Congenital Myasthenic Syndromes



Congenital myasthenic syndromes are inherited disorders of neuromuscular transmission. This chapter discusses the clinical and electrophysiological manifestations of these relatively rare disorders as well as their pathophysiology, genetics, and management.


Neuromuscular Transmission Congenital Myasthenic Syndromes Acetylcholine Receptor Acetylcholinesterase Rapsyn Dok-7 Glutamine-fructose-6-phosphate transaminase deficiency (GFPT1) Mutation Analysis Expression Studies 


  1. 1.
    Engel AG, Ohno K, Sine SM. Congenital myasthenic syndromes. In: Engel AG, Franzini-Armstrong C, editors. Myology. 3rd ed. New York: McGraw-Hill; 2004. p. 1755–90.Google Scholar
  2. 2.
    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;1:315–30.PubMedGoogle Scholar
  3. 3.
    Beeson D, Higuchi O, Palace J, et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 2006;313:1975–8.PubMedGoogle Scholar
  4. 4.
    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.PubMedGoogle Scholar
  5. 5.
    Maselli RA, Ng JJ, Andreson JA, et al. Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. J Med Genet. 2009;46:203–8.PubMedGoogle Scholar
  6. 6.
    Liewluck T, Lovell TL, Bite AV, Engel AG. Sporadic centronuclear myopathy with muscle pseudohypertrophy, neutropenia, and necklace fibers due to a DNM2 mutation. Neuromuscul Disord. 2010;20:801–4.PubMedGoogle Scholar
  7. 7.
    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;5:1217–27.PubMedGoogle Scholar
  8. 8.
    Ohno K, Anlar B, Özdirim E, Brengman JM, De Bleecker JL, Engel AG. Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor. Ann Neurol. 1998;44:234–41.PubMedGoogle Scholar
  9. 9.
    Senderek J, Muller JS, Dusl M, et al. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet. 2011;88:162–72.PubMedGoogle Scholar
  10. 10.
    Denning L, Anderson JA, Davis R, Kuzdenyi J, Maselli R. High throughput genetic analysis of congenital myasthenic syndromes using resequencing microarrays. PLoS One. 2007;2:e918.PubMedGoogle Scholar
  11. 11.
    Byring RF, Pihko H, Shen X-M, et al. Congenital myasthenic syndrome associated with episodic apnea and sudden infant death. Neuromuscul Disord. 2002;12:548–53.PubMedGoogle Scholar
  12. 12.
    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.PubMedGoogle Scholar
  13. 13.
    Shen X-M, Crawford TO, Brengman J, et al. Functional consequences and structural interpretation of mutations in human choline acetyltransferase. Hum Mutat. 2011;32:1259–67.PubMedGoogle Scholar
  14. 14.
    Kraner S, Lufenberg I, Strassburg HM, Sieb JP, Steinlein OK. Congenital myasthenic syndrome with episodic apnea in patients homozygous for a CHAT missense mutation. Arch Neurol. 2003;60:761–3.PubMedGoogle Scholar
  15. 15.
    Mora M, Lambert EH, Engel AG. Synaptic vesicle abnormality in familial infantile myasthenia. Neurology. 1987;37:206–14.PubMedGoogle Scholar
  16. 16.
    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;681:461–8.PubMedGoogle Scholar
  17. 17.
    Bady B, Chauplannaz G, Carrier H. Congenital Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 1987;50:476–8.PubMedGoogle Scholar
  18. 18.
    Engel AG, Ohno K, Sine SM. Congenital myasthenic syndromes. In: Engel AG, editor. Myasthenia gravis and myasthenic disorders. New York: Oxford University Press; 1999. p. 251–97.Google Scholar
  19. 19.
    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.PubMedGoogle Scholar
  20. 20.
    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.PubMedGoogle Scholar
  21. 21.
    Hutchinson DO, Walls TJ, Nakano S, et al. Congenital endplate acetylcholinesterase deficiency. Brain. 1993;116:633–53.PubMedGoogle Scholar
  22. 22.
    Ohno K, Engel AG, Brengman JM, et al. The spectrum of mutations causing endplate acetylcholinesterase deficiency. Ann Neurol. 2000;47:162–70.PubMedGoogle Scholar
  23. 23.
    Bestue-Cardiel M, de-Cabazon-Alvarez AS, Capablo-Liesa JL, et al. Congenital endplate acetylcholinesterase deficiency responsive to ephedrine. Neurology. 2005;65:144–6.PubMedGoogle Scholar
  24. 24.
    Brengman JM, Capablo-Liesa JL, Lopez-Pison J, et al. Ephedrine treatment of seven patients with congenital endplate acetylcholinesterase deficiency. Neuromuscul Disord. 2006;16 Suppl 1Suppl 1:S129.Google Scholar
  25. 25.
    Mihaylova V, Muller JS, Vilchez JJ, Salih MA, et al. Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes. Brain. 2008;131:747–59.PubMedGoogle Scholar
  26. 26.
    Liewluck T, Selcen D, Engel AG. Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and DOK-7 myasthenia. Muscle Nerve. 2011;44:789–94.PubMedGoogle Scholar
  27. 27.
    Galzi JL, Revah F, Bessis A, Changeux JP. Functional architecture of the nicotinic acetylcholine receptor: from electric organ to brain. Annu Rev Pharmacol Toxicol. 1991;31:37–72.PubMedGoogle Scholar
  28. 28.
    Sine SM. The nicotinic receptor ligand binding domain. J Neurobiol. 2002;53:431–46.PubMedGoogle Scholar
  29. 29.
    Unwin N. Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J Mol Biol. 2005;346:967–89.PubMedGoogle Scholar
  30. 30.
    Brejc K, van Dijk WV, Schuurmans M, van der Oost J, Smit AB, Sixma TK. Crystal structure of ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature. 2001;411:269–76.PubMedGoogle Scholar
  31. 31.
    Lysine scanning mutagenesis delineates structural model of the nicotinic receptor ligand binding domain. J Biol Chem. 2002;277:2921–29213.Google Scholar
  32. 32.
    Dellisanti CD, Yao Y, Stroud JC, Wang ZZ, Chen L. Crystal structure of the extracellular domain of the nAChR α1 bound to α-bungarotoxin at 1.94 Å resolution. Nat Neurosci. 2007;10:953–62.PubMedGoogle Scholar
  33. 33.
    Li SX, Huang S, Bren N, et al. Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist. Nat Neurosci. 2011;14:1253–9.PubMedGoogle Scholar
  34. 34.
    Ohno K, Wang H-L, Milone M, et al. Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit. Neuron. 1996;17:157–70.PubMedGoogle Scholar
  35. 35.
    Engel AG, Ohno K, Bouzat C, Sine SM, Griggs RG. End-plate acetylcholine receptor deficiency due to nonsense mutations in the ε subunit. Ann Neurol. 1996;40:810–7.PubMedGoogle Scholar
  36. 36.
    Ohno K, Quiram P, Milone M, et al. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor ε subunit gene: identification and functional characterization of six new mutations. Hum Mol Genet. 1997;6:753–66.PubMedGoogle Scholar
  37. 37.
    Milone M, Wang H-L, Ohno K, et al. Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor ε subunit. Neuron. 1998;20:575–88.PubMedGoogle Scholar
  38. 38.
    Abicht A, Stucka R, Karcagi V, et al. A common mutation (ε1267delG) in congenital myasthenic patients of Gypsy ethnic origin. Neurology. 1999;53:1564–9.PubMedGoogle Scholar
  39. 39.
    Middleton L, Ohno K, Christodoulou K, et al. Congenital myasthenic syndromes linked to chromosome 17p are caused by defects in acetylcholine receptor ε subunit gene. Neurology. 1999;53:1076–82.PubMedGoogle Scholar
  40. 40.
    Croxen R, Newland C, Betty M, et al. Novel functional ε-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome. Ann Neurol. 1999;46:639–47.PubMedGoogle Scholar
  41. 41.
    Abicht A, Stucka R, Schmidt C, et al. A newly identified chromosomal microdeletion and an N-box mutation of the AChR ε gene cause a congenital myasthenic syndrome. Brain. 2002;125:1005–13.PubMedGoogle Scholar
  42. 42.
    Ealing J, Webster R, Brownlow S, et al. Mutations in congenital myasthenic syndromes reveal an ε subunit C-terminal cysteine, C470, crucial for maturation and surface expressions of adult AChR. Hum Mol Genet. 2002;11:3087–96.PubMedGoogle Scholar
  43. 43.
    Sadeh M, Shen X-M, Engel AG. Beneficial effect of albuterol in congenital myasthenic syndrome with ε subunit mutations. Muscle Nerve. 2011;44:289–91.PubMedGoogle Scholar
  44. 44.
    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;11:553–69.PubMedGoogle Scholar
  45. 45.
    Milone M, Wang H-L, Ohno K, et al. Slow-channel syndrome caused by enhanced activation, desensitization, and agonist binding affinity due to mutation in the M2 domain of the acetylcholine receptor alpha subunit. J Neurosci. 1997;17:5651–65.PubMedGoogle Scholar
  46. 46.
