Skip to main content
SpringerLink
Log in

Congenital Myasthenic Syndromes

  • Chapter
Myasthenia Gravis and Related Disorders

Part of the book series: Current Clinical Neurology ((CCNEU))

Abstract

Congenital myasthenic syndromes (CMS) are a heterogeneous group of neuromuscular disorders that share clinical features with other neuromuscular transmission disorders but differ from acquired syndromes and among each other by their underlying molecular, genetic, and cellular pathogenesis. CMS may present in infancy or may not be recognized until childhood or later. Thus, a CMS may resemble neonatal or adult-onset myasthenia gravis (MG) or Lambert-Eaton syndrome (LES). Although impairment of neuromuscular transmission gives rise to similar clinical presentations, the sophisticated analysis of biopsied intact, muscle ifbers from CMS patients using electrophysiologic, microscopic, and molecular techniques has identified several varieties of CMS in which impairment of neuromuscular transmission occurs through distinct molecular and cellular mechanisms. In many cases, recording of evoked or spontaneous miniature endplate potentials (MEPPs) or miniature endplate currents (MEPCs) or single channel currents has identified the presence and type of pre- or postsynaptic defect of neuromuscular transmission. Coupled with electron microscopic, biochemical, and genetic data, these studies have led to the identification of the affected protein, gene, and mutation in several patients. This detailed molecular information has provided insights into disease mechanisms that have begun to guide the development of therapeutic strategies.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 74.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Engel AE. 73rd ENMC International Workshop: congenital myasthenic syndromes. 22–23 October, 1999, Naarden, The Netherlands. Neuromuscul Disord 2001; 11: 315–321.

    Google Scholar 

  2. Banwell BL, Russel J, Fukudome T, et al. Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J Neuropathol Exp Neurol 1999; 58: 832–846.

    Article  PubMed  CAS  Google Scholar 

  3. Greer M, Schotland M. Myasthenia gravis in the newborn. Pediatrics 1960; 26: 101–108.

    PubMed  CAS  Google Scholar 

  4. Conomy JP, Levinsohn M, Fanaroff A. Familial infantile myasthenia gravis: a cause of sudden death in young children. J Pediatr 1975; 87: 428–430.

    Article  PubMed  CAS  Google Scholar 

  5. Hart Z, Sahashi K, Lambert EH, Engel AG, Lindstrom J. A congenital, familial, myasthenic syndrome caused by a presynaptic defect of transmitter resynthesis or mobilization. Neurology 1979; 29: 559.

    Article  Google Scholar 

  6. Robertson WC, Chun RW, Kornguth SE. Familial infantile myasthenia. Arch Neurol 1980; 37: 117–119.

    Article  PubMed  CAS  Google Scholar 

  7. Gieron MA, Korthals JK. Familial infantile myasthenia gravis. Report of three cases with follow-up until adult life. Arch Neurol 1985; 42: 143–144.

    Article  PubMed  CAS  Google Scholar 

  8. Mora M, Lambert EH, Engel AG. Synaptic vesicle abnormality in familial infantile myasthenia. Neurology 1987; 37: 206–214.

    Article  PubMed  CAS  Google Scholar 

  9. Engel AG, Lambert EH. Congenital myasthenic syndromes. Electroencephalogr Clin Neurophysiol Suppl 1987; 39: 91–102.

    PubMed  CAS  Google Scholar 

  10. Wolters C, Leeuwin RS, Van Wijngaarden KV. The effect of prednisolone on the rat phrenic nerve-diaphragm preparation treated with hemicholinium. Eur J Pharmacol 1974; 29: 165–167.

    Article  PubMed  CAS  Google Scholar 

  11. Jones S, Kwanbunbumpen, S. Some effects of nerve stimulation and hemicholinium on quantal transmitter release at the mammalian neuromuscular junction. J Physiol (Lond)1970; 207: 51–61.

    Google Scholar 

  12. Jones S, Kwanbunbumpen S. The effects of nerve stimulation and hemicholinium on synaptic vesicles at the mammalian neuromuscular junction. J Physiol (Lond) 1970; 207: 31–50.

