 10.4061/2011/404101
79. Dresser L, Wlodarski R, Rezania K, Soliven B. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021; 10, 2235. http://doi.org/10.3390/jcm10112235
80. Kaminski HJ, Maas E, Spiegel P, Ruff RL. Why are eye muscles frequently involved in myasthenia gravis? Neurology. 1990; 40:1663-1669.
81. Horton RM, Manfredi AA, Conti-Tronconi BM. The ‘embrionic’ gamma subunit of the nicotinic acetylcholine receptor is expressed in adult extraocular muscle. Neurology.1993; 43:983-986. Doi:10.1212/wnl.43.5.983.
82. Missias AC, Chu GC, Klocke BJ, Sanes JR, Merlie JP. Maturation of the acetylcholine receptor in skeletal muscle: Regulation of the AChR γ-to-ε switch. Develop Biol. 1996; 179:223-238.
83. Oda K. Motor innervation and acetylcholine receptor distribution of human extraocular muscle fibers. J Neurol Sci. 1986; 74:125-133. Doi: 10.1016/0022-510x(86)90099-7.
84. Kaminski HJ, Kusner LL, Block CH. Expression of acetylcholine receptor isoforms at extraocular muscle endplates. Invest Ophthalmol Vis Sci. 1996; 37:345-351.
85. Ruff RL, Lennon VA. How myasthenia gravis alters the safety factor for neuromuscular transmission? J Neuroimmunol. 2008; 201-202:13-20. Doi: 10.1016/j.jneuroim.2008.04.038.
86. Serra A, Ruff R, Leigh RJ. Neuromuscular transmission failure in myasthenia gravis: decrement of safety factor and susceptibility of extraocular muscle. Ann N Y Acad Sci. 2012; 1275:129-135. Doi: 10.1111/j.1749-6632.2012.06841.x.
87. Zhao G, Wang X, Yu X, Zhang X, Guan Y, Jiang J. Clinical application of clustered-AChR for the detection SNMG. Sci Rep. 2015; 5:10193. Doi: 10.1038/srep10193
88. Oda K. Differences in acetylcholine receptor-antibody interactions between extraocular and extremity muscle fibers. Ann N Y Acad Sci. 1993;681:238-255. Doi:10.1111/j.1749-6632.1993. tb 22889.x.
89. Nomura Y, Hachimori K, Nagao Y, Masamio S, Kimura K, Segawa M. Childhood myasthenia gravis in Japan; Clinical analysis of 184 cases at Segawa Neurological Clinic for Children for 30 years. Neuro-Ophthalmol. 2007;31:201-205.
90. Hayashi M, Nomura Y. Aims of the childhood myasthenia gravis study group in Japan. Clin Exp Neuroimmunol. 2020;11:185-191. Doi:10.1111/cen3.12585.
91. Abraham A, Breiner A, Barnett C, et al. Electrophysiological testing is correlated with myasthenia gravis severity. Muscle Nerve. 2017;56:445-448.
92. Tomschill M, Renaud E, Jager F, et al. The diagnostic and prognostic utility of repetitive nerve stimulation in patients with myasthenia gravis. Sci Rep. 2023;23:2985.
93. Yoshikawa H, Adachi Y, Nakamura Y, Kuriyama N, Murai H, Nomura Y, et al. Two-step nationwide epidemiological survey of myasthenia gravis in Japan 2018. PLOS ONE. 2018; 17(9):e0274161. http://doi.org/10.1371/journak.pone.0274161.
94. Park J-S, Eah KY, Park J-M. Epidemiological profile of myasthenia gravis in South Korea using the national health insurance database. Acta Neurol Scand. 2022; 145:633-640. Doi: 10.1111/ane.13596.
