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Review
. 2018 Feb;1413(1):25-34.
doi: 10.1111/nyas.13539. Epub 2018 Jan 21.

The Unfolding Landscape of the Congenital Myasthenic Syndromes

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Free PMC article
Review

The Unfolding Landscape of the Congenital Myasthenic Syndromes

Andrew G Engel et al. Ann N Y Acad Sci. .
Free PMC article

Abstract

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is impaired by one or more specific mechanisms. Since the advent of next-generation sequencing methods, the discovery of novel CMS targets and phenotypes has proceeded at an accelerated rate. Here, we review the current classification of CMS and describe our findings in five of these targets identified and investigated in our laboratory in the past 5 years. Defects in LRP4 hinder synaptic development and maintenance; the defects in PREPL are predicted to diminish filling of the synaptic vesicle with acetylcholine; and defects in SNAP25, Munc13-1, and synaptotbrevin-1 impede synaptic vesicle exocytosis.

Keywords: LRP4; Munc13-1; PREPL; SNAP25B; congenital myasthenic syndromes; synaptobrevin.

Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Classification of the currently recognized congenital myasthenic syndromes.
Figure 2
Figure 2
Structural EP abnormalities in LRP4 myasthenia. In cholinesterase-stained transverse sections, the patient EPs (B) are much smaller than the control EPs (A). (C) Some EPs display poorly developed or degenerating junctional folds (asterisk), and some postsynaptic regions show focal myofibrillar degeneration. NT, nerve terminal; SC, Schwann cell.
Figure 3
Figure 3
PREPL and AChR localization in muscle fibers and EPs. (A) PREPL immunolocalization in control muscle fibers and EPs (green signal). (B) Serial section stained for AChR with rhodamine-labeled α-bungarotoxin shows presence of AChR at EPs (red signal). (C) Merged image of (A) and (B). (D) Patient muscle fibers and EPs fail to stain for PREPL. (E) Serial section to (E) stained for AChR shows presence of EPs. Color version shown online. Reproduced from Ref. with permission of Kluwer and Bucy.
Figure 4
Figure 4
Schematic diagram of the SNARE complex. Synaptobrevin anchored in the SV membrane (V-snare) and syntaxin-1 and SNAP25B (T-snares) anchored in the presynaptic membrane subserve vesicle exocytosis. Each SNARE protein is in a coiled-coil configuration. Complexin clamps the SNARE proteins at rest by binding to the groove between synaptobrevin and syntaxin. Ca2+ entry into the nerve terminal removes the inhibitory effect of complexin. Munc18-1 inhibits fast exocytosis by binding to a folded inactive form of syntaxin-1. Upon Ca2+ entry into the nerve terminal, Munc13 opens syntaxin-1 by displacing Munc18-1. This enables the SNARE complex to assemble, which primes the synaptic vesicles for release.
Figure 5
Figure 5
SNAP25B CMS. (A) Patient at age 10 cannot rise from the floor or walk without assistance. (B) Electron micrograph of patient EP shows that the nerve terminal harbors abundant synaptic vesicles. Asterisks indicate vesicles focused on the active zones. The postsynaptic region is well developed. Bar = 0.5 μm. (C) Histograms of the quantal content of the EPP (m). The patient values are not normally distributed, with some values much lower and some normal or higher than normal. (D) Vertical scatter plot of readily releasable quanta (n) at patient and control EPs. Some values at patient EPs are much lower and some as high or higher than at control EPs. Reproduced from Ref. with permission of Kluwer and Bucy.
Figure 6
Figure 6
Expression studies. (A) Mixing liposomes incorporating wild-type v- and t-SNARES causes a significant right shift in particle size distribution. (B) Mixing liposomes incorporating wild-type v-SNARE with t-SNARE liposomes harboring mutant Snap25B causes no significant shift in particle size distribution. (C) Representative amperometric traces from depolarized chromaffin cells. Each spike represents a single exocytotic event. Mutant SNAP25B- and mutant SNAP25B plus wild-type–transfected cells generate fewer and lower-amplitude spikes than wild-type SNAP25B–transfected cells. (D) Cumulative exocytotic events during the first minute after depolarization from 15 nontransfected, 11 wild-type SNAP25B–transfected, 14 mutant SNAP25B–transfected, and 17 mutant SNAP25B plus wild type–transfected cells. For each group of cells, each point indicates the mean number of spikes over 5 seconds. Vertical lines indicate one SE. Compared with nontransfected or wild type–transfected cells, mutant- transfected, or mutant plus wild-type–transfected cells, cells exocytose vesicles at similar markedly reduced rates. Reproduced from Ref. with permission of Kluwer and Bucy.
Figure 7
Figure 7
Head MRI at age 4 months. The image shows small brain reflected by the size of the small corpus callosum (arrow). Reproduced from Ref. with permission of Kluwer and Bucy.

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