Rare slow channel congenital myasthenic syndromes without repetitive compound muscle action potential and dramatic response to low dose fluoxetine (original) (raw)
Related papers
The Journal of Neuroscience, 1997
We describe a novel genetic and kinetic defect in a slow-channel congenital myasthenic syndrome. The severely disabled propositus has advanced endplate myopathy, prolonged and biexponentially decaying endplate currents, and prolonged acetylcholine receptor (AChR) channel openings. Genetic analysis reveals the heterozygous mutation ␣V249F in the propositus and mosaicism for ␣V249F in the asymptomatic father. Unlike mutations described previously in the M2 transmembrane domain, ␣V249F is located N-terminal to the conserved leucines and is not predicted to face the channel lumen. Expression of the ␣V249F AChR in HEK fibroblasts demonstrates increased channel openings in the absence of ACh, prolonged openings in its presence, enhanced steady-state desensitization, and nanomolar rather than micromolar affinity of one of the two binding sites in the resting activatable state. Thus, neuromuscular transmission is compromised because cationic overloading leads to degenerating junctional folds and loss of AChR, because an increased fraction of AChR is desensitized in the resting state, and because physiological rates of stimulation elicit additional desensitization and depolarization block of transmission.
Human Molecular Genetics, 1996
Mutations in genes encoding the ε, δ, β and α subunits of the end plate acetylcholine (ACh) receptor (AChR) are described and functionally characterized in three slow-channel congenital myasthenic syndrome patients. All three had prolonged end plate currents and AChR channel opening episodes and an end plate myopathy with loss of AChR from degenerating junctional folds. Genetic analysis revealed heterozygous mutations: εL269F and δQ267E in Patient 1, βV266M in Patient 2, and αN217K in Patient 3 that were not detected in 100 normal controls. Patients 1 and 2 have no similarly affected relatives; in Patient 3, the mutation cosegregates with the disease in three generations. εL269F, δQ267E and βV266M occur in the second and αN217K in the first transmembrane domain of AChR subunits; all have been postulated to contribute to the lining of the upper half of the channel lumen and all but δQ267E are positioned toward the channel lumen, and introduce an enlarged side chain. Expression studies in HEK cells indicate that all of the mutations express normal amounts of AChR. εL269F, βV266M, and αN217K slow the rate of channel closure in the presence of ACh and increase apparent affinity for ACh; εL269F and αN217K enhance desensitization, and εL269F and βV266M cause pathologic channel openings in the absence of ACh, rendering the channel leaky. δQ267E has none of these effects and is therefore a rare polymorphism or a benign mutation. The end plate myopathy stems from cationic overloading of the postsynaptic region. The safety margin of neuromuscular transmission is compromised by AChR loss from the junctional folds and by a depolarization block owing to temporal summation of prolonged end plate potentials at physiologic rates of stimulation.
Human Molecular Genetics, 1997
Congenital myasthenic syndromes are a group of rare genetic disorders that compromise neuromuscular transmission. A subset of these disorders, the slowchannel congenital myasthenic syndrome (SCCMS), is dominantly inherited and has been shown to involve mutations within the muscle acetylcholine receptor (AChR). We have identified three new SCCMS mutations and a further familial case of the αG153S mutation. Single channel recordings from wild-type and mutant human AChR expressed in Xenopus oocytes demonstrate that each mutation prolongs channel activation episodes. The novel mutations αV156M, αT254I and αS269I are in different functional domains of the AChR α subunit. Whereas αT254I is in the pore-lining region, like five of six previously reported SCCMS mutations, αS269I and αV156M are in extracellular domains. αS269I lies within the short extracellular sequence between M2 and M3, and identifies a new region of muscle AChR involved in ACh binding/channel gating. αV156M, although located close to αG153S which has been shown to increase ACh binding affinity, appears to alter channel function through a different molecular mechanism. Our results demonstrate heterogeneity in the SCCMS, indicate new regions of the AChR involved in ACh binding/channel gating and highlight the potential role of mutations outside the pore-lining regions in altering channel function in other ion channel disorders.
Journal of neuromuscular diseases, 2021
Congenital myasthenic syndromes (CMS) result from genetic mutations that cause aberrations in structure and/or function of proteins involved in neuromuscular transmission. The slow-channel CMS (SCCMS) is an autosomal dominant postsynaptic defect caused by mutations in genes encoding alpha, beta, delta, or epsilon subunits of the acetylcholine receptor resulting in a functional defect which is an increase of the opening time of the receptor. We report a case of SCCMS due to a heterozygous mutation in the M2 domain of the AChR alpha subunit-CHRNA1:ENST00000348749.6:exon7:c.806T>G:p.Val269Gly and corresponding kinetic defect. A substitution of valine with phenylalanine in the same position has been previously described. This is the first reported case of a new CHRNA1 variant in a patient with SCCMS from South Asia. We also highlight the phenotype that would favour a genetic basis over an autoimmune one, in an adult presenting with fatigable weakness.