95. Heckmann JM, Europa TA, Soni AJ, Nel M. The epidemiology and phenotypes of ocular manifestations in childhood and juvenile myasthenia gravis: A review. Front Neurol. 2022; 13: Article 834212. Doi: 10.3380/fneur.2022.834212
96. Thapa P, Farber DI. The role of the thymus in the immune response. Thorac Surg Clin. 2019; 29:123-1312.
97. Kondo K, Ohigashi I, Takahama Y. Thymus machinery for T-cell selection. Int Immunol. 2019; 31:119-125.
98. Thome JJ, Grinshpun B, Kumar BV, et al. Long-term maintenance of human naïve T cell through in situ homeostasis in lymphoid tissue sites. Sci Immunol. 2016;1: eaah6506.
99. Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immunity & Ageing. 2019; 16:25. https://doi.org/10.1186/s12979-019-0164-9
100. Perlo VP, Poskanzer DC, Schwab RS, Viets HR, Osserman KE, Genkins G. Myasthenia gravis: Evaluation of treatment in 1,355 patients. Neurology. 1966; 16:431-439.
101. Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC neurology. 2010; 10:46. http://www.biomedcentral.com/1471-2377/10/46
102. Compston DAS, Vincent A, Newsom-Davis J, Batchelor JR. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain. 1980; 103:579-601.
103. Vandiedonck C, Beaurain G, Giraud M, et al. Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia. Proc Nat Acad Sci. 2004; 101(43):15464-15469. http://www.pnas.org/cgi/doi/10.1073/pnas.0406756101
104. Popperud TH, Viken MK, Kerty E, Lie BA. Juvnile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset. PLOS ONE. 2017; 12(10): e0186383. https://doi.org/10.1371/journal.pone.0186383
105. Fang F, Sveinsson O, Thormar G, et al. The autoimmune spectrum of myasthenia gravis: a Swedish population-based study. J Int Med. 2015; 277:594-604. Doi: 10.1111/joim.12310
106. Santos E, Bettencourt A, Duarte S, et al. Refractory myasthenia gravis: Characteristics of a Portuguese cohort. Muscle Nerve. 2019; 60(2):188-191. Doi: 10.1002/mus.26507.Epub 2019 May 15.
107. Fekih-Mrissa N, Klai S, Zaouali J, Gritli N, Mrissa R. Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients. Clin Neurol Neurosurg. 2013; 115(1):32-36. Doi: 10.1016/j.clineuro.2012.04.001.Epub 2012 Apr 18.
108. Feng H-y, Yang L-x, Liu W-b, Huang X, Qiu L, Li Y. The HLA-B*4601-DRB1*0901 haplotype is positively correlated with juvenile ocular myasthenia gravis in a southern Chinese Han population. Neurol Sci. 2015; 36:1135-1140. Doi:10.1007/ｓ10072-015-2235-9
109. Matsuki K, Juji T, Tokunaga K, et al. HLA antigen in Japanese patients with myasthenia gravis. J Clin Invest. 1990; 86:392-399.
110. Shinomiya N, Nomura Y, Segawa M. A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan. Clin Immunol. 2004; 110:154-158. Doi:10.1016/j.clim.2003.10.004.
111. Tokunaga K, Kay PH, Christiansen FT, Saueracker G, Dawkins RL. Comparative mapping of the human major histocompatibility complex in different racial groups by pulsed field gel electrophoresis. Human Immunol. 1989; 26(2):99-106. Doi:10.1016/0198-8859(89)90095-5
112. Kida K, Hayashi M, Yamada I, et al. Heterogeneity in myasthenia gravis: HLA phenotypes and autoantibody responses in ocular and generalized types. Ann Neurol. 1987;21:274-278.
113. Hayashi M, Kida K, Yamada I, et al. Involvement of HLA in clinical courses of myasthenia gravis. J Neuroimmunol. 1988; 18:171-179.
114. Berman PW, Patrick J. Experimental myasthenia gravis: A murine system. J Exp Med. 1980; 151:204-223.
115. Christadoss P, Lennon VA, Krco CJ, David CS. Genetic control of experimental autoimmune myasthenia gravis in mice III. Ia molecules mediate cellular immune responsiveness to acetylcholine receptors. J Immunol. 1982; 128(3):1141-1144.
