, Volume 4, Issue 2, pp 252–257 | Cite as

The therapy of congenital myasthenic syndromes

  • Andrew G. EngelEmail author


Congenital myasthenic syndromes (CMSs) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more mechanisms. Specific diagnosis of a CMS is important as some medications that benefit one type of CMS can be detrimental in another type. In some CMSs, strong clinical clues point to a specific diagnosis. In other CMSs, morphologic and in vitro electrophysiologic studies of the neuromuscular junction, determination of the number of acetylcholine receptors (AchRs) per junction, and molecular genetic studies may be required for a specific diagnosis. Strategies for therapy are based on whether a given CMS decreases or increases the synaptic response to acetylcholine (ACh). Cholinesterase inhibitors that increase the synaptic response to ACh and 3,4-diaminopyridine, which increases ACh release, are useful when the synaptic response to ACh is attenuated. Long-lived open-channel blockers of the AChR, quinidine, and fluoxetine, are useful when the synaptic response is increased by abnormally prolonged opening episodes of the AChR channel. Ephedrine has beneficial effects in some CMSs but its mechanism of action is not understood.

Key Words

Congenital myasthenic syndromes acetylcholine receptor acetylcholinesterase choline acetyltransferase rapsyn Dok-7 MuSK cholinesterase inhibitors 3,4-diaminopyridine quinidine fluoxetine 


