A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine‐induced ion channel

Engel, Andrew G.; Lambert, Edward H.; Mulder, Donald W.; Torres, Carlos F.; Sahashi, Ko; Bertorini, Tulio E.; Whitaker, John N.

doi:10.1002/ana.410110603

Cited by 249 publications

(149 citation statements)

References 47 publications

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“…The side effects include nervousness, insomnia, palpitation, and hypertension. 37,45 • There may be no similarly affected relatives • The symptoms can be episodic 7,13,44 • EMG abnormalities may not be present in all muscles, or are present only intermittently 7,13 • Weakness may not involve cranial muscles 40 Clinical • Proximal greater than distal limb and axial muscle weakness, mild facial weakness and ptosis, and normal ocular ductions in the majority • Bulbar muscles affected in some patients • May deteriorate on exposure to pyridostigmine AChE, acetylcholinesterase; AChR, acetylcholine receptor; CMAP, compound muscle fiber action potential; EP, endplate; MuSK, muscle specific tyrosine kinase. *There are no clinical clues to the diagnosis of the fast channel CMS, primary EP AChR deficiency, and most cases of rapsyn deficiency.…”

Section: Therapeutic Agentsmentioning

confidence: 99%

The Therapy of Congenital Myasthenic Syndromes

Engel

2007

Neurotherapeutics

Self Cite

104

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Section: Therapeutic Agentsmentioning

confidence: 99%

The Therapy of Congenital Myasthenic Syndromes

Engel

2007

Neurotherapeutics

Self Cite

104

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“…Between the ages of 3 and 8 years, he could walk only short distance before having to rest and subsequently he became wheelchair-dependent. He had negative tests for anti-AChR antibodies, a decremental electromyographic response on stimulation of motor nerves, and a repetitive action potential response to single nerve stimuli, as seen in the SCCMS (Engel et al, 1982) or in EP acetylcholinesterase deficiency (Engel et al, 1977a). …”

Section: Clinical Datamentioning

confidence: 99%

Slow-Channel Myasthenic Syndrome Caused By Enhanced Activation, Desensitization, and Agonist Binding Affinity Attributable to Mutation in the M2 Domain of the Acetylcholine Receptor α Subunit

Milone¹,

Wang

Ohno³

et al. 1997

J. Neurosci.

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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.Key words: slow-channel congenital myasthenic syndrome; neuromuscular transmission; endplate myopathy; acetylcholine receptor ␣ subunit gene; mutation analysis; single-channel recording; desensitization; agonist binding affinity Recent studies of congenital myasthenic syndromes (CMS) revealed mutations in acetylcholine receptor (AChR) subunit genes that either reduce expression of AChR (Engel et al., 1996a) or alter its kinetic properties to decrease (Ohno et al., 1996) or increase Sine et al., 1995; Engel et al., 1996b;Gomez et al., 1996) the response to ACh. Mutations that increase response to ACh prolong elementary activation episodes, and these disorders are referred to as slow-channel C MS (SCCMS). Mutations underlying SCC MS have been identified in different AChR subunits, and in different domains of the subunits, and affect AChR f unction through different mechanisms. The mutation ␣G153S is in the major extracellular domain and near residues that contribute to ligand binding; it increases affinity of ACh for the resting closed state and prolongs activation episodes by allowing multiple reopenings before ACh can dissociate . The mutation ␣N217K is in the M1 transmembrane domain and both slows the rate of channel closing and allows multiple reopenings per activation episode (Engel et al., 1996b). Mutations in the M2 domain, ⑀T264P, ⑀L269F, and ␤V266M Engel et al., 1996b), increase spontaneous opening of the channel, increase apparent affinity for ACh, and slow the rate of channel closing.Here we describe and functionally characterize the mutation ␣V249F in the M2 domain that causes severe SCCMS through a novel combination of mechanisms. Our mechanistic studies reveal functional consequences attributable to local perturbation of the M2 domain, including increased opening in the absence and prolonged opening in the p...

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“…O diagnóstico de SCL pode ser sugerido pela manifestação clínica e história familiar, discreta melhora ao uso de i n i b i d o res da acetilcolinesterase, piora ao uso de corticosteróides, sendo confirmado através do estudo da condução nervosa motora e da análise molecular do AChR 3,4,7,8 .…”

Section: Discussionunclassified

“…O diagnóstico de SCL é confirmado pela resposta decremental ao estímulo re p e t i t ivo do nervo com captação em músculos clinicamente afetados e pelo repetitivo potencial de ação muscular composto após estímulo único do nervo. O quadro clínico, distribuição assimétrica da fraqueza muscular, história familiar e a resposta aos inibidores da acetilcolinesterase, fazem a suspeita diagnóstica 3,4,7,8 . Desde a primeira descrição da doença, poucos casos foram descritos na literatura nacional, o que nos levou a apresentar este caso.…”

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Estudo neurofisiológico na síndrome miastênica congênita do canal lento: relato de caso

Lorenzoni

Kay

Arruda

et al. 2006

Arq. Neuro-Psiquiatr.

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A síndrome do canal lento é uma das síndromes miastênicas congênitas atribuída a desordem dinâmica do canal iônico do receptor de acetilcolina da junção neuromuscular. Descrevemos o caso de um homem de 25 anos com progressiva ptose palpebral e limitação da movimentação ocular desde infância, que evoluiu há 6 anos com piora da oftalmoparesia externa e diminuição da força muscular em ombros e mãos. O estudo da condução nervosa motora após estímulo único demonstrou duplo potencial de ação muscular composto (PAMC) com desaparecimento do segundo após esforço de 30 segundos. Ao estímulo repetitivo dos nervos facial e acessório observou-se um decremento da amplitude do PAMC maior que 10% com desaparecimento do segundo potencial. O paciente fez uso de fluoxetina mostrando discreta melhora da força muscular, porém persiste com: ptose palpebral, limitação dos movimentos oculares e PAMC repetitivo ao estudo da condução nervosa motora. As características da doença são discutidas.

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A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine‐induced ion channel

Cited by 249 publications

References 47 publications

The Therapy of Congenital Myasthenic Syndromes

The Therapy of Congenital Myasthenic Syndromes

Slow-Channel Myasthenic Syndrome Caused By Enhanced Activation, Desensitization, and Agonist Binding Affinity Attributable to Mutation in the M2 Domain of the Acetylcholine Receptor α Subunit

Estudo neurofisiológico na síndrome miastênica congênita do canal lento: relato de caso

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