VCP p.Arg191Gln mutation in a patient with semantic dementia: a case report.

Variants in VCP (encoding valosin-containing protein) lead to inclusion body myopathy, which is typically associated with Paget's disease of the bones and frontotemporal dementia (FTD). When symptoms of frontotemporal lobar degeneration (FTLD) develop in patients with pathogenic VCP variants, the symptoms mainly present as behavioral-variant (bv) FTD and rarely as semantic dementia (SD). Various pathogenic VCP variants have been reported to cause bvFTD, whereas the only variant previously linked to SD is VCP p.Arg155Cys. Here, we report the case of a female Japanese patient with SD carrying the pathogenic VCP variant p.Arg191Gln. The patient developed naming difficulties, word-finding difficulties, stereotypical behavior, decreased spontaneity, and executive dysfunction at 55 years old and was diagnosed with SD at our hospital at 56 years old. At 59 years, there were no clinical findings suggestive of myopathy, pyramidal signs, or bone involvement. Genetic analyses, including whole-exome and Sanger sequencing, identified the VCP p.Arg191Gln variant in the patient with isolated SD. She required wheelchair assistance for 62 years and was mute. She later died from complications of malnutrition due to feeding difficulties. This case suggests that VCP variants may result in not only bvFTD but also SD, indicating a broader spectrum of FTLD-related phenotypes linked to pathogenic VCP variants.