    CAS  Google Scholar 

  13. Ohno K, Tsujino A, Brengman JM, et al. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci USA 2001; 98: 2017–2022.

    Article  PubMed  CAS  Google Scholar 

  14. Engel AG, Walls TJ, Nagel A, Uchitel O. Newly recognized congenital myasthenic syndromes: I. Congenital paucity of synaptic vesicles and reduced quantal release. II. High-conductance fast-channel syndrome. III. Abnormal acetylcholine receptor (AChR) interaction with acetylcholine. IV. AChR deficiency and short channel-open time. Prog Brain Res 1990; 84: 125–137.

    Article  PubMed  CAS  Google Scholar 

  15. Walls TJ, Engel AG, Nagel AS, Harper CM, Trastek VF. Congenital myasthenic syndrome associated with paucity of synaptic vesicles and reduced quantal release. Ann NY Acad Sci 1993; 681: 461–468.

    Article  PubMed  CAS  Google Scholar 

  16. Patrosso M, Maselli R, Gospe SM, et al. Synapsin I gene analysis in a boy affected by an unusual congenital myasthenic syndrome. Muscle Nerve 1994: (Suppl 1 ): S187.

    Google Scholar 

  17. Bady B, Chauplannaz G, Carrier H. Congenital Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1987; 50: 476–478.

    Article  PubMed  CAS  Google Scholar 

  18. Engel A, Ohno K, Sine S. Congenital myasthenic syndromes. In: Engel A, ed. Myasthenia Gravis and Myasthenic Disorders. New York, Oxford University Press, 1999, pp. 251–297.

    Google Scholar 

  19. Maselli RA, Kong DZ, Bowe CM, et al. Presynaptic congenital myasthenic syndrome due to quantal release deficiency. Neurology 2001; 57: 279–289.

    Article  PubMed  CAS  Google Scholar 

  20. Engel AG, Lambert EH, Gomez MR. A new myasthenic syndrome with end-plate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release. Ann Neurol 1977; 1: 315–330.

    Article  PubMed  CAS  Google Scholar 

  21. Hutchinson DO, Walls TJ, Nakano S, et al. Congenital endplate acetylcholinesterase deficiency. Brain 1993; 116: 633–653.

    Article  PubMed  Google Scholar 

  22. Hutchinson DO, Engel AG, Walls TJ, et al. The spectrum of congenital end-plate acetylcholinesterase deficiency. Ann NY Acad Sci 1993; 681: 469–486.

    Article  PubMed  CAS  Google Scholar 

  23. Ohno K, Brengman J, Tsujino A, Engel AG. Human endplate acetylcholinesterase deficiency caused by mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme. Proc Natl Acad Sci USA 1998; 95: 9654–9659.

    Article  PubMed  CAS  Google Scholar 

  24. Ohno K, Brengman JM, Milone M, et al. Congenital end-plate acetylcholinesterase deficiency: novel missense and null mutations in the collagen-like tail subunit of the asymmetric enzyme. Am J Hum Genet 1998; 63: A377.

    Google Scholar 

  25. Breningstall GN, Kurachek SC, Fugate JH, Engel AG. Treatment of congenital endplate acetylcholinesterase deficiency by neuromuscular blockade. J Child Neurol 1996; 11: 345–346.

    Article  PubMed  CAS  Google Scholar 

  26. Salpeter M, Kasprzak H, Feng H, Fertuck H. End-plates after esterase inactivation in vivo: correlation between esterase concentration, functional response and fine structure. J Neurocytol 1979; 8: 95–115.

    Article  PubMed  CAS  Google Scholar 

  27. Donger C, Krejci E, Serradell AP, et al. Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic). Am J Hum Genet 1998; 63: 967–975.

    Article  PubMed  CAS  Google Scholar 

  28. Ohno K, Engel AG. Congenital myasthenic syndromes: gene mutations. Neuromuscul Disord 2000; 10: 534–536.

    Article  PubMed  CAS  Google Scholar 

  29. Ohno K, Engel AG, Brengman JM, et al. The spectrum of mutations causing endplate acetylcholinesterase deficiency. Ann Neurol 2000; 47: 162–170.