116. McIntyre KR, Seidman JG. Nucleotide sequence of mutant I-Aβbm12 gene is evidence for genetic exchange between mouse immune response genes. Nature. 1984; 308:551-553.
117. Bellone M, Ostlie N, Lei S, et al. The I-Abm12 mutation, which confers resistance to experimental myasthenia gravis, drastically affects the epitope repertoire of murine CD4+ cells sensitized to nicotinic acetylcholine receptor. J Immunol. 1991; 147(5):1484-1491.
118. Infante AJ, Thompson PA, Krolick KA, Wall KA. Determinant selection in murine experimental autoimmune myasthenia gravis: Effect of the bm12 mutation on T cell recognition of acetylcholine receptor epitopes. J Immunol. 1991; 146(9):2977-2982.
119. Christadoss P, Lindstrom JM, Melvold RW, Talal N. Mutation at I-A beta chain prevents experimental autoimmune myasthenia gravis. Immunogenet. 1985; 21:33-38.
120. Namba T, Shapiro MS, Brunner NG, Grob D. Myasthenia gravis occurring in twins. J Neurol Neurosurg Psychiat. 1971; 34:531-534.
121. Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis—autoantibody characteristics and their implications for therapy. Nature Review Neurology. 2016; 12: 259-268. Doi: 10.1038/nrneurol.2016.44
122. Hayashi M, Kida K, Yoshinaga J. Possible distinct pathogenesis in low responder myasthenia gravis: association of soluble interleukin-2 receptor with acetylcholine receptor antibody titre or abnormal thymus. J Neurol Neurosurg Psychiat. 1996; 61:207-208. Doi: 10.1136/jnnp.61.2.207.
123. Wiesendanger M, D’Alessandri A. Myasthenia gravis mit fokaler infiltration der endplattenzone. Acta Neuropathologica. 1963; 2:246-252.
124. Fenichel GM, Shy GM, Bethesda. Muscle biopsy experience in myasthenia gravis. Arch Neurol. 1963; 9:237-243.
125. Fenichel GM. Muscle lesions in myasthenia gravis. Ann N Y Acad Sci. 1966; 135:60-67.
126. Pascuzzi RM, Campa JF. Lymphorrhage localized to the muscle end-plate in myasthenia gravis. Arch Pathol Lab Med. 1988; 112:934-937.
127. Maselli RA, Richman DP, Wollmann RL. Inflammation at the neuromuscular junction in myasthenia gravis. Neurology. 1991; 41:1497-1504.
128. Nakano S, Engel AG. Myasthenia gravis: Quantitative immunocytochemical analysis of inflammatory cells and detection of complement membrane attack complex at the end-plate in 30 patients. Neurology. 1993; 43:1167-72.
129. Oosterhuis HJGH. Animal model of myasthenia gravis. In Myasthenia gravis. Clinical Neurology Neurosurgery Monographs; Gilbert H Glaser, Andre Barbeau, eds; Churchilll Livingstone; Edinburgh, London, Melbourne and New York,1984; Vol 5, pp. 131-141.
130. Lindstrom JM, Engel AG, Seybold ME, Lennon VA, Lambert EH. Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine receptor antibodies. J Exp Med. 1976; 144:739-753.
131. Gomez CM, Wollmann RL, DP Richman. Induction of morphologic changes of both acute and chronic experimental myasthenia by monoclonal antibody directed against acetylcholine receptor. Acta Neuropathol. 1984; 63(2):131-143. Doi: 10.1007/BF00697195
132. Zhou Y, Kaminski HJ, Gong B, Cheng G, Feuerman JM, Kusner L. RNA expression analysis of passive transfer myasthenia supports extraocular muscle as a unique immunological environment. Invest Ophthalmol Vis Sci. 2014;55:4348-4359. Doi: 10.1167/iovs.14-14422.