Disease relevance of Myasthenic Syndromes, Congenital

• Chronic treatment of rodents with 2,4-dithiobiuret (DTB) induces a neuromuscular syndrome of flaccid muscle weakness that mimics signs seen in several human neuromuscular disorders such as congenital myasthenic syndromes, botulism, and neuroaxonal dystrophy [1].

High impact information on Myasthenic Syndromes, Congenital

• By defining the functional defect in a congenital myasthenic syndrome (CMS), we show that the third transmembrane domain (M3) of the muscle acetylcholine receptor governs the speed and efficiency of gating of its channel [2].
• We describe a highly disabling congenital myasthenic syndrome (CMS) associated with rapidly decaying, low-amplitude synaptic currents, and trace its cause to a valine to leucine mutation in the signature cystine loop (cys-loop) of the AChR alpha subunit [3].
• Defects of utrophin could underlie some forms of congenital myasthenic syndrome in which a reduction of postsynaptic folds is observed [4].
• Serum choline activates mutant acetylcholine receptors that cause slow channel congenital myasthenic syndromes [5].
• Congenital myasthenic syndrome (CMS) with end-plate acetylcholinesterase (AChE) deficiency is a rare autosomal recessive disease, recently classified as CMS type Ic (CMS-Ic) [6].

Chemical compound and disease context of Myasthenic Syndromes, Congenital

• Mutations in congenital myasthenic syndromes reveal an epsilon subunit C-terminal cysteine, C470, crucial for maturation and surface expression of adult AChR [7].
• Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome [8].
• Fluoxetine has recently been proposed as an alternative treatment for 'slow channel' congenital myasthenic syndrome [9].
• Because this concentration of quinidine is attainable in clinical practice, the findings predict a therapeutic effect for quinidine in the slow-channel congenital myasthenic syndrome [10].
• Ephedrine in the treatment of congenital myasthenic syndrome [11].

Biological context of Myasthenic Syndromes, Congenital

• We here report two novel E-box mutations in the RAPSN promoter region in eight congenital myasthenic syndrome patients [12].
• Recently, the first molecular genetic defect resulting in a presynaptic congenital myasthenic syndrome has been reported: Recessive loss-of-function mutations in CHAT, the gene encoding choline acetyltransferase, were described in five congenital myasthenic syndrome families [13].
• A congenital myasthenic syndrome in Brahman cattle is caused by a homozygous 20 base pair deletion (470del20) in the gene coding for the epsilon subunit of the acetylcholine receptor at the neuromuscular junction [14].

Anatomical context of Myasthenic Syndromes, Congenital

• Thus, slow-channel congenital myasthenic syndrome AChRs at the neuromuscular junction are likely to be activated both by steady exposure to serum choline and by transient exposure to synaptically released transmitter [5].
• Using Xenopus oocyte in vitro expression studies we confirmed that the deltaS268F mutation, as with other slow-channel congenital myasthenic syndrome mutations, causes delayed closure of acetylcholine receptor ion channels [15].
• Newly recognized congenital myasthenic syndromes: I. Congenital paucity of synaptic vesicles and reduced quantal release. II. High-conductance fast-channel syndrome. III. Abnormal acetylcholine receptor (AChR) interaction with acetylcholine. IV. AChR deficiency and short channel-open time [16].
• The authors found that fluoxetine significantly shortens at 5 microM/L and nearly normalizes at 10 microM/L the prolonged opening bursts of slow-channel congenital myasthenic syndrome (SCCMS) acetylcholine receptors (AChR) expressed in fibroblasts [17].

Gene context of Myasthenic Syndromes, Congenital

• CONCLUSIONS: 1) After mutations in the AChR epsilon subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes [18].
• A frameshifting 7 bp deletion (epsilon553del7) in exon 7 of CHRNE encoding the acetylcholine receptor epsilon subunit, observed in seven congenital myasthenic syndrome patients, enhances expression of an aberrantly spliced transcript that skips the preceding 101 bp exon 6 [19].
• Analysis of the rapsyn promoter revealed a consensus site for the transcription factor Kaiso within a region that is mutated in a subset of patients with congenital myasthenic syndrome [20].
• Similarly to AChR, MuSK and several of its partners are the target of mutations responsible for diseases of the NMJ, such as congenital myasthenic syndromes [21].
• Arg-442 is mutated spontaneously (R442H) in congenital myasthenic syndrome, rendering ChAT inactive and causing neuromuscular failure [22].

References