2010
Despite the fact that they are orphan diseases, congenital myasthenic syndromes (cMS) challenge those who suffer from it by causing fatigable muscle weakness, in the most benign cases, to a progressive wasting of muscles that may sentence patients to a wheelchair or even death. compared to other more common neurological diseases, cMS are rare. Nevertheless, extensive research in cMS is performed in laboratories such as ours. among the diverse neuromuscular disorders of cMS, we are focusing in the slow-channel congenital myasthenic syndrome (ScS), which is caused by mutations in genes encoding acetylcholine receptor subunits. the study of ScS has evolved from clinical electrophysiological studies to in vitro expression systems and transgenic mice models. the present review evaluates the methodological approaches that are most commonly employed to assess synaptic impairment in ScS and also provides perspectives for new approaches. electrophysiological methodologies typically employed ...
A ?-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome
Annals of Neurology, 1996
Point mutations in the genes encoding the acetylcholine receptor (AChR) subunits have been recognized in some patients with slow-channel congenital myasthenic syndromes (CMS). Clinical, electrophysiological, and pathological differences between these patients may be due to the distinct effects of individual mutations. We report that a spontaneous mutation of the p subunit that interrupts the leucine ring of the AChR channel gate causes an eightfold increase in channel open time and a severe CMS characterized by severe endplate myopathy and extensive remodeling of the postsynaptic membrane. The pronounced abnormalities in neuromuscular synaptic architecture and function, muscle fiber damage and weakness, resulting from a single point mutation are a dramatic example of a mutation having a dominant gain of function and of hereditary excitotoxicity.
Balkan Journal of Medical Genetics, 2019
Congenital myasthenic syndrome (CMS) constitutes a group of inherited disorders of neuromuscular junctions. The majority of postsynaptic syndromes result from mutations in the CHRNE gene that causes muscle nicotine acetylcholine deficiency. In this study, we report on a 2 and a half-year-old boy with normal developmental milestones and bilateral ptosis. Clinical courses, electrophysiological studies and molecular genetic analysis were assessed. Polymerase chain reaction (PCR) and direct DNA sequencing of the CHRNE gene were performed for the proband and all the family members. A novel homozygous missense mutation of c.973G>T was found in the CHRNE gene. Segregation studies were suggested to be the genetic cause of the disease. Using three in silico tools and the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant classification guidelines indicated that the novel variant c.973G>T was likely pathogenic. Our results recommende...
We describe a novel genetic and kinetic defect in a slow-channel congenital myasthenic syndrome. The severely disabled propositus has advanced endplate myopathy, prolonged and biexponentially decaying endplate currents, and prolonged acetylcholine receptor (AChR) channel openings. Genetic analysis reveals the heterozygous mutation ␣V249F in the propositus and mosaicism for ␣V249F in the asymptomatic father. Unlike mutations described previously in the M2 transmembrane domain, ␣V249F is located N-terminal to the conserved leucines and is not predicted to face the channel lumen. Expression of the ␣V249F AChR in HEK fibroblasts demonstrates increased channel openings in the absence of ACh, prolonged openings in its presence, enhanced steady-state desensitization, and nanomolar rather than micromolar affinity of one of the two binding sites in the resting activatable state. Thus, neuromuscular transmission is compromised because cationic overloading leads to degenerating junctional folds and loss of AChR, because an increased fraction of AChR is desensitized in the resting state, and because physiological rates of stimulation elicit additional desensitization and depolarization block of transmission.
Neuron, 1996
We describe the genetic and kinetic defects for a low- affinity fast channel disease of the acetylcholine receptor (AChR) that causes a myasthenic syndrome. In two unrelated patients with very small miniature end plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR channel events, diminished channel reopenings during ACh occupancy, and resistance to desensitization by ACh. Each patient had two heteroallelic AChR ε subunit gene mutations: a common εP121L mutation, a signal peptide mutation (εG-8R) (patient 1), and a glycosylation consensus site mutation (εS143L) (patient 2). AChR expression in HEK fibroblasts was normal with εP121L but was markedly reduced with the other mutations. Therefore, εP121L defines the clinical phenotype. Studies of the engineered εP121L AChR revealed a markedly decreased rate of channel opening, little change in affinity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.