Abstract
Valosin-containing protein (VCP) gene mutations are an under recognised autosomal dominant genetic disease presenting with both neurological and non-neurological phenotypes. A missense mutation in VCP can cause a myopathy, Paget’s disease of the bone or frontal temporal dementia. Less commonly seen phenotypes are amyotrophic lateral sclerosis, parkinsonism or axonal CMT. These conditions are not classically recognised as genetically related by clinicians when taking a family history, so the pattern of autosomal dominance is under recognised. This report will describe a case series with varied clinical presentations, gender, and age where VCP missense pathogenic variants were found. It will also describe a case with a variant of uncertain significance in the VCP gene. Valosin-containing protein is involved in regulatory cellular processes such as autophagy, membrane fusion, transcription and cellular degradation. Most pathogenic missense variants alter the N-terminal ubiquitin binding domains. These missense variants result in failure of regulatory cellular processes, which is thought to account for the wide spectrum of body systems affected. This has led to these diseases to be more recently termed VCP Multisystem Proteinopathies (VCP-MSP). It is pertinent that any family history with a combination of these conditions, including varying severity of symptoms, should raise the question of testing for this condition.