    Article  PubMed  CAS  Google Scholar 

  30. Magleby KL, Pallotta BS. A study of desensitization of acetylcholine receptors using nerve-released transmitter in the frog. J Physiol 1981; 316: 225–250.

    PubMed  CAS  Google Scholar 

  31. Katz B, Thesleff, S. A study of the ‘desensitization’ produced by acetylcholine at the motor end-plate. J Physiol (Lond) 1957; 138: 63–80.

    CAS  Google Scholar 

  32. Sieb JP, Kraner S, Schrank B, et al. Severe congenital myasthenic syndrome due to homozygosity of the 1293insG epsilon-acetylcholine receptor subunit mutation. Ann Neurol 2000; 48: 379–383.

    Article  PubMed  CAS  Google Scholar 

  33. Engel AG, Ohno K, Bouzat C, Sine SM, Griggs RC. End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit. Ann Neurol 1996; 40: 810–817.

    Article  PubMed  CAS  Google Scholar 

  34. Milone M, Shen X-M, Ohno K, et al. Unusual congenital myasthenic syndrome caused by alpha subunit mutations and a relapsing-remitting clinical course. Neurology 1999; 52: A185.

    Article  Google Scholar 

  35. Palace J, Wiles CM, Newsom-Davis J. 3,4-Diaminopyridine in the treatment of congenital (hereditary) myasthenia. J Neurol Neurosurg Psychiatry 1991; 54: 1069–1072.

    Article  PubMed  CAS  Google Scholar 

  36. Ohno K, Quiram PA, Milone M, et al. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations. Hum Mol Genet 1997; 6: 753–766.

    Article  PubMed  CAS  Google Scholar 

  37. Milone M, Wang HL, Ohno K, et al. Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor epsilon subunit. Neuron 1998; 20: 575–588.

    Article  PubMed  CAS  Google Scholar 

  38. Middleton L, Ohno K, Christodoulou K, et al. Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene. Neurology 1999; 53: 1076–1082.

    Article  PubMed  CAS  Google Scholar 

  39. Ohno K, Anlar B, Ozdirim E, et al. Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor. Ann Neurol 1998; 44: 234–241.

    Article  PubMed  CAS  Google Scholar 

  40. Ohno K, Fukudome T, Nakano S, et al. Mutational analysis in a congenital myasthenic syndrome reveals a novel acetylcholine receptor epsilon subunit mutation. Soc Neurosci Abstr 1996; 22: 234.

    Google Scholar 

  41. Brownlow S, Webster R, Croxen R, et al. Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. Clin Invest 2001; 108: 125–130.

    CAS  Google Scholar 

  42. Ohno K, Wang HL, Milone M, et al. Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit. Neuron 1996; 17: 157–170.

    Article  PubMed  CAS  Google Scholar 

  43. Nichols P, Croxen R, Vincent A, et al. Mutation of the acetylcholine receptor epsilon-subunit promoter in congenital myasthenic syndrome. Ann Neurol 1999; 45: 439– 443

    Google Scholar 

  44. Quiram PA, Ohno K, Milone M, et al. Mutation causing congenital myasthenia reveals acetylcholine receptor beta/delta subunit interaction essential for assembly. J Clin Invest 1999; 104: 1403–1410.

    Article  PubMed  CAS  Google Scholar 

  45. Uchitel O, Engel AG, Walls TJ, et al. Congenital myasthenic syndromes: II. Syndrome attributed to abnormal interaction of acetylcholine with its receptor. Muscle Nerve 1993; 16: 1293–1301.

    Article  PubMed  CAS  Google Scholar 

  46. Milone M, Ohno K, Brengman JM, et al. Low-affinity fast-channel congenital myasthenic syndrome caused by new missense mutations in the acetylcholine receptor alpha subunit. Neurology 1998; 50: A432–A433.

    Google Scholar 

  47. Engel AG, Uchitel OD, Walls TJ, et al. Newly recognized congenital myasthenic syndrome associated with high conductance and fast closure of the acetylcholine receptor channel. Ann Neurol 1993; 34: 38–47.

    Article  PubMed  CAS  Google Scholar 

  48. Engel AG, Nagel A, Walls TJ, Harper CM, Waisburg HA. Congenital myasthenic syndromes: I. Deficiency and short open-time of the acetylcholine receptor. Muscle Nerve 1993; 16: 1284–1292.

