Kato Hideki, Kokunai Yosuke, Dalle Carine, Kubota Tomoya, Madokoro Yuta, Yuasa Hiroyuki, Uchida Yuto, Ikeda Tomomasa, Mochizuki Hideki, Nicole Sophie, Fontaine Bertrand, Takahashi Masanori P, Mitake Shigehisa
Department of Neurology, Tosei General Hospital, Japan.
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.
J Neurol Sci. 2016 Oct 15;369:254-258. doi: 10.1016/j.jns.2016.08.030. Epub 2016 Aug 13.
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.
非营养不良性肌强直由骨骼肌氯离子（CLCN1）或钠离子通道（SCN4A）基因突变引起。它们表现出几种不同的表型，包括先天性肌强直、先天性副肌强直和钠通道性肌强直，并且已经建立了基因型与表型的相关性。然而，存在一些不符合标准分类的非典型病例。我们报告一例27岁男性，患有非营养不良性肌强直伴周期性瘫痪，存在两个杂合突变，CLCN1基因中的E950K和SCN4A基因中的F1290L。他的母亲表现为肌强直但无麻痹发作，仅携带E950K突变，而其无症状的父亲未发现突变。因此，尽管E950K突变被报道为极其罕见的基因变异，但推测其具有致病性。先证者经历了持续数周的麻痹发作，不太可能仅由CLCN1突变引起。对在培养细胞中异源表达的F1290L突变通道进行功能分析，发现其激活增强，导致膜兴奋性过高。因此，我们认为这两个突变对膜兴奋性具有累加作用，导致先证者出现更明显的肌强直。我们的病例强调了对具有非典型表型的肌强直患者进行CLCN1和SCN4A基因遗传分析的价值。
