Abstract Details

Valosin-containing protein (VCP) mutations are associated with frontotemporal dementia (FTD), inclusion body myopathy (IBM) and other neuromuscular diseases. Parkinsonism has also been reported in some VCP mutation carriers.  Here we present two novel cases with VCP-related parkinsonism.  The first case carries a R191G mutation which has only been reported in association with parkinsonism in a single family.¹ The second case carries a R155C mutation previously reported in only one case in association with parkinsonism.²

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The first case with the R191G mutation is a 53-year-old male who presented with limb weakness secondary to IBM followed by asymmetric rest and action tremor six years later.  His mother had FTD, IBM, and tremor. He was started on carbidopa/levodopa for his parkinsonism but reported no benefit with levodopa doses of up to 1,200 mg/day.  

Our second case with the R155C mutation is a 40-year-old male who presented with two years of progressive proximal weakness from IBM associated with Paget’s disease of bone and FTD (IBMPFD). He developed tremor-predominant parkinsonism one year later with a robust response to levodopa (1,750mg/day).  He had an extensive autosomal dominant patrilineal family history of muscular dystrophy with comorbid hepatic and cardiac disease.

A reduction in VCP expression in Parkinson’s disease may play a role in the accumulation of misfolded proteins such as Lewy bodies.⁴ While codon 155 is a mutation hotspot, R191G and R155C mutations associated with parkinsonism are rare. Our cases highlight phenotypic heterogeneity of VCP-associated parkinsonism when compared to prior reports.  The existing literature suggests that VCP-parkinsonism has robust levodopa responsiveness,³ however, our patient with the R191G mutation was not levodopa-responsive. Future studies should look for correlations between genotype, phenotype, and levodopa responsiveness, which can be useful in discussions of expected treatment response and quality of life.