title: A case of non-dystrophic myotonia with concomitant mutations in the SCN4A and CLCN1 genes.
abstract: Non-dystrophic myotonias are caused by mutations of either the skeletal muscle chloride (CLCN1) or sodium channel (SCN4A) gene. They exhibit several distinct phenotypes, including myotonia congenita, paramyotonia congenita and sodium channel myotonia, and a genotype-phenotype correlation has been established. However, there are atypical cases that do not fit with the standard classification. We report a case of 27-year-old male who had non-dystrophic myotonia with periodic paralysis and two heterozygous mutations, E950K in CLCN1 and F1290L in SCN4A. His mother, who exhibited myotonia without paralytic attack, only harbored E950K, and no mutations were identified in his asymptomatic father. Therefore, the E950K mutation was presumed to be pathogenic, although it was reported as an extremely rare genetic variant. The proband experienced paralytic attacks that lasted for weeks and were less likely to be caused by CLCN1 mutation alone. Functional analysis of the F1290L mutant channel heterologously expressed in cultured cells revealed enhanced activation inducing membrane hyperexcitability. We therefore propose that the two mutations had additive effects on membrane excitability that resulted in more prominent myotonia in the proband. Our case stresses the value of performing genetic analysis of both CLCN1 and SCN4A genes for myotonic patients with an atypical phenotype.
authors.affiliation: Department of Neurology, Tosei General Hospital, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Japan; INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière - ICM and National Reference Center for Muscular Channelopathies, University Hospital Pitié-Salpêtrière, France.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kokunai
authors.affiliation: INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière - ICM and National Reference Center for Muscular Channelopathies, University Hospital Pitié-Salpêtrière, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Dalle
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Japan; Department of Biochemistry and Molecular Biology, The University of Chicago, United States; Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Neurology, Tosei General Hospital, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Madokoro
authors.affiliation: Department of Neurology, Tosei General Hospital, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yuasa
authors.affiliation: Department of Neurology, Tosei General Hospital, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Department of Neurology, Tosei General Hospital, Japan.
authors.forename: Tomomasa
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière - ICM and National Reference Center for Muscular Channelopathies, University Hospital Pitié-Salpêtrière, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Nicole
authors.affiliation: INSERM U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière - ICM and National Reference Center for Muscular Channelopathies, University Hospital Pitié-Salpêtrière, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Japan; Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Japan. Electronic address: mtakahas@neurol.med.osaka-u.ac.jp.
authors.forename: Masanori P
authors.initials: MP
authors.lastname: Takahashi
authors.affiliation: Department of Neurology, Tosei General Hospital, Japan.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Mitake
mesh_terms: D000328:Adult; D018118:Chloride Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D004576:Electromyography; D019054:Evoked Potentials, Motor / Q000235:genetics; D005080:Exercise Test; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009222:Myotonia / Q000235:genetics* / Q000503:physiopathology; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics*
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human
keywords: Channelopathy; Chloride channel; Non-dystrophic myotonia; Paralysis; Sodium channel