    Zhou M, Engel AG, Auerbach A. Serum choline activates mutant acetylcholine receptors that cause slow channel congenital myasthenic syndrome. Proc Natl Acad Sci USA. 1999;96:10466–71.PubMedGoogle Scholar
  47. 47.
    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.PubMedGoogle Scholar
  48. 48.
    Sine SM, Ohno K, Bouzat C, et al. Mutation of the acetylcholine receptor α subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron. 1995;15:229–39.PubMedGoogle Scholar
  49. 49.
    Wang H-L, Auerbach A, Bren N, Ohno K, Engel AG, Sine SM. Mutation in the M1 domain of the acetylcholine receptor alpha subunit decreases the rate of agonist dissociation. J Gen Physiol. 1997;109:757–66.PubMedGoogle Scholar
  50. 50.
    Gomez CM, Maselli R, Gammack J, et al. A beta-subunit mutation in the acetylcholine receptor gate causes severe slow-channel syndrome. Ann Neurol. 1996;39:712–23.PubMedGoogle Scholar
  51. 51.
    Croxen R, Newland C, Beeson D, et al. Mutations in different functional domains of the human muscle acetylcholine receptor α subunit in patients with the slow-channel congenital myasthenic syndrome. Hum Mol Genet. 1997;6:767–74.PubMedGoogle Scholar
  52. 52.
    Ohno K, Milone M, Brengman JM, et al. Slow-channel congenital myasthenic syndrome caused by a novel mutation in the acetylcholine receptor ε subunit. Neurology. 1998;50:A432. Abstract.Google Scholar
  53. 53.
    Ohno K, Wang H-L, Shen X-M, et al. Slow-channel mutations in the center of the M1 transmembrane domain of the acetylcholine receptor α subunit. Neurology. 2000;54 Suppl 3Suppl 3:A183.Google Scholar
  54. 54.
    Gomez CM, Maselli R, Staub J, et al. Novel δ and β subunit acetylcholine receptor mutations in the slow-channel syndrome demonstrate phenotypic variability. Soc Neurosci Abstr. 1998;24:484. Abstract.Google Scholar
  55. 55.
    Gomez CM, Maselli R, Vohra BPS, et al. Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanism. Ann Neurol. 2002;51:102–12.PubMedGoogle Scholar
  56. 56.
    Shen X-M, Ohno K, Adams C, Engel AG. Slow-channel congenital myasthenic syndrome caused by a novel epsilon subunit mutation in the second AChR transmembrane domain. J Neurol Sci. 2002;199 Suppl 1Suppl. 1:S96.Google Scholar
  57. 57.
    Sieb JP, Milone M, Engel AG. Effects of the quinoline derivatives quinine, quinidine, and chloroquine on neuromuscular transmission. Brain Res. 1996;712:179–89.PubMedGoogle Scholar
  58. 58.
    Fukudome T, Ohno K, Brengman JM, Engel AG. Quinidine normalizes the open duration of slow-channel mutants of the acetylcholine receptor. Neuroreport. 1998;9:1907–11.PubMedGoogle Scholar
  59. 59.
    Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol. 1998;43:480–4.PubMedGoogle Scholar
  60. 60.
    Harper CM, Fukudome T, Engel AG. Treatment of slow channel congenital myasthenic syndrome with fluoxetine. Neurology. 2003;60:170–3.Google Scholar
  61. 61.
    Sine SM, Shen X-M, Wang H-L, et al. Naturally occurring mutations at the acetylcholine receptor binding site independently alter ACh binding and channel gating. J Gen Physiol. 2002;120:483–96.PubMedGoogle Scholar
  62. 62.
    Wang H-L, Milone M, Ohno K, et al. Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating. Nature Neurosci. 1999;2:226–33.PubMedGoogle Scholar
  63. 63.
    Engel AG, Brengman J, Edvardson S, Shen X-M. Highly fatal low-affinity fast-channel congenital myasthenic syndrome caused by a novel AChR ε subunit mutation at the agonist binding site. Neurology, 2012;79:440–454.Google Scholar
  64. 64.
    Shen X-M, Fukuda T, Ohno K, Sine SM, Engel AG. Congenital myasthenia-related AChR δ subunit mutation interferes with intersubunit communication essential for channel gating. J Clin Invest. 2008;118:1867–76.PubMedGoogle Scholar
  65. 65.
    Sine SM, Engel AG. Recent advances in Cys-loop receptor structure and function. Nature. 2006;440:448–55.PubMedGoogle Scholar
  66. 66.
