title: A sodium channel myotonia due to a novel SCN4A mutation accompanied by acquired autoimmune myasthenia gravis.
abstract: Mutations of the voltage gated sodium channel gene (SCN4A) are responsible for non-dystrophic myotonia including hyperkalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonia, as well as congenital myasthenic syndrome. In vitro functional analyses have demonstrated the non-dystrophic mutants to show a gain-of-function defect of the channel; a disruption of fast inactivation, an enhancement of activation, or both, while the myasthenic mutation presents a loss-of function defect. This report presents a case of non-dystrophic myotonia that is incidentally accompanied with acquired myasthenia. The patient presented a marked warm-up phenomenon of myotonia but the repeated short exercise test suggested mutations of the sodium channel. The genetic analysis identified a novel mutation, G1292D, of SCN4A. A functional study of the mutant channel revealed marked enhancement of activation and slight impairment of fast inactivation, which should induce muscle hyperexcitability. The effects of the alteration of channel function to the myasthenic symptoms were explored by using stimulation of repetitive depolarization pulses. A use-dependent channel inactivation was reduced in the mutant in comparison to normal channel, thus suggesting an opposing effect to myasthenia.
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kokunai
authors.forename: Keigo
authors.initials: K
authors.lastname: Goto
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kubota
authors.forename: Takaaki
authors.initials: T
authors.lastname: Fukuoka
authors.forename: Saburo
authors.initials: S
authors.lastname: Sakoda
authors.forename: Tohru
authors.initials: T
authors.lastname: Ibi
authors.forename: Manabu
authors.initials: M
authors.lastname: Doyu
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Ko
authors.initials: K
authors.lastname: Sahashi
authors.forename: Masanori P
authors.initials: MP
authors.lastname: Takahashi
mesh_terms: D000328:Adult; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009157:Myasthenia Gravis / Q000235:genetics*; D009222:Myotonia / Q000235:genetics*; D062553:NAV1.4 Voltage-Gated Sodium Channel; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels