Congenital Myasthenic Syndromes

A paradigm shift


  • Ricardo Maselli University of California Davis



Congenital myasthenic syndrome, neuromuscular junction, presynaptic, synaptic, postsynaptic


Very few areas of medical genetics have been so profoundly impacted by the advent of next- generation sequencing (NGS) as the field of congenital myasthenic syndromes (CMS). This is due to the formidable genetic heterogeneity of CMS, a dearth of diagnostic clinical clues of CMS types, and the imperative need to establish an accurate molecular diagnosis of CMS type before any medication is started. A molecular diagnosis of CMS is fundamental not only to provide an appropriate therapy, but more importantly, to avoid potential deleterious treatments. Thus, NGS has transformed the tedious and expensive task of searching for causative mutations in an ever-expanding list of genes linked to CMS into an effective, and relatively inexpensive process that can rapidly identify the variant of CMS in question. One of the consequences of this transformation is a paradigm shift in the clinical practice of CMS that no longer requires, with rare exceptions, the use of special muscle biopsies that enable the analysis of the function and ultrastructure of the neuromuscular junction to determine the type of CMS. Another technological advance of recent years is CRISPR/Cas9, which allows genome editing at the zygotic stage, thus greatly simplifying the generation of mouse models carrying the same human CMS mutations in orthologous mouse genes. This permits an in-depth analysis of the pathogenesis and treatments of CMS caused by specific gene mutations. In terms of therapy, in addition to the classical pharmacologic treatments of CMS, including pyridostigmine sulfate, albuterol and 3,4 diaminopyridine, AAV-based gene therapies are now at the preclinical stage for several types of CMS. In this brief review, CMS are classified in six major groups: (1). presynaptic CMS, (2) synaptic CMS, (3) postsynaptic CMS; 4. CMS affecting the agrin-signal transduction pathway, (5) CMS linked to disorders of glycosylation, and (6) CMS associated with abnormalities of the cytoskeleton.


Metrics Loading ...


Download data is not yet available.


Ohno K, Hutchinson DO, Milone M, Brengman JM, Bouzat C, Sine SM, 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 –762.

Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, et al. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet. 1996 Sep;5(9):1217-27. doi: 10.1093/hmg/5.9.1217.

Herrmann DN, Horvath R, Sowden JE, Gonzalez M, Sanchez-Mejias A, Guan Z, et al. Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. Am J Hum Genet. 2014 Sep 4;95(3):332-9. doi: 10.1016/j.ajhg.2014.08.007. PMID: 25192047.

Shen XM, Selcen D, Brengman J, Engel AG. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology. 2014; 83:2247–2255. PMID: 25381298. PMCID: PMC4277673 DOI: 10.1212/WNL.0000000000001079

Reynolds HM, Wen T, Farrell A, Mao R, Moore B, Boyden SE, et al. Rapid genome sequencing identifies a novel de novo SNAP25 variant for neonatal congenital myasthenic syndrome. Cold Spring Harb Mol Case Stud. 2022 Dec 28;8(7):a006242. doi: 10.1101/mcs.a006242. Print 2022 Dec. PMID: 36379720.

Robertson WC, Chun RW, Kornguth SE. Familial infantile myasthenia. Arch Neurol. 1980 Feb;37(2):117-9. doi: 10.1001/archneur.1980.00500510075018. PMID: 6243929.

Ohno K, Tsujino A, Brengman JM, Harper CM, Bajzer Z, Udd B, et al. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2017-22. doi: 10.1073/pnas.98.4.2017. PMID: 11172068.

Liu Z, Zhang L, Shen D, Ding C, Yang X, Zhang W, et al. Compound Heterozygous CHAT Gene Mutations of a Large Deletion and a Missense Variant in a Chinese Patient With Severe Congenital Myasthenic Syndrome With Episodic Apnea. Front Pharmacol. 2019 Mar 12;10:259. doi: 10.3389/fphar.2019.00259. eCollection 2019. PMID: 30914958.