    Wang H-L, Ohno K, Milone M, et al. Fundamental gating mechanism of nicotinic receptor channel revealed by mutation causing a congenital myasthenic syndrome. J Gen Physiol. 2000;116:449–60.PubMedGoogle Scholar
  67. 67.
    Shen X-M, Ohno K, Fukudome T, et al. Congenital myasthenic syndrome caused by low-expressor fast-channel AchR δ subunit mutations. Neurology. 2002;59:1881–8. Abstract.PubMedGoogle Scholar
  68. 68.
    Shen X-M, Ohno K, Tsujino A, et al. Mutation causing severe myasthenia reveals functional asymmetry of AChR signature Cys-loops in agonist binding and gating. J Clin Invest. 2003;111:497–505.PubMedGoogle Scholar
  69. 69.
    Brownlow S, Webster R, Croxen R, et al. Acetylcholine receptor δ subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. J Clin Invest. 2001;108:125–30.PubMedGoogle Scholar
  70. 70.
    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.PubMedGoogle Scholar
  71. 71.
    Cartaud A, Coutant S, Petrucci TC, Cartaud J. Evidence for in situ and in vitro association between β-dystroglycan and the subsynaptic 43 K rapsyn protein Consequence for acetylcholine receptor clustering at the synapse. J Biol Chem. 1998;273:11321–6.PubMedGoogle Scholar
  72. 72.
    Mittaud P, Camillieri AA, Willmann R, Erb-Vogtli S, Burden SJ, et al. A single pulse of agrin triggers a pathway that acts to cluster acetylcholine receptors. Mol Cell Biol. 2004;24:7841–54.PubMedGoogle Scholar
  73. 73.
    Okada K, Inoue A, Okada M, et al. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006;312:1802–5.PubMedGoogle Scholar
  74. 74.
    Zhang B, Luo S, Wang Q, et al. LRP4 serves as a coreceptor of agrin. Neuron. 2008 Oct 23;60:285–97.PubMedGoogle Scholar
  75. 75.
    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.PubMedGoogle Scholar
  76. 76.
    Maselli RA, Dris H, Schnier J, Cockrell JL, Wollmann RL. Congenital myasthenic syndrome caused by two non-N88K rapsyn mutations. Clin Genet. 2007;72:63–5.PubMedGoogle Scholar
  77. 77.
    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.PubMedGoogle Scholar
  78. 78.
    Cossins J, Burke G, Maxwell S, et al. Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations. Brain. 2006;129:2773–83.PubMedGoogle Scholar
  79. 79.
    Ohno K, Sadeh M, Blatt I, Brengman JM, Engel AG. E-box mutations in RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum Mol Genet. 2003;12:739–48.PubMedGoogle Scholar
  80. 80.
    Burke G, Cossins J, Maxwell S, et al. Rapsyn mutations in hereditary myasthenia distinct early- and late-onset phenotypes. Neurology. 2003;61:826–8.PubMedGoogle Scholar
  81. 81.
    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.PubMedGoogle Scholar
  82. 82.
    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.PubMedGoogle Scholar
  83. 83.
    Skeie GO, Aurlien H, Müller JS, Norgard G, Bindoff LA. Unusual features in a boy with rapsyn N88K mutation. Neurology. 2006;67:2262–3.PubMedGoogle Scholar
  84. 84.
    Elliott CE, Becker B, Oehler S, Castanon MJ, Hauptmann R, Wiche G. Plectin transcript diversity: identification and tissue distribution of variants with distinct first coding exons and rodless isoforms. Genomics. 1997;42:115–25.PubMedGoogle Scholar
  85. 85.
    Fuchs P, Zorer M, Rezniczek GA, et al. Unusual 5′ transcript complexity of plectin isoforms: novel tissue-specific exons modulate actin binding activity. Hum Mol Genet. 1999 Dec 1;8:2461–72.PubMedGoogle Scholar
  86. 86.
    Konieczny P, Fuchs P, Reipert S, et al. Myofiber integrity depends on desmin network targeting to Z-disks and costameres via distinct plectin isoforms. J Cell Biol. 2008;181:667–81.PubMedGoogle Scholar
  87. 87.
    Banwell BL, Russel J, Fukudome T, Shen X-M, Stilling G, Engel AG. Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J Neuropathol Exp Neurol. 1999;58:832–46.PubMedGoogle Scholar
  88. 88.
    Selcen D, Juel VC, Hobson-Webb LD, et al. Myasthenic syndrome caused by plectinopathy. Neurology. 2011;76:327–36.PubMedGoogle Scholar
  89. 89.
    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.PubMedGoogle Scholar
  90. 90.
    Maselli R, Arredondo J, Cagney O, et al. Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE. Clin Genet. 2011;80:444–51.PubMedGoogle Scholar
  91. 91.
    Gundesli H, Talim B, Korkusuz P, et al. Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal-recessive limb-girdle muscular dystrophy. Am J Hum Genet. 2010;87:834–41.PubMedGoogle Scholar
  92. 92.
    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.PubMedGoogle Scholar
  93. 93.
    Muller JS, Herczegfalvi A, Vilchez JJ, et al. Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain. 2007;130:1497–506.PubMedGoogle Scholar
  94. 94.
    Anderson JA, Ng JJ, Bowe C, et al. Variable phenotypes associated with mutations in DOK7. Muscle Nerve. 2008;37:448–56.PubMedGoogle Scholar
  95. 95.
    Ammar AB, Petit F, Alexandri K, et al. Phenotype-genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7. J Neurol. 2010;257:754–66.PubMedGoogle Scholar
  96. 96.
    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.PubMedGoogle Scholar
  97. 97.
    Wu H, Xiong WC, Mei L. To build a synapse: signaling pathways in neuromuscular junction assembly. Development. 2010;137:1017–33.PubMedGoogle Scholar
  98. 98.
    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.Google Scholar
  99. 99.
    Palace J, Lashley D, Newsom-Davis J, et al. Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain. 2007 Jun 1;130:1507–15.PubMedGoogle Scholar
  100. 100.
    Srour M, Bolduc V, Guergueltcheva V, et al. DOK7 mutations presenting as a proximal myopathy in French Canadians. Neuromuscul Disord. 2010;20:453–7.PubMedGoogle Scholar
  101. 101.
    Jephson CG, Mills NA, Pitt MC, et al. Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome. Int J Pediatr Otolaryngol. 2010;74:991–4.Google Scholar
  102. 102.
    Lashley D, Palace J, Jayawant S, Robb S, Beeson D. Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7. Neurology. 2010;74:1517–23.PubMedGoogle Scholar
  103. 103.
    Schara U, Barisic N, Deschauer M, et al. Ephedrine therapy in eight patients with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord. 2010;19:828–32.Google Scholar
  104. 104.
    DeChiara TM, Bowen DC, Valenzuela DM, et al. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell. 1996;85:501–12.PubMedGoogle Scholar
  105. 105.
    Herbst R, Burden SJ. The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling. EMBO J. 2000;19:67–77.PubMedGoogle Scholar
  106. 106.
    Nguyen QT, Son Y-J, Sanes J, Lichtman JW. Nerve terminals form but fail to mature when postsynaptic differentiation is blocked: In vivo analysis using mammalian nerve-muscle chimeras. J Neurosci. 2000;20:6077–86.PubMedGoogle Scholar
  107. 107.
    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.PubMedGoogle Scholar
  108. 108.
    Chevessier F, Girard E, Molgo J, et al. A mouse model for congenital myasthenic syndrome due to MuSK mutations reveals defects in structure and function of neuromuscular junctions. Hum Mol Genet. 2008;17:3577–95.PubMedGoogle Scholar
  109. 109.
    Maselli R, Arredondo J, Cagney O, et al. Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. Hum Mol Genet. 2010;19:2370–9.PubMedGoogle Scholar
  110. 110.
    Mihaylova V, Salih MA, Mukhtar MM, et al. Refinement of the clinical phenotype in Musk-related congenital myasthenic syndromes. Neurology. 2009 Dec 1;73:1926–8.PubMedGoogle Scholar
  111. 111.
    Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L. LRP4 serves as a coreceptor for agrin. Neuron. 2008;60:285–97.PubMedGoogle Scholar
  112. 112.
    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.PubMedGoogle Scholar
  113. 113.
    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 Aug;85:155–67.PubMedGoogle Scholar
  114. 114.
    Romero NB. Centronuclear myopathies: a widening concept. Neuromuscul Disord. 2010;20:223–8.PubMedGoogle Scholar
  115. 115.
    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.PubMedGoogle Scholar
  116. 116.
    Baradello A, Vita G, Girlanda P, Roberto ML, Carozza G. Adult-onset centronuclear myopathy: evidence against a neurogenic pathology. Acta Neurol Scand. 1989;80:162–6.PubMedGoogle Scholar
  117. 117.
    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;21:387–95.PubMedGoogle Scholar
  118. 118.
    Robb SA, Sewry CA, Dowling JJ, et al. Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathy. Neuromuscul Disord. 2011;21:379–86.PubMedGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of NeurologyMayo Clinic College of Medicine, Mayo ClinicRochesterUSA

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