臨床神経学

短報

A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease type 2D with facial and respiratory muscle involvement

Nobuko Kawakami, M.D.1)2), Kenichi Komatsu, M.D.2)3)*, Hirofumi Yamashita, M.D., Ph.D.2), Kengo Uemura, M.D., Ph.D.2)4)*, Nobuyuki Oka, M.D., Ph.D.2)5), Hiroshi Takashima, M.D., Ph.D.6), and Ryosuke Takahashi, M.D., Ph.D.2)

Corresponding author: Department of Neurology, Kitano Hospital, The Tazuke Kofukai Medical Research Institute〔2-4-20 Ohgimachi, Kita-ku, Osaka-shi, Osaka 530-8480〕
1)Department of Neurology, Shizuoka General Hospital
2)Department of Neurology, Kyoto University Graduate School of Medicine
3)Department of Neurology, Kitano Hospital, The Tazuke Kofukai Medical Research Institute
4)Ishiki Hospital
5)Department of Neurology, National Hospital Organization Minami Kyoto Hospital
6)Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences

BACKGROUND: 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. CASE REPORT: 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 nonfunctional 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.
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(臨床神経, 54:911−915, 2014)
key words:Charcot-Marie-Tooth disease, hereditary sensory and motor neuropathy, glycine-tRNA ligase, spinal muscular atrophy, respiratory distress

(受付日:2014年1月14日)