Arredondo J, Lara M, Gospe SM Jr, Mazia CG, Vaccarezza M, Garcia-Erro M, et al. Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations. Hum Mutat. 2015 Sep;36(9):881-93. doi: 10.1002/humu.22823. Epub 2015 Jul 24. PMID: 26080897.

Maselli RA, Chen D, Mo D, Bowe C, Fenton G, Wollmann RL. Choline acetyltransferase mutations in myasthenic syndrome due to deficient acetylcholine resynthesis. Muscle Nerve. 2003 Feb;27(2):180-7. doi: 10.1002/mus.10300. PMID: 12548525.

Mora M, Lambert EH, Engel AG. Synaptic vesicle abnormality in familial infantile myasthenia. Neurology. 1987 Feb;37(2):206-14. doi: 10.1212/wnl.37.2.206. PMID: 3027611

Barisic N, Müller JS, Paucic-Kirincic E, Gazdik M, Lah-Tomulic K, Pertl A, et al. Clinical variability of CMS-EA (congenital myasthenic syndrome with episodic apnea) due to identical CHAT mutations in two infants. Eur J Paediatr Neurol. 2005;9(1):7-12. doi: 10.1016/j.ejpn.2004.10.008. Epub 2004 Dec 13. PMID: 15701560.

Proschowsky HF, Flagstad A, Cirera S, Joergensen CB, Fredholm M. Identification of a mutation in the CHAT gene of Old Danish Pointing Dogs affected with congenital myasthenic syndrome. J Hered. 2007;98(5):539-43. doi: 10.1093/jhered/esm026. Epub 2007 Jun 22. PMID: 17586598.

Joshi S, Virdi S, Etard C, Geisler R, Strähle U. Mutation of a serine near the catalytic site of the choline acetyltransferase a gene almost completely abolishes motility of the zebrafish embryo. PLoS One. 2018 Nov 20;13(11):e0207747. doi: 10.1371/journal.pone.0207747. eCollection 2018.

Duerr JS, McManus JR, Crowell JA, Rand JB. Analysis of Caenorhabditis elegans acetylcholine synthesis mutants reveals a temperature-sensitive requirement for cholinergic neuromuscular function. Genetics. 2021 Aug 9;218(4):iyab078. doi: 10.1093/genetics/iyab078. PMID: 34028515.

Kitamoto T, Ikeda K, Salvaterra PM. Analysis of cis-regulatory elements in the 5' flanking region of the Drosophila melanogaster choline acetyltransferase gene. J Neurosci. 1992 May;12(5):1628-39. doi: 10.1523/JNEUROSCI.12-05-01628.1992.

Shen XM, Crawford TO, Brengman J, Acsadi G, Iannaconne S, Karaca E, et al. Functional consequences and structural interpretation of mutations of human choline acetyltransferase. Hum Mutat. 2011 Nov;32(11):1259-67. doi: 10.1002/humu.21560. Epub 2011 Sep 23. PMID: 21786365

Schwartz M, Sternberg D, Whalen S, Afenjar A, Isapof A, Chabrol B, et al. How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome. Am J Med Genet A. 2018 Jan;176(1):151-155. doi: 10.1002/ajmg.a.38515. Epub 2017 Nov 12. PMID: 29130637.

Schara U, Christen HJ, Durmus H, Hietala M, Krabetz K, Rodolico C, et al. Eur J Paediatr Neurol. Long-term follow-up in patients with congenital myasthenic syndrome due to CHAT mutations.2010 Jul;14(4):326-33. PMID: 19900826.

Aharoni S, Sadeh M, Shapira Y, Edvardson S, Daana M, Dor-Wollman T, et al. Congenital myasthenic syndrome in Israel: Genetic and clinical characterization. Neuromuscul Disord. 2017 Feb;27(2):136-140. doi: 10.1016/j.nmd.2016.11.014. Epub 2016 Nov 24. PMCID: PMC5280189.

