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Phenotypic variability in three families with valosin-containing protein mutation
S Spina1, A D Van Laar, J R Murrell
1Department of Pathology and Laboratory Medicine, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Background And Purpose:
The phenotype of IBMPFD [inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (FTD)] associated with valosin-containing protein (VCP) mutation is described in three families.
Methods:
Probands were identified based on a pathological diagnosis of frontotemporal lobar degeneration with TDP-43-positive inclusions type IV. VCP sequencing was carried out. Clinical data on affected family members were reviewed.
Results:
Ohio family: four subjects presented muscle weakness and wasting. (One subject had both neuropathic and myopathic findings and another subject showed only evidence of myopathy. The etiology of weakness could not be ascertained in the remaining two subjects.) Two individuals also showed Parkinsonism (with associated FTD in one of the two). The proband's brain displayed FTLD-TDP type IV and Braak stage five Parkinson's disease (PD). A VCP R191Q mutation was found. Pennsylvania family: 11 subjects developed IBMPFD. Parkinsonism was noted in two mutation carriers, whilst another subject presented with primary progressive aphasia (PPA). A novel VCP T262A mutation was found. Indiana family: three subjects developed IBMPFD. FTD was diagnosed in two individuals and suspected in the third one who also displayed muscle weakness. A VCP R159C mutation was found.
Conclusions:
We identified three families with IBMPFD associated with VCP mutations. Clinical and pathological PD was documented for the first time in members of two families. A novel T262A mutation was found. One individual had PPA: an uncommon presentation of IBMPFD.
Insights
Inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) linked to valosin-containing protein (VCP) mutations was studied in three families. Parkinsonism was observed in two families, a novel mutation identified.
Area of Science:
- Genetics
- Neurology
- Pathology
Background:
- Inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) is a rare genetic disorder.
- Valosin-containing protein (VCP) mutations are associated with IBMPFD.
Purpose of the Study:
- To describe the phenotype of IBMPFD associated with VCP mutations in three families.
- To identify novel VCP mutations and document clinical presentations.
Main Methods:
- Probands diagnosed with frontotemporal lobar degeneration with TDP-43-positive inclusions type IV were identified.
- VCP gene sequencing was performed.
- Clinical data from affected family members were reviewed.
Main Results:
- Three families with IBMPFD and VCP mutations (R191Q, T262A, R159C) were identified.
- Parkinsonism was observed in two families, with one proband showing FTLD-TDP type IV and Braak stage five Parkinson's disease.
- Primary progressive aphasia (PPA) was noted in one individual, an uncommon presentation.
Conclusions:
- VCP mutations are confirmed in IBMPFD across three families.
- Clinical and pathological Parkinson's disease is documented for the first time in IBMPFD patients from two families.
- A novel VCP T262A mutation and PPA as an IBMPFD presentation were identified.
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