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1/10. Congenital myasthenic syndrome: a rare, potentially treatable cause of respiratory failure in a "floppy" infant.

    A four-month-old infant, thought to suffer from cerebral palsy, presented with respiratory failure on the background of a gradually deteriorating general level of function. Whilst being ventilated in intensive care he was noted to have severe muscle weakness. A disorder of the neuromuscular junction was suspected and he was subsequently demonstrated to have a congenital myasthenic syndrome. Anticholinesterase therapy produced a dramatic recovery. The congenital myasthenic syndromes and the diagnosis of a "floppy baby" are briefly reviewed.
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ranking = 1
keywords = neuromuscular junction, junction
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2/10. Congenital myasthenic syndrome: report of four cases and brief review of literature.

    The term 'congenital myasthenic syndrome' (CMS) encompasses a number of heterogeneous disorders characterised by myasthenic symptoms since birth, usually with positive family history and absence of acetyl choline receptor antibodies. Recent advances in electrophysiology and ultrastructural analysis of neuromuscular junction have made it possible to identify the various defects underlying these disorders. We report four cases of CMS, with a review of literature.
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ranking = 1
keywords = neuromuscular junction, junction
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3/10. Familial infantile myaesthenia.

    We report a family of two brothers with familial infantile myaesthenia which is an autosomal recessive congenital myaesthenic syndrome. It is a presynaptic neuro muscular junction disorder, responsive to treatment and has got good prognosis.
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ranking = 4.4895916004231E-5
keywords = junction
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4/10. Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission.

    OBJECTIVE: To examine the functional consequences of episodic ataxia type 2 (EA2)-causing nonsense and missense mutations in vitro and to characterize the basis of fluctuating weakness in patients with E2A. BACKGROUND: Mutations in CACNA1A encoding the Ca(v)2.1 calcium channel subunit cause EA2 through incompletely understood mechanisms. Although the Ca(v)2.1 subunit is important for neurotransmission at the neuromuscular junction, weakness has not been considered a feature of EA2. methods: The disease-causing mutations in three unrelated patients with EA2 and fluctuating weakness were identified by mutation screening and sequencing. Mutant constructs harboring mutations R1281X, F1406C, R1549X were transfected into COS7 cells and expressed for patch clamp studies. Single-fiber electromyography (SFEMG) was performed in patients to examine synaptic transmission at the neuromuscular junction. RESULTS: Functional studies in COS7 cells of nonsense and missense EA2 mutants demonstrated markedly decreased current densities compared with wild type. SFEMG demonstrated jitter and blocking in these patients with EA2, compared with normal subjects and three patients with SCA-6. CONCLUSION: EA2-causing missense and nonsense mutations in CACNA1A produced mutant channels with diminished whole cell calcium channel activity in vitro due to loss of function. Altered biophysical properties or reduced efficiency of plasma membrane targeting of mutant channels may contribute to abnormal neuromuscular transmission, manifesting as myasthenic syndrome.
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ranking = 2
keywords = neuromuscular junction, junction
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5/10. Mutation causing severe myasthenia reveals functional asymmetry of AChR signature cystine loops in agonist binding and gating.

    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. The recently solved crystal structure of an ACh-binding protein places the cys-loop at the junction between the extracellular ligand-binding and transmembrane domains where it may couple agonist binding to channel gating. We therefore analyzed the kinetics of ACh-induced single-channel currents to identify elementary steps in the receptor activation mechanism altered by the alphaV132L mutation. The analysis reveals that alphaV132L markedly impairs ACh binding to receptors in the resting closed state, decreasing binding affinity for the second binding step 30-fold, but attenuates gating efficiency only about twofold. By contrast, mutation of the equivalent valine residue in the delta subunit impairs channel gating approximately fourfold with little effect on ACh binding, while corresponding mutations in the beta and epsilon subunits are without effect. The unique functional contribution of the alpha subunit cys-loop likely owes to its direct connection via a beta strand to alphaW149 at the center of the ligand-binding domain. The overall findings reveal functional asymmetry between cys-loops of the different AChR subunits in contributing to ACh binding and channel gating.
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ranking = 4.4895916004231E-5
keywords = junction
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6/10. Electrophysiological and morphological characterization of a case of autosomal recessive congenital myasthenic syndrome with acetylcholine receptor deficiency due to a N88K rapsyn homozygous mutation.