Tan JS, Ambang T, Ahmad-Annuar A, Rajahram GS, Wong KT, Goh KJ. Congenital myasthenic syndrome due to novel CHAT mutations in an ethnic kadazandusun family. Muscle Nerve. 2016 May;53(5):822-6. doi: 10.1002/mus.25037. Epub 2016 Mar 23.

Bauché S, O'Regan S, Azuma Y, Laffargue F, McMacken G, Sternberg D, et al. Impaired presynaptic high-affinity choline transporter causes a congenital myasthenic syndrome with episodic apnea. Am J Hum Genet 2016; 99: 753–61.

O'Grady GL, Verschuuren C, Yuen M, Webster R, Menezes M, Fock JM, et al. Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. Neurology. 2016 Oct 4;87(14):1442-1448. doi: 10.1212/WNL.0000000000003179. Epub 2016 Sep 2. PMID: 27590285.

Régal L, Shen XM, Selcen D, Verhille C, Meulemans S, Creemers JW, et al. PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. Neurology. 2014 Apr 8;82(14):1254-60. doi: 10.1212/WNL.0000000000000295. Epub 2014 Mar 7. PMID: 24610330.

Chaouch A, Porcelli V, Cox D, Edvardson S, Scarcia P, De Grassi A, et al. Mutations in the Mitochondrial Citrate Carrier SLC25A1 are Associated with Impaired Neuromuscular Transmission. J Neuromuscul Dis. 2014;1(1):75-90. doi: 10.3233/JND-140021. PMID: 26870663.

Balaraju S, Töpf A, McMacken G, Kumar VP, Pechmann A, Roper H, et al. Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. Eur J Hum Genet. 2020 Mar;28(3):373-377. doi: 10.1038/s41431-019-0506-2. Epub 2019 Sep 16. PMID: 31527857.

Salpietro V, Lin W, Delle Vedove A, Storbeck M, Liu Y, et al. Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome. Ann Neurol. 2017 Apr;81(4):597-603. doi: 10.1002/ana.24905. Epub 2017 Mar 29.

Herrmann DN, Horvath R, Sowden JE, Gonzalez M, Sanchez-Mejias A, Guan Z, et al. Synaptotagmin 2 mutations cause an autosomal-dominant form of lambert-eaton myasthenic syndrome and nonprogressive motor neuropathy. Am J Hum Genet. 2014 Sep 4;95(3):332-9. doi: 10.1016/j.ajhg.2014.08.007. PMID: 25192047.

Maselli RA, van der Linden H Jr, Ferns M. Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C-terminal amino acid sequence. Am J Med Genet A. 2020 Jul;182(7):1744-1749. doi: 10.1002/ajmg.a.61579. Epub 2020 Apr 6. PMID: 32250532

Donkervoort S, Mohassel P, Laugwitz L, Zaki MS, Kamsteeg EJ, Maroofian R, et al. Biallelic loss of function variants in SYT2 cause a treatable congenital onset pre-synaptic myasthenic syndrome. Am J Med Genet A. 2020;182(10):2272-2283.9.

Bauché S, Sureau A, Sternberg D, Rendu J, Buon C, Messéant J, et al. New recessive mutations in SYT2 causing severe presynaptic congenital myasthenic syndromes. Neurol Genet. 2020;6:e354. PMID: 33659639.

Engel AG, Selcen D, Shen XM, Milone M, Harper CM. Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. Neurol Genet. 2016 Sep 8;2(5):e105. doi: 10.1212/NXG.0000000000000105. eCollection 2016 Oct. PMID: 27648472.

