PDF(Sci-hub)
Abstract：
The phenotypic spectrum associated with the skeletal muscle voltage-gated sodium channel gene (SCN4A) has expanded with advancements in genetic testing. Autosomal dominant SCN4A mutations were first linked to hyperkalemic periodic paralysis, then subsequently included paramyotonia congenita, several variants of myotonia, and finally hypokalemic periodic paralysis. Biallelic recessive mutations were later identified in myasthenic myopathy and in infants showing a severe congenital myopathy with hypotonia. We report a patient with a pathogenic de novo SCN4A variant, c.2386C>G p.L769V at a highly conserved leucine. The phenotype was manifest at birth with arthrogryposis multiplex congenita, severe episodes of bronchospasm that responded immediately to carbamazepine therapy, and electromyographic evidence of widespread myotonia. Another de novo case of p.L769V has been reported with hip dysplasia, scoliosis, myopathy, and later paramyotonia. Expression studies of L796V mutant channels showed predominantly gain-of-function changes, that included defects of slow inactivation. Computer simulations of muscle excitability reveal a strong predisposition to myotonia with exceptionally prolonged bursts of discharges, when the L796V defects are included. We propose L769V is a pathogenic variant, that along with other cases in the literature, defines a new dominant SCN4A disorder of myotonic myopathy with secondary congenital joint and skeletal involvement.
摘要：
与骨骼肌电压门控钠通道基因（SCN4A）相关的表型谱随着基因测试的进步而扩展。常染色体显性遗传SCN4A突变首先与高钾血症性周期性麻痹有关，随后包括先天性副肌强直症，肌强直的几种变体，最后是低钾性周期性瘫痪。后来在肌无力肌病和表现出严重的先天性肌病伴张力减退的婴儿中发现了双等位基因隐性突变。我们报告了一名患有致病性从头SCN4A变异的患者，c.2386C>Gp.L769V，亮氨酸高度保守。表型在出生时表现为多发性先天性关节炎，对卡马西平治疗立即反应的支气管痉挛的严重发作，和广泛的肌强直的肌电图证据。据报道，另一例p.L769V伴髋关节发育不良，脊柱侧弯,肌病,和后来的副肌强直。L796V突变通道的表达研究显示主要是功能获得改变，其中包括缓慢失活的缺陷。对肌肉兴奋性的计算机模拟显示，肌强直倾向于异常长时间的放电爆发，当包含L796V缺陷时。我们认为L769V是一种致病变体，连同文献中的其他案例，定义了继发性先天性关节和骨骼受累的强直性肌病的新显性SCN4A疾病。