    Congenital myasthenic syndromes are rare heterogeneous hereditary disorders, which lead to defective neuromuscular transmission resulting in fatigable muscle weakness. Post-synaptic congenital myasthenic syndromes are caused by acetylcholine receptor kinetic abnormalities or by acetylcholine receptor deficiency. Most of the congenital myasthenic syndromes with acetylcholine receptor deficiency are due to mutations in acetylcholine receptor subunit genes. Some have recently been attributed to mutations in the rapsyn gene. Here, we report the case of a 28-year-old French congenital myasthenic syndrome patient who had mild diplopia and fatigability from the age of 5 years. His muscle biopsy revealed a marked reduction in rapsyn and acetylcholine receptor at neuromuscular junctions together with a simplification of the subneural apparatus structure. In this patient, we excluded mutations in the acetylcholine receptor subunit genes and identified the homozygous N88K rapsyn mutation, which has already been shown by cell expression to impair rapsyn and acetylcholine receptor aggregation at the neuromuscular junction. The detection of the N88K mutation at the heterozygous state in five of 300 unrelated control subjects shows that this mutation is not infrequent in the healthy population. Electrophysiological measurements on biopsied intercostal muscle from this patient showed that his rapsyn mutation-induced fatigable weakness is expressed not only in a diminution in acetylcholine receptor membrane density but also in a decline of endplate potentials evoked at low frequency.
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ranking = 2
keywords = neuromuscular junction, junction
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7/10. Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine.

    Rapsyn is essential for clustering the acetylcholine receptor at the postsynaptic membrane of the neuromuscular junction. Direct sequencing of RAPSN in two children with congenital myasthenic syndromes with no mutation in any of the AChR subunits identified two heterozygous recessive mutations in each: a previously characterized N88K mutation in both, and a second frameshifting mutation in Patient (Pt) 1 and a nonsense mutation in Pt 2. An intercostal muscle biopsy in Pt 1 revealed decreased AChRs per endplate and decreased amplitude of the miniature endplate potential, predicted consequences of rapsyn deficiency. Clinically, both children manifested with hypomotility in utero, fatigable ocular and limb weakness since birth, decreased strength during viral illness, decremental response on electromyography, and absence of AChR antibodies. Pt 1, however, had a more severe clinical course with recurrent episodes of respiratory failure, contractures, and craniofacial malformations. In both patients, treatment with pyridostigmine was of some benefit, but the addition of 3,4-diaminopyridine led to significant clinical improvement. Thus, rapsyn deficiency predicting similar consequences at the cellular level can result in phenotypes with marked differences in severity of symptoms, risk of respiratory failure, and presence of contractures and craniofacial malformations.
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ranking = 1
keywords = neuromuscular junction, junction
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8/10. A newly identified chromosomal microdeletion of the rapsyn gene causes a congenital myasthenic syndrome.

    The objective is mutation analysis of the RAPSN gene in a patient with sporadic congenital myasthenic syndrome (CMS). Mutations in various genes encoding proteins expressed at the neuromuscular junction may cause CMS. Most mutations affect the epsilon subunit gene of the acetylcholine receptor (AChR) leading to endplate AChR deficiency. Recently, mutations in the RAPSN gene have been identified in several CMS patients with AChR deficiency. In most patients, RAPSN N88K was identified, either homozygously or heteroallelic to a second missense mutation. A sporadic CMS patient from germany was analyzed for RAPSN mutations by RFLP, long-range PCR and sequence analysis. Clinically, the patient presents with an early onset CMS, associated with arthrogryposis multiplex congenita, recurrent episodes of respiratory insufficiency provoked by infections, and a moderate general weakness, responsive to anticholinesterase treatment. The mutation RAPSN N88K was found heterozygously to a large deletion of about 4.5 kb disrupting the RAPSN gene. Interestingly, an Alu-mediated unequal homologous recombination may have caused the deletion. We hypothesize that numerous interspersed alu elements may predispose the RAPSN locus for genetic rearrangements.
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ranking = 1
keywords = neuromuscular junction, junction
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9/10. Novel congenital myasthenic syndromes associated with defects in quantal release.

