Abstract
Over fifty missense mutations in the gene coding for valosin-containing protein (VCP) are associated with a unique autosomal dominant adult-onset progressive disease associated with combinations of proximo-distal inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). We report the clinical, histological, and molecular findings in four new patients/families carrying novel VCP mutations: c.474 G > A (p.M158I); c.478 G > C (p.A160P); c.383G > C (p.G128A); and c.382G > T (p.G128C). Clinical features included myopathy, PDB, ALS and Parkinson's disease though frontotemporal dementia was not an associated feature in these families. One of the patients was noted to have severe manifestations of PDB and was suspected of having neoplasia. There were wide inter- and intra-familial variations making genotype-phenotype correlations difficult between the novel mutations and frequency or age of onset of IBM, PDB, FTD, ALS and Parkinson's disease. Increasing awareness of the full spectrum of clinical presentations will improve diagnosis of VCP-related diseases and thus proactively manage or prevent associated clinical features such as PDB.
Highlights
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) or multisystem proteinopathy is an adult-onset progressive, autosomal dominant inherited, lethal disease caused by heterozygous missense mutations in valosin-containing protein (VCP) [1, 2]
Discussion we report patients with four novel mutations to expand the genotypic spectrum of VCP disease most commonly characterized by progressive limb-girdle inclusion body myopathy (IBM), Paget’s disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) and Parkinson’s disease
G>A, p.M158I and c.478G>C, A160P are located in exon 5 which is involved in ubiquitin and cofactor binding
Summary
Title: Novel valosin-containing protein mutations associated with multisystem proteinopathy. This is a PDF file of an unedited manuscript that has been accepted for publication. Novel Valosin-Containing Protein Mutations Associated With Multisystem Proteinopathy. PDB, ALS and Parkinson’s disease though frontotemporal dementia was not an associated feature in these families. There was wide inter and intra-familial variation making genotype-phenotype correlations difficult between the novel mutations and frequency or age of onset of IBM, PDB, FTD, ALS and Parkinson’s disease. Diagnosis of VCP-related diseases and proactively manage or prevent associated clinical features such as PDB
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