Genetic Basis of Congenital Myasthenic Syndrome: A Review Study

Document Type : Review Article

Authors

1 Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.

2 Poostchi Eye Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

10.32598/jamsat.3.4.179

Abstract

The neuromuscular junction is a highly specialized cholinergic synapse, essential for initiating nerve-evoked muscle contractions by means of neuromuscular transmission. Loss or dysfunction of any component of this junction might affect synaptic performance. Congenital Myasthenic Syndromes (CMSs) are rare heterogeneous disorders of autosomal inheritance caused by genetic defects affecting neuromuscular transmission that results in skeletal muscle weakness and abnormal fatigability on exertion.  The onset is usually from birth to childhood. CMSs are more uncommon than autoimmune myasthenia gravis. CMSs are classified based on their genetic and clinical presentations into presynaptic, synaptic basal lamina, and postsynaptic CMSs. To date, mutations in more than 25 genes have been implicated in the pathogenesis of CMSs. In this review article, different CMSs diagnostic procedures are investigated, and the genetic, clinical, and molecular aspects of CMSs are outlined.

Keywords

References

  1. Hantaï D, Richard P, Koenig J, Eymard B. Congenital myasthenic syndromes. Current Opinion in Neurology. 2004; 17(5):539-51. [DOI:10.1097/00019052-200410000-00004] [PMID]
  2. Souza PVSd, Batistella GNdR, Lino VC, Pinto WBVdR, Annes M, Oliveira ASB. Clinical and genetic basis of congenital myasthenic syndromes. Arquivos de Neuro-Psiquiatria. 2016; 74(9):750-60. [DOI:10.1590/0004-282X20160106] [PMID]
  3. Rodriguez Cruz PM, Palace J, Beeson D. Congenital myasthenic syndromes and the neuromuscular junction. Current Opinion in Neurology. 2014; 27(5):566-75. [DOI:10.1097/WCO.0000000000000134] [PMID]
  4. Engel AG. Current status of the congenital myasthenic syndromes. Neuromuscular Disorders. 2012; 22(2):99-111. [DOI:10.1016/j.nmd.2011.10.009] [PMID] [PMCID]
  5. McMacken G, Abicht A, Evangelista T, Spendiff S, Lochmuller H. The increasing genetic and phenotypical diversity of congenital myasthenic syndromes. Neuropediatrics. 2017; 48(4):294-308. [DOI:10.1055/s-0037-1602832] [PMID]
  6. Engel AG, Shen X-M, Selcen D, Sine SM. Congenital myasthenic syndromes: Pathogenesis, diagnosis, and treatment. The Lancet Neurology. 2015; 14(4):420-34. [DOI:10.1016/S1474-4422(14)70201-7]
  7. Arredondo J, Lara M, Gospe SM, Mazia CG, Vaccarezza M, Garcia-Erro M, et al. Choline acetyltransferase mutations causing congenital myasthenic syndrome: Molecular findings and genotype–phenotype correlations. Human Mutation. 2015; 36(9):881-93. [DOI:10.1002/humu.22823] [PMID] [PMCID]
  8. Kraner S, Laufenberg I, Straßburg HM, Sieb JP, Steinlein OK. Congenital myasthenic syndrome with episodic apnea in patients homozygous for a CHAT missense mutation. Archives of Neurology. 2003; 60(5):761-3. [DOI:10.1001/archneur.60.5.761] [PMID]
  9. 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. Proceedings of the National Academy of Sciences. 2001; 98(4):2017-22. [DOI:10.1073/pnas.98.4.2017] [PMID] [PMCID]
  10. Herrmann DN, Horvath R, Sowden JE, Gonzales 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. The American Journal of Human Genetics. 2014; 95(3):332-9. [DOI:10.1016/j.ajhg.2014.08.007] [PMID] [PMCID]
  11. Baker K, Gordon SL, Grozeva D, van Kogelenberg M, Roberts NY, Pike M, et al. Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling. The Journal of Clinical Investigation. 2015; 125(4):1670-8. [DOI:10.1172/JCI79765]
  12. Shen XM, Selcen D, Brengman J, Engel AG. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology. 2014; 83(24):2247-55. [DOI:10.1212/WNL.0000000000001079] [PMID] [PMCID]
  13. Mohrmann R, de Wit H, Connell E, Pinheiro PS, Leese C, Bruns D, et al. Synaptotagmin interaction with SNAP-25 governs vesicle docking, priming, and fusion triggering. Journal of Neuroscience. 2013; 33(36):14417-30. [DOI:10.1523/JNEUROSCI.1236-13.2013] [PMID] [PMCID]
  14. Omelchenko T, Hall A. Myosin-IXA regulates collective epithelial cell migration by targeting RhoGAP activity to cell-cell junctions. Current Biology. 2012; 22(4):278-88. [DOI:10.1016/j.cub.2012.01.014] [PMID] [PMCID]
  15. 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; 139(8):2143-53. [DOI:10.1093/brain/aww130] [PMID] [PMCID]
  16. Barwick Katy E, Wright J, Al-Turki S, McEntagart Meriel M, Nair A, Chioza B, et al. Defective presynaptic choline transport underlies hereditary motor neuropathy. American Journal of Human Genetics. 2012; 91(6):1103-7. [DOI:10.1016/j.ajhg.2012.09.019] [PMID] [PMCID]
  17. Bauche 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. The American Journal of Human Genetics. 2016; 99(3):753-61. [DOI:10.1016/j.ajhg.2016.06.033] [PMID] [PMCID]
  18. Ohno K, Brengman J, Tsujino A, Engel AG. Human endplate acetylcholinesterase deficiency caused by mutations in the Collagen-Like tail subunit (ColQ) of the asymmetric enzyme. Proceedings of the National Academy of Sciences. 1998; 95(16):9654-9. [DOI:10.1073/pnas.95.16.9654]
  19. Donger C, Krejci E, Serradell AP, Eymard B, Bon S, Nicole S, et al. Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic). The American Journal of Human Genetics. 1998; 63(4):967-75. [DOI:10.1086/302059] [PMID]
  20. Mihaylova V, Müller JS, Vilchez JJ, Salih MA, Kabiraj MM, D’amico A, et al. Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes. Brain. 2008; 131(3):747-59. [DOI:10.1093/brain/awm325] [PMID]
  21. Bestue-Cardiel M, de Cabezon-Alvarez AS, Capablo-Liesa J, Lopez-Pison J, Pe-a-Segura J, Martin-Martinez J, et al. Congenital endplate acetylcholinesterase deficiency responsive to ephedrine. Neurology. 2005; 65(1):144-6. [DOI:10.1212/01.wnl.0000167132.35865.31] [PMID]
  22. Yeung WL, Lam CW, Ng PC. Intra-familial variation in clinical manifestations and response to ephedrine in siblings with congenital myasthenic syndrome caused by novel COLQ mutations. Developmental Medicine & Child Neurology. 2010; 52(10):e243-e4. [DOI:10.1111/j.1469-8749.2010.03663.x] [PMID]
  23. Rinz CJ, Levine J, Minor KM, Humphries HD, Lara R, Starr-Moss AN, et al. A COLQ missense mutation in Labrador Retrievers having congenital myasthenic syndrome. PloS one. 2014; 9(8):e106425. [DOI:10.1371/journal.pone.0106425] [PMID] [PMCID]
  24. Zenker M, Aigner T, Wendler O, Tralau T, Müntefering H, Fenski R, et al. Human laminin β2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Human Molecular Genetics. 2004; 13(21):2625-32. [DOI:10.1093/hmg/ddh284] [PMID]
  25. Zemrani B, Cachat F, Bonny O, Giannoni E, Durig J, Fellmann F, et al. A novel LAMB2 gene mutation associated with a severe phenotype in a neonate with Pierson syndrome. European Journal of Medical Research. 2016; 21(1):19. [DOI:10.1186/s40001-016-0215-z] [PMID] [PMCID]
  26. Ohno K, Quiram PA, Milone M, Wang H-L, Harper MC, Ned Pruitt J, 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. Human Molecular Genetics. 1997; 6(5):753-66. [DOI:10.1093/hmg/6.5.753] [PMID]
  27. Rinz CJ, Lennon VA, James F, Thoreson JB, Tsai KL, Starr-Moss AN, et al. A CHRNE frameshift mutation causes congenital myasthenic syndrome in young Jack Russell Terriers. Neuromuscular Disorders. 2015; 25(12):921-7. [DOI:10.1016/j.nmd.2015.09.005] [PMID]
  28. Kraner S, Burgunder JM, Rösler K, Steinlein O, Sieb J. Congenital myasthenic syndrome due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene. European Journal of Neurology. 2002; 9(6):694-5. [DOI:10.1046/j.1468-1331.2002.00447_7.x] [PMID]
  29. 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 epsilon subunit. Proceedings of the National Academy of Sciences. 1995; 92(3):758-62. [DOI:10.1073/pnas.92.3.758]
  30. Croxen R, Newland C, Beeson D, Oosterhuis H, Chauplannaz G, Vincent A, et al. Mutations in different functional domains of the human muscle acetylcholine receptor α subunit in patients with the slow-channel congenital myasthenic syndrome. Human Molecular Genetics. 1997; 6(5):767-74. [DOI:10.1093/hmg/6.5.767] [PMID]
  31. Shen XM, Brengman JM, Edvardson S, Sine SM, Engel AG. Highly fatal fast-channel syndrome caused by AChR -subunit mutation at the agonist binding site. Neurology. 2012; 79(5):449-54. [DOI:10.1212/WNL.0b013e31825b5bda] [PMID] [PMCID]
  32. Engel AG, Walls TJ, Nagel A, Uchitel O. Newly recognized congenital myasthenic syndromes: I. Congenital paucity of synaptic vesicles and reduced quantal release: I. Congenital paucity of synaptic vesicles and reduced quantal release, II. High-conductance fast-channel syndrome, III. Abnormal Acetylcholine Receptor (AChR) interaction with acetylcholine, IV. AChR deficiency and short channel-open time. Progress in Brain Research. 1990; 84:125-37. [DOI:10.1016/S0079-6123(08)60896-1]
  33. Fattahi Z, Kahrizi K, Nafissi S, Fadaee M, Abedini SS, Kariminejad A et al. Report of a patient with limb-girdle muscular dystrophy, ptosis and ophthalmoparesis caused by plectinopathy. Archives of Iranian Medicine. 2015; 18(1):60-4. [DOI: 0151801/AIM.0014] [PMID]
  34. Selcen D, Juel V, Hobson-Webb L, Smith E, Stickler D, Bite A, et al. Myasthenic syndrome caused by plectinopathy. Neurology. 2011; 76(4):327-36. [DOI:10.1212/WNL.0b013e31820882bd] [PMID] [PMCID]
  35. Maselli R, Arredondo J, Cagney O, Mozaffar T, Skinner S, Yousif S, et al. Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE. Clinical Genetics. 2011; 80(5):444-51. [DOI:10.1111/j.1399-0004.2010.01602.x] [PMID]
  36. Regal 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; 82(14):1254-60. [DOI:10.1212/WNL.0000000000000295] [PMID] [PMCID]
  37. Jaeken J, Martens K, François I, Eyskens F, Lecointre C, Derua R, et al. Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome. The American Journal of Human Genetics. 2006; 78(1):38-51. [DOI:10.1086/498852] [PMID] [PMCID]
  38. Natera-de Benito D, Bestue M, Vilchez J, Evangelista T, Töpf A, Garcia-Ribes A, et al. Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations. Neuromuscular Disorders. 2016; 26(2):153-9. [DOI:10.1016/j.nmd.2015.10.013] [PMID]
  39. Milone M, Shen X, Selcen D, Ohno K, Brengman J, Iannaccone S, et al. Myasthenic syndrome due to defects in rapsyn Clinical and molecular findings in 39 patients. Neurology. 2009;73(3):228-35. [DOI:10.1212/WNL.0b013e3181ae7cbc] [PMID] [PMCID]
  40. Visser AC, Laughlin RS, Litchy WJ, Benarroch EE, Milone M. Rapsyn congenital myasthenic syndrome worsened by fluoxetine. Muscle & Nerve. 2017; 55(1):131-5. [DOI:10.1002/mus.25244] [PMID]
  41. Tsujino A, Maertens C, Ohno K, Shen X-M, Fukuda T, Harper CM, et al. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proceedings of the National Academy of Sciences. 2003; 100(12):7377-82. [DOI:10.1073/pnas.1230273100] [PMID] [PMCID]
  42. Wu F, Mi W, Fu Y, Struyk A, Cannon SC. Mice with an NaV1. 4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis. Brain. 2016; 139(6):1688-99. [DOI:10.1093/brain/aww070] [PMID] [PMCID]
  43. Arnold WD, Feldman DH, Ramirez S, He L, Kassar D, Quick A, et al. Defective fast inactivation recovery of Nav1. 4 in congenital myasthenic syndrome. Annals of Neurology. 2015; 77(5):840-50. [DOI:10.1002/ana.24389] [PMID] [PMCID]
  44. Huze C, Bauche S, Richard P, Chevessier F, Goillot E, Gaudon K, et al. Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. The American Journal of Human Genetics. 2009; 85(2):155-67. [DOI:10.1016/j.ajhg.2009.06.015] [PMID] [PMCID]
  45. Karakaya M, Ceyhan-Birsoy O, Beggs AH, Topaloglu H. A Novel Missense Variant in the AGRN Gene; congenital myasthenic syndrome presenting with head drop. Journal of Clinical Neuromuscular Disease. 2017; 18(3):147. [DOI:10.1097/CND.0000000000000132] [PMID] [PMCID]
  46. Luan X, Tian W, Cao L. Limb-girdle congenital myasthenic syndrome in a Chinese family with novel mutations in MUSK gene and literature review. Clinical Neurology and Neurosurgery. 2016; 150:41-5. [DOI:10.1016/j.clineuro.2016.08.021] [PMID]
  47. Giarrana ML, Joset P, Sticht H, Robb S, Steindl K, Rauch A, et al. A severe congenital myasthenic syndrome with “dropped head” caused by novel MUSK mutations. Muscle & Nerve. 2015; 52(4):668-73. [DOI:10.1002/mus.24687] [PMID]
  48. 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. Human Molecular Genetics. 2013; 23(7):1856-68. [DOI:10.1093/hmg/ddt578] [PMID] [PMCID]
  49. Selcen D, Ohkawara B, Shen XM, McEvoy K, Ohno K, Engel AG. Impaired synaptic development, maintenance, and neuromuscular transmission in LRP4-related myasthenia. JAMA Neurology. 2015; 72(8):889-96. [DOI:10.1001/jamaneurol.2015.0853] [PMID] [PMCID]
  50. 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 to Cells. 2016; 21(6):670-6. [DOI:10.1111/gtc.12370] [PMID]
  51. Azuma Y, Töpf A, Evangelista T, Lorenzoni PJ, Roos A, Viana P, et al. Intragenic DOK7 deletion detected by whole-genome sequencing in congenital myasthenic syndromes. Neurology Genetics. 2017; 3(3):e152. [DOI:10.1212/NXG.0000000000000152] [PMID] [PMCID]
  52. Lorenzoni PJ, Scola RH, Kay CS, Filla L, Miranda AP, Pinheiro JM, et al. Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation. Journal of the Neurological Sciences. 2013; 331(1):155-7. [DOI:10.1016/j.jns.2013.05.017] [PMID]
  53. Kvist AP, Latvanlehto A, Sund M, Eklund L, Väisänen T, Hägg P, et al. Lack of cytosolic and transmembrane domains of type XIII collagen results in progressive myopathy. The American Journal of Pathology. 2001; 159(4):1581-92. [DOI:10.1016/S0002-9440(10)62542-4]
  54. Logan CV, Cossins J, Cruz PMR, Parry DA, Maxwell S, Martinez-Martinez P, et al. Congenital myasthenic syndrome type 19 is caused by mutations in COL13A1, encoding the atypical non-fibrillar collagen type XIII α1 chain. The American Journal of Human Genetics. 2015; 97(6):878-85. [DOI:10.1016/j.ajhg.2015.10.017] [PMID] [PMCID]
  55. Monies DM, Al-Hindi HN, Al-Muhaizea MA, Jaroudi DJ, Al-Younes B, Naim EA, et al. Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome. Neuromuscular Disorders. 2014; 24(4):353-9. [DOI:10.1016/j.nmd.2013.12.010] [PMID]
  56. Maselli R, Arredondo J, Nguyen J, Lara M, Ng F, Ngo M, et al. Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia. Clinical Genetics. 2014; 85(2):166-71. [DOI:10.1111/cge.12118] [PMID]
  57. Bauche S, Vellieux G, Sternberg D, Fontenille M-J, De Bruyckere E, Davoine C-S, et al. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy. Journal of Neurology. 2017; 264(8):1791-803. [DOI:10.1007/s00415-017-8569-x] [PMID]
  58. Selcen D, Shen XM, Brengman J, Li Y, Stans AA, Wieben E, et al. DPAGT1 myasthenia and myopathy Genetic, phenotypic, and expression studies. Neurology. 2014; 82(20):1822-30. [DOI:10.1212/WNL.0000000000000435] [PMID] [PMCID]
  59. Iba-ez-Mico S, Domingo JR, Perez-Cerda C, Ghandour-Fabre D. Congenital myasthenia and congenital disorders of glycosylation caused by mutations in the DPAGT1 gene. Neurologia. 2017; pii: S0213-4853(17)30215-3. [DOI:10.1016/j.nrl.2017.05.002] [PMID]
  60. Schorling DC, Rost S, Lefeber DJ, Brady L, Müller CR, Korinthenberg R, et al. Early and lethal neurodegeneration with myasthenic and myopathic features A new ALG14-CDG. Neurology. 2017; 89(7):657-64. [DOI:10.1212/WNL.0000000000004234] [PMID]
  61. Belaya K, Rodriguez 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; 138(9):2493-504. [DOI:10.1093/brain/awv185] [PMID] [PMCID]
Journal of Advanced Medical Sciences and Applied Technologies
Volume 3, Issue 4 - Serial Number 4
14
December 2017
Pages 179-188

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