    BACKGROUND: Most congenital myasthenic syndromes are caused by defects in postsynaptic or synaptic basal lamina-associated proteins; congenital myasthenic syndromes (CMSs) associated with presynaptic defects are uncommon. Here, the authors describe clinical, electrophysiologic, and morphologic features of two novel and highly disabling CMSs, one determined by presynaptic and the other determined by combined presynaptic and postsynaptic defects. methods: Microelectrode, single channel patch clamp, immunocytochemical, [(125)I]alpha-bungarotoxin binding, and quantitative electron microscopy studies of endplates were performed. Candidate genes were directly sequenced. RESULTS: Patient 1, a 7-year-old boy, had severe myasthenic symptoms since infancy. Patient 2, a 48-year-old man, had delayed motor milestones and became progressively weaker after age 2 years. Both used wheelchairs and had a 30-50% EMG decrement on 2-Hz stimulation. Evoked quantal release was reduced to approximately 25% of normal in both. In Patient 2, the synaptic response to acetylcholine was further compromised by degeneration of the junctional folds with concomitant loss of the acetylcholine receptor (AChR). A search for mutations in components of the synaptic vesicle release complex and in other candidate proteins failed to identify the molecular basis of the two syndromes. CONCLUSIONS: Combined clinical, morphologic, and in vitro electrophysiologic findings define two novel congenital myasthenic syndromes. The molecular basis of these syndromes awaits discovery.
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ranking = 4.4895916004231E-5
keywords = junction
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10/10. CHRND mutation causes a congenital myasthenic syndrome by impairing co-clustering of the acetylcholine receptor with rapsyn.

    The objective of this study was to analyse the mutations of the acetylcholine receptor (AChR) delta subunit gene (CHRND) in a patient with sporadic congenital myasthenic syndrome (CMS). Mutations in various genes encoding proteins expressed at the neuromuscular junction may cause CMS. Mutations of AChR subunit genes lead to end-plate AChR deficiency or to altered kinetic properties of the receptor. Mutations in the alpha, beta and delta subunits of the AChR are less frequent than mutations of the epsilon subunit; mutations in these subunits leading to AChR deficiency are often associated with a severe phenotype. A sporadic patient from germany was studied, who presented with an early onset CMS associated with feeding difficulties, ptosis, a moderate general weakness responsive to anticholinesterase treatment and recurrent episodes of respiratory insufficiency provoked by infections. The CHRND gene was screened for mutations by RFLP, long-range PCR and sequence analysis. Subsequently, we conducted functional studies of AChR mutants co-transfected with rapsyn in HEK 293 cells. Heterozygously to a 2.2 kb microdeletion disrupting the CHRND gene, we identified a novel point mutation in the long cytoplasmic loop, CHRND E381K. The cytoplasmic loop of the AChR subunits is known to be essential for AChR-rapsyn co-clustering. We therefore studied the interaction of AChR containing the CHRND E381K mutation with rapsyn by evaluating expression and co-localization of rapsyn and mutated AChR subunits in co-transfected HEK 293 cells. Interestingly, the mutated receptor showed severely reduced cluster formation compared with the wild-type receptor. In contrast, the corresponding amino acid substitution in the cytoplasmic loop of the AChR epsilon (CHRNE E376K) as well as a recently reported CMS mutation affecting this domain (CHRNE N436del) had no impact on cluster formation. CHRND mutations are a rare cause for CMS but should be considered in patients with a severe, early onset disease form, clinically resembling a rapsyn phenotype with recurrent episodic apnoeas. Our results suggest that impairment of AChR-rapsyn co-clustering--a well-known molecular mechanism for rapsyn mutations--could also result from mutations in the delta subunit. Introduction of the same mutation in the epsilon subunit had no effect on AChR clustering indicating a special role of the delta subunit in AChR-rapsyn interactions.
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ranking = 1
keywords = neuromuscular junction, junction
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