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Congenital Myasthenic Syndromes in 2012

  • Nerve and Muscle (M Hirano and LH Weimer, Section Editors)
  • Published:
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Abstract

Congenital myasthenic syndromes (CMS) represent a heterogeneous group of disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Clinical, electrophysiologic, and morphologic studies have paved the way for detecting CMS-related mutations in proteins residing in the nerve terminal, the synaptic basal lamina, or in the postsynaptic region of the motor endplate. The disease proteins identified to date include the acetylcholine receptor, acetylcholinesterase, choline acetyltransferase, rapsyn, and Nav1.4, muscle-specific kinase, agrin, β2-laminin, downstream of tyrosine kinase 7, and glutamine-fructose-6-phosphate transaminase 1. Analysis of electrophysiologic and biochemical properties of mutant proteins expressed in heterologous systems have contributed crucially to defining the molecular consequences of the observed mutations and have resulted in improved therapy of most CMS.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Rothbart HB. Myasthenia gravis. Familial occurrence. JAMA. 1937;108:715–7.

    Article  Google Scholar 

  2. Selcen D, Juel VC, Hobson-Webb LD, et al. Myasthenic syndrome caused by plectinopathy. Neurology. 2011;76:327–36.

    Article  PubMed  CAS  Google Scholar 

  3. Tsujino A, Maertens C, Ohno K, et al. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci USA. 2003;100:7377–82.

    Article  PubMed  CAS  Google Scholar 

  4. Engel AG, Ohno K, Wang H-L, et al. Molecular basis of congenital myasthenic syndromes: Mutations in the acetylcholine receptor. Neuroscientist. 1998;4:185–94.

    Article  CAS  Google Scholar 

  5. 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 USA. 1998;95:9654–9.

    Article  PubMed  CAS  Google Scholar 

  6. •• Beeson D, Higuchi O, Palace J, et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 2006;313:1975–8.

    Article  PubMed  CAS  Google Scholar 

  7. Kaiser J. Affordable ‘exomes’ fill gaps in a catalog of rare diseases. Science. 2010;330:903.

    Article  PubMed  CAS  Google Scholar 

  8. Walls TJ, Engel AG, Nagel AS, et al. Congenital myasthenic syndrome associated with paucity of synaptic vesicles and reduced quantal release. Ann N Y Acad Sci. 1993;681:461–8.

    Article  PubMed  CAS  Google Scholar 

  9. Ohno K, Tsujino A, Shen XM, et al. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci USA. 2001;98:2017–22.

    Article  PubMed  CAS  Google Scholar 

  10. Schara U, Christen H-J, Durmus H, et al. Long-term follow-up in patients with congenital myasthenic syndrome due to CHAT mutations. Eur J Paediatr Neurol. 2010;14:326–33.

    Article  PubMed  Google Scholar 

  11. • Shen X-M, Crawford TO, Brengman J, et al. Functional consequences and structural interpretation of mutations in human choline acetyltransferase. Hum. Mutat. Published online on 23 Sep 2011. This paper identifies divergent effects of different ChAT mutations on enzyme activation and shows that the most severely affected patients carry at least one mutation near the active site of the enzyme.

  12. Massoulié J, Pezzementi L, Bon S, et al. Molecular and cellular biology of cholinesterases. Prog Neurobiol. 1993;41:31–91.

    Article  PubMed  Google Scholar 

  13. Bon S, Coussen F, Massoulié J. Quaternary associations of acetylcholinesterase. II. The polyproline attachment domain of the collagen tail. J Biol Chem. 1997;272:3016–21.

    Article  PubMed  CAS  Google Scholar 

  14. Deprez PN, Inestrosa NC. Two heparin-binding domains are present on the collagenic tail of asymmetric acetylcholinesterase. J Biol Chem. 1995;270:11043–6.

    Article  PubMed  CAS  Google Scholar 

  15. Cartaud A, Strochlic L, Guerra M, et al. MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. J Cell Biol. 2004;165:505–15.

