Congenital myasthenic syndromes: Recent advances

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Abstract

Congenital myasthenic syndromes (CMS) can arise from presynaptic, synaptic, or postsynaptic defects. Mutations of the acetylcholine receptor (AChR) that increase or decrease the synaptic response to acetylcholine (ACh) are a common cause of the postsynaptic CMS. An increased response occurs in the slow-channel syndromes. Here, dominant mutations in different AChR subunits and in different domains of the subunits prolong the activation episodes of AChR by either delaying channel closure or increasing the affinity of AChR for ACh. A decreased synaptic response to ACh occurs with recessive, loss-of-function mutations. Missense mutations in the low- affinity, fast-channel syndrome and in a disorder associated with mode- switching kinetics of AChR result in brief activation episodes and reduce the probability of channel opening. Mutations causing premature termination of the translational chain or missense mutations preventing the assembly or glycosylation of AChR curtail the expression of AChR. These mutations are concentrated in the ε subunit, probably because substitution of the fetal γ for the adult e subunit can rescue humans from fatal null mutations in ε. Recent molecular genetic studies have also elucidated the pathogenesis of the CMS caused by absence of the asymmetric form of acetylcholinesterase from the synaptic basal lamina. Endplate acetylcholinesterase deficiency is now known to be caused by mutations in the collagenic tail subunit of the asymmetric enzyme that prevents the association of the collagenic tail subunit with the catalytic subunit or its insertion into the basal lamina.

Original languageEnglish (US)
Pages (from-to)163-167
Number of pages5
JournalArchives of Neurology
Volume56
Issue number2
DOIs
StatePublished - Feb 1999

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Congenital Myasthenic Syndromes
Cholinergic Receptors
Mutation
Acetylcholine
Missense Mutation
Basement Membrane
Tail
Acetylcholinesterase
Syndrome
Glycosylation
Molecular Biology
Catalytic Domain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Congenital myasthenic syndromes : Recent advances. / Engel, Andrew G; Ohno, Kinji; Sine, Steven M.

In: Archives of Neurology, Vol. 56, No. 2, 02.1999, p. 163-167.

Research output: Contribution to journalArticle

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