Inherited Disorders of the Neuromuscular Junction: an Update

Overview

Journal J Neurol

Specialty Neurology

Date 2014 Oct 12

PMID 25305004

Citations 15

Authors

Pedro M Rodriguez Cruz

Jacqueline Palace

David Beeson

Affiliations

Soon will be listed here.

Abstract

Congenital myasthenic syndromes (CMSs) are a group of heterogeneous inherited disorders caused by mutations in genes affecting the function and structure of the neuromuscular junction. This review updates the reader on established and novel subtypes of congenital myasthenia, and the treatment strategies for these increasingly heterogeneous disorders. The discovery of mutations associated with the N-glycosylation pathway and in the family of serine peptidases has shown that causative genes encoding ubiquitously expressed molecules can produce defects at the human neuromuscular junction. By contrast, mutations in lipoprotein-like receptor 4 (LRP4), a long-time candidate gene for congenital myasthenia, and a novel phenotype of myasthenia with distal weakness and atrophy due to mutations in AGRN have now been described. In addition, a pathogenic splicing mutation in a nonfunctional exon of CHRNA1 has been reported emphasizing the importance of analysing nonfunctional exons in genetic analysis. The benefit of salbutamol and ephedrine alone or combined with pyridostigmine or 3,4-DAP is increasingly being reported for particular subtypes of CMS.

Citing Articles

Novel copy number variation of COLQ gene in a Moroccan patient with congenital myasthenic syndrome: a case report and review of the literature.

El Kadiri Y, Ratbi I, Sefiani A, Lyahyai J BMC Neurol. 2022; 22(1):292.

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The First Case of Congenital Myasthenic Syndrome Caused by a Large Homozygous Deletion in the C-Terminal Region of COLQ (Collagen Like Tail Subunit of Asymmetric Acetylcholinesterase) Protein.

Laforgia N, De Cosmo L, Palumbo O, Ranieri C, Sesta M, Capodiferro D Genes (Basel). 2020; 11(12).

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Congenital myasthenic syndrome due to a mutation: a new disease pathway for impaired synaptic transmission.

Cossins J, Webster R, Maxwell S, Rodriguez Cruz P, Knight R, Llewelyn J Brain Commun. 2020; 2(2):fcaa174.

PMID: 33215087 PMC: 7660151. DOI: 10.1093/braincomms/fcaa174.

Pathogenic effects of agrin V1727F mutation are isoform specific and decrease its expression and affinity for HSPGs and LRP4.

Rudell J, Maselli R, Yarov-Yarovoy V, Ferns M Hum Mol Genet. 2019; 28(16):2648-2658.

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Finsterer J Orphanet J Rare Dis. 2019; 14(1):57.

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References

Rahman M, Masuda A, Ohe K, Ito M, Hutchinson D, Mayeda A . HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. Sci Rep. 2013; 3:2931. PMC: 3796306. DOI: 10.1038/srep02931. View

Mihaylova V, Muller J, Vilchez J, Salih M, Kabiraj M, DAmico A . Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes. Brain. 2008; 131(Pt 3):747-59. DOI: 10.1093/brain/awm325. View

Shen X, Brengman J, Edvardson S, Sine S, Engel A . Highly fatal fast-channel syndrome caused by AChR ε subunit mutation at the agonist binding site. Neurology. 2012; 79(5):449-54. PMC: 3405251. DOI: 10.1212/WNL.0b013e31825b5bda. View

Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T . The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006; 312(5781):1802-5. DOI: 10.1126/science.1127142. View

Chaouch A, Beeson D, Hantai D, Lochmuller H . 186th ENMC international workshop: congenital myasthenic syndromes 24-26 June 2011, Naarden, The Netherlands. Neuromuscul Disord. 2012; 22(6):566-76. DOI: 10.1016/j.nmd.2011.12.004. View

Cossins J, Liu W, Belaya K, Maxwell S, Oldridge M, Lester T . The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome. Hum Mol Genet. 2012; 21(17):3765-75. DOI: 10.1093/hmg/dds198. View

Webster R, Cossins J, Lashley D, Maxwell S, Liu W, Wickens J . A mouse model of the slow channel myasthenic syndrome: Neuromuscular physiology and effects of ephedrine treatment. Exp Neurol. 2013; 248:286-98. DOI: 10.1016/j.expneurol.2013.06.012. View

Finlayson S, Beeson D, Palace J . Congenital myasthenic syndromes: an update. Pract Neurol. 2013; 13(2):80-91. DOI: 10.1136/practneurol-2012-000404. View

Bretthauer R . Structure, expression, and regulation of UDP-GlcNAc: dolichol phosphate GlcNAc-1-phosphate transferase (DPAGT1). Curr Drug Targets. 2009; 10(6):477-82. DOI: 10.2174/138945009788488369. View

10.

Huh S, Kim H, Jang H, Park Y, Kim D . Limb-girdle myasthenia with tubular aggregates associated with novel GFPT1 mutations. Muscle Nerve. 2012; 46(4):600-4. DOI: 10.1002/mus.23451. View

11.

DeChiara T, Bowen D, Valenzuela D, Simmons M, Poueymirou W, Thomas S . The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell. 1996; 85(4):501-12. DOI: 10.1016/s0092-8674(00)81251-9. View

12.

Zoltowska K, Webster R, Finlayson S, Maxwell S, Cossins J, Muller J . Mutations in GFPT1 that underlie limb-girdle congenital myasthenic syndrome result in reduced cell-surface expression of muscle AChR. Hum Mol Genet. 2013; 22(14):2905-13. DOI: 10.1093/hmg/ddt145. View

13.

Park J, Mott M, Williams T, Ikeda H, Wen H, Linhoff M . A single mutation in the acetylcholine receptor δ-subunit causes distinct effects in two types of neuromuscular synapses. J Neurosci. 2014; 34(31):10211-8. PMC: 4115133. DOI: 10.1523/JNEUROSCI.0426-14.2014. View

14.

Lorenzoni P, Scola R, Kay C, Filla L, Miranda A, Pinheiro J . Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation. J Neurol Sci. 2013; 331(1-2):155-7. DOI: 10.1016/j.jns.2013.05.017. View

15.

Burke G, Hiscock A, Klein A, Niks E, Main M, Manzur A . Salbutamol benefits children with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord. 2012; 23(2):170-5. DOI: 10.1016/j.nmd.2012.11.004. View

16.

Thiel C, Schwarz M, Peng J, Grzmil M, Hasilik M, Braulke T . A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. J Biol Chem. 2003; 278(25):22498-505. DOI: 10.1074/jbc.M302850200. View

17.

Nicole S, Chaouch A, Torbergsen T, Bauche S, De Bruyckere E, Fontenille M . Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. Brain. 2014; 137(Pt 9):2429-43. DOI: 10.1093/brain/awu160. View

18.

Wargon I, Richard P, Kuntzer T, Sternberg D, Nafissi S, Gaudon K . Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations. Neuromuscul Disord. 2011; 22(4):318-24. DOI: 10.1016/j.nmd.2011.09.002. View

19.

Merlie J, Sebbane R, Tzartos S, Lindstrom J . Inhibition of glycosylation with tunicamycin blocks assembly of newly synthesized acetylcholine receptor subunits in muscle cells. J Biol Chem. 1982; 257(5):2694-701. View

20.

Belaya K, Finlayson S, Slater C, Cossins J, Liu W, Maxwell S . Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am J Hum Genet. 2012; 91(1):193-201. PMC: 3397259. DOI: 10.1016/j.ajhg.2012.05.022. View