  1. 1.
    Salpeter MM. Vertebrate neuromuscular junctions: general morphology, molecular organization, and functional consequences. In: Salpeter MM, ed. The vertebrate neuromuscular junction. New York: Wiley; 1987: 1–54.Google Scholar
  2. 2.
    Flucher BE, Daniels MP. Distribution of Na+ channels and ankyrin in neuromuscular junctions is complementary to that of acetylcholine receptors and the 43 kd protein. Neuron 1989;3: 163–175.CrossRefPubMedGoogle Scholar
  3. 3.
    Ruff RL. Sodium channel slow inactivation and the distribution of sodium channels on skeletal muscle fibres enable the performance properties of different skeletal muscle fiber types. Acta Physiol Scand 1996;156: 159–168.CrossRefPubMedGoogle Scholar
  4. 4.
    Martin AR. Amplification of neuromuscular transmission by postjunctional folds. Proc R Soc Lond B Biol Sci 1994;258: 321–326.CrossRefGoogle Scholar
  5. 5.
    Wood SJ, Slater CP. Safety factor at the neuromuscular junction. Prog Neurobiol 2001;64: 393–429.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    Ohno K, Tsujino A, Brengman JM, et al. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci U S A 2001;98: 2017–2022.CrossRefPubMedGoogle Scholar
  8. 8.
    Engel AG. The investigation of congenital myasthenic syndromes. Ann NY Acad Sci 1993;681: 425–434.CrossRefPubMedGoogle Scholar
  9. 9.
    Fukudome T, Ohno K, Brengman JM, Engel AG. Quinidine normalizes the open duration of slow-channel mutants of the acetylcholine receptor. Neuroreport 1998;9: 1907–1911.CrossRefPubMedGoogle Scholar
  10. 10.
    Harper CM, Fukudome T, Engel AG. Treatment of slow channel congenital myasthenic syndrome with fluoxetine. Neurology 2003; 60: 170–173.Google Scholar
  11. 11.
    Ohno K, Brengman JM, 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 U S A 1998;95: 9654–9659.CrossRefPubMedGoogle Scholar
  12. 12.
    Ohno K, Quiram PA, Milone M, et al. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor e subunit gene: identification and functional characterization of six new mutations. Hum Mol Genet 1997;6: 753–766.CrossRefPubMedGoogle Scholar
  13. 13.
    Ohno K, Engel AG, Shen XM, et al. Rapsyn mutations in humans cause endplate acetylcholine receptor deficiency and myasthenic syndrome. Am J Hum Genet 2002;70: 875–885.CrossRefPubMedGoogle Scholar
  14. 14.
    Chevessier F, Faraut B, Ravel-Chapuis A, et al. MUSK, a new target for mutations causing congenital myasthenic syndrome. Hum Mol Genet 2004; 13: 3229–3240.CrossRefPubMedGoogle Scholar
  15. 15.
    Beeson D, Higuchi O, Palace J, et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 2006;313: 1975–1978.CrossRefPubMedGoogle Scholar
  16. 16.
    Ohno K, Anlar B, Ozdirim E, Brengman JM, DeBleecker JL, Engel AG. Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor. Ann Neurol 1998;44: 234–241.CrossRefPubMedGoogle Scholar
  17. 17.
    Middleton L, Ohno K, Christodoulou K, Sine SM. Congenital myasthenic syndromes linked to chromosome 17p are caused by defects in acetylcholine receptor e subunit gene. Neurology 1999; 53: 1076–1082.PubMedGoogle Scholar
  18. 18.
    Croxen R, Hatton C, Shelley C, et al. Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology 2002;59: 162–168.PubMedGoogle Scholar
  19. 19.
    Maeno T. Kinetic analysis of a large facilitatory action of 4-aminopyridine on the motor nerve terminal of the neuromuscular junction. Proc Jpn Acad 1980;56: 241–245.CrossRefGoogle Scholar
  20. 20.
    Saint DA. The effects of 4-aminopyridine and tetraethylammonium on the kinetics of transmitter release at the mammalian neuromuscular synapse. Can J Physiol Pharmacol 1989;67: 1045–1050.PubMedGoogle Scholar
  21. 21.
    McEvoy KM, Windebank AJ, Daube JR, Low PA. 3,4-Diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. N Engl J Med 1989;321: 1567–1571.CrossRefPubMedGoogle Scholar
  22. 22.
    Sanders DB, Howard JF Jr, Massey JM. 3,4-diaminopyridine in Lambert-Eaton myasthenic syndrome and myasthenia gravis. Ann NY Acad Sci 1993;681: 588–590.CrossRefPubMedGoogle Scholar
  23. 23.
    Harper CM, Engel AG. Treatment of 31 congenital myasthenic syndrome patients with 3,4-diaminopyridine. Neurology 2000; 54(suppl 3): A395.Google Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    Anlar B, Varli K, Ozdirim E, Ertan M. 3,4-diaminopyridine in childhood myasthenia: double blind, placebo controlled trial. J Child Neurol 1996;11: 458–461.CrossRefPubMedGoogle Scholar
  26. 26.
    Engel AG, Ohno K, Bouzat C, Sine SM, Griggs RG. End-plate acetylcholine receptor deficiency due to nonsense mutations in the e subunit. Ann Neurol 1996;40: 810–817.CrossRefPubMedGoogle Scholar
  27. 27.
    Engel AG, Ohno K, Sine SM. Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat Rev Neurosci 2003;4: 339–352.CrossRefPubMedGoogle Scholar
  28. 28.
    Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol 1998;43: 480–484.CrossRefPubMedGoogle Scholar
  29. 29.
    Drug Evaluations Annual, 7th ed. Milwaukee, WI: American Medical Association; 1995:677–679.Google Scholar
  30. 30.
    Drug Evaluations Annual, 7th ed. Milwaukee, WI: American Medical Association; 1995:310–311.Google Scholar
  31. 31.
    Whittington CJ, Kendall T, Pilling S. Are the SSRIs and atypical antidepressants safe and effective for children and adolescents? Curr Opin Psychiatry 2005;18: 21–25.PubMedGoogle Scholar
  32. 32.
    Bailly D. Efficacy of selective serotonin reuptake inhibitor treatment in children and adolescents. Presse Med 2006;35: 1293–1302.CrossRefPubMedGoogle Scholar
  33. 33.
    Engel AG, Ohno K, Sine SM. Congenital myasthenic syndromes. In: Engel AG, ed. Myasthenia gravis and myasthenic disorders. New York: Oxford University Ress; 1999: 251–297.Google Scholar
  34. 34.
    Bestue-Cardiel M, Saenz de Cabezon-Alvarez A, Capablo-Liesa JL, et al. Congenital endplate acetylcholinesterase deficiency responsive to ephedrine. Neurology 2005;65: 144–146.CrossRefPubMedGoogle Scholar
  35. 35.
    Hutchinson DO, Walls TJ, Nakano S, et al. Congenital endplate acetylcholinesterase deficiency. Brain 1993;116: 633–653.CrossRefPubMedGoogle Scholar
  36. 36.
    Breningstall GN, Kurachek SC, Fugate JH, Engel AG. Treatment of congenital endplate acetylcholinesterase deficiency by neuromuscular blockade. J Child Neurol 1996;11: 345–346.CrossRefPubMedGoogle Scholar
  37. 37.
    Burke G, Cossins J, Maxwell S, et al. Rapsyn mutations in hereditary myasthenia: distinct early- and late-onset phenotypes. Neurology 2003;61: 826–828.PubMedGoogle Scholar
  38. 38.
    Banwell BL, Ohno K, Sieb JP, Engel AG. Novel truncating RAPSN mutation causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine. Neuromuscul Disord 2004;14: 202–207.CrossRefPubMedGoogle Scholar
  39. 39.
    Okada K, Inoue A, Okada M, et al. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science 2006;312: 1802–1805.CrossRefPubMedGoogle Scholar
  40. 40.
    Slater CR, Fawcett PRW, Walls TJ, et al. Re- and postsynaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with ‘limb-girdle myasthenia’. Brain 2006;129: 2061–2076.CrossRefPubMedGoogle Scholar
  41. 41.
    Walls TJ, Engel AG, Nagel AS, Harper CM, Trastek VF. Congenital myasthenic syndrome associated with paucity of synaptic vesicles and reduced quantal release. Ann N Y Acad Sci 1993;681: 461–468.CrossRefPubMedGoogle Scholar
  42. 42.
    Tim RW, Massey JM, Sanders DB. Lambert-Eaton myasthenic syndrome: electrodiagnostic findings and response to treatment. Neurology 2000;54: 2176–2178.PubMedGoogle Scholar
  43. 43.
    Banwell BL, Russel J, Fukudome T, Shen XM, Stilling G, Engel AG. Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J Neuropathol Exp Neurol 1999; 58: 832–846.CrossRefPubMedGoogle Scholar
  44. 44.
    Tsujino A, Maertens C, Ohno K, et al. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A 2003;100: 7377–7382.CrossRefPubMedGoogle Scholar
  45. 45.
    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.CrossRefPubMedGoogle Scholar
  46. 46.
    Byring RF, Pihko H, Tsujino A, et al. Congenital myasthenic syndrome associated with episodic apnea and sudden infant death. Neuromuscul Disord 2002;12: 548–553.CrossRefPubMedGoogle Scholar

Copyright information

© Springer New York 2007

Authors and Affiliations

  1. 1.Department of NeurologyMayo ClinicRochester

Personalised recommendations