Maselli RA, Kong DZ, Bowe CM, McDonald CM, Ellis WG, Agius MA, et al. Presynaptic congenital myasthenic syndrome due to quantal release deficiency. Neurology. 2001 Jul 24;57(2):279-89. doi: 10.1212/wnl.57.2.279. PMID: 11468313

Maselli RA, Vázquez J, Schrumpf L, Arredondo J, Lara M, Strober JB, et al. Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A. Mol Genet Genomic Med. 2018 May;6(3):434-440. doi: 10.1002/mgg3.370. Epub 2018 Feb 14. PMID: 29441694

O'Connor E, Töpf A, Müller JS, Cox D, Evangelista T, Colomer J, et al. Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome. Brain. 2016 Aug;139(Pt 8):2143-53. doi: 10.1093/brain/aww130. Epub 2016 Jun 3. PMID: 27259756.

O'Connor E, Phan V, Cordts I, Cairns G, Hettwer S, Cox D, et al. MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion. Hum Mol Genet. 2018 Apr 15;27(8):1434-1446. doi: 10.1093/hmg/ddy054. PMID: 29462312.

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 Apr;1(4):315-30. doi: 10.1002/ana.410010403. PMID: 214017.

Krejci E, Thomine S, Boschetti N, Legay C, Sketelj J, Massoulié J. The mammalian gene of acetylcholinesterase-associated collagen. J Biol Chem. 1997 Sep 5;272(36):22840-7. doi: 10.1074/jbc.272.36.22840. PMID: 9278446.

Logan CV, Cossins J, Rodríguez Cruz PM, Parry DA, Maxwell S, et al. Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain. Am J Hum Genet. 2015 Dec 3;97(6):878-85. doi: 10.1016/j.ajhg.2015.10.017. Epub 2015 Nov 25. PMID: 26626625.

Rodríguez Cruz PM, Cossins J, Estephan EP, Munell F, Selby K, et al. The clinical spectrum of the congenital myasthenic syndrome resulting from COL13A1 mutations. Brain. 2019 Jun 1;142(6):1547-1560. doi: 10.1093/brain/awz107. PMID: 31081514.

Maselli RA, Ng JJ, Anderson JA, Cagney O, Arredondo J, Williams C, et al. Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. J Med Genet. 2009 Mar;46(3):203-8. doi: 10.1136/jmg.2008.063693. PMID: 19251977.

Engel AG, Shen XM, Selcen D, Sine S. New horizons for congenital myasthenic syndromes. Ann N Y Acad Sci. 2012 Dec;1275(1):54-62. doi: 10.1111/j.1749-6632.2012.06803.x. PMID: 23278578.

Maselli RA, Arredondo J, Vázquez J, Chong JX; University of Washington Center for Mendelian Genomics; Bamshad MJ, et al. Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission. Am J Med Genet A. 2017 Aug;173(8):2240-2245. doi: 10.1002/ajmg.a.38291. Epub 2017 May 25. PMID: 28544784.

Taniguchi Y, Nagano C, Sekiguchi K, Tashiro A, Sugawara N, Sakaguchi H, et al. Clear Evidence of LAMA5 Gene Biallelic Truncating Variants Causing Infantile Nephrotic Syndrome. Kidney360. 2021 Oct 15;2(12):1968-1978. doi: 10.34067/KID.0004952021. eCollection 2021 Dec 30. PMID: 35419533.

Barad M, Csukasi F, Bosakova M, Martin JH, Zhang W, Paige Taylor S, et al. Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia. EBioMedicine. 2020 Dec;62:103075. doi: 10.1016/j.ebiom.2020.103075. Epub 2020 Nov 23. PMID: 33242826.

Engel AG, Ohno K, Sine SM. Congenital myasthenic syndromes: progress over the past decade. Muscle Nerve. 2003 Jan;27(1):4-25. doi: 10.1002/mus.10269. PMID: 12508290.

