Myasthenia Gravis Development and Crisis Subsequent to Multiple Sclerosis

During the last decade, sporadic combination of multiple sclerosis (MS) and myasthenia gravis (MG) has been reported repeatedly. Although these are anecdotal, they are important enough to raise concerns about co-occurrence of MG and MS. Here, we present a case of an MS patient who developed an MG crisis. She had received interferon for relapsing remitting MS. Interestingly, she developed an MG crisis 4 years after the diagnosis of MS. MS and MG have relatively the same distribution for age, corresponding to the younger peak of the bimodal age distribution in MG. They also share some HLA typing characteristics. Furthermore, some evidences support the role of systemic immune dysregulation due to a genetic susceptibility that is common to these two diseases. The association may be underdiagnosed because of the possible overlap of symptoms especially bulbar manifestations in which either MG or MS can mimic each other, leading to underestimating incidence of the combination. The evidence warrants physicians, especially neurologists, to always consider the possibility of the other disease when encountering any patients either with MS or MG. Anecdotal and sporadic reports of combination of multiple sclerosis (MS) and myasthenia gravis (MG) have been raised concerns about co-occurrence of them

Correction: A Mutation Causes MuSK Reduced Sensitivity to Agrin and Congenital Myasthenia.

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient’s biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation

A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation

Effect of the mutation on agrin-dependent MuSK phosphorylation.

<p>HEK 293 cells expressing both Lrp4 and MuSK were incubated with recombinant rat agrin. (<b>A</b>) HA-MuSK was immunoprecipitated (IP) with an anti-HA antibody (α HA) and immunoblots (IB) for MuSK (α HA) and phosphorylated MuSK (α pTyr) were performed. A representative experiment out of three realized in duplicate is shown. MuSK amount and phosphorylation were then estimated with ImageJ software. (<b>B</b>) Phosphorylation is expressed as n-fold activation as compared to WT MuSK without Lrp4 and agrin. Error bars indicate mean±SD (n = 3; **, P<0.01, paired <i>t</i> test). Comparison between MV and WT MuSK shows that while WT MuSK needs the presence of both agrin and Lrp4 to be phosphorylated, MV MuSK is already phosphorylated even in the absence of Lrp4 and agrin.</p

Quantification of nAChRs in patient’s biopsied muscle.

<p>(<b>A</b>) nAChR expression in MuSK mutated muscle from the patient was decreased by about 50% compared with biopsied control muscle. (<b>B</b>) The nAChR γ-subunit mRNA level, which is synonymous with denervation, was measured in the extrasynaptic zone in patient and was increased by 5-fold compared with the control. The mean value of control AChR (A) or AChR γ-subunit mRNA levels were defined as 1 in arbitrary units. Error bars indicate mean±SD (**, P<0.01, Student <i>t</i> test).</p

Morphological study of the patient’s biopsied muscle.

<p>(<b>A</b>) Whole-mount preparations stained with α-bungarotoxin for nAChR in red and with an anti-neurofilament (NF) antibody for axons in green. In the normal NMJ, the axonal branch typically ends as a fork innervating a well-defined synaptic structure. In denervated NMJ, axons are absent. In some cases, axonal sprouts induce aggregation of nAChR forming ectopic junctions as a rosary. The histogram shows the classification of the NMJs observed in the patient muscle-biopsy specimen into four categories (expressed as percentage of the 25 NMJs examined). (<b>B</b>) In remodeled NMJs, nodal (arrow) or terminal (asterisk) axonal sprouts reinnervate synaptic gutters. The histogram shows the classification of the sprouting profiles observed into two categories (expressed as a percentage of the 16 NMJs exhibiting sprouts identified amongst the 25 NMJs analyzed). Scale bar = 10 µm and applies to all prints in A and B.</p

Morphological study of electroporated mice.

<p>(<b>A</b>). Denervated junctions were fragmented and dispersed without terminal axons. Remodeled junctions were partially reinnervated and showed nodal sprouts forming more or less mature ectopic junctions (<b>B</b>). The arrow shows a mature ectopic junction with well-defined borders synonymous with subneural fold formation. The asterisk and the zoom show the first steps of ectopic junction formation characterized by very simplified AChR clusters induced by emergent nodal sprouts or axonal varicosity. Histograms show the distribution of different types of NMJs and sprouting in MV MuSK electroporated mice. The scale bar represents 10 µm and applies to all prints except to the blowup where the scale bar represents 2.5 µm.</p