    Article  PubMed  CAS  Google Scholar 

  16. Kimbell LM, Ohno K, Engel AG, Rotundo RL. C-terminal and heparin-binding domains of collagenic tail subunit are both essential for anchoring acetylcholinesterase at the synapse. J Biol Chem. 2004;279:10997–1005.

    Article  PubMed  CAS  Google Scholar 

  17. Engel AG, Ohno K, Sine SM. Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nature Rev Neurosci. 2003;4:339–52.

    Article  CAS  Google Scholar 

  18. Bestue-Cardiel M, de-Cabazon-Alvarez AS, Capablo-Liesa JL, et al. Congenital endplate acetylcholinesterase deficiency responsive to ephedrine. Neurology. 2005;65:144–6.

    Article  PubMed  CAS  Google Scholar 

  19. Mihaylova V, Muller JS, Vilchez JJ, et al. Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes. Brain. 2008;131:747–59.

    Article  PubMed  Google Scholar 

  20. • Liewluck T, Selcen D, Engel AG. Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and DOK-7 myasthenia. Muscle Nerve. Published online 23 SEP 2011. This paper reports significant therapeutic response in two CMS to a readily available medication.

  21. Maselli RA, Ng JJ, Andreson JA, et al. Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. J Med Genet 2009, 46:203–208.

    Google Scholar 

  22. Harper CM, Engel AG. Treatment of 31 congenital myasthenic syndrome patients with 3,4-diaminopyridine. Neurology. 2000; 54(Suppl 3):A395 (Abstr.)

    Google Scholar 

  23. Sadeh M, Shen X-M, Engel AG. Beneficial effect of albuterol in congenital myasthenic syndrome with epsilon subunit mutations. Muscle Nerve In press. 2011.

  24. 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 ε subunit. Proc Natl Acad Sci USA. 1995;92:758–62.

    Article  PubMed  CAS  Google Scholar 

  25. Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol. 1998;43:480–4.

    Article  PubMed  CAS  Google Scholar 

  26. Harper CM, Fukudome T, Engel AG. Treatment of slow channel congenital myasthenic syndrome with fluoxetine. Neurology. 2003;60:170–3.

    Google Scholar 

  27. Shen X-M, Fukuda T, Ohno K, et al. Congenital myasthenia-related AChR δ subunit mutation interferes with intersubunit communication essential for channel gating. J Clin Invest. 2008;118:1867–76.

    Article  PubMed  CAS  Google Scholar 

  28. Sine SM, Engel AG. Recent advances in Cys-loop receptor structure and function. NAT. 2006;440:448–55.

    Article  CAS  Google Scholar 

  29. Engel AG, Brengman J, Edvardson S, Shen X-M. Highly fatal low-affinity fast-channel congenital myasthenic syndrome caused by a novel AChR epsilon subunit mutation at the agonist binding site. Neurology. 2011;76 Suppl 4:A644.

    Google Scholar 

  30. Froehner SC, Luetje CW, Scotland PB, Patrick J. The postsynaptic 43 K protein clusters muscle nicotinic acetylcholine receptors in Xenopus oocytes. Neuron. 1990;5:403–10.

    Article  PubMed  CAS  Google Scholar 

  31. Cartaud A, Coutant S. Petrucci TC, Cartaud J: Evidence for in situ and in vitro association between β-dystroglycan and the subsynaptic 43K rapsyn protein. Consequence for acetylcholine receptor clustering at the synapse. J Biol Chem. 1998;273:11321–6.

    Article  PubMed  CAS  Google Scholar 

  32. Okada K, Inoue A, Okada M, et al. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006;312:1802–5.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang B, Luo S, Wang Q, et al. LRP4 serves as a coreceptor of agrin. Neuron. 2008;60:285–97.

    Article  PubMed  CAS  Google Scholar 

  34. Burke G, Cossins J, Maxwell S, et al. Rapsyn mutations in hereditary myasthenia. Distinct early- and late-onset phenotypes. Neurology. 2003;61:826–8.

    PubMed  CAS  Google Scholar 

  35. Ohno K, Engel AG, Shen X-M, et al. Rapsyn mutations in humans cause endplate acetylcholine receptor deficiency and myasthenic syndrome. Am J Hum Genet. 2002;70:875–85.

