11. CONGENITAL MYASTHENIC SYNDROMES (Return to Disease group)
Disease phenotype
Item in this table
References
Gene symbol (chromosome)
protein
Myasthenic syndrome, congenital, 1A, Slow-channel - (AD)
11.1
Sine SM, Ohno K, Bouzat C, Auerbach A, Milone M, Pruitt JN, Engel AG. Mutation of the acetylcholine receptor alpha subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron. 1995 Jul;15(1):229-39. (7619526)
Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, Pruitt JN 2nd, Hutchinson DO, Brengman JM, Bren N, Sieb JP, Sine SM. 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. (8872460)
Croxen R, Newland C, Beeson D, Oosterhuis H, Chauplannaz G, Vincent A, Newsom-Davis J. Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome. Hum Mol Genet. 1997 May;6(5):767-74. (9158151)
CHRNA1 (2q24-q32)
Cholinergic receptor, nicotinic, alpha polypeptide 1
Myasthenic syndrome, congenital, 2A, Slow-channel - (AD)
11.2
Gomez CM, Maselli R, Gammack J, Lasalde J, Tamamizu S, Cornblath DR, Lehar M, McNamee M, Kuncl RW. A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome. Ann Neurol. 1996 Jun;39(6):712-23. (8651643)
Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, Pruitt JN 2nd, Hutchinson DO, Brengman JM, Bren N, Sieb JP, Sine SM. 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. (8872460)
CHRNB1 (17p13.1)
Cholinergic receptor, nicotinic, beta 1 muscle
Myasthenic syndrome, congenital, 3A, Slow-channel - (AD)
11.3
Gomez, C. M.; Maselli, R. A.; Vohra, B. P. S.; Navedo, M.; Stiles, J. R.; Charnet, P.; Schott, K.; Rojas, L.; Keesey, J.; Verity, A.; Wollmann, R. W.; Lasalde-Dominicci, J. : Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms. Ann. Neurol. 51: 102-112, 2002. (11782989)
CHRND (2q33-q34)
Cholinergic receptor, nicotinic, delta
Myasthenic syndrome, congenital, 4A, Slow-channel - (AD, AR)
11.4
Ohno K, Hutchinson DO, Milone M, Brengman JM, Bouzat C, Sine SM, Engel AG. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):758-62. (12034803)
Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, Pruitt JN 2nd, Hutchinson DO, Brengman JM, Bren N, Sieb JP, Sine SM. 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. (7531341)
Croxen, R.; Vincent, A.; Newsom-Davis, J.; Beeson, D. : Myasthenia gravis in a woman with congenital AChR deficiency due to epsilon-subunit mutations. Neurology 58: 1563-1565, 2002. (8872460)
CHRNE (17p13-p12)
Cholinergic receptor, nicotinic, epsilon
Myasthenic syndrome, congenital, 1B, Fast-channel - (AR)
11.5
Wang, H.-L.; Milone, M.; Ohno, K.; Shen, X-M.; Tsujino, A.; Batocchi,m A. P.; Tonali, P.; Brengman, J.; Engel, A. G.; Sine, S. M. : Acetylcholine receptor M3 domain: sterochemical and volume contributions to channel gating. Nature Neurosci. 2: 226-233, 1999. (10195214)
CHRNA1 (2q24-q32)
Cholinergic receptor, nicotinic, alpha polypeptide 1
Myasthenic syndrome, congenital, 3B, Fast-channel - (AR)
11.6
Brownlow, S.; Webster, R.; Croxen, R.; Brydson, M.; Neville, B.; Lin, J.-P.; Vincent, A.; Newsom-Davis, J.; Beeson, D. : Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. J. Clin. Invest. 108: 125-130, 2001. (11435464)
CHRND (2q33-q34)
Cholinergic receptor, nicotinic, delta
Myasthenic syndrome, congenital, 4B, Fast-channel - (AR)
11.7
Ohno K, Wang HL, Milone M, Bren N, Brengman JM, Nakano S, Quiram P, Pruitt JN, Sine SM, Engel AG. 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. (8755487)
CHRNE (17p13-p12)
Cholinergic receptor, nicotinic, epsilon
Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency - (AR)
11.8
Quiram, P. A.; Ohno, K.; Milone, M.; Patterson, M. C.; Pruitt, N. J.; Brengman, J. M.; Sine, S. M.; Engel, A. G. : Mutation causing congenital myasthenia reveals acetylcholine receptor beta/delta subunit interaction essential for assembly. J. Clin. Invest. 104: 1403-1410, 1999. (10562302)
CHRNB1 (17p13.1)
Cholinergic receptor, nicotinic, beta 1 muscle
Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency - (AR)
11.9
Shen, X.-M.; Ohno, K.; Fukudome, T.; Tsujino, A.; Brengman, J. M.; De Vivo, D. C.; Packer, R. J.; Engel, A. G. : Congenital myasthenic syndrome caused by low-expressor fast-channel AChR-delta subunit mutation. Neurology 59: 1881-1888, 2002. (12499478)
CHRND (2q33-q34)
Cholinergic receptor, nicotinic, delta
Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency - (AR)
11.10
Engel AG, Ohno K, Bouzat C, Sine SM, Griggs RC. End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon sub-unit. Ann Neurol 1996;40:810-817. (8957026)
Ohno K, Quiram PA, Milone M, et al. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of 6 new mutations. Hum Mol Genet 1997;6:753-767. (9158150)
CHRNE (17p13-p12)
Cholinergic receptor, nicotinic, epsilon
Myasthenic syndrome, congenital, 5 - (AR)
11.11
Donger C, Krejci E, Serradell AP, Eymard B, Bon S, Nicole S, Chateau D, Gary F, Fardeau M, Massoulie J, Guicheney P. Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic). Am J Hum Genet. 1998 Oct;63(4):967-75. (9758617)
COLQ (3p25)
Acetylcholinesterase collagen-like tail subunit
Myasthenic syndrome, congenital, 6, presynaptic - (AR)
11.12
Strauss, W. L.; Kemper, R. R.; Jayakar, P.; Kong, C. F.; Hersh, L. B.; Hilt, D. C.; Rabin, M. : Human choline acetyltransferase gene maps to region 10q11-q22.2 by in situ hybridization. Genomics 9: 396-398, 1991. (1840566)
Ohno, K.; Tsujino, A.; Brengman, J. M.; Harper, C. M.; Bajzer, Z.; Udd, B.; Beyring, R.; Robb, S.; Kirkham, F. J.; Engel, A. G. : Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc. Nat. Acad. Sci. 98: 2017-2022, 2001. (11172068)
CHAT (10q11.2)
Choline acetyltransferase isoform
Myasthenic syndrome, congenital, 7, presynaptic - (AD)
11.13
Herrmann, D. N., Horvath, R., Sowden, J. E., Gonzalez, M., Sanchez-Mejias, A., Guan, Z., Whittaker, R. G., Almodovar, J. L., Lane, M., Bansagi, B., Pyle, A., Boczonadi, V., Lochmuller, H., Griffin, H., Chinnery, P. F., Lloyd, T. E., Littleton, J. T., Zuchner, S. Synaptotagmin 2 mutations cause an autosomal-dominant form of Lambert-Eaton myasthenic syndrome and nonprogressive motor neuropathy. Am. J. Hum. Genet. 95: 332-339, 2014. Note: Erratum: Am. J. Hum. Genet. 95: 472 only, 2014. (25192047)
SYT2 (1q32.1)
Synaptotagmin II
Myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects - (AR)
11.14
Huz²© C, Bauch²© S, Richard P, Chevessier F, Goillot E, Gaudon K, Ben Ammar A, Chaboud A, Grosjean I, Lecuyer HA, Bernard V, Rouche A, Alexandri N, Kuntzer T, Fardeau M, Fournier E, Brancaccio A, R²ºegg MA, Koenig J, Eymard B, Schaeffer L, Hanta²Ø D. Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet. 2009 Aug;85(2):155-67. Epub 2009 Jul 23. (19631309)
AGRN (1p36.33)
Agrin
Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency - (AR)
11.15
Chevessier, F.; Faraut, B.; Ravel-Chapuis A., Richard, P.; Gaudon, K.; Bauch²©, S.; Prioleau, C.; Herbst, R.; Goillot, E.; Ioos, C.; Azulay, J.P.; Attarian, S.; Leroy, J.P.; Fournier, E.; Legay, C.; Schaeffer, L.; Koenig, J.; Fardeau, M.; Eymard, B.; Pouget, J.; Hanta²Ø, D. MUSK, a new target for mutations causing congenital myasthenic syndrome. J. Med. Genet. 13: 3229-3240, 2004. (15496425)
MUSK (9q31.3-q32)
Muscle, skeletal, receptor tyrosine kinase
Myasthenic syndrome, congenital, 10 - (AR)
11.16
Beeson, D.; Higuchi, O.; Palace, J.; Cossins, J.; Spearman, H.; Maxwell, S.; Newsom-Davis, J.; Burke, G.; Fawcett, P.; Motomura, M.; M²ºller, J. S.; Lochm²ºller, H.; Slater, C.; Vincent, A.; Yamanashi, Y. : Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 313: 1975-1978, 2006. (16917026)
Selcen D, Milone M, Shen XM, Harper CM, Stans AA, Wieben ED, Engel AG. Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann Neurol. 2008 Jul;64(1):71-87. (18626973)
DOK7 (4p16.2)
Docking protein 7
Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency - (AR)
11.17
Ohno, K.; Engel, A. G.; Shen, X.-M.; Selcen, D.; Brengman, J.; Harper, C. M.; Tsujino, A.; Milone, M. : Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome. Am. J. Hum. Genet. 70: 875-885, 2002. (11791205)
Ohno, K.; Sadeh, M.; Blatt, I.; Brengman, J. M.; Engel, A. G. : E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum. Molec. Genet. 12: 39-748, 2003 (12651869)
RAPSN (11p11.2-p11.1)
Rapsyn
Myasthenia, congenital, 12, with tubular aggregates - (AR)
11.18
Senderek, J., Muller, J. S., Dusl, M., Strom, T. M., Guergueltcheva, V., Diepolder, I., Laval, S. H., Maxwell, S., Cossins, J., Krause, S., Muelas, N., Vilchez, J. J., and 27 others. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am. J. Hum. Genet. 88: 162-172, 2011. (21310273)
GFPT1 (2p12-p15)
Glutamine-fructose-6-phosphate transaminase 1
Myasthenic syndrome, congenital, 13, with tubular aggregates - (AR)
11.19
Belaya, K., Finlayson, S., Slater, C. R., Cossins, J., Liu, W. W., Maxwell, S., McGowan, S. J., Maslau, S., Twigg, S. R. F., Walls, T. J., Pascual Pascual, S. I., Palace, J., Beeson, D. Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am. J. Hum. Genet. 91: 193-201, 2012. (22742743)
DPAGT1 (11q23.3)
Dolichyl-phosphate (UDP-N-acetylglucosamine) N-acetylglucosaminephosphotransferase 1 (GlcNAc-1-P transferase)
Myasthenic syndrome, congenital, 14, with tubular aggregates - (AR)
11.20
Cossins J, Belaya K, Hicks D, et al. Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain. 2013 Mar;136 (Pt3):944–56. (23404334)
ALG2 (9q31.1)
Alpha-1,3/1,6-mannosyltransferase
Myasthenic syndrome, congenital, 15, without tubular aggregates - (AR)
11.21
Cossins J, Belaya K, Hicks D, et al. Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain. 2013 Mar;136 (Pt3):944–56. (23404334)
ALG14 (1p21.3)
UDP-N-acetylglucosaminyltransferase
Myasthenic syndrome, congenital, 16 - (AR)
11.22
Tsujino A, Maertens C, Ohno K, Shen XM, Fukuda T, Harper CM, Cannon SC, Engel AG. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7377-82. Epub 2003 May 23. (12766226)
SCN4A (17q23-q25.3)
Sodium channel, voltage-gated, type IV, alpha
Myasthenic syndrome, congenital, 17 - (AR)
11.23
Ohkawara B., Cabrera-Serrano M., Nakata T. LRP4 third betapropeller domain mutations cause novel congenital (24234652)
LRP4 (11p11.2)
LDL receptor related protein 4
Myasthenic syndrome, congenital, 18 - (AD)
11.24
Shen, X.-M., Selcen, D., Brengman, J., Engel, A. G. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology 83: 2247-2255, 2014. (25381298)
SNAP25 (20p12.2)
Synaptosome associated protein 25
Congenital myasthenic syndrome type 19 - (AR)
11.25
Logan, C. V., Cossins, J., Rodriguez Cruz, P. M., Parry, D. A., Maxwell, S., Martinez-Martinez, P., Riepsaame, J., Abdelhamed, Z. A., Lake, A. V. R., Moran, M., Robb, S., Chow, G., Sewry, C., Hopkins, P. M., Sheridan, E., Jayawant, S., Palace, J., Johnson, C. A., Beeson, D. Congenital myasthenic syndrome type 19 is caused by mutations in COL13A1, encoding the atypical non-fibrillar collagen type XIII alpha-1 chain. Am. J. Hum. Genet. 97: 878-885, 2015. (26626625)
COL13A1 (10q22.1)
Collagen type XIII alpha 1 chain
Myasthenic syndrome, congenital, 20, presynaptic - (AR)
11.26
Bauche, S., O'Regan, S., Azuma, Y., Laffargue, F., McMacken, G., Sternberg, D., Brochier, G., Buon, C., Bouzidi, N., Topf, A., Lacene, E., Remerand, G., and 30 others. Impaired presynaptic high-affinity choline transporter causes a congenital myasthenic syndrome with episodic apnea. Am. J. Hum. Genet. 99: 753-761, 2016. (27569547)
SLC5A7 (2q12.31)
Solute carrier family 5 (sodium/choline cotransporter), member 7
Myasthenic syndrome, congenital, 21, presynaptic - (AR)
11.27
O'Grady, G. L., Verschuuren, C., Yuen, M., Webster, R., Menezes, M., Fock, J. M., Pride, N., Best, H. A., Benavides Damm, T., Turner, C., Lek, M., Engel, A. G., North, K. N., Clarke, N. F., MacArthur, D. G., Kamsteeg, E.-J., Cooper, S. T. Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. Neurology 87: 1442-1448, 2016. (27590285)
SLC18A3 (10q11.2)
Solute Carrier Family 18 (Vesicular Acetylcholine), Member 3
11.28
Régal L, Shen XM, Selcen D, Verhille C, Meulemans S, Creemers JW, Engel AG. 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. (24610330)
PREPL (2p21)
Prolyl endopeptidase-like
Presynaptic congenital myasthenic syndrome 23 - (AR)
11.29
Chaouch A, Porcelli V, Cox D, Edvardson S, Scarcia P, De Grassi A, Pierri CL, Cossins J, Laval SH, Griffin H, Müller JS, Evangelista T, Töpf A, Abicht A, Huebner A, von der Hagen M, Bushby K, Straub V, Horvath R, Elpeleg O, Palace J, Senderek J, Beeson D, Palmieri L, Lochmüller H. Mutations in the Mitochondrial Citrate Carrier SLC25A1 are Associated with Impaired Neuromuscular Transmission. J Neuromuscul Dis. 2014;1(1):75-90. (26870663)
SLC25A1 (22q11.21)
Solute carrier family 25 (mitochondrial carrier, citrate transporter), member 1
Presynaptic congenital myasthenic syndrome 24 - (AR)
11.30
O’Connor E., Topf A., Müller J.S., et al. Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome. Brain 2016; 139:2143–2153. (27259756)
MYO9A (15q23)
Myosin IXA
Presynaptic congenital myasthenic syndrome 25 - (AR)
11.31
Shen X.M., Scola R.H., Lorenzoni P.J., Kay C.S., Werneck L.C., Brengman J., et al. Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome. Ann Clin Transl Neurol. 2017 Jan 16;4(2):130-138. doi: 10.1002/acn3.387. eCollection 2017. (28168212)
Salpietro V., Lin W., Delle Vedove A., Storbeck M., Liu Y., Efthymiou S., 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. (28253535)
VAMP1 (12p13)
Vesicle associated membrane protein (synaptobrevin 1)
Congenital myasthenic syndrome with nephrotic syndrome - (AR)
11.32
Maselli, R. A., Ng, J. J., Anderson, J. A., Cagney, O., Arredondo, J., Williams, C., Wessel, H. B., Abdel-Hamid, H., Wollmann, R. L. Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. J. Med. Genet. 46: 203-208, 2009. (19251977)
LAMB2 (3p21)
Laminin, beta 2 (laminin S)
Escobar syndrome (multiple pterygium syndrome) - (AR)
11.33
Hoffmann, K.; M²ºller, J. S.; Stricker, S.; Megarbane, A.; Rajab, A.; Lindner, T. H.; Cohen, M.; Chouery, E.; Adaimy, L.; Ghanem, I.; Delague, V.; Boltshauser, E.; Talim, B.; Horvath, R.; Robinson, P. N.; Lochm²ºller, H.; Hubner, C.; Mundlos, S. : Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am. J. Hum. Genet. 79: 303-312, 2006. (16826520)
Morgan, N. V.; Brueton, L. A.; Cox, P.; Greally, M. T.; Tolmie, J.; Pasha, S.; Aligianis, I. A.; van Bokhoven, H.; Marton, T.; Al-Gazali, L.; Morton, J. E. V.; Oley, C.; Johnson, C. A.; Trembath, R. C.; Brunner, H. G.; Maher, E. R. : Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome. Am. J. Hum. Genet. 79: 390-395, 2006. (16826531)
CHRNG (2q33-q34)
Cholinergic receptor, nicotinic, gamma polypeptide
Myasthenic syndrome, with plectin defect - (AR)
11.34
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 Aug;58(8):832-46. (10446808)
Selcen, D., Juel, V. C., Hobson-Webb, L. D., Smith, E. C., Stickler, D. E., Bite, A. V., Ohno, K., Engel, A. G. Myasthenic syndrome caused by plectinopathy. Neurology 76: 327-336, 2011. (21263134)
PLEC (8q24.3)
Plectin
Congenital Myasthenic syndrome related to GMPPB - (AR)
11.35
Belaya K., Rodriguez Cruz P.M., Liu W.W., et al. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. Brain 2015;138:2493–504 (26133662)
GMPPB (3p21.31)
GDP-mannose pyrophosphorylase B
Presynaptic congenital myasthenic syndrome - (AR)
11.36
Maselli R.A., Arredondo J., Vázquez J., Chong J.X., Bamshad M.J., Nickerson D.A., 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. (28544784)
LAMA5 (20q13.33)
Laminin, Alpha 5
Presynaptic congenital myasthenic syndrome related to MUNC13-1 - (AR)
11.37
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. (27648472)
UNC13A (19p13.11)
Unc-13 homolog A (C. elegans)
Congenital myasthenic syndrome related to RPH3A - (AR)
11.38
Maselli RA, Vázquez J, Schrumpf L, Arredondo J, Lara M, Strober JB, Pytel P, Wollmann RL, Ferns M. 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. (29441694)
RPH3A (12q23.3)
Rabphilin 3A
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