    Article  PubMed  CAS  Google Scholar 

  49. Engel AG, Lambert EH, Mulder DM, et al. A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel. Ann Neurol 1982; 11: 553–569.

    Article  PubMed  CAS  Google Scholar 

  50. Oosterhuis HJ, Newsom-Davis J, Wokke JH, et al. The slow channel syndrome. Two new cases. Brain 1987; 110: 1061–1079.

    Article  PubMed  Google Scholar 

  51. Ohno K, Hutchinson DO, Milone M, et al. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. Proc Natl Acad Sci USA 1995; 92: 758–762.

    Article  PubMed  CAS  Google Scholar 

  52. Engel AG, Ohno K, Milone M, et al. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet 1996; 5: 1217–1227.

    Article  PubMed  CAS  Google Scholar 

  53. Milone M, Wang HL, Ohno K, et al. Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor alpha subunit. J Neurosci 1997; 17: 5651–5665.

    PubMed  CAS  Google Scholar 

  54. Sine SM, Ohno K, Bouzat C, et al. Mutation of the acetylcholine receptor alpha subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron 1995; 15: 229–239.

    Article  PubMed  CAS  Google Scholar 

  55. Wang HL, Auerbach A, Bren N, et al. Mutation in the M1 domain of the acetylcholine receptor alpha subunit decreases the rate of agonist dissociation. J Gen Physiol 1997; 109: 757–766.

    Article  PubMed  CAS  Google Scholar 

  56. Gomez CM, Maselli R, Gammack J, et al. A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome. Ann Neurol 1996; 39: 712–723.

    Article  PubMed  CAS  Google Scholar 

  57. Gomez CM, Gammack JT. A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome. Neurology1995; 45: 982–985.

    Google Scholar 

  58. Croxen R, Newland C, Beeson D, et al. Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome. Hum Mol Genet 1997; 6: 767–774.

    Article  PubMed  CAS  Google Scholar 

  59. Gomez CM, Maselli R, Staub J, et al. Novel S and ß subunit acetylcholine receptor mutations in the slow-channel syndrome demonstrate phenotypic variability. Soc Neurosci Abstr 1998; 24: A573.

    Google Scholar 

  60. Ohno K, Wang H-L, Shen X-M, et al. Slow-channel mutations in the center of the M1 transmembrane domain of acetylcholine receptor alpha subunit. Neurology 2000; 54 (Suppl 3): A183.

    Google Scholar 

  61. Gomez CM, Maselli RA, Vohra BP, et al. Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms. Ann Neurol 2002; 51: 102–112.

    Article  PubMed  CAS  Google Scholar 

  62. Evans RH. The entry of labelled calcium into the innervated region of the mouse diaphragm muscle. J Physiol 1974; 240: 517–533.

    PubMed  CAS  Google Scholar 

  63. Takeuchi N. Effects of calcium on the conductance change of the end-plate membrane during the action of the transmitter. J Physiol (Lond) 1963; 167: 141–155.

    CAS  Google Scholar 

  64. Jackson MJ, Jones DA, Edwards RH. Experimental skeletal muscle damage: the nature of the calcium-activated degenerative processes. Eur J Clin Invest 1984; 14: 369–374.

    Article  PubMed  CAS  Google Scholar 

  65. Sieb JP, Milone M, Engel AG. Effects of the quinoline derivatives quinine, quinidine, and chloroquine on neuromuscular transmission. Brain Res 1996; 712: 179–189.

    Article  PubMed  CAS  Google Scholar 

  66. Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol 1998; 43: 480–484.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Suraj A. Muley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher M. Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Departments of Neurology and Neurosciences, University Hospitals of Cleveland, Louis Stokes Cleveland Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, OH, USA

    Henry J. Kaminski MD

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Muley, S.A., Gomez, C.M. (2003). Congenital Myasthenic Syndromes. In: Kaminski, H.J. (eds) Myasthenia Gravis and Related Disorders. Current Clinical Neurology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-341-5_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-341-5_14

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4757-5942-6

  • Online ISBN: 978-1-59259-341-5

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation