Determinants of the Repetitive-CMAP Occurrence and Therapy Efficacy in Slow-channel Myasthenia

Overview

Journal Neurology

Specialty Neurology

Date 2020 Sep 10

PMID 32907971

Citations 3

Authors

Li Di

Hai Chen

Yan Lu

Duygu Selcen

Andrew G Engel

Yuwei Da

Xin-Ming Shen

Affiliations

Soon will be listed here.

Abstract

Objective: To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and to assess the efficacy of channel blocker therapy in slow-channel congenital myasthenic syndrome (SCCMS).

Methods: Neurologic examination, EMG study, laboratory test, muscle biopsy, and next-generation and Sanger sequencing; literature review of reported patients with SCCMS, including EMG, kinetics of mutant acetylcholine receptors (AChRs), and response to therapy; and simulation of the decay phase of endplate potential (EPP) were performed.

Results: Three newly characterized and 57 reported patients with SCCMS with mutations of AChR subunits were included. In patients with R-CMAP, the length of channel opening bursts of mutant AChR was increased 8.68 ± 2.82 (mean ± SD)-fold compared to wild-type; in patients without R-CMAP, the length was increased 3.84 ± 0.65-fold (95% confidence interval 3.18-6.50, = 0.000014). The EPP amplitude after refractory period of action potential in muscle fiber is above the threshold in patients with R-CMAP but below the threshold in patients without R-CMAP. In patients with good results from channel blocker therapy, treatment was initiated 11.60 ± 5.17 years after onset of symptoms; in patients with no to moderate benefit from channel blocker therapy, treatment was initiated 30.70 ± 12.72 years after onset (95% confidence interval -28.57 to -9.63, = 0.00089).

Conclusions: In SCCMS, the R-CMAP occurrence is related to the extent of prolongation of the opening episodes of mutant AChR channel. Channel blocker treatment is more effective the sooner it is started after the onset of symptoms.

Classification Of Evidence: This study provides Class IV evidence that channel blocker therapy in patients with SCCMS improves symptoms.

Citing Articles

Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis.

Theuriet J, Masingue M, Behin A, Ferreiro A, Bassez G, Jaubert P Brain. 2024; 147(11):3849-3862.

PMID: 38696726 PMC: 11531845. DOI: 10.1093/brain/awae124.

Impaired gating of γ- and ε-AChR respectively causes Escobar syndrome and fast-channel myasthenia.

Shen X, Nakata T, Mizuno S, Imoto I, Selcen D, Ohno K Ann Clin Transl Neurol. 2023; 10(5):732-743.

PMID: 36891870 PMC: 10187723. DOI: 10.1002/acn3.51756.

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.

Ohno K, Ohkawara B, Shen X, Selcen D, Engel A Int J Mol Sci. 2023; 24(4).

PMID: 36835142 PMC: 9961056. DOI: 10.3390/ijms24043730.

References

Mihaylova V, Scola R, Gervini B, Lorenzoni P, Kay C, Werneck L . Molecular characterisation of congenital myasthenic syndromes in Southern Brazil. J Neurol Neurosurg Psychiatry. 2010; 81(9):973-7. DOI: 10.1136/jnnp.2009.177816. View

Engel A, LAMBERT E, Mulder D, Torres C, Sahashi K, Bertorini T . A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel. Ann Neurol. 1982; 11(6):553-69. DOI: 10.1002/ana.410110603. View

Fidzianska A, Ryniewicz B, Shen X, Engel A . IBM-type inclusions in a patient with slow-channel syndrome caused by a mutation in the AChR epsilon subunit. Neuromuscul Disord. 2005; 15(11):753-9. DOI: 10.1016/j.nmd.2005.07.009. View

Fukudome T, Ohno K, Brengman J, Engel A . AChR channel blockade by quinidine sulfate reduces channel open duration in the slow-channel congenital myasthenic syndrome. Ann N Y Acad Sci. 1998; 841:199-202. DOI: 10.1111/j.1749-6632.1998.tb10928.x. View

Chaouch A, Muller J, Guergueltcheva V, Dusl M, Schara U, Rakocevic-Stojanovic V . A retrospective clinical study of the treatment of slow-channel congenital myasthenic syndrome. J Neurol. 2011; 259(3):474-81. DOI: 10.1007/s00415-011-6204-9. View

Vohra B, Groshong J, Maselli R, Verity M, Wollmann R, Gomez C . Focal caspase activation underlies the endplate myopathy in slow-channel syndrome. Ann Neurol. 2004; 55(3):347-52. DOI: 10.1002/ana.10823. View

Oury J, Liu Y, Topf A, Todorovic S, Hoedt E, Preethish-Kumar V . MACF1 links Rapsyn to microtubule- and actin-binding proteins to maintain neuromuscular synapses. J Cell Biol. 2019; 218(5):1686-1705. PMC: 6504910. DOI: 10.1083/jcb.201810023. View

Tan J, Man Y, Xiao F . A Missense Mutation in Epsilon-subunit of Acetylcholine Receptor Causing Autosomal Dominant Slow-channel Congenital Myasthenic Syndrome in a Chinese Family. Chin Med J (Engl). 2016; 129(21):2596-2602. PMC: 5125339. DOI: 10.4103/0366-6999.192780. View

Shen X, Okuno T, Milone M, Otsuka K, Takahashi K, Komaki H . Mutations Causing Slow-Channel Myasthenia Reveal That a Valine Ring in the Channel Pore of Muscle AChR is Optimized for Stabilizing Channel Gating. Hum Mutat. 2016; 37(10):1051-9. PMC: 5021579. DOI: 10.1002/humu.23043. View

10.

Outteryck O, Richard P, Lacour A, Fournier E, Zephir H, Gaudon K . Novel epsilon subunit mutation of the muscle acetylcholine receptor causing a slow-channel congenital myasthenic syndrome. J Neurol Neurosurg Psychiatry. 2009; 80(4):450-1. DOI: 10.1136/jnnp.2008.148189. View

11.

Durmus H, Shen X, Serdaroglu-Oflazer P, Kara B, Parman-Gulsen Y, Ozdemir C . Congenital myasthenic syndromes in Turkey: Clinical clues and prognosis with long term follow-up. Neuromuscul Disord. 2018; 28(4):315-322. PMC: 5924610. DOI: 10.1016/j.nmd.2017.11.013. View

12.

Harper C, Fukodome T, Engel A . Treatment of slow-channel congenital myasthenic syndrome with fluoxetine. Neurology. 2003; 60(10):1710-3. DOI: 10.1212/01.wnl.0000061483.11417.1b. View

13.

Azuma Y, Nakata T, Tanaka M, Shen X, Ito M, Iwata S . Congenital myasthenic syndrome in Japan: ethnically unique mutations in muscle nicotinic acetylcholine receptor subunits. Neuromuscul Disord. 2014; 25(1):60-9. DOI: 10.1016/j.nmd.2014.09.002. View

14.

Colomer J, Muller J, Vernet A, Nascimento A, Pons M, Gonzalez V . Long-term improvement of slow-channel congenital myasthenic syndrome with fluoxetine. Neuromuscul Disord. 2006; 16(5):329-33. DOI: 10.1016/j.nmd.2006.02.009. View

15.

Ohno K, Hutchinson D, Milone M, Brengman J, Bouzat C, Sine S . 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; 92(3):758-62. PMC: 42699. DOI: 10.1073/pnas.92.3.758. View

16.

Groshong J, Spencer M, Bhattacharyya B, Kudryashova E, Vohra B, Zayas R . Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome. J Clin Invest. 2007; 117(10):2903-12. PMC: 1974862. DOI: 10.1172/JCI30383. View

17.

Shen X, Milone M, Wang H, Banwell B, Selcen D, Sine S . Slow-channel myasthenia due to novel mutation in M2 domain of AChR delta subunit. Ann Clin Transl Neurol. 2019; 6(10):2066-2078. PMC: 6801167. DOI: 10.1002/acn3.50902. View

18.

Croxen R, Hatton C, Shelley C, Brydson M, Chauplannaz G, Oosterhuis H . Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes. Neurology. 2002; 59(2):162-8. DOI: 10.1212/wnl.59.2.162. View

19.

Croxen R, Newland C, Beeson D, Oosterhuis H, Chauplannaz G, Vincent A . 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; 6(5):767-74. DOI: 10.1093/hmg/6.5.767. View

20.

Gomez C, Maselli R, Gammack J, Lasalde J, Tamamizu S, Cornblath D . A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome. Ann Neurol. 1996; 39(6):712-23. DOI: 10.1002/ana.410390607. View