Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Department of Neurology, National Hospital Organization Suzuka National Hospital, Suzuka, Mie, Japan.
Neurobiol Aging. 2021 Apr;100:120.e1-120.e6. doi: 10.1016/j.neurobiolaging.2020.10.028. Epub 2020 Nov 14.
Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.
已知包含缬氨酸蛋白（VCP）基因突变可引起各种神经退行性疾病。在此，我们报告了来自 5 个无关联家族的 8 名日本患者（6 名男性，2 名女性；发病中位年龄：49.5 岁[范围，35-58 岁]），他们均携带 VCP 错义突变。虽然 8 名患者中有 7 名被诊断为包涵体肌病或肌萎缩性侧索硬化症，但 1 名患者表现为脱髓鞘性多发性神经病，这通过纵向神经传导研究得到了证实。该患者的腓肠神经活检显示 Schwann 细胞内核内泛素染色。检测到 3 种已知的致病性 VCP 突变（p.Arg191Gln、p.Arg155Cys 和 p.Ile126Phe）。在 1 名肌萎缩性侧索硬化症和额颞叶痴呆患者中还发现了一种新的突变，c.293A>T（p.Asp98Val）。使用计算机突变分析预测该突变是“有害的”或“致病变异”。总之，脱髓鞘性多发性神经病可能是由 VCP 突变引起的一种新表型。p.Asp98Val 突变被发现是 VCP 蛋白病的一种新的致病性突变。我们认为我们的病例代表了 VCP 突变的广泛临床谱。