    Article  PubMed  CAS  Google Scholar 

  36. Milone M, Shen XM, Selcen D, et al. Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients. Neurology. 2009;73:228–35.

    Article  PubMed  CAS  Google Scholar 

  37. Müller JS, Mildner G, Müller-Felber W, et al. Rapsyn N88K is a frequent cause of CMS in European patients. Neurology. 2003;60:1805–11.

    PubMed  Google Scholar 

  38. Ohno K, Sadeh M, Blatt I, et al. E-box mutations in RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum Mol Genet. 2003;12:739–48.

    Article  PubMed  CAS  Google Scholar 

  39. Banwell BL, Ohno K, Sieb JP, Engel AG. Novel truncating RAPSN mutation causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine. Neuromuscul Disord. 2004;14:202–7.

    Article  PubMed  Google Scholar 

  40. Milone M, Shen XM, Selcen D, et al. Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients. Neurology 2009;73:228-235

    Google Scholar 

  41. Kim N, Stiegler AL, Cameron TO, et al. Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell. 2008;135:334–42.

    Article  PubMed  CAS  Google Scholar 

  42. Hallock PT, Xu C-F, Neubert TA, Curran T. Dok-7 regulates neuromuscular synapse formation by recruiting Crk and Crk-L. Genes Dev. 2010;24:2451–61.

    Article  PubMed  CAS  Google Scholar 

  43. Linnoila J, Wang Y, Yao Y, Wang Z-S. A mammalian homolog of Drosophila tumorous imaginal disks, Tid1, mediates agrin signaling at the neuromuscular junction. Neuron. 2010;60:625–41.

    Article  Google Scholar 

  44. Huze C, Bauche S, Richard P, et al. Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet. 2009;85:155–67.

    Article  PubMed  CAS  Google Scholar 

  45. Chevessier F, Faraut B, Ravel-Chapuis A, et al. MUSK, a new target for mutations causing congenital myasthenic syndrome. Hum Mol Genet. 2004;13:3229–40.

    Article  PubMed  CAS  Google Scholar 

  46. • Maselli R, Arredondo J, Cagney O, et al.: Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. Hum Mol Genet 2010, 19:2370–2379. This paper provides important insight into the mechanism of interaction between MuSK and Dok-7.

    Article  PubMed  CAS  Google Scholar 

  47. Mihaylova V, Salih MA, Mukhtar MM, et al. Refinement of the clinical phenotype in Musk-related congenital myasthenic syndromes. Neurology. 2009;73:1926–8.

    Article  PubMed  CAS  Google Scholar 

  48. •• Selcen D, Milone M, Shen X-M, et al.: Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann Neurol 2008, 64:71–87. This paper shows that Dok-7 is important not only for the development but also for the maintenace of the neuromuscular junction throughout life and that some mutations can be detected only by cloning patient complementary DNA.

    Article  PubMed  CAS  Google Scholar 

  49. Lashley D, Palace J, Jayawant S, et al. Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7. Neurology. 2010;74:1517–23.

    Article  PubMed  CAS  Google Scholar 

  50. Slater CR, Fawcett PRW, Walls TJ, et al. Pre- and postsynaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with ‘limb-girdle myasthenia’. Brain. 2006;127:2061–76.

    Article  Google Scholar 

  51. •• Senderek J, Muller JS, Dusl M, et al.: Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet 2011, 88:162–172. This paper describes a novel myasthenic syndrome with a limb-girdle phenotype associated with tubular aggregates in muscle caused by a defect in protein glycosylation.

    Article  PubMed  CAS  Google Scholar 

  52. Banwell BL, Russel J, Fukudome T, et al. Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J Neuropathol Exp Neurol. 1999;58:832–46.

    Article  PubMed  CAS  Google Scholar 

  53. Forrest K, Mellerio JE, Robb S, et al. Congenital muscular dystrophy, myasthenic symptoms and epidermolysis bullosa simplex (EBS) associated with mutations in the PLEC1 gene encoding plectin. Neuromuscul Disord. 2010;20:709–11.

    Article  PubMed  Google Scholar 

  54. Maselli R, Arredondo J, Cagney O, et al. Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutaions in PLEC1 and CHRNE. Clin. Genet. 2010 In press.

  55. Romero NB. Centronucelar myopathies: a widening concept. Neuromuscul Disord. 2010;20:223–8.

    Article  PubMed  Google Scholar 

  56. Claeys KG, Maisonobe T, Bohm J, et al. Phenotype of a patient with recessive centronuclear myopathy and a novel BIN1 mutation. Neurology. 2010;74:519–21.

    Article  PubMed  CAS  Google Scholar 

  57. Baradello A, Vita G, Girlanda P, et al. Adult-onset centronuclear myopathy: evidence against a neurogenic pathology. Acta Neurol Scand. 1989;80:162–6.

    Article  PubMed  CAS  Google Scholar 

  58. • Liewluck T, Shen X-M, Milone M, Engel AG: Endplate structure and parameters of neuromuscular transmission in sporadic centronuclear myopathy associated with myasthenia. Neuromuscul Disord 2011, 21:387–395. This paper identifies both pre- and postsynaptic changes accounting for the defect in neuromuscular transmission.

    Article  PubMed  Google Scholar 

  59. Robb SA, Sewry CA, Dowling JJ, et al. Impaired neuromuscular transmission and response to aceylcholinesterase inhibitors in centronuclear myopathy. Neuromuscul Disord. 2011;21:379–86.

    Article  PubMed  Google Scholar 

  60. Oskoui M, Jacobson L, Chung WK, et al. Fetal acetylcholine receptor inactivation syndrome and maternal myasthenia gravis. Neurology. 2008;71:2010–2.

    Article  PubMed  CAS  Google Scholar 

  61. Reimann J, Jacobson L, Vincent A, Kornblum C. Endplate destruction due to maternal antibodies in arthrogryposis multiplex congenita. Neurology. 2009;73:1806–8.

    Article  PubMed  CAS  Google Scholar 

  62. Hesselmans LFGM, Jennekens FGI, Vand Den Oord CJM, et al. Development of innervation of skeletal muscle fibers in man: Relation to acetylcholine receptors. Anat Rec. 1993;236:553–62.

    Article  PubMed  CAS  Google Scholar 

  63. Hoffmann K, Muller JS, Stricker S, et al. Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am J Hum Genet. 2006;79:303–12.

    Article  PubMed  CAS  Google Scholar 

  64. Morgan NV, Brueton LA, Cox P, et al. Mutations in the embryonal subunit of the acetylcholine receptor (CHNRG) cause lethal and Escobar variants of the multiple pterygium syndrome. Am J Hum Genet. 2006;79:390–5.

    Article  PubMed  CAS  Google Scholar 

  65. • Michalk A, Stricker S, Becker J, et al.: Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet 2008, 82:464–476. This paper identifies heretofore unsuspected causes of the fetal dyskinesia and deformation syndrome causing myasthenia in utero.

    Article  PubMed  CAS  Google Scholar 

  66. Vogt J, Harrison BJ, Spearman H, et al. Mutation Analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Am J Hum Genet. 2008;82:222–7.

    Article  PubMed  CAS  Google Scholar 

  67. Vogt J, Morgan NV, Marton T, et al. Germline mutation in DOK7 associated with fetal akinesia deformation sequence. J Med Genet. 2009;46:338–40.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

Work in the author’s laboratory was supported by a National Institutes of Health Research Grant NS6277 and by the Muscular Dystrophy Association.

Disclosure

Conflicts of interest: A.G. Engel: has received honorarium from the American Academy of Neurology for serving on the editorial board of the journal Neurology; and has received royalties from McGraw-Hill for editing the textbook entitled “Myology.”

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  1. Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Andrew G. Engel

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Engel, A.G. Congenital Myasthenic Syndromes in 2012. Curr Neurol Neurosci Rep 12, 92–101 (2012). https://doi.org/10.1007/s11910-011-0234-7

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  • DOI: https://doi.org/10.1007/s11910-011-0234-7

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