Abicht A, Stucka R, Karcagi V, Herczegfalvi A, Horváth R, Mortier W, et al. A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin. Neurology. 1999 Oct 22;53(7):1564-9. doi: 10.1212/wnl.53.7.1564. PMID: 10534268

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

Hoffmann K, Muller JS, Stricker S, Megarbane A, Rajab A, Lindner TH, et al. Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am J Hum Genet. 2006 Aug;79(2):303-12. doi: 10.1086/506257. Epub 2006 Jun 20. PMID:16826520.

Otero-Cruz JD, Báez-Pagán CA, Dorna-Pérez L, Grajales-Reyes GE, Ramírez-Ordoñez RT, et al. Decoding pathogenesis of slow-channel congenital myasthenic syndromes using recombinant expression and mice models. P R Health Sci J. 2010 Mar;29(1):4-17. PMID: 20222328.

Milone M, Wang H-L, Ohno K, Fukudome T, Pruitt JN, Bren N, 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;17:5651–5665.

Harper CM, Fukudome T, Engel AG. Treatment of slow channel congenital myasthenic syndrome with fluoxetine. Neurology. 2003;60:170–173.

Uchitel O, Engel AG, Walls TJ, Nagel A, Atassi ZM, Bril. Congenital myasthenic syndromes. II. Syndrome attributed to abnormal interaction of acetylcholine with its receptor. Muscle Nerve 1993:16, 1293–1301.

Ohno K, Wang HL, Milone M, Bren N, Brengman JM, Nakano S, et al. Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit. Neuron. 1996 Jul;17(1):157-70. doi: 10.1016/s0896-6273(00)80289-5. PMID: 8755487.

Ramarao MK, Cohen JB. Mechanism of nicotinic acetylcholine receptor cluster formation by rapsyn. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4007-12. doi: 10.1073/pnas.95.7.4007. PMID: 9520483.

Bartoli M, Ramarao MK, Cohen JB. Interactions of the rapsyn RING-H2 domain with dystroglycan. J Biol Chem. 2001 Jul 6;276(27):24911-7. doi: 10.1074/jbc.M103258200. Epub 2001 May 7. PMID: 11342559.

Milone M, Shen XM, Selcen D, Ohno K, Brengman J, Iannaccone ST, et al. Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients. Neurology. 2009 Jul 21;73(3):228-35. doi: 10.1212/WNL.0b013e3181ae7cbc. PMID: 19620612.

Ohno K, Sadeh M, Blatt I, Brengman JM, Engel AG. E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum Mol Genet. 2003 Apr 1;12(7):739-48. doi: 10.1093/hmg/ddg089. PMID: 12651869.

Müller JS, Mildner G, Müller-Felber W, Schara U, Krampfl K, Petersen B, et al. Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. Neurology. 2003 Jun 10;60(11):1805-10. doi: 10.1212/01.wnl.0000072262.14931.80. PMID: 12796535.

Dunne V, Maselli RA. Common founder effect of rapsyn N88K studied using intragenic markers. J Hum Genet. 2004;49(7):366-369. doi: 10.1007/s10038-004-0159-y. Epub 2004 Jun 8. PMID: 15252722.

Tsujino A, Maertens C, Ohno K, Shen XM, Fukuda T, Harper CM, et al. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7377-82. doi: 10.1073/pnas.1230273100. Epub 2003 May 23. PMID: 12766226.

Arnold WD, Feldman DH, Ramirez S, He L, Kassar D, Quick A, et al. Defective fast inactivation recovery of Nav 1.4 in congenital myasthenic syndrome. Ann Neurol. 2015 May;77(5):840-50. doi: 10.1002/ana.24389. Epub 2015 Mar 27. PMID: 25707578.

Chevessier F, Faraut B, Ravel-Chapuis A, Richard P, Gaudon K, Bauché S, et al. MUSK, a new target for mutations causing congenital myasthenic syndrome. Hum Mol Genet. 2004 Dec 15;13(24):3229-40. doi: 10.1093/hmg/ddh333. Epub 2004 Oct 20. PMID: 15496425.

Beeson D, Higuchi O, Palace J, Cossins J, Spearman H, Maxwell S, et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 2006 Sep 29;313(5795):1975-8. doi: 10.1126/science.1130837. Epub 2006 Aug 17. PMID: 16917026.

Huzé C, Bauché S, Richard P, Chevessier F, Goillot E, Gaudon K, et al. Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet. 2009 Aug;85(2):155-67. doi: 10.1016/j.ajhg.2009.06.015. Epub 2009 Jul 23. PMID: 19631309.

Ohkawara B, Cabrera-Serrano M, Nakata T, Milone M, Asai N, Ito K, et al. LRP4 third β-propeller domain mutations cause novel congenital myasthenia by compromising agrin-mediated MuSK signaling in a position-specific manner. Hum Mol Genet. 2014 Apr 1;23(7):1856-68. doi: 10.1093/hmg/ddt578. Epub 2013 Nov 13. PMID: 24234652.

Jephson CG, Mills NA, Pitt MC, Beeson D, Aloysius A, Muntoni F, et al. Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome. Int J Pediatr Otorhinolaryngol. 2010 Sep;74(9):991-4. doi: 10.1016/j.ijporl.2010.05.022. Epub 2010 Jun 15. PMID: 20554332.

Lozowska D, Ringel SP, Winder TL, Liu J, Liewluck T. Anticholinesterase Therapy Worsening Head Drop and Limb Weakness Due to a Novel DOK7 Mutation. J Clin Neuromuscul Dis. 2015 Dec;17(2):72-7. doi: 10.1097/CND.0000000000000095. PMID: 26583494.

Karakaya M, Ceyhan-Birsoy O, Beggs AH, Topaloglu H. A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop. J Clin Neuromuscul Dis. 2017 Mar;18(3):147-151. doi: 10.1097/CND.0000000000000132. PMID: 28221305.

Nicole S, Chaouch A, Torbergsen T, Bauché S, de Bruyckere E, Fontenille MJ, et al. Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. Brain. 2014 Sep;137(Pt 9):2429-43. doi: 10.1093/brain/awu160. Epub 2014 Jun 20. PMID: 24951643.

Nishimune H, Sanes JR & Carlson SS 2004. A synaptic laminin-calcium channel interaction organizes active zones in motor nerve terminals. Nature 432:580–587.

Cossins J, Liu WW, Belaya K, Maxwell S, Oldridge M, Lester T, et al. The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome. Hum Mol Genet. 2012 Sep 1;21(17):3765-75. doi: 10.1093/hmg/dds198. Epub 2012 Jun 1. PMID: 22661499.

Senderek J, Müller JS, Dusl M, Strom TM, Guergueltcheva V, Diepolder I, et al. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet. 2011 Feb 11;88(2):162-72. doi: 10.1016/j.ajhg.2011.01.008. PMID: 21310273.

Guergueltcheva V, Müller JS, Dusl M, Senderek J, Oldfors A, Lindbergh C, et al. J. Congenital myasthenic syndrome with tubular aggregates caused by GFPT1 mutations. Neurol. 2012 May;259(5):838-50. doi: 10.1007/s00415-011-6262-z. Epub 2011 Oct 6. PMID: 21975507.

Finlayson S, Palace J, Belaya K, Walls TJ, Norwood F, Burke G, et al. Clinical features of congenital myasthenic syndrome due to mutations in DPAGT1. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1119-25. doi: 10.1136/jnnp-2012-304716. Epub 2013 Feb 27. PMID: 23447650.

Cossins J, Belaya K, Hicks D, Salih MA, Finlayson S, Carboni N, et al. Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain. 2013 Mar;136(Pt 3):944-56. doi: 10.1093/brain/awt010. Epub 2013 Feb 11. PMID: 23404334.

Belaya K, Rodríguez Cruz PM, Liu WW, Maxwell S, McGowan S, Farrugia ME, et al. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. Brain. 2015 Sep;138(Pt 9):2493-504. doi: 10.1093/brain/awv185. Epub 2015 Jun 30. PMID: 26133662.

