Abstract
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.
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References
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.
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.
Beeson D, Higuchi O, Palace J, et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 2006;313:1975–8.
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.
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.
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.
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.
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.
Senderek J, Muller JS, Dusl M, et al. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet. 2011;88:162–72.
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.
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.
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.
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.
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.
Mora M, Lambert EH, Engel AG. Synaptic vesicle abnormality in familial infantile myasthenia. Neurology. 1987;37:206–14.
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.
Bady B, Chauplannaz G, Carrier H. Congenital Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 1987;50:476–8.
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.
Ohno K, Brengman JM, Tsujino A, Engel AG. Human endplate acetylcholinesterase deficiency caused by mutations in the Âcollagen-like tail subunit (COlQ) of the asymmetric enzyme. Proc Natl Acad Sci USA. 1998;95:9654–9.
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.
Hutchinson DO, Walls TJ, Nakano S, et al. Congenital endplate acetylcholinesterase deficiency. Brain. 1993;116:633–53.
Ohno K, Engel AG, Brengman JM, et al. The spectrum of mutations causing endplate acetylcholinesterase deficiency. Ann Neurol. 2000;47:162–70.
Bestue-Cardiel M, de-Cabazon-Alvarez AS, Capablo-Liesa JL, et al. Congenital endplate acetylcholinesterase deficiency responsive to ephedrine. Neurology. 2005;65:144–6.
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.
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.
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.
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.
Sine SM. The nicotinic receptor ligand binding domain. J Neurobiol. 2002;53:431–46.
Unwin N. Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J Mol Biol. 2005;346:967–89.
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.
Lysine scanning mutagenesis delineates structural model of the nicotinic receptor ligand binding domain. J Biol Chem. 2002;277:2921–29213.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Sieb JP, Milone M, Engel AG. Effects of the quinoline derivatives quinine, quinidine, and chloroquine on neuromuscular transmission. Brain Res. 1996;712:179–89.
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.
Harper CM, Engel AG. Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome. Ann Neurol. 1998;43:480–4.
Harper CM, Fukudome T, Engel AG. Treatment of slow channel congenital myasthenic syndrome with fluoxetine. Neurology. 2003;60:170–3.
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.
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.
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.
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.
Sine SM, Engel AG. Recent advances in Cys-loop receptor structure and function. Nature. 2006;440:448–55.
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.
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.
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.
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.
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.
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.
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.
Okada K, Inoue A, Okada M, et al. The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006;312:1802–5.
Zhang B, Luo S, Wang Q, et al. LRP4 serves as a coreceptor of agrin. Neuron. 2008 Oct 23;60:285–97.
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.
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.
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.
Cossins J, Burke G, Maxwell S, et al. Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations. Brain. 2006;129:2773–83.
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.
Burke G, Cossins J, Maxwell S, et al. Rapsyn mutations in hereditary myasthenia distinct early- and late-onset phenotypes. Neurology. 2003;61:826–8.
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.
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.
Skeie GO, Aurlien H, Müller JS, Norgard G, Bindoff LA. Unusual features in a boy with rapsyn N88K mutation. Neurology. 2006;67:2262–3.
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.
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.
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.
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.
Selcen D, Juel VC, Hobson-Webb LD, et al. Myasthenic syndrome caused by plectinopathy. Neurology. 2011;76:327–36.
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.
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.
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.
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.
Muller JS, Herczegfalvi A, Vilchez JJ, et al. Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes. Brain. 2007;130:1497–506.
Anderson JA, Ng JJ, Bowe C, et al. Variable phenotypes associated with mutations in DOK7. Muscle Nerve. 2008;37:448–56.
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.
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.
Wu H, Xiong WC, Mei L. To build a synapse: signaling pathways in neuromuscular junction assembly. Development. 2010;137:1017–33.
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.
Palace J, Lashley D, Newsom-Davis J, et al. Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain. 2007 Jun 1;130:1507–15.
Srour M, Bolduc V, Guergueltcheva V, et al. DOK7 mutations presenting as a proximal myopathy in French Canadians. Neuromuscul Disord. 2010;20:453–7.
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.
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.
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.
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.
Herbst R, Burden SJ. The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling. EMBO J. 2000;19:67–77.
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.
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.
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.
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.
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.
Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L. LRP4 serves as a coreceptor for agrin. Neuron. 2008;60:285–97.
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.
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.
Romero NB. Centronuclear myopathies: a widening concept. Neuromuscul Disord. 2010;20:223–8.
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.
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.
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.
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.
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Engel, A.G. (2014). Congenital Myasthenic Syndromes. In: Katirji, B., Kaminski, H., Ruff, R. (eds) Neuromuscular Disorders in Clinical Practice. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6567-6_51
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