Kawakami Nobuko, Komatsu Kenichi, Yamashita Hirofumi, Uemura Kengo, Oka Nobuyuki, Takashima Hiroshi, Takahashi Ryosuke
Department of Neurology, Shizuoka General Hospital.
Rinsho Shinkeigaku. 2014;54(11):911-5. doi: 10.5692/clinicalneurol.54.911.
Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy; symptoms include distal wasting and weakness, usually with some sensory impairment. The clinical course is typically benign and the disease is not life threatening; however, in some cases, severe phenotypes include serious respiratory distress.
Here we describe a 45-year-old woman with a long course of motor-dominant neuropathy. Distal weakness appeared in childhood and became worse with age. After a diagnosis of CMT type 2, the symptoms progressed, and in her fourth decade, facial and respiratory muscle weakness appeared, ultimately requiring non-invasive mechanical ventilation. There was no family history of CMT. Comprehensive analysis of known CMT-related genes revealed a novel heterozygous c.815T>A, p.L218Q mutation in glycyl-tRNA synthetase (GARS), a causative gene for both CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). This mutation was considered pathogenic based on molecular evidence; notably, it was unique in that all other reported GARS mutations associated with severe phenotypes are located in an anticodon-binding domain, while in this case in an apparently non-functional region of the GARS gene. Not a simple loss-of-function mechanism, but rather gain-of-function mechanisms have also been reported in GARS mutations. This case provided useful information for understanding the mechanism of CMT2D/dSMA-V.
夏科-马里-图思病（CMT）是一种遗传性周围神经病；症状包括远端肌肉萎缩和无力，通常伴有一些感觉障碍。临床病程通常为良性，该疾病不危及生命；然而，在某些情况下，严重的表型包括严重的呼吸窘迫。
在此，我们描述一名45岁患有以运动为主的周围神经病病程较长的女性。远端无力在儿童期出现，并随年龄增长而加重。在诊断为2型CMT后，症状进展，在她四十多岁时，面部和呼吸肌无力出现，最终需要无创机械通气。无CMT家族史。对已知的CMT相关基因进行综合分析，发现在甘氨酰-tRNA合成酶（GARS）基因中有一个新的杂合c.815T>A、p.L218Q突变，GARS是2D型CMT（CMT2D）和Ⅴ型远端脊髓性肌萎缩（dSMA-V）的致病基因。基于分子证据，该突变被认为是致病的；值得注意的是，它的独特之处在于，所有其他报道的与严重表型相关的GARS突变都位于反密码子结合域，而在本例中位于GARS基因的一个明显无功能区域。GARS突变中也报道过不是简单的功能丧失机制，而是功能获得机制。该病例为理解CMT2D/dSMA-V的机制提供了有用信息。