Pulkkinen L, Smith FJ, Shimizu H, Murata S, Yaoita H, Hachisuka H, et al. Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy. Hum Mol Genet 1996: 10: 1539– 1546.

Nakamura H, Sawamura D, Goto M, Nakamura H, McMillan JR, Park S, et al. Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). J Mol Diagn 2005: 7: 28– 35.

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.

Cossins J, Webster R, Maxwell S, Rodríguez Cruz PM, Knight R, Llewelyn JG, et al. Congenital myasthenic syndrome due to a TOR1AIP1 mutation: a new disease pathway for impaired synaptic transmission. Brain Commun. 2020 Oct 18;2(2):fcaa174. doi: 10.1093/braincomms/fcaa174. eCollection 2020. PMID: 33215087.

Qashqari H, McNiven V, Gonorazky H, Mendoza-Londono R, Hassan A, Kulkarni T, et al. JJ.Neuromuscul Disord. 2022 Oct;32(10):842-844. doi: 10.1016/j.nmd.2022.09.007. Epub 2022 Sep 22.PMID: 36210261.

Mroczek M, Iyadurai S. PURA syndrome: neuromuscular junction manifestations with potential therapeutic implications. Neuromuscular and Neuromuscular Junction Manifestations of the PURA-NDD: A Systematic Review of the Reported Symptoms and Potential Treatment Options. Int J Mol Sci. 2023 Jan 23;24(3):2260. doi: 10.3390/ijms24032260. PMID: 36768582.

Lee C.Y., Petkova M., Morales-Gonzalez S., Gimber N., Schmoranzer J., Meisel A, et al. A spontaneous missense mutation in the chromodomain helicase DNA-binding protein 8 (CHD8) gene: A novel association with congenital myasthenic syndrome. Neuropathol. Appl. Neurobiol. 2020;46:588–601. doi: 10.1111/nan.12617.

Barisic N, Weckhuysen S, De Jonghe P, Helbig I, Suls A, Ivanovic V, et al. De Novo Mutation In Sodium Channel Gene SCN8A Causes Neuromuscular Junction Disorder In Early Onset Epileptic Encephalopathy Neurology. April 08, 2014; 82 (10 Supplement) APRIL 29, 2014.

Nicolau S, Kao JC, Liewluck T. Trouble at the junction: When myopathy and myasthenia overlap. Muscle Nerve. 2019 Dec;60(6):648-657. doi: 10.1002/mus.26676. Epub 2019 Sep 10. PMID: 31449669.

Oury J, Zhang W, Leloup N, Koide A, Corrado AD, Ketavarapu G, et al. Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia. Nature. 2021 Jul;595(7867):404-408. doi: 10.1038/s41586-021-03672-3. Epub 2021 Jun 23.

PMID: 34163073.

Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, et al. Protein-anchoring strategy for delivering acetylcholinesterase to the neuromuscular junction. Mol Ther. 2012 Jul;20(7):1384-92. doi: 10.1038/mt.2012.34. Epub 2012 Feb 28. PMID: 22371845.

Arimura S, Okada T, Tezuka T, Chiyo T, Kasahara Y, Yoshimura T, et al. Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction. Science. 2014 Sep 19;345(6203):1505-8. doi: 10.1126/science.1250744. PMID: 25237101.

Eguchi T, Tezuka T, Miyoshi S, Yamanashi Y. Postnatal knockdown of dok-7 gene expression in mice causes structural defects in neuromuscular synapses and myasthenic pathology. Genes Cells. 2016 Jun;21(6):670-6. doi: 10.1111/gtc.12370. Epub 2016 Apr 18. PMID: 27091576.






MGFA International Conference Proceedings

How to Cite

Maselli, R. (2023). Congenital Myasthenic Syndromes: A paradigm shift. RRNMF Neuromuscular Journal, 4(3).