The wide-ranging clinical and genetic features in Japanese families with valosin-containing protein proteinopathy

Abstract1 Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 males, 2 females; 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 (ALS), 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.293A>T (p.Asp98Val), was also identified in